VICP Registry Case Source Bundle Canonical URL: https://vicp-registry.org/case/USCOURTS-cofc-1_13-vv-00349 Package ID: USCOURTS-cofc-1_13-vv-00349 Petitioner: Cristal Bello Filed: 2013-05-22 Decided: 2023-09-12 Vaccine: HPV Vaccination date: 2010-06-04 Condition: premature ovarian failure Outcome: denied Award amount USD: AI-assisted case summary: On May 22, 2013, Cristal Bello filed a petition alleging that the Human Papillomavirus (HPV) vaccine, Gardasil, administered on June 4, 2010, caused her to develop premature ovarian failure (POF). Her case was consolidated with other petitioners alleging the HPV vaccine caused POF. Special Master Herbrina Sanders issued a decision on February 23, 2023, dismissing Bello's claim. Special Master Sanders found that Bello failed to establish by a preponderant standard that her POF was autoimmune in nature, thus failing Althen prong two. She also found that the onset of Bello's POF was not consistent with the proposed molecular mimicry mechanism, failing Althen prong three, as the onset of symptoms did not occur within the expected acute-onset window following vaccination. The Court of Federal Claims, in an opinion issued September 12, 2023, denied Bello's motion for review, finding the Special Master's ultimate decision was not arbitrary and capricious, despite identifying some errors in the Special Master's reasoning regarding the timing of Bello's symptoms and the interpretation of her medical records. Petitioner was represented by Mark T. Sadaka, and Respondent was represented by Kimberly Davey. An earlier decision on November 24, 2015, by Special Master Lisa Hamilton-Fieldman, awarded Petitioner $1,015.47 for costs incurred personally, based on a stipulation between the parties. Petitioner was represented by Mark L. Krueger in this matter. Theory of causation field: Cristal Bello received the HPV (Gardasil) vaccine on June 4, 2010, and subsequently developed premature ovarian failure (POF). Her claim was consolidated with other petitioners alleging the HPV vaccine caused POF. Special Master Sanders denied entitlement, finding that Petitioner failed to prove by a preponderant standard that her POI was autoimmune in nature (Althen prong two) and that the onset of her POI was inconsistent with the proposed molecular mimicry mechanism (Althen prong three), as the symptoms did not manifest within the expected acute-onset window following vaccination. The Court of Federal Claims denied review, finding the Special Master's decision was not arbitrary and capricious. Petitioner was represented by Mark T. Sadaka and Respondent by Kimberly Davey. An earlier stipulation awarded Petitioner $1,015.47 in costs, with counsel Mark L. Krueger involved. The public decision does not describe the specific mechanism of molecular mimicry or name specific experts for the respondent in the final decision, though multiple experts testified for both sides regarding autoimmunity and onset timing. Public staged source text: ================================================================================ DOCUMENT 1: USCOURTS-cofc-1_13-vv-00349-0 Date issued/filed: 2015-12-16 Pages: 2 Docket text: PUBLIC DECISION (Originally filed: 11/24/2015) regarding 65 DECISION Fees Stipulation/Proffer. Signed by Special Master Lisa Hamilton-Fieldman. (mb) Copy to parties. -------------------------------------------------------------------------------- Case 1:13-vv-00349-SSS Document 69 Filed 12/16/15 Page 1 of 2 In the United States Court of Federal Claims OFFICE OF SPECIAL MASTERS No. 13-349V Filed: November 24, 2015 * * * * * * * * * * * * * * * * * * * * * * * * * UNPUBLISHED CRISTAL BELLO, * * Special Master Hamilton-Fieldman Petitioner, * v. * Petitioner’s Costs; Reasonable Amount * Requested to which Respondent SECRETARY OF HEALTH * Does Not Object. AND HUMAN SERVICES, * * Respondent. * * * * * * * * * * * * * * * * * * * * * * * * * * Mark L. Krueger, Krueger & Hernandez, S.C., Baraboo, WI, for Petitioner. Lara Englund and Claudia Gangi, United States Department of Justice, Washington, DC, for Respondent. DECISION1 On May 22, 2013, Cristal Bello (“Petitioner”) filed a petition for compensation under the National Childhood Vaccine Injury Act of 1986, 42 U.S.C. §§ 300aa-1 et seq. (2006) (“Vaccine Act”). Petitioner alleged that the administration of a Human Papillomavirus (“HPV”) vaccine on June 4, 2010 caused her to suffer from premature ovarian failure. On November 24, 2015, the parties filed a Stipulation of Fact Concerning Petitioner’s Costs. Pursuant to their stipulation, the parties have agreed to an award of $1,015.47 for costs incurred personally by Petitioner. The undersigned finds that an award for costs is appropriate pursuant to 42 U.S.C. § 300aa-15(b) and (e)(1). Further, the proposed amount seems reasonable and appropriate. Accordingly, the undersigned hereby awards the amount of $1,015.47, in the form of a check made payable solely to Petitioner, Cristal Bello. In the absence of a motion for review filed pursuant to RCFC Appendix B, the clerk of 1 The undersigned intends to post this unpublished decision on the United States Court of Federal Claims’ website, in accordance with the E-Government Act of 2002, Pub. L. No. 107 347, § 205, 116 Stat. 2899, 2913 (codified as amended at 44 U.S.C. § 3501 note (2006)). As provided by Vaccine Rule 18(b), each party has 14 days within which to file a motion for redaction “of any information furnished by that party (1) that is trade secret or commercial or financial information and is privileged or confidential, or (2) that are medical files and similar files the disclosure of which would constitute a clearly unwarranted invasion of privacy.” In the absence of such motion, the entire decision will be available to the public. Id. 1 Case 1:13-vv-00349-SSS Document 69 Filed 12/16/15 Page 2 of 2 the court SHALL ENTER JUDGMENT in accordance with the terms of the parties’ stipulation.2 IT IS SO ORDERED. /s/ Lisa D. Hamilton-Fieldman Lisa D. Hamilton-Fieldman Special Master 2 Pursuant to Vaccine Rule 11(a), entry of judgment is expedited by the parties’ joint filing of notice renouncing the right to seek review. 2 ================================================================================ DOCUMENT 2: USCOURTS-cofc-1_13-vv-00349-2 Date issued/filed: 2021-10-20 Pages: 24 Docket text: PUBLIC ORDER/RULING (Originally filed: 08/30/2021) regarding 147 Findings of Fact & Conclusions of Law. Signed by Special Master Herbrina Sanders. (rig) Service on parties made. -------------------------------------------------------------------------------- Case 1:13-vv-00349-SSS Document 148 Filed 10/20/21 Page 1 of 24 In the United States Court of Federal Claims OFFICE OF SPECIAL MASTERS Filed: August 30, 2021 * * * * * * * * * * * * * * * LAKIA BRAYBOY, * No. 15-183V * Petitioner, * Special Master Sanders * v. * * Ruling on Althen Prong One; Human SECRETARY OF HEALTH * Papillomavirus (“HPV”) Vaccine; AND HUMAN SERVICES, * Primary Ovarian Insufficiency/Failure * (“POI”) Respondent. * * * * * * * * * * * * * * * * Mark T. Sadaka, Law Offices of Sadaka Associates, LLC, Englewood, NJ, for Petitioner. Lara A. Englund, United States Department of Justice, Washington, DC, for Respondent. RULING ON ALTHEN PRONG ONE1 This matter concerns eight petitioners2 who have filed petitions for compensation in the National Vaccine Injury Compensation Program (“the Program”).3 The petitioners have alleged that human papillomavirus (“HPV”) vaccinations they received between 2008 and 2013 caused them to suffer primary ovarian insufficiency/failure (“POI”).4 The petitioners have consolidated 1 This Ruling shall be posted on the United States Court of Federal Claims’ website, in accordance with the E-Government Act of 2002, 44 U.S.C. § 3501 note (2012) (Federal Management and Promotion of Electronic Government Services). In accordance with Vaccine Rule 18(b), a party has 14 days to identify and move to delete medical or other information that satisfies the criteria in § 300aa-12(d)(4)(B). Further, consistent with the rule requirement, a motion for redaction must include a proposed redacted Ruling. If, upon review, I agree that the identified material fits within the requirements of that provision, such material will be deleted from public access. 2 This ruling will be filed in Alexander (14-868V); Bello (13-349V); Bond (16-1615V); Drummond (16- 702V); Nunez (14-996V); Root (16-20V); Tilley (14-818V); and Brayboy (15-183V), which is the named case. 3 National Childhood Vaccine Injury Act of 1986, Pub L. No. 99-660, 100 Stat. 3755 (“the Vaccine Act” or “Act”). Hereinafter, for ease of citation, all “§” references to the Vaccine Act will be to the pertinent subparagraph of 42 U.S.C. § 300aa (2012). 4 Primary ovarian insufficiency, also known as premature or primary ovarian failure, is the “absence or irregularity of menses lasting at least four months, with menopausal levels of serum gonadotrophins in an adolescent girl or woman under 40 years of age. It may be temporary or permanent.” Primary Ovarian Insufficiency, DORLAND’S MEDICAL DICTIONARY ONLINE [hereinafter “DORLAND’S”], https://www.dorlandsonline.com (last visited June 23, 2021). Gonadotropins are “any hormone[s] that stimulate[ ] the gonads[.]” Gonadotropin, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). Gonads, also referred to as genital glands and sex glands, are “gamete-producing gland[s,]” such as ovaries. Gonad, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). 1 Case 1:13-vv-00349-SSS Document 148 Filed 10/20/21 Page 2 of 24 their claims for the purpose of determining whether they have presented a sufficient causation theory pursuant to Althen prong one. For the reasons discussed herein, I find that the petitioners have satisfied Althen prong one. Petitioners have articulated a sound and reliable theory of how HPV vaccines could cause autoimmune POI via molecular mimicry. More specifically, Petitioners’ expert described how autoantibodies can attack multiple short peptide chains contained within proteins needed for normal ovarian function, when said peptides are also contained within viral proteins identified by the immune system for destruction. I. Procedural History Several petitioners in recent years have filed claims alleging that they suffered POI due to HPV vaccinations. Those cases were contested by Respondent, who argued that many of the claims were barred from entitlement because the statute of limitations had run. The special master presiding over the cases determined that case timeliness would depend on the onset of each petitioner’s POI. On November 20, 2014, the special master held a status conference and identified the cases in which a finding regarding onset was relevant to the statute of limitations or causation, even if timeliness was not an issue. See, e.g., Bello, No. 13-349V, ECF No. 53 at 1. During the status conference, “the parties agreed that in all pending POI cases . . . an expert hearing would be held to address the question of what constitutes the first symptom or manifestation of POI onset recognized as such by the medical profession at large.” Culligan v. Sec’y of Health & Hum. Servs., No. 14-318V, 2016 WL 3101981, at *3 (Fed. Cl. Spec. Mstr. June 2, 2016) (internal citations omitted). The special master established that the Culligan case would serve as the test case, with all others trailing, and 1) “a timeliness determination would be made based on the evidence presented at the Culligan hearing;” 2) all petitioners would consent to share their medical records; and 3) “similar hearings would not be conducted in other POI cases[.]” Id. at *3–*4. In advance of the onset hearing, the special master ordered petitioners to file an expert report addressing several questions, including “what constitutes ‘the first symptom or manifestation of [POI/POF] onset[.]’” Id. (citing Cloer v. Sec’y of Health & Hum. Servs., 654 F.3d 1322, 1340 (Fed. Cir. 2011)). A consolidated hearing regarding the issue of onset of POI was held in June 2015, after which the cases discussed below have been allowed to proceed to a determination on entitlement. See Sched. Order, ECF No. 15; see also Culligan, 2016 WL 3101981, at *5. Culligan was ultimately dismissed after the special master determined the case was time-barred. See Culligan, 2016 WL 3101981, at *11. Following the special master’s decision in Culligan, petitioners’ counsel indicated that he would likely retain the same causation expert for all of the cases, and Respondent indicated that his stance on consolidation may depend on whether the petitioners all presented the same theory of causation. E.g., No. 15-183V, ECF No. 15 at 1. After initial expert reports were filed in all cases, the parties ultimately agreed that consolidation remained appropriate to determine if any of the cases could proceed in light of the causation theory that had been proposed in each of the petitioners’ cases. See, e.g., No. 15-183V, ECF No. 41. I will now address whether these consolidated cases can meet their burden with respect to Althen prong one. A. Trailing Cases a. Bello 2 Case 1:13-vv-00349-SSS Document 148 Filed 10/20/21 Page 3 of 24 On May 22, 2013, Cristal Bello filed the first of these cases, alleging in her petition that an HPV vaccine she received on June 4, 2010, caused her to develop POI. No. 13-349V, Pet. at 1, ECF No. 1. She filed medical records on July 12, 2013, October 3, 2013, and December 13, 2013. ECF Nos. 8, 15, 23. On February 20, 2014, Respondent filed his Rule 4(c) report and denied that Petitioner was entitled to compensation. ECF No. 35 at 7. Petitioner filed additional medical records on July 16, 2014, and November 18, 2014. ECF Nos. 46, 52. Pursuant to the presiding special master’s consolidation of this case following Culligan, Petitioner filed a status report on September 8, 2016, indicating “consent[] to the disclosure of her case information to other POI petitioners, including the POI petitioners whose petitions were filed after [after Culligan].” ECF No. 73 at 2; ECF No. 76. Petitioner submitted additional medical records on January 5, 2017, and March 23, 2017, as well as a final statement of completion on March 23, 2017. ECF Nos. 80, 90– 92. b. Tilley On September 5, 2014, Lisa Tilley filed a petition in which she claimed that her then- seventeen-year-old daughter, Olivia Tilley, suffered from POI as a result of HPV vaccines administered on June 26, 2009, August 26, 2009, and August 10, 2011. No. 14-818V, Pet. at 1, ECF No. 1. The case caption was amended on June 15, 2015, because Olivia Tilley reached the age of majority. ECF No. 19 at 1. Petitioner filed medical records on September 30, 2014. ECF No. 8. On October 1, 2014, Petitioner submitted a status report indicating that her case should be included in the POI/POF onset cases and that she consented to disclosure of her case information. ECF No. 9 at 1. During the November 20, 2014 status conference, the presiding special master stated that this case would trail Culligan because an onset determination was necessary for this case to proceed. ECF No. 15 at 1. Following the Culligan decision and August 11, 2016 status conference, Petitioner filed a status report indicating consent to disclosure of her case information to other POI petitioners. ECF No. 25. On September 28, 2016, Respondent contested Petitioner’s entitlement to compensation in a Rule 4(c) report. ECF No. 27 at 5. Petitioner filed additional medical records on November 1, 2016, and January 5, 2017, as well as a final statement of completion on January 5, 2017. ECF Nos. 28, 32–33. c. Alexander On September 18, 2014, Howard and Sharyn Alexander filed a petition alleging that their then-eighteen-year-old daughter, Whitney Alexander, experienced POI due to HPV vaccines she received on February 25, 2008, April 28, 2008, and October 15, 2008. No. 14-868V, Pet. at 1, ECF No. 1. The caption was amended to identify Whitney Alexander as the sole petitioner on June 15, 2015. ECF No. 20. Petitioner filed medical records and her affidavit on October 1, 2014. ECF Nos. 8–9. On October 1, 2014, Petitioner indicated that her case should be included in the POI cases which required a finding of onset prior to a determination of causation, which the presiding special master acknowledged during the November 20, 2014 status conference. ECF No. 10 at 1; ECF No. 15 at 1. Petitioner indicated in her status report that she consented to disclosure of her case information to the other POI petitioners. ECF No. 10 at 1. Following Culligan and the August 11, 2016 status conference, Petitioner reaffirmed her consent to disclosure on September 8, 2016. ECF No. 32. Respondent filed his Rule 4(c) report asserting that compensation was inappropriate in this case on September 29, 2016. ECF No. 34 at 2. Petitioner filed additional medical records and a final statement of completion on November 3, 2016. ECF Nos. 35–36. d. Nunez 3 Case 1:13-vv-00349-SSS Document 148 Filed 10/20/21 Page 4 of 24 On October 16, 2014, Monica Chenowith filed a petition and alleged that her then- seventeen-year-old daughter, Alexandra Nunez, suffered POI as a result of HPV vaccines administered on October 20, 2011, and January 4, 2012. No. 14-996V, Pet. at 1, ECF No. 1. On June 15, 2015, the presiding special master amended the case caption to reflect that Alexandra Nunez had reached the age of majority. ECF No. 14. During the November 20, 2014 status conference, the presiding special master identified this case as one in which an onset finding was relevant to causation even though the statute of limitations was not then at issue. ECF No. 7 at 1. Petitioner filed medical records on November 25, 2014. ECF No. 8. On December 9, 2014, Petitioner filed a status report indicating consent to the disclosure of her case information to other POI petitioners. ECF No. 10. Petitioner filed additional medical records on December 16, 2014. ECF No. 11. On June 21, 2016, following Culligan, the presiding special master held a status conference to discuss whether this case was precluded from proceeding on statute of limitations grounds. ECF No. 19 at 1. The presiding special master did not make a finding regarding preclusion at that time but instead ordered Petitioner to submit additional medical records. Id. Petitioner filed her status report reaffirming her consent to the disclosure of her case information on September 8, 2016. ECF No. 23. Petitioner submitted additional medical records on October 12, 2016, and November 1, 2016, and a statement of completion on the latter date. ECF Nos. 26, 28–29. The presiding special master held a status conference on December 12, 2016, to again discuss whether Petitioner’s case was time-barred. ECF No. 33 at 1. The presiding special master concluded that, based on the medical records, “this case would not be considered presumptively time-barred[]” and would “move forward with the same deadlines as the remaining consolidated [POI] cases.” Id. e. Brayboy On February 26, 2015, Lynette Brayboy filed a petition as the parent of then-fifteen-year- old LaKia Brayboy. No. 15-183V, Pet. at 1, ECF No. 1. Petitioner alleged that LaKia Brayboy experienced POI due to HPV vaccines administered on July 21, 2012, September 26, 2012, and February 6, 2013. Id. The case caption was amended on December 28, 2016, to reflect that LaKia Brayboy had reached the age of majority. ECF No. 29. Petitioner filed medical records on March 2, 2015. ECF No. 5. Also on March 2, 2015, Petitioner filed a status report indicating that she would participate as a trailing case in the Culligan onset matter. ECF No. 6. In her status report, Petitioner consented to the disclosure of her information to the other POI petitioners. Id. On September 8, 2016, Petitioner filed her status report indicating consent to the disclosure of her case information. ECF No. 16. On September 19, 2016, Respondent filed a Rule 4(c) report denying that Petitioner had demonstrated entitlement to compensation. ECF No. 17 at 5. Petitioner filed additional medical records on September 28, 2016, October 12, 2016, and November 3, 2016, as well as a final statement of completion on November 3, 2016. ECF No. 20–21, 23–24. On December 28, 2016, Petitioner filed a status report indicating that she consented to disclosure of her information to other POI petitioners. ECF No. 31. f. Root On January 5, 2016, Frederick and Lisa Root filed a petition alleging that their then-fifteen- year-old daughter, M.A.R., suffered from POI due to HPV vaccines she received on January 21, 2013, March 8, 2013, and August 26, 2013. No. 16-20V, Pet. at 1, ECF No. 1. Petitioners filed medical records on January 26, 2016. ECF Nos. 7–8. On August 25, 2016, Respondent filed a Rule 4(c) report denying that Petitioners were entitled to compensation. ECF No. 15 at 5. 4 Case 1:13-vv-00349-SSS Document 148 Filed 10/20/21 Page 5 of 24 Petitioners submitted a status report indicating consent to disclosure of their case information to other POI petitioners on September 8, 2016. ECF No. 17. On October 31, 2016, Petitioners filed additional medical records and a statement of completion. ECF Nos. 21–22. g. Drummond On June 16, 2016, Grace Drummond filed a petition alleging that she “suffered Postural Orthostatic Tachycardia Syndrome (“POTS”),5 and diminishing ovarian reserve leading to [POI]” as a result of HPV vaccines she received on July 22, 2013 and October 23, 2013. No. 16-702V, Pet. at 1, ECF No. 1. She filed medical records on July 11, 2016. ECF Nos. 7–8. On September 8, 2016, Petitioner filed a status report indicating consent “to disclosure of her case information to other POI petitioners[.]” ECF No. 13. Petitioner submitted additional medical records between September 2016 and January 2017 and a statement of completion on January 24, 2017. ECF Nos. 15–16, 19, 23–24, 28–29. h. Bond On December 6, 2016, Mary Ellouise Bond filed a petition and claimed that she suffered POI due HPV vaccines administered on February 15, 2013, April 23, 2013, and September 27, 2013. No. 16-1615V, Pet. at 1, ECF No. 1. She submitted medical records along with her petition as well as a statement of completion on December 12, 2016. ECF Nos. 1, 6. In his Rule 4(c) report filed on March 2, 2017, Respondent argued that Petitioner had not demonstrated entitlement to compensation. ECF No. 11 at 4. I held a Rule 5 status conference on April 6, 2017, and ordered Petitioner to submit an expert report regarding causation. ECF No. 12. On August 3, 2017, I held an additional status conference with the parties, and we discussed whether Petitioner would join her case with the other POI cases. I ordered Petitioner to file a status report indicating how she wished to proceed. ECF No. 17. Instead, Petitioner’s attorney filed a motion to withdraw on August 24, 2017, due to a conflict of interest. ECF No. 18. The attorney then-representing the other POI petitioners began representing Petitioner. See ECF Nos. 19–21. B. Althen Compartmentalization The presiding special master held a status conference regarding how to proceed with the consolidated POI cases on December 1, 2016. No. 15-183V,6 Sched. Order at 1, ECF No. 26. In addition to agreeing that the POI petitioners would submit outstanding medical records, the parties agreed that they would file expert reports regarding all three Althen prongs. Id. The parties also indicated that they would explore how to further proceed once expert reports were filed in the record. Id. On August 1, 2017, Petitioner Brayboy filed an expert report from Dr. Yehuda Shoenfeld, regarding her theory of causation. Pet’r’s Ex. 17, ECF No. 40-4. This expert report authored by Dr. Shoenfeld has been filed in support of each of the POI petitioners’ cases and does not discuss case-specific information. The report was filed in Bello, Alexander, Nunez, Root, and Tilley on 5 Postural Orthostatic Tachycardia Syndrome refers to “a group of symptoms (not including hypotension) that sometimes occur when a person assumes an upright position, including tachycardia, tremulousness, lightheadedness, sweating, and hyperventilation[.]” Postural Orthostatic Tachycardia Syndrome, DORLAND’S, https://www.dorlandsonline.com (last visited June 23, 2021). 6 All further docket citations will refer to this case unless otherwise noted. 5 Case 1:13-vv-00349-SSS Document 148 Filed 10/20/21 Page 6 of 24 August 1, 2017, in Drummond on August 2, 2017, and in Bond on January 10, 2018.7 Petitioner Brayboy also produced reports on August 1, 2017, from Drs. Orit Pinhas-Hamiel and Felice Gersh, which were tailored to her specific case, as well as a piece of medical literature. Pet’r’s Exs. 11, 15, ECF Nos. 39–40. Drs. Pinhas-Hamiel and Gersh also filed case-specific reports in the other POI cases.8 Petitioner Brayboy followed up with additional medical literature on September 26, 2017 and January 3, 2018. ECF Nos. 42–48, 50. During a status conference I held on August 15, 2017, regarding all of the POI cases, Respondent suggested that he file an expert report addressing only the first prong of Althen, since all of the petitioners presented the same causation theory in each of the consolidated POI cases. ECF No. 41. I ordered Respondent to produce an expert report in accordance with his suggestion. Id. Respondent filed expert reports from Drs. Thomas Forsthuber, David Frankfurter, and Robert Yokel, as well as accompanying medical literature, on May 14, 2018. Resp’t’s Exs. A, C, E, ECF Nos. 53–58. Respondent filed additional medical literature on compact discs on June 18, 2018. ECF Nos. 59–60. On September 11, 2018, Petitioner filed responsive supplemental expert reports from Drs. Pinhas-Hamiel and Shoenfeld in support of the POI petitioners’ claims. Pet’r’s Exs. 77, 78, ECF No. 62. Petitioner filed an additional piece of medical literature on October 17, 2018. ECF No. 63. Respondent filed responsive supplemental expert reports from Drs. Forsthuber, Frankfurter, and Yokel on November 19, 2018. Resp’t’s Exs. G, H, I, ECF No. 65. Respondent filed additional medical literature on a compact disc on December 10, 2018. ECF No. 67. Petitioner filed an additional expert report from Dr. Shoenfeld on May 6, 2019, and medical literature the next day. Pet’r’s Ex. 80, ECF Nos. 73–74. Respondent then filed additional expert reports from Drs. Forsthuber and Frankfurter on September 30, 2019, as well as medical literature on September 27, 2019 and September 30, 2019. Resp’t’s Exs. K, L, ECF Nos. 76–78. Petitioner submitted additional medical literature on October 1, 2019. ECF No. 79. I held a status conference with the parties on December 6, 2019. Sched. Order at 1, ECF No. 80. I explained to the parties that “the next step for the group of petitioners with claims alleging premature ovarian failure following HPV is to present arguments with respect to the viability of a causation theory pursuant to Althen prong one.” Id. I indicated that “the best way to proceed is for the parties to submit briefs supported by the literature and expert opinions as needed.” Id. Although the facts in each case vary, the causation theory asserted in all the cases was the same and the same experts were used. In order for the experts to provide some degree of specificity to their opinions, the parties agreed that the facts from one case could be used for context. Id. The Brayboy case was ultimately selected as the lead case. See id. Because the POI petitioners’ counsel requested the 7 See No. 13-349V, ECF No. 98-6; No. 14-868V, ECF No. 47-4; No. 14-996V, ECF No. 42-4; No. 16- 20V, ECF No. 33-4; No. 14-818V, ECF No. 42-3; No. 16-702V, ECF No. 37-4; No. 16-1615V, ECF No. 23-5. 8 Reports from Drs. Pinhas-Hamiel and Gersh were filed on August 1, 2017 in Bello, Alexander, Nunez, Root, and Tilley. See No. 13-349V, ECF Nos. 98-2, 98-4; No. 14-868V, ECF Nos. 46-2, 47-2; No. 14- 996V, ECF Nos. 41-2, 42-2; No. 16-20V, ECF Nos. 32-2, 33-2; No. 14-818V, ECF Nos. 41-1, 42-2. In Drummond, the petitioner filed a report from Dr. Gersh on August 2, 2017, but did not file a case specific report from Dr. Pinhas-Hamiel. See No. 16-702V, ECF No. 37-2. In Bond, the petitioner filed reports from Drs. Pinhas-Hamiel and Gersh on January 10, 2018. See No. 16-1615, ECF Nos. 23-1, 23-3. 6 Case 1:13-vv-00349-SSS Document 148 Filed 10/20/21 Page 7 of 24 opportunity to use facts from the Brayboy case briefings, I ordered counsel to obtain Health Insurance Portability and Accountability Act (“HIPAA”) waivers from each of the petitioners. Id. Petitioner filed her Authorization to Disclose Health Information and Other Records pursuant to HIPAA [hereinafter “HIPPA waiver”] on February 4, 2020, to allow her filings to be shared with the other petitioners in the consolidated POI cases. ECF No. 81. Root filed a HIPAA waiver on February 4, 2020.9 No. 16-20V, ECF No. 78. Nunez and Tilley also filed HIPAA waivers on February 4, 2020. No. 14-996V, ECF No. 83; No. 14-818V, ECF No. 85. On February 5, 2020, Alexander filed her HIPAA waiver. No. 14-868V, ECF No. 91. Bond and Drummond filed HIPAA waivers on February 28, 2020. No. 16-1615V, ECF No. 66; No. 16-702V, ECF No. 84. Bello filed her HIPAA waiver on May 1, 2020. No. 13-349V, ECF No. 145. On June 18, 2020, Petitioner10 filed medical literature as well as her brief regarding Althen prong one. ECF Nos. 85–86. Respondent followed with medical literature and his response to Petitioner’s brief on September 22, 2020. ECF Nos. 87–88. Petitioner filed her reply on November 20, 2020. ECF No. 90. II. Experts A. Petitioner’s Expert, Dr. Yehuda Shoenfeld, M.D. Dr. Shoenfeld received his medical degree from the Hebrew University's Hadassa Medical School in Israel in 1972. Pet’r’s Ex. 24 at 2, ECF No. 40-3. He was appointed a Professor of Medicine at Tel-Aviv University, Sackler Faculty of Medicine in 1990 and has been the Incumbent of the Laura Schwarz-Kipp Chair for Research of Autoimmune Diseases at that university since 2003. Id. at 2, 4. Dr. Shoenfeld has also been the Head of Zabludowicz Center for Autoimmune Diseases at the Sheba Medical Center in Israel since 2011. Id. at 2. Additionally, he has been the Head of the Hybridoma Unit and Research Laboratory for Autoimmune Diseases at Soroka Medical Center since 1985 as well as the Head of Department of Medicine at “B” Sheba Medical Center and the Head of the Center for Autoimmune Diseases at Tel-Aviv University since 1989. Id. Dr. Shoenfeld has authored or co-authored over 1,900 articles, fifty books, and 158 chapters in medical texts, many of them focusing on autoimmune diseases. See id. at 22–139. He has served on the editorial boards of numerous journals. See id. at 9–12. B. Petitioner’s Expert, Dr. Orit Pinhas-Hamiel, M.D. Dr. Pinhas-Hamiel received his medical degree from the Sackler School of Medicine at Tel-Aviv University in Israel in 1986. Pet’r’s Ex. 12 at 1, ECF No. 39-2. He has been Head of the National Juvenile Diabetes Center at Maccabi Health Care Services since 2000. Id. at 4. Dr. Pinhas-Hamiel has also been Head of the Endocrine and Diabetes Unit at Edmond & Lily Safra Children’s Hospital, which is part of The Chaim Sheba Medical Center, in Israel since 2002. Id. He is the author or co-author of eighty-nine articles as well as numerous case reports, review 9 Although M.A.R. had reached the age of majority prior to this date, Lisa Root was her designated health care proxy and both Lisa and Frederick Root had power of attorney. Root Ex. 115 at 3–4, ECF No. 78-1. Lisa Root signed the HIPAA waiver. Id. at 2. 10 As the Brayboy case was selected to be the lead, or named, case for the POI petitioners, the briefs in support of Althen prong one were filed in her case only but on behalf of all POI petitioners. 7 Case 1:13-vv-00349-SSS Document 148 Filed 10/20/21 Page 8 of 24 articles, book chapters, and other works. Id. at 11–62. He has been a member of the editorial boards of Pediatric Diabetes and Frontiers in Endocrinology since 2011 and a member of the World Journal of Diabetes editorial board since 2014. Id. at 63. C. Petitioner’s Expert, Dr. Felice Lauren Gersh, M.D. Dr. Gersh received her medical degree from the University of Southern California School of Medicine in 1977. Pet’r’s Ex. 14 at 1, ECF No. 40-1. She completed a residency in obstetrics and gynecology in 1981 and a fellowship in integrative medicine between 2010 and 2012. Id. Dr. Gersh has practiced in gynecology and integrative women’s health care since 1981. Id. She has been certified by the American Board of Obstetrics and Gynecology since 1984. Id. D. Respondent’s Expert, Dr. Thomas Günter Forsthuber, M.D. Dr. Forsthuber received medical and doctoral degrees from the University of Tübingen in Germany between 1987 and 1989. Resp’t’s Ex. B at 2, ECF No. 56-3. He completed post-doctoral programs at the University of Mainz in Germany, the University of California at Los Angeles’s Department of Microbiology and Molecular Genetics, and Case Western Reserve University. Id. Dr. Forsthuber has been a Professor of Immunology in the University of Texas at San Antonio’s Department of Biology since 2005. Id. at 2–3. He is also an Adjunct Professor of Pathology and of Microbiology & Immunology at the UT Health Sciences Center. Id. He currently serves in editorial positions on multiple journals, including, for example, Clinical Immunology as well as Autoimmunity. Id. at 10. He is a listed author on eighty-five articles and four book chapters as well as numerous abstracts. Id. at 19–27, 32–40. Much of Dr. Forsthuber’s research is focused on autoimmunity and related topics. See id. E. Respondent’s Expert, Dr. David Frankfurter, M.D. Dr. Frankfurter received his medical degree from Yale University in 1991. Resp’t’s Ex. D at 1, ECF No. 57-2. Following his medical degree, Dr. Frankfurter completed a residency in obstetrics and gynecology and a fellowship in reproductive endocrinology at Yale University and Harvard University, respectively. Resp’t’s Ex. C at 1, ECF No. 57-1. Dr. Frankfurter practices as a “Board Certified Reproductive Endocrinologist.” Id. He currently serves as the Division Director of Reproductive Endocrinology, Fertility, and IVF and as Professor of Obstetrics and Gynecology at The George Washington University. Id. He has twenty years of experience treating women with POI. Id. A “significant proportion of [his] practice is comprised of women with diminished ovarian reserve (DOR) or POI.” Id. He has published on and “developed therapeutic protocols aimed at” these conditions and patients. Id. He has “reviewed multiple trials involving women with POI[]” in his capacity as a member of the National Institutes of Child Health and Human Development (NICHD) Intramural Institutional Review Board (IRB). Id. He is an author of various articles, abstracts, book chapters, and presentations. Resp’t’s Ex. D at 5–13. F. Respondent’s Expert, Dr. Robert A. Yokel, Ph.D. Dr. Yokel received his B.S. degree in pharmacy at the University of Wisconsin in 1968 and his Ph.D. in pharmacology at the University of Minnesota in 1973. Resp’t’s Ex. E at 1, ECF No. 58-1; Resp’t’s Ex. F at 1, ECF No. 58-2. He completed post-doctoral research at Concordia University in Canada. Resp’t’s Ex. F at 2. Dr. Yokel has been a member of the faculty at the University of Kentucky’s College of Pharmacy since 1979 and has been a full Professor of Pharmacology and Toxicology since 1993. Id. Dr. Yokel began researching “the pharmacokinetics 8 Case 1:13-vv-00349-SSS Document 148 Filed 10/20/21 Page 9 of 24 and effects (pharmacodynamics) of aluminum” in 1979. Resp’t’s Ex. E at 1. He has “received nine major research grant awards from the United States National Institutes of Health (NIH) and Environmental Protection Agency (EPA) to conduct research on aluminum[.]” Id. He is an author of “approximately 150 peer-reviewed publications, over half [of which] focus on aluminum and/or its chelation.” Id.; Resp’t’s Ex. F at 38–49. III. Analysis I find that Petitioners who are able to establish by a preponderant standard that their POI is autoimmune in nature have presented a sound and reliable causation theory pursuant to Althen prong one. Thus, I begin this analysis with a discussion of how autoimmune POI is identified. Next, I discuss the various theories Petitioners have proposed. Although Petitioners’ hypotheses pertaining to adjuvants do not aid them in satisfying prong one, Petitioners have, through their explanation of the cross-reaction between specific proteins necessary for ovarian function and viral proteins, presented a sound and reliable medical theory. A. POI Diagnosis and Etiology As a factual predicate to proving vaccine-causation, it is each petitioner’s burden to demonstrate by a preponderant standard that she actually suffers from the injury alleged to have been caused by her HPV vaccination(s). See Hibbard v. Sec’y of Health & Hum. Servs., 698 F.3d 1358, 1364-65 (Fed. Cir. 2012); Lombardi v. Sec’y of Health & Hum. Servs., 656 F.3d 1343, 1353 (Fed. Cir. 2011); Broekelschen v. Sec’y of Health & Hum. Servs., 618 F.3d 1339, 1346 (Fed. Cir. 2010) (finding that in a case where the injury itself is in dispute, it is appropriate for the special master to “first determine which injury was best supported by the evidence presented in the record before applying the Althen test so that the special master could subsequently determine causation relative to the injury.”). The Vaccine Act provides that a treating physician’s diagnosis “shall not be binding on the special master or court,” but that the special master should consider the “entire record and the course of the injury” when evaluating how much weight to afford a treating physician’s diagnosis. 42 U.S.C. § 300aa-13(b)(1). In these cases, each petitioner must show by preponderant evidence that she suffers from POI. See Broekelschen, 618 F.3d at 1349; see also Lombardi, 656 F.3d at 1353. POI is defined as amenorrhea11 that lasts more than four months in women younger than 40. Pet’r’s Ex. 26 at 1, ECF No. 42-9.12 The amenorrhea is accompanied by a “hypoestrogenic- hypergonadotropic serum profile (follicle stimulating hormone (“FSH”)13 levels [greater than] 40 11 Amenorrhea is “absence or abnormal stoppage of the menses[.]” Amenorrhea, DORLAND’S, https://www.dorlandsonline.com (last visited June 11, 2021). 12 Mahbod Ebrahimi et al., The role of autoimmunity in premature ovarian failure, IRAN J. REPROD. MED. 13(8):461–472 (2015). 13 The follicular stimulating hormone is “an anterior pituitary [ ] hormone that is a gonadotropic hormone[ ] . . . that stimulates the growth and maturation of ovarian follicles, stimulates estrogen secretion, [and] promotes the endometrial changes characteristic of the first portion (proliferative phase) of the mammalian menstrual cycle . . . .” Follicle-stimulating hormone, DORLAND’S, https://www.dorlandsonline.com (last visited June 11, 2021). Ovarian follicles are “oocyte[s] and [their] encasing (follicular) cells, at any stage of development.” Ovarian follicle, DORLAND’S, https://www.dorlandsonline.com (last visited June 11, 2021). Oocytes are “the immature female 9 Case 1:13-vv-00349-SSS Document 148 Filed 10/20/21 Page 10 of 24 mlU/mL on two occasions).” Id. Other clinical symptoms include “hot flushes and night sweats[], sleep disturbances[,] and dyspareunia14 related to vaginal dryness.” Pet’r’s Ex. 25 at 3, ECF No. 42-8.15 POI is a rare disease affecting “0.3-1% of [the] general population [ ].” Pet’r’s Ex. 26 at 1. It is even rarer among young women, with an incidence rate of “0.01% of women under age 20 [and] 0.1% of women under age 30[.]” Pet’r’s Ex. 13 at 1, ECF No. 39-3.16 A significant number of patients have cases classified as idiopathic, but known causes include: “chromosomal/genetic abnormalities, metabolic/enzymatic factors, autoimmunity, infections, environmental toxins, and iatrogenic influences[.]” Pet’r’s Ex. 26 at 1. Furthermore, “[t]he exact mechanism in pathophysiology of this disorder remains obscure[.]” Id. at 2. An ovarian biopsy is the definitive procedure for diagnosis, however it is “not recommended due to unknown clinical value, expense[,] and risks [ ].” Id. at 7. There is some dispute regarding the prevalence of autoimmune POI, with studies that report it constitutes between 4% to 30% of all POI cases. See Pet’r’s Ex. 13 at 2; Pet’r’s Ex. 25 at 2; Pet’r’s Ex. 26 at 2. Autoimmune cases can be hard to identify because “there is no clinically proven sensitive and specific serum test to confirm the diagnosis . . . .” Pet’r’s Ex. 26 at 1. Autoimmune POI has traditionally been characterized by “the presence of lymphocytic oophoritis,17 autoantibodies18 to ovarian antigens, and associated autoimmune disorders.” Pet’r’s Ex. 25 at 2. Lymphocytic oophoritis is characterized by “[c]ellular infiltration of follicles by macrophages,19 natural killer cells T-lymphocytes,20 plasma cells,21 and B-lymphocytes[.]22” Pet’r’s Ex. 26 at 4. While “[g]irls and young women who have POI on the basis of autoimmune lymphocytic reproductive cell[s] prior to fertilization[.]” Oocyte, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). 14 Dyspareunia refers to “difficult or painful sexual intercourse.” Dyspareunia, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). 15 Jana Petríková and Ivica Lazúrová, Ovarian failure and polycystic ovary syndrome, AUTOIMMUNITY REVIEWS 11(6–7):A471–A478 (2012). 16 Catherine M. Gordon et al., Update on primary ovarian insufficiency in adolescents, CURR. OPIN. PEDIATR. 27(4):511–19 (2015). 17 Lymphocytes are “any of the mononuclear, nonphagocytic leukocytes [also known as white blood cells], found in the blood, lymph, and lymphoid tissues, that are the body’s immunologically competent cells and their precursors.” Lymphocyte, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021); Leukocyte, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). Oophoritis is “inflammation of an ovary.” Oophoritis, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). 18 Autoantibodies are “antibod[ies] formed in response to, and reacting against, a self antigen (i.e., one of the individual’s own normal tissue constituents).” Autoantibody, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). 19 Macrophages are “any of the many forms of mononuclear phagocytes found in tissues.” Macrophage, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). 20 T lymphocytes are “the cells primarily responsible for cell-mediated immunity[,]” which “are characterized by specific surface antigens[.]” T Lymphocytes, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). 21 Plasma cells are “terminally differentiated cell[s] of the B-lymphocyte lineage that produce[] antibodies[.]” Plasma Cell, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). 22 B lymphocytes are “the cells primarily responsible for humoral immunity, the precursors of antibody- producing cells (plasma cells).” B Lymphocytes, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). 10 Case 1:13-vv-00349-SSS Document 148 Filed 10/20/21 Page 11 of 24 oophoritis test positive for serum antiadrenal antibodies,” in general, “[a]ntiovarian antibodies . . . are too nonspecific to be of use in identifying which patients have an autoimmune mechanism.” Pet’r’s Ex. 13 at 4. In cases where oophoritis is apparent, the “follicular depletion is the final stage of autoimmune attack,” but “the size of the involved ovaries could [remain] normal or [become] enlarged on sonographic view.” Pet’r’s Ex. 26 at 4. One process to identify an autoimmune etiology of POI includes, “testing for the presence of 21-hydroxylase autoantibodies as an indicator for autoimmune lymphocytic oophoritis related to steroidogenic23 cell autoimmunity.” Pet’r’s Ex. 13 at 2. In addition to lymphocytic oophoritis, “antibodies binding to the various steroid hormone- producing cells [ ], gonadotropins and their receptors [ ], zona pellucida24 [ ], oocyte [ ], corpus luteum25 [ ], and several other antibodies such as anticardiolipin26 and antinuclear27 antibodies [ ] have been reported as the markers of ovarian autoimmunity.” Pet’r’s Ex. 26 at 2. Without identifying specific antiovarian autoantibodies, the research points to “antibodies directed against steroid-producing cells of various endocrine glands such as adrenal cortex28 cells, . . . and theca cells29 of the ovary . . . .” Pet’r’s Ex. 26 at 2. The main targets of steroid cell antibodies are also present in autoimmune diseases with POI comorbidity. As a result, these diseases, including autoimmune polyendocrine syndromes30 and Addison’s disease,31 can also be effective predictors of autoimmune POI. 23 Steroidogenic means “producing or giving rise to steroids[,]” which are “any of a group of lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system [and] include progesterone, adrenocortical hormones, sex hormones, [etc.]” Steroidogenic, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021); Steroid, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). 24 Also known as the “pellucid zone[,]” the zona pellucida is “a thick, transparent, noncellular layer or envelope of uniform thickness surrounding an oocyte[.]” Zona Pellucida, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). 25 The corpus lutem, or yellow body of ovary, is “a yellow glandular mass in the ovary formed by an ovarian follicle that has matured and discharged its oocyte.” Corpus luteum, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). 26 Anticardiolipin antibodies are “directed against cardiolipin[,]” which is a “phospholipid occurring primarily in mitochondrial inner membranes and in bacterial plasma membranes.” Anticardiolipin antibody, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021); Cardiolipin, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). 27 Antinuclear antibodies are “antibodies directed against nuclear antigens[.]” Antinuclear antibodies, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). 28 The adrenal cortex is “the outer firm yellowish layer that comprises the larger part of the suprarenal gland,” which “secretes . . . many steroid hormones.” Cortex Glandulae Suprarenalis, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). The suprarenal, or adrenal, gland is “a flattened endocrine gland found in the retroperitoneal tissues at the superior pole of the kidney.” Glandula Suprarenalis, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). 29 Theca cells are “cells of the theca interna and theca externa that surround developing ovarian follicles.” Theca Cells, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). 30 Autoimmune polyendocrine syndromes, or polyendocrine autoimmune syndromes, are “syndromes comprising combinations of endocrine and nonendocrine autoimmune diseases.” Polyendocrine Autoimmune Syndromes, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). 31 Addison disease is “a chronic type of adrenocortical insufficiency, characterized by hypotension, weight loss, anorexia, weakness, and a bronze like hyperpigmentation of the skin[]” that “is due to 11 Case 1:13-vv-00349-SSS Document 148 Filed 10/20/21 Page 12 of 24 Petitioner’s expert, Dr. Shoenfeld, writes that studies on the reliability of using specific antiovarian antibodies to predict autoimmune POI are inconsistent. Pet’r’s Ex. 17 at 7. Therefore, he notes that some authors advocate against relying “exclusively on the presence or absence of [antiovarian antibodies]” to determine the pathogenesis of any particular case of POI. Id. He opines that the “multiplicity of the suspected auto antigens and related antibodies illustrates the variety of pathological autoimmune processes that can cause ovarian damage.” Id. However, he does note the “positive correlation between the presence of autoimmune oophoritis and serum adrenal cortex antibodies” in individuals suffering from POI. Id. at 8. Respondent’s expert, Dr. Forsthuber, identifies “three scenarios when autoimmune POI is presumed by clinicians [ ]: (1) POI associated with adrenal autoimmune disease (i.e. autoimmune Addison’s disease); (2) POI associated with non-adrenal autoimmune diseases (e.g. autoimmune thyroid disease); [and] (3) [c]ases of isolated, idiopathic POI.” Resp’t’s Ex. A at 2–3. Despite conflicting evidence about which autoantibodies are markers for autoimmune POI, Dr. Forsthuber notes that steroid-cell autoantibodies (“StCA”) are the most frequently reported in this context. Id. at 3. Of these StCAs, Dr. Forsthuber identifies two that are expressed in the ovaries, and a third, 21-hydroxylase, that is only expressed in the adrenal cortex, but has “the highest diagnostic sensitivity for autoimmune POI [ ].” Id. He continues that “only women that are positive for StCAs show histopathological evidence of autoimmune infiltration of the ovaries (autoimmune oophoritis) on biopsy [ ].” Id. Despite this definitive language, Dr. Forsthuber then concedes that if said autoantibodies “are not present in women with POI, autoimmune oophoritis is typically not found on ovarian biopsy, even in woman that present with other autoimmune diseases, such as autoimmune thyroiditis32 [ ].” Id. Dr. Forsthuber’s use of the word “typically” suggests there may be atypical cases that do not fit his conclusion. In his report, Dr. Forsthuber notes that the majority (60%) of POI patients have “enlarged, multicystic ovaries,” but normal or small ovaries can be found in a significant minority of cases, 33% and 7% respectively. Id. at 4. He continues that “[a]utoimmune cell infiltration of the ovary, i.e.[,] autoimmune oophoritis, is essentially only observed when POI is associated with [Addison’s disease], but is absent when POI occurs in combination with other autoimmune diseases . . . .” Id. at 5. Dr. Forsthuber entertains the hypothesis “that in autoimmune POI associated with [Addison’s disease], the theca cells of the ovary may be attacked by the autoimmune response because they express the antigens targeted by StCA in ovaries and adrenal glands . . . and because of infiltration of lymphocytes around these cells [ ].” Id. While he does not reject outright this possibility, Dr. Forsthuber restates that the process by which “immune tolerance to steroid cells enzymes in the ovaries may be broken in POI and autoantibodies and autoimmune inflammation of the ovaries induced has remained unresolved.” Id. Dr. Forsthuber also presents the possibility that these “autoantibodies arose secondarily due to tissue damage, and [ ] may therefore represent an epiphenomenon [without] pathogenic function.” Id. He is unable to provide an opinion on the underlying mechanisms of POI cases “presumed to be of an autoimmune etiology because of their association with autoimmune disease conditions other than [Addison’s disease.]” Id. at 6. He notes tuberculosis- or autoimmune-induced destruction of the adrenal cortex . . . .” Addison Disease, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). Adrenocortical insufficiency refers to “abnormally diminished secretion of corticosteroids by the suprarenal (adrenal) cortex.” Adrenocortical Insufficiency, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). 32 Thyroiditis refers to “inflammation of the thyroid gland[.]” Thyroiditis, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). 12 Case 1:13-vv-00349-SSS Document 148 Filed 10/20/21 Page 13 of 24 that “convincing evidence or probable disease mechanism[s] are lacking[ ]” to show an autoimmune etiology in these cases where there is no evidence of autoantibodies and autoimmune inflammation. Id. Dr. Forsthuber suggests that these cases “may [actually] be due to the hormonal and/or other metabolic disturbances created by autoimmune thyroiditis . . . or due to other genetic or environmental factors.” Id. While acknowledging that “[i]mportant insights into the mechanisms promoting human autoimmune diseases have come from experimental animal models[,]” Dr. Forsthuber remains skeptical of the use of animal models to determine an autoimmune etiology for POI. See id. at 6– 7. He argues that these studies are “limited by the lack of spontaneous disease models . . . .” Id. The studies have revealed that “disease in most of these models is primarily mediated by cellular immunity, i.e.[,] CD4+ T cells[.]33” Id. at 7. Furthermore, “[a]utoantibodies against ovarian antigens [have] develop[ed] in some of these models, . . . after immunization with inhibin-[alpha] peptide,34” and this can lead to a premature primordial follicle depletion. Id. This appears to be a clear and logical autoimmune pathology, but Dr. Forsthuber notes that unlike in some animals, “the primordial follicle pool is preserved for a long period in [human] POI patients [ ].” Id. Dr. Forsthuber uses this difference as support for his argument that animal studies cannot be used as a basis for establishing autoimmune etiology in humans. See id. Both Drs. Shoenfeld and Forsthuber agree that autoimmune POI has traditionally been diagnosed in association with autoimmune antibodies, oophoritis, and autoimmune disease comorbidity. Dr. Frankfurter, however, cautions that this evidence of POI must be evaluated in the context of adrenal insufficiency. Resp’t’s Ex. C at 7, ECF No. 57-1. Dr. Frankfurter asserts that “[m]aking this conclusion outside of [this context] is not practical and no longer routinely pursued.” Id. In support of this contention, he notes that diagnosing oophoritis requires sectioning the entire ovary, lest the areas of inflammation are missed. Id. He also reiterates that antiovarian antibody testing lacks sufficient specificity and sensitivity to be definitive. Id. Lastly, he notes that without an inciting event, “the chronology of POI relative to other autoimmune conditions is highly variable.” Id. Therefore, he concludes, “the relative frequency of clear autoimmune POI remains small.” Id. Dr. Frankfurter has responded to Dr. Shoenfeld’s theory as it relates to the autoimmune etiology of POI by characterizing it as speculative and overly broad. See id. at 7–8. He argues that “competing theories on the potential role of autoimmunity illustrate the lack of a unified theory or 33 CD4 cells are “T lymphocytes that carry the CD4 antigen; they are helper T cells.” CD4 Cells, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). CD antigens are “any of a number of cell surface markers, expressed by leukocytes and used to distinguish cell lineages, developmental stages, and functional subsets; [they] can be identified by specific monoclonal antibodies . . . .” CD Antigen, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). Helper cells are “differentiated T lymphocytes whose cooperation [ ] is required for the production of antibody against most (T-dependent) antigens.” Helper Cells, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). 34 Inhibin refers to “either of two glycoproteins, A and B, each composed of a common alpha subunit and one of two beta subunits; they are secreted by the gonads and found in seminal plasma and follicular fluid, and inhibit pituitary production of [FSH].” Inhibin, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). A peptide is “any member of a class of compounds of low molecular weight that yield two or more amino acids on hydrolysis. They are the constituent parts of proteins . . . .” Peptide, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). 13 Case 1:13-vv-00349-SSS Document 148 Filed 10/20/21 Page 14 of 24 clear understanding of the process at hand.” Id. at 8. Dr. Frankfurter further concludes that the presence of antibodies cannot be a marker for autoimmune POI “[b]ecause these antibodies are found in normal women and those without POI[; therefore,] it can be assumed that they may be present before the onset of POI.” Id. Dr. Frankfurter refers to Dr. Shoenfeld’s statement “that the exact mechanism of autoimmunity in the pathophysiology of [POI] remains obscure[,]” Pet’r’s Ex. 17 at 7, and opines that without a “valid and clinically appropriate test . . . (excluding that associated with the adrenal gland), it is difficult to conclude that a case is autoimmune in nature versus of unexplained etiology.” Resp’t’s Ex. C at 9. Dr. Frankfurter makes clear that his expectation for each petitioner is that she provide definitive proof of an autoimmune etiology for POI. Petitioners, however, are under no obligation to meet this standard. Instead, each petitioner must show it is more likely than not that she suffers from POI with an autoimmune etiology. In cases where there is evidence of lymphocytic oophoritis, adrenal or ovarian autoantibodies, and comorbid autoimmune disorders, I will presume the POI is autoimmune in nature. If all three of these factors are not present, a petitioner may still be able to establish it more-likely-than-not that her POI is autoimmune, given her particular medical history. If, for example, a petitioner has another autoimmune disorder associated with POI such as Addison’s disease, along with anti-ovarian antibodies, that may be sufficient. Other more common characteristics of a systemic immune reaction, such as inflammation, prolonged fever, and fatigue, may also be considered with other POI symptoms to assess if an individual diagnosis is autoimmune. If a petitioner’s clinical presentation is not at all consistent with a POI etiology, i.e., there is no evidence of oophoritis or anti-steroid antibodies, it is unlikely that she will be able to show how her POI could be characterized as autoimmune in nature. The presence of autoimmune co-morbidities without other factors will not be sufficient to meet the more likely than not autoimmune etiology. The causation theories that the petitioners have presented all rely on a pathogenic immune response to vaccination. Therefore, a POI diagnosis with an autoimmune etiology is a necessary condition for further analysis pursuant to Althen. See Hibbard, 698 F.3d at 1365 (determining that a petitioner’s “failure to show that she had autonomic neuropathy would be fatal to her case[]” when that injury “was a necessary component of her theory of vaccine– induced injury[]”). Each petitioner should take care to evaluate whether it is reasonable to assert an autoimmune POI in light of her specific medical history. The factors for consideration will not be re-litigated nor expanded absent advances in the research. B. Althen Prong One Under the first prong of Althen, a petitioner must offer a scientific or medical theory that answers in the affirmative the question: “can the vaccine[] at issue cause the type of injury alleged?” See Pafford v. Sec’y of Health & Hum. Servs., No. 01-0165V, 2004 WL 1717359, at *4 (Fed. Cl. Spec. Mstr. July 16, 2004), mot. for rev. denied, 64 Fed. Cl. 19 (2005), aff’d, 451 F.3d 1352 (Fed. Cir. 2006). To satisfy this prong, a petitioner’s theory must be based on a “sound and reliable medical or scientific explanation.” Knudsen, 35 F.3d at 548. Such a theory must only be “legally probable, not medically or scientifically certain.” Knudsen, 35 F.3d at 548–49. A petitioner is not required to identify “specific biological mechanisms” to establish causation, nor are they required to present “epidemiologic studies, rechallenge[] the presence of pathological markers or genetic disposition, or general acceptance in the scientific or medical communities.” Capizzano, 440 F.3d at 1325 (quoting Althen, 418 F.3d at 1280). However, as the Federal Circuit has made clear, “simply identifying a ‘plausible’ theory of causation is insufficient for a petitioner to meet her burden of proof.” LaLonde v. Sec’y of Health & Hum. Servs., 746 F.3d 14 Case 1:13-vv-00349-SSS Document 148 Filed 10/20/21 Page 15 of 24 1334, 1339 (Fed. Cir. 2014) (citing Moberly, 592 F.3d at 1322). Rather, “[a] petitioner must provide a reputable medical or scientific explanation that pertains specifically to the petitioner’s case.” Moberly, 592 F.3d at 1322. In general, “the statutory standard of preponderance of the evidence requires a petitioner to demonstrate that the vaccine more likely than not caused the condition alleged.” LaLonde, 746 F.3d at 1339. Here, Dr. Shoenfeld proposes several different theories. For purposes of organization, his theories that involve the adjuvant (aluminum) in the vaccine will be discussed first. Then, his theory involving the viral components of the vaccine will be evaluated. i. Adjuvant / Aluminum-Based Theories In his reports, Dr. Shoenfeld presents multiple mechanisms to explain how the HPV vaccine can cause POI. While known for his Autoimmune Syndrome Induced by Adjuvants (“ASIA”) theory, Dr. Shoenfeld does not refer to this theory here. Instead, he explains that “the presence of an adjuvant in conjunction with the vaccine can greatly increase the innate immune response to the antigen by augmenting the activity of dendritic cells35 [ ], lymphocytes, and macrophages by mimicking natural infection.” Pet’r’s Ex. 17 at 8. He writes that the “[a]djuvants [added to the HPV vaccine] accomplish this task by mimicking specific sets of evolutionarily conserved molecules . . . .” Id. This theory could still be described as an autoimmune syndrome induced by adjuvants, but unlike his traditional ASIA theory, here potential causes of the pathogenic immune response are identified. His argument suggests that pathogenic cross-reactivity between components of the HPV vaccine and the female reproductive system occurs because a molecular mimic is in the adjuvant. He is combining molecular mimicry with an adjuvant-induced injury and lists “liposomes,36 LPSs,37 molecular cages for antigens, components of bacterial cell walls, and endocytosed nucleic acids38” as examples of potential mimicked molecules. Id. Although Dr. Shoenfeld did not present his ASIA theory in this case, the role of the aluminum adjuvant in his adjuvant-induced, molecular mimicry hypothesis is quite similar to his trademark theory in its reliance on adjuvants for a pathogenic immune response. He developed ASIA for several types of vaccine injuries and has tried without success to establish that this phenomenon, often in conjunction with molecular mimicry, can result in various autoimmune diseases. In fact, the validity of the ASIA theory has been repeatedly called into doubt in the 35 Dendritic cells are “a heterogeneous group of antigen-presenting cells derived from myeloid precursors that have numerous branching processes[.]” Dendritic Cells, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). 36 Liposomes are “spherical particle[s] in an aqueous medium, formed by a lipid bilayer enclosing an aqueous compartment.” Liposome, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). 37 An LPS, or lipopolysaccharide, is “a complex of lipid and polysaccharide [that is] is a major component of the cell wall of gram-negative bacteria, a type of endotoxin and important group-specific antigen (O antigen).” Lipopolysaccharide, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). 38 Endocytosis is “the uptake by a cell of material from the environment by invagination of its plasma membrane[.]” Endocytosis, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). A nucleic acid is “a high-molecular-weight nucleotide polymer[,]” such as DNA or RNA. Nucleic Acid, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). 15 Case 1:13-vv-00349-SSS Document 148 Filed 10/20/21 Page 16 of 24 Program. See D’Angiolini v. Sec’y of Health & Hum. Servs., 122 Fed. Cl. 86, 102 (2015) (upholding the special master’s “determin[ation] that ASIA does not provide[] a biologically plausible theory for recovery”), aff’d, 645 Fed. Appx. 1002 (Fed. Cir. 2016); Garner v. Sec’y of Health & Hum. Servs., No. 15–063V, 2017 WL 1713184, at *8 (Fed. Cl. Spec. Mstr. Mar. 24, 2017) (observing that the ASIA theory “is, at a minimum, incomplete and preliminary—and therefore unreliable from an evidentiary standpoint”); Rowan v. Sec’y of Health & Hum. Servs., No. 10–272V, 2014 WL 7465661, at *12 (Fed. Cl. Spec. Mstr. Dec. 8, 2014) (rejecting the ASIA theory because it “is not a proven theory” and no “persuasive or reliable evidence” supports it); Johnson v. Sec’y of Health & Hum. Servs., No. 10–578V, 2016 WL 4917548, at *7–9 (Fed. Cl. Spec. Mstr. Aug. 18, 2016) (rejecting Dr. Shoenfeld’s expansive medical theory that “any adjuvant [is] capable of causing any autoimmune disease,” finding it “overbroad, generalized, and vague, to the point that it could apply to virtually everyone in the world who received a vaccine containing an adjuvant and then at some time in their lives developed an autoimmune disease.”). The primary reason for ASIA’s rejection is its “changing and imprecise” diagnostic criteria, which are unable to “distinguish between afflicted and un-afflicted patients.” D’Angiolini, 122 Fed. Cl. at 102. Dr. Shoenfeld’s proposed theory here suffers from flaws similar to his ASIA theory. If, as Dr. Shoenfeld asserts, the cross-reactivity occurs between a biological system and the aluminum adjuvant, this theory could be applied to any adjuvanted vaccine and body system with homologous peptide chains consisting of five or six amino acids. Dr. Frankfurter argues that “[t]here are hundreds of human proteins that contain [one or more of the homologous penta- peptide39 chains] in question.” Resp’t’s Ex. L at 7, ECF No. 78-1. Dr. Frankfurter reasoned that “given the short sequence[s] identified by Dr. Shoenfeld [are] found in many other proteins within the human proteome, if an autoimmune attack targeted the penta-peptide in question, one would expect, a patient to experience consequences beyond isolated POI.” Id. A second mechanism Dr. Shoenfeld discusses is disruption in ovarian cyclicity as the result of ovo-toxicity. Dr. Shoenfeld notes that women are born “with a finite number of undeveloped, primordial follicles that cannot be further generated after birth.” Pet’r’s Ex. 17 at 9. He continues that the number of viable follicles that any one woman possesses may be affected by environmental or occupational chemicals. Id. Dr. Shoenfeld writes that “[a] number of studies have shown that exposure to direct ovarian toxicants often leads to destruction of oocytes and POI.” Id. Dr. Shoenfeld discusses “[c]hemicals that selectively damage large growing or antral follicles40 only temporarily interrupt reproductive function because these follicles can be replaced by recruitment from the pool of primordial follicles.” Id. He writes, “chemicals that destroy oocytes contained in primordial and primary follicles often lead to permanent infertility and [POI], because once a primordial follicle is destroyed, it cannot be replaced.” Id. Consequently, Dr. Shoenfeld cautions that vaccine components “must be examined for the [possible components that may cause] ovarian toxicity.” Id. at 12. He specifically includes “both adjuvants, used to enhance the immune reaction, 39 A pentapeptide is “a polypeptide containing five amino acids.” Pentapeptide, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). 40 Antral follicles, or tertiary ovarian follicles or vesicular ovarian follicles, are “growing ovarian follicle[s] comprising a primary oocyte surrounded by multiple layers of follicular cells and containing a fluid-filled vesicle [.]” Tertiary Ovarian Follicle, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). 16 Case 1:13-vv-00349-SSS Document 148 Filed 10/20/21 Page 17 of 24 and in the case of most vaccines involves an aluminum adjuvant, as well as various ‘excipients’, [i.e.,] emulsifiers and other sunstances [sic] for solubilization and stabilization of the vaccine.” Id. Dr. Shoenfeld asserts that “[a]luminum has long been recognized as a neurotoxin[.]” Id. at 13. He does not, however, provide any evidence that “aluminum’s inherent neurotoxic and immunotoxic properties [that] are well known in the medical literature” had any negative effects when used in Gardasil vaccine trials or as an adjuvant. Id. In fact, the studies that Dr. Shoenfeld relies on note that “few studies focused on the potential immunological responses induced by Al [aluminum].” Pet’r’s Ex. 37 at 1, ECF No. 43-10.41 While there is evidence that a “[h]igh Al dose or long time Al exposure will make humans and animals exert toxic effect[,]” id. at 2, Dr. Shoenfeld was unable to provide support that a one-time, limited aluminum exposure through vaccination will also lead to the development of reproductive dysfunction, cognitive deficiency, or immune disease. Special masters have previously concluded that evidence of adverse effects from chronic exposure to a substance does not constitute evidence of adverse effects from a single exposure to that substance. See Spahn v. Sec’y of Health & Hum. Servs., No. 09-386V, 2014 WL 12721080, at *17 (Fed. Cl. Spec. Mstr. Sept. 11, 2014) (determining that evidence that chronic or repeated exposures to mercury could cause tics or other issues was not evidence that a one-time mercury exposure through vaccination could cause tics), aff’d, 133 Fed. Cl. 588, 603 (2017). Dr. Shoenfeld was also unable to provide any studies that show that aluminum is an ovary toxin in humans. One mouse study submitted by Dr. Shoenfeld, wherein the animals were administered drinking water with aluminum for four months, showed the rats suffered from “a drop in serum levels of estrogen, progestogen, and testosterone, and the pituitary hormones LH and FSH.” Pet’r’s Ex. 17 at 15 (citing Pet’r’s Ex. 42, ECF No. 44-542). Another study showed that subchronic exposure of aluminum “was shown to disrupt the structure of the [rat] ovary.” Id. (citing Pet’r’s Ex. 43, ECF No. 44-643). In mammal studies, it is clear that chronic, prolonged exposure is needed for these pathological effects. A study done on hamster ovary cells also “revealed a dose-related cytotoxic effect on both ovarian structure and size . . . .” Id. at 16 (citing Pet’r’s Ex. 45, ECF No. 44-844). Dr. Forsthuber responds to these models by pointing out that Dr. Shoenfeld relies on studies that require repeated exposure to aluminum, “without specifying how much or how many doses are required.” Resp’t’s Ex. A at 16. Dr. Forsthuber notes that even Dr. Shoenfeld stated that “repeated exposure to the ‘toxin’ is often required[.]” Id. Dr. Shoenfeld also submitted a study that hypothesized that exposure to aluminum may affect cognitive function. See Pet’r’s Ex. 39 at 1, ECF No. 44-2.45 However, that study identified “metal inert gas welders” and “people accidentally exposed to drinking aluminum sulfate-contaminated water” as likely sufferers. Id. at 7. These individuals endure chronic exposure in higher doses than 41 Y.Z. Zhu et al., Impact of aluminum exposure on the immune system: A mini review, ENV’T TOXICOLOGY & PHARMACOLOGY 35:82–87 (2013). 42 Nan Wang et al., Effects of Subchronic Aluminum Exposure on the Reproductive Function in Female Rats, BIOL. TRACE ELEM. RES. 145:382–87 (2012). 43 Fu Y et al., Effects of sub-chronic aluminum chloride exposure on rat ovaries, LIFE SCI. 100(1):61–66 (2014). 44 AL Di Virgillo et al., Comparative study of the cytotoxic and genotoxic effects of titanium oxide and aluminum oxide nanoparticles in Chinese hamster ovary (CHO-K1) cells, J. HAZARD. MATER., 177(1– 3):711–18 (2010). 45 Maryline Couette et al., Long-term persistence of vaccine-derived aluminum hydroxide is associated with chronic cognitive dysfunction, J. OF INORGANIC BIOCHEMISTRY 103:1571–78 (2009). 17 Case 1:13-vv-00349-SSS Document 148 Filed 10/20/21 Page 18 of 24 one would expect from the Gardasil vaccine. One case study that contemplated an association between macrophage myofasciitis46 and aluminum exposure focused on a man whose “[o]pen muscle biopsy of the [vaccination] site three years later revealed the presence of aluminum hydroxide[,]” but there is nothing in the article that explores a causal connection between the vaccination as the significant cause of aluminum exposure and the development of disease. See generally Pet’r’s Ex. 39. It is unclear how Dr. Shoenfeld relies so heavily on chronic exposure as analogous to a limited, one-time exposure during vaccination. Furthermore, the human studies do not relate back to ovarian injury or even reproductive dysfunction. At best, these studies call for additional studies, and Dr. Shoenfeld’s own writings criticize the medical and research community for a refusal to adequately study aluminum adjuvants. Given the limited, one-time exposure to aluminum at the time of vaccination, these studies do not provide strong support for Dr. Shoenfeld’s ovo-toxicity theory. Despite Dr. Shoenfeld’s criticisms, “[the World Health Organization] and Global Advisory Committee on Vaccine Safety [ ] have stated that there is ‘no evidence of a health risk from aluminum-containing vaccines[.]” Resp’t’s Ex. A at 17 (citing http://www.who.int/vaccine_safety/ committee/topics/aluminum/questions/en/). Dr. Forsthuber also notes that aluminum “is ubiquitous in the environment,” including in foods and health products, and “is present at substantial levels in healthy individuals and distributed throughout the body and in every organ.” Id. It is unclear how Dr. Shoenfeld would ever be able to make the case that the relatively small, isolated “amount of aluminum that could hypothetically be absorbed by vaccination with the HPV vaccine has the toxic effects [he] claim[s.]” Id. Dr. Forsthuber describes Dr. Shoenfeld’s assertions regarding the role of adjuvants in the induction of autoimmune disease as “concepts or theories” that are “really nothing that can be learned from, commented on, or discussed.” Id. at 15. He follows these strong allegations by making the point that although “[a]luminum adjuvants induce local inflammatory reactions[,] . . . they have little systemic effects, and in fact, reduce systemic adverse reactions.” Id. More “[i]mportantly,” Dr. Forsthuber argues “a number of studies showed that antibody production after vaccination with adjuvanted vaccine remained specific for the vaccine antigens and did not induce autoantibodies [ ].” Id. at 15–16 (citing Resp’t’s Ex. A, Tab 5, ECF No. 53-6;47 Resp’t’s Ex. A, Tab 20, ECF No. 55-148). He concludes that even with a much stronger adjuvant, complete Freund’s adjuvant49 “autoimmune pathology of the ovaries could not be induced in [a] model of 46 Myofasciitis is “inflammation of a muscle and its fascia, particularly of the fascial insertion of muscle to bone.” Myofasciitis, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). 47 Gianfranco Di Genova et al., Vaccination of human subjects expands both specific and bystander memory T cells but antibody production remains vaccine specific, BLOOD 107(7): 2806–13 (2006). 48 F. Eun-Hyung Lee et al., Circulating human antibody-secreting cells during vaccinations and respiratory viral infections are characterized by high specificity and lack of bystander effect, J. OF IMMUNOLOGY, 186(9): 5514–21 (2011). 49 A complete Freund adjuvant is “a water-in-oil emulsion incorporating antigen . . . The addition of killed, dried mycobacteria . . . to the oil phase . . . elicits cell-mediated immunity (delayed hypersensitivity), as well as humoral antibody formation.” Freund Adjuvant, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). 18 Case 1:13-vv-00349-SSS Document 148 Filed 10/20/21 Page 19 of 24 experimental autoimmune oophoritis” in the absence of ovarian autoantigen. Id. at 16 (citing Resp’t’s Ex. A, Tab 1, ECF No. 53-250). Petitioners ultimately do not focus on adjuvant-induced toxicity or adjuvant molecular mimics to establish causation. Dr. Shoenfeld has been unable to identify any human studies that directly support these theories centered around adjuvants. There is also the difficulty of conducting a study on a condition that is often discovered in an individual several years post any relevant vaccination. Studies are not required to establish causation in the Program, and I will not hold the lack of studies against Petitioners here. However, Petitioners are required to provide more than speculation that short, unidentified, homologous peptide sequences between the aluminum adjuvant in the HPV vaccine and various parts of female reproductive and endocrine systems necessarily mean pathogenic cross-reaction. Plainly put, the causation theory must be applicable to the specific vaccine and injury in question. Dr. Shoenfeld has not persuasively responded to the concern that his adjuvant-based theories are simply vague conjecture applicable to any adjuvanted vaccine followed by autoimmune disease, regardless of the amount of time that passed between vaccination and injury. I do not find that Petitioners have established by a preponderant standard that the HPV vaccine can cause POI via adjuvant-induced autoimmunity solely, or in conjunction with any other mechanism that focuses on an aluminum adjuvant, including ovo-toxicity. Petitioners have not developed either of those arguments outside of vague assertions and have narrowed their causation theory significantly in subsequent filings. ii. Viral Component Cross-Reaction Indeed, Petitioners ultimately focus on the cross-reaction between specific proteins necessary for ovarian function and viral proteins. Dr. Shoenfeld explains that molecular mimicry is hypothesized to occur when “a susceptible host acquires an infection or gets vaccinated with an agent that has antigens that are immunologically similar to the host antigens but differ sufficiently to induce an immune response when presented to T cells.” Pet’r’s Ex. 17 at 2. He continues that this causes “the host’s tolerance to its own antigens [to] break[] down[,] and the host mounts an attack on its own tissue, mistaking it for a foreign substance that needs to be neutralized. This is termed a ‘cross-reaction[.]’” Id. Petitioners argue that “[a]ll four of the HPV strains contained in Gardasil share homology or mimic human proteins associated with ovarian function.” Pet’r’s Br. at 4, ECF No. 86. Petitioners assert that “molecular mimicry [occurs] between L1 proteins contained in Gardasil and proteins essential to proper ovarian function, [and] antibodies produced in response to the four L1 proteins cross[-]react[] with these proteins resulting in binding or damage to those proteins.” Id. Citing medical literature, Petitioners note that “ATM [ataxia telangiectasia] is an enzyme that helps a cell repair DNA damage [ ]” and mutations. Id. at 8 (citing Pet’r’s Ex. 81, ECF No. 74-1;51 Pet’r’s Ex.106, ECF No. 85-152). They continue that the resulting 50 Cengiz Z. Altuntas et al., Autoimmune Targeted Disruption of the Pituitary-Ovarian Axis Causes Premature Ovarian Failure, J. OF IMMUNOLOGY 177(3): 1988–96 (2006). 51 Carrolee Barlow et al., Atm deficiency results in severe meiotic disruption as early as leptonema of prophase I, DEVELOPMENT 125:4007–17 (1998). 52 Elena J. Tucker et al., Premature Ovarian Insufficiency: New Perspectives on Genetic Cause and Phenotypic Spectrum, ENDOCRINE REVIEWS 37(6):609–35 (2016). 19 Case 1:13-vv-00349-SSS Document 148 Filed 10/20/21 Page 20 of 24 dysfunctional proteins, have been associated with the development of POI.” Pet’r’s Br. at 8. This could, therefore, be the protein that cross-reacts in a specific case to cause autoimmune POI. Furthermore, Dr. Shoenfeld asserts that “Gardasil contains molecular mimics for sixteen (16) proteins that relate to the function of the ovaries.” Id. Dr. Shoenfeld identifies many of these proteins, including: ATM (serine-protein kinase that is involved in oocytes degeneration, infertility); ATS (disintegrin metalloproteinase with thrombospondin motifs – an ovulatory protein that correlates with oocyte fertilization capacity); and EGFR (epidermal growth factor receptor essential for the production of matured and developmentally competent oocytes). Pet’r’s Ex. 80 at 2–3, ECF No. 73-1. Dr. Shoenfeld also identifies four other proteins with homologous peptides from at least three strains of HPV, although their specific functions are not described. See id. at 2. Petitioners argue this alone “should be enough.” Pet’r’s Br. at 9. Petitioners also note that “in another case[,] there may be autoantibodies to the adrenal glands, which would add an additional piece to [their] medical theory.” Id. Respondent’s experts agree that the proteins identified by Dr. Shoenfeld contain peptide chains that also appear in HPV. Dr. Frankfurter notes that some of the proteins relate to newborn low birth weight and intrauterine growth restrictions. See Resp’t’s Ex. L at 6. Dr. Frankfurter points out that POI “preclude[s] pregnancy[;]” therefore, any theory including proteins that relate to these conditions “is without biological basis, and considering them in the context of the current discussion creates a distraction.” Id. Dr. Forsthuber also questions the relevance of peptides shared between HPV and human proteins that are not specifically related to oocyte function. See Resp’t’s Ex. K at 3, ECF No. 77. While Dr. Shoenfeld identified some proteins that are present in more pertinent proteins, both of Respondent’s experts remain critical of Dr. Shoenfeld’s theory. Dr. Forsthuber goes on to note that one amino acid sequence that Dr. Shoenfeld identified “is present in 425 human, animal, and microbial proteins[.]” Id. Indeed, “essentially all of the other amino acid sequences claimed by Dr. Shoenfeld as relevant for ovarian dysfunction are also found in other human proteins.” Id. at 4. Dr. Frankfurter notes Dr. Shoenfeld is very selective in his “reporting [of] the full breadth of human and non-human (bacterial, fungal, and viral) proteins that share the searched penta- peptide sequence[s]” he identifies. Resp’t’s Ex. L at 7. These short sequences, Dr. Frankfurter explains, lack specificity “and it should not be surprising that proteins with reproductive function would be among those that contain [these] amino acid sequence[s]. Id. Due to the presence of these sequences in so many other bodily systems, Dr. Frankfurter again argues that if the sequences were material to the function of a specific bodily system or organ, “one would expect a patient to experience consequences beyond isolated POI.” Id. Dr. Frankfurter also criticizes the claim that the peptides identified by Dr. Shoenfeld can lead to ovarian dysfunction when “mutated or improperly functioning[.]” Id. He explains that “immunogenicity[, or how effectively an antigen provokes an immune response] is not specific to a tissue, but rather a particular epitope[, which is the part of the antigen that the immune system recognizes].” Id. Dr. Frankfurter continues that if Dr. Shoenfeld’s theory was correct, “immune targeting should lead to phenotypic features seen in gene mutation syndromes involving the same target protein.” Id. Because autoimmune tissue damage does not manifest in the same way as genetic mutation, Dr. Frankfurter reasons that the homologous peptides identified by Dr. Shoenfeld 20 Case 1:13-vv-00349-SSS Document 148 Filed 10/20/21 Page 21 of 24 and “expressed in multiple tissues” cannot cross-react and result in pathogenesis “just in one organ system.” Id. Dr. Frankfurter concedes that “patients with ATM mutations manifest ovarian failure[.]” Id. at 8. He continues, however, that “they also demonstrate an unstable gait, progressive motor degeneration and telangectasias53 [sic] [ ].” Id. Dr. Frankfurter is skeptical that Dr. Shoenfeld’s theory is sound without a requirement of other symptoms consistent with “the known phenotype seen with that particular gene mutation.” Id. Indeed, a case wherein a petitioner is exhibiting these additional symptoms would provide strong evidence of the applicability of Dr. Shoenfeld’s theory in that instance. All of the Petitioners alleging vaccine-caused POI are young adults and some were children at the time of diagnosis. Dr. Frankfurter argues that he does not believe cross-reactivity with ATM would cause POI in a child or young adult. See id. While conceding that ATM “affect[s] the progression of prophase I54 prior to oocyte arrest in meiosis I55 and lead[s] to oocyte degeneration prior to birth[,]” he notes that “meiosis I arrest occurs in utero during fetal development[ and] well before HPV vaccination [ ].” Id. Dr. Frankfurter is “not aware of evidence on the influence of ATM on egg development post[-]natally and how that would affect egg function or number.” Id. Put plainly, he argues that any effect this type of cross-reaction would have must occur prior to the birth of a petitioner while ATM is still active. Respondent did not submit evidence that ATM was limited to its role in oocyte development, and it has not been asserted that ATM’s function has been completely identified and understood. Respondent submitted a study by Naleway et al. 56 which acknowledged that there had been some “[c]oncern about a potential association between HPV and POI” within the medical community due to case reports. Resp’t’s Ex. J at 6, ECF No. 72-1. However, the Naleway study “found no evidence of increased risk of POI after HPV vaccination[.]” Id. Notwithstanding their ultimate conclusion, the researchers went on to explain that the often-extended temporal relationship between symptom onset and diagnosis and the difficulty in accurately identifying POI makes, “[s]tudying POI as a vaccine adverse event [ ] challenging[.]” Id. at 5–6. The researchers cautioned that “this study was underpowered to detect small increases in POI risk associated with vaccination.” Id. at 5. Dr. Shoenfeld responds to the Naleway study with an article by Dr. Gayle DeLong.57 Dr. Shoenfeld argues that Dr. DeLong’s article supports his contention that women have become 53 A telangiectasia is a “permanent dilation of preexisting small blood vessels . . . to form focal, discolored lesions, usually in the skin or mucous membranes.” Telangiectasia, DORLAND’S, https://www.dorlandsonline.com (last visited June 15, 2021). 54 Prophase is “the first stage in cell reduplication[,]” which “consists of five stages[]” in meiosis I. Prophase, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). 55 Meiosis is “a special type of cell division occurring in the maturation of germ cells . . . During meiosis I, homologous chromones are paired and segregated . . . .” Meiosis, DORLAND’S, https://www.dorlandsonline.com (last visited June 14, 2021). 56 Allison L. Naleway et al., Primary Ovarian Insufficiency and Adolescent Vaccination, PEDIATRICS 142(3) (2018). 57 Gayle DeLong, A lowered probability of pregnancy in females in the USA aged 25–29 who received a human papillomavirus vaccine injection, J. OF TOXICOLOGY AND ENV’T HEALTH, Part A, 81:14, 661–74 (2018). 21 Case 1:13-vv-00349-SSS Document 148 Filed 10/20/21 Page 22 of 24 increasingly infertile since the development and widespread administration of the human papillomavirus vaccine. See Pet’r’s Ex. 80 at 1. Dr. DeLong argues that “[d]ata suggest[s] that the HPV vaccine is associated with a lower probability of having been pregnant.” Pet’r’s Ex. 79 at 13, ECF No. 63-1. Dr. DeLong, however, has no medical background. She is an economist. See id. at 2. Furthermore, her findings do not control for contraception use or other medical, professional, or personal considerations of modern women. She oversimplifies the reproduction rates and conflates the decrease in pregnancy and childbirth with infertility. Dr. Shoenfeld builds on her conclusions and implicitly argues that if able, every woman would choose to have children at the same rate as previous generations, despite the fact that modern women have alternative professional and personal opportunities that may not have been available in the past. The refusal to acknowledge the potential impact of changes in female reproductive medicine or economic circumstances, and other alternative causes before making a determination of causation with respect to Dr. DeLong’s work, undercuts Dr. Shoenfeld’s opinions regarding causation here. He recognizes that association is not causation but seems to rely almost entirely on association to establish causation regarding the infertility of women in the general population. As I have noted in the past, I do not find Dr. DeLong’s work to be applicable to identifying a vaccine-caused injury. See Decker v. Sec’y of Health & Hum. Servs., No. 15-17V, 2020 WL 7889059, at *33 (Fed. Cl. Spec. Mstr. Dec. 14, 2020). I do not find that her methodology is sound, nor are the conclusions Dr. Shoenfeld draws from her articles reasoned. Her article holds little to no probative value and will be weighed accordingly. Dr. Shoenfeld also asserts that the Naleway researchers had a conflict of interest because they were paid by vaccine manufacturers. Pet’r’s Ex. 80 at 1. He notes that Naleway is “a single center study.” Id. Additionally, Dr. Shoenfeld takes issue with the follow-up reviews done on select patients and criticized the clinical adjusters for potentially “second guess[ing] a treating physician’s diagnosis of POI.” Id. He argues that “a massive peptide sharing exists between Gardasil HPV L1s peptides and human proteins” related to ovarian failure and other forms of reproductive dysfunction. Id. at 2. Among those peptides, Petitioners focus specifically on “serine- protein kinase ATM [that Dr. Shoenfeld states] is involved in oocytes degeneration[.]” Id. In his final report, Dr. Shoenfeld identifies several other peptide chains with a “powerful immunologic impact and the highest cross[-]reactivity risk . . . when considering that a penta[-]peptide acts as a minimal determinant in humoral and cellular immune recognition [ ].” Id. at 5. Unlike with Petitioners’ adjuvant-based causation theories presented here, and in other cases where Respondent is able to directly attack the cause and effect sequence of a petitioner’s biological mechanism, see Nunez v. Sec’y of Health & Hum. Servs., No. 14-863V, 2019 WL 2462667 (Fed. Cl. Spec. Mstr. Mar. 29, 2019); Dougherty v. Sec’y of Health & Hum. Servs., No. 15-1333V, 2018 WL 3989519 (Fed. Cl. Spec. Mstr. July 5, 2018), Respondent has not presented a persuasive rebuttal of the mechanical explanation of Petitioners’ molecular mimicry theory. Dr. Forsthuber acknowledges that “[m]olecular mimicry between microbes and human self-antigens as the cause of human autoimmune diseases has been implicated as a potential mechanism of human autoimmune diseases.” Resp’t’s Ex. A at 12. However, he notes that “to date, there are only very few examples of human autoimmune diseases that could be potentially attributed to molecular mimicry.” Id. He then argues that because his “extensive literature search of PubMed has not revealed any evidence that autoimmune POI is linked to any particular microorganism, being it viral, bacterial, or fungal[,] . . . there is no evidence for a causative role of molecular mimicry in POI . . . .” Id. 22 Case 1:13-vv-00349-SSS Document 148 Filed 10/20/21 Page 23 of 24 Dr. Frankfurter argues that “[i]f Dr. Shoenfeld’s theory were correct, [ ] people who have had HPV infections would be at heightened risk of POI for several years, whenever they received another vaccine or had another infection.” Resp’t’s Ex. L at 6. Dr. Frankfurter explains this is “because during the course of an infection, the resultant tissue damage can create an almost limitless potential of small amino acid chains.” Id. He continues that “[w]ith an HPV infection, viral shedding and tissue inflammation can last years, during which the immune response to HPV peptides/immunogens would be ongoing.” Id. This person would also likely be exposed to annual vaccines, boosters, or “various natural phenomena like insect bites, common scrapes/wounds, . . . all of which would induce a heightened immune response and therefore serve to facilitate the mimicry response.” Id. Despite this logical sequence, Dr. Frankfurter notes that “there is no evidence that people with HPV are at heightened risk of developing POI, or any autoimmune disease.” Id. He concludes that without a corresponding increase in POI among women who suffer from HPV, it is not likely that the vaccine is causative. See id. The pervasiveness of HPV in the general population is further evidence, according to Dr. Frankfurter, of the unlikelihood of Petitioners’ theory. See id. Respondent is over relying on the rarity of the event underlying Petitioners’ theory to deem it unlikely. Petitioners have established by a preponderant standard that POI can be autoimmune. In those instances, molecular mimicry can occur if there is an immune response triggered by vaccination, and homology between peptides in the reproductive system specifically relating to ovarian function and components of the vaccine. This can lead to cross-reaction, and it is logical that the production of autoantibodies, particularly in an individual already susceptible due to autoimmune comorbidities, could lead to the development of autoimmune POI. Dr. Shoenfeld has identified several proteins that contain short peptide chains that play a role in oocyte development and function. Respondent’s experts counter that these peptide chains are too short to be material. They argue that these sequences are seen in many other pathogens, as well as throughout the body, and the medical community has not seen the wide-spread triggering of other types of organ- specific autoimmune disease when individuals are exposed to said pathogens. All of the experts agree, however, that POI is multi-factorial, and there are many opportunities for cross-reactions between multiple homologous peptide chains within the same individual. It is probable that a specific combination of vaccination history, predisposition to autoimmune disease, and cross- reaction with several sequences in multiple specific proteins can precipitate this rare event. If the exact mechanism and progression of all autoimmune diseases had been discovered, we would have better luck predicting, treating, and curing these diseases, even within families. Our inability to account for the somewhat random nature and extreme rarity of a disease like autoimmune POI should not be an insurmountable hurdle for a logical theory that affirmatively answers the question: “can the vaccine at issue cause the type of injury alleged?” A plausible theory of causation is not enough, but scientific certainty as established through epidemiology is too much to require. The presence of presumed vaccine-caused injuries on the Program’s Table that are believed to be the result of molecular mimicry provides a potential analogous baseline plausibility for all other autoimmune illnesses. However, it is not enough to simply assert that a petitioner has an autoimmune disease and molecular mimicry is the mechanism. At that point, a theory is, as Respondent argues here, simply speculation. It also cannot be enough that a medical expert can simply identify homologous peptides from a generic BLAST search that are not, in any way, linked to the biological process that is dysfunctional or has suffered injury. The line must be drawn somewhere between speculation and certainty. Here, Petitioners identified cross-reaction between 23 Case 1:13-vv-00349-SSS Document 148 Filed 10/20/21 Page 24 of 24 components of the vaccine and proteins in the body that are directly responsible for the health and productivity of the organ at issue. Respondent is requiring an additional step and insisting on direct, testable evidence of pathology. Respondent is also looking for a statistically significant rise in the disease, despite its rarity, and an explanation for why only the ovary would be targeted, despite the opportunity for cross reactivity in “almost every second human protein that shares at least one 5-amino acid sequence with [a strain of] HPV[.]” Resp’t’s Ex. K at 9. That is a step too far to establish a right to entitlement here. In cases where a petitioner can establish by a preponderant standard that her POI diagnosis is autoimmune, Petitioners will have detailed a causation theory that is sound and reliable pursuant to Althen prong one. It is true that a penta-peptide chain is undisputedly short. However, given the multifactorial pathogenesis of POI, I find it logical that cross-reactions between multiple, short peptides within proteins relevant to oocyte function and in HPV vaccines may produce an ovary- specific autoimmune attack. Other factors helpful in determining the applicability of this theory to any specific case include an appropriate temporal relationship, the types of autoantibodies produced by a petitioner, adjacent symptoms, and comorbidities. Although I find Dr. Shoenfeld presents a theory I believe is sound and reliable, I do not expect it to be applicable to every case submitted. Indeed, these are rare effects, and that will hold true even within the Program. Petitioners are still expected to establish it more likely than not that they suffer from autoimmune POI and that Dr. Shoenfeld’s theory is applicable to each of them. They must also provide preponderant evidence that molecular mimicry did occur and that there exists a temporal relationship between vaccination and injury. Each petitioner’s medical record should be analyzed to see if her claim can proceed to Althen prongs two and three in accordance with this Ruling. IV. Conclusion The petitioners in the above-mentioned cases have presented a causation theory that, while not applicable to all of them, does survive Althen prong one under specific circumstances. In instances where a petitioner can establish by a preponderant standard that she suffers from autoimmune POI, the case should continue to a determination of whether the causation theory presented is applicable to said petitioner based on her specific medical history. A petitioner whose condition does not present evidence of an autoimmune etiology, such as lymphocytic oophoritis, adrenal or ovarian autoantibodies, and comorbid autoimmune disorders, will not be able to establish that the causation theory presented here is applicable to her claim. There should be autoimmune indicators in the medical record and not simply arguments from experts that despite a lack of direct support in the medical record, the claim should proceed because an autoimmune etiology cannot be definitively ruled out. Petitioners should proceed with the prosecution of their claims in accordance with this Ruling. IT IS SO ORDERED. s/Herbrina D. Sanders Herbrina D. Sanders Special Master 24 ================================================================================ DOCUMENT 3: USCOURTS-cofc-1_13-vv-00349-3 Date issued/filed: 2023-03-10 Pages: 42 Docket text: PUBLIC DECISION (Originally filed: 02/23/2023) regarding 174 DECISION of Special Master. Signed by Special Master Herbrina Sanders. (arm) Service on parties made. -------------------------------------------------------------------------------- Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 1 of 42 In the United States Court of Federal Claims OFFICE OF SPECIAL MASTERS Filed: February 23, 2023 * * * * * * * * * * * * * * * * * * * * * * * * * CRISTAL BELLO, * No. 13-349V * Petitioner, * Special Master Sanders v. * * SECRETARY OF HEALTH * Denial of Entitlement; Human AND HUMAN SERVICES, * Papillomavirus (“HPV” or “Gardasil”) * Vaccine; Premature Ovarian Failure/ Respondent. * Primary Ovarian Insufficiency (“POF/POI”) * * * * * * * * * * * * * * * * * * * * * * * * * * Mark T. Sadaka, Law Offices of Sadaka Associates, LLC, Englewood, NJ, for Petitioner. Kimberly Davey, U.S. Department of Justice, Washington, DC, for Respondent. ENTITLEMENT DECISION1 On May 22, 2013, Cristal Bello (“Petitioner”) filed a petition for compensation under the National Vaccine Injury Compensation Program2 (“Vaccine Program” or “Program”). 42 U.S.C. § 300aa-10 to 34 (2012). Pet. at 1, ECF No. 1. The petition alleges that the human papillomavirus (“HPV” or “Gardasil”) vaccination Petitioner received on June 4, 2010, caused her to suffer from premature ovarian failure (“POF”).3 Id. Petitioner’s case was ultimately consolidated with a group of other cases all alleging that the HPV vaccine caused POF. On August 30, 2021, I issued a Ruling on Althen prong one for this and seven other petitioners who had “consolidated their claims for the purpose of determining whether they have 1 This Decision shall be posted on the United States Court of Federal Claims’ website, in accordance with the E-Government Act of 2002, 44 U.S.C. § 3501 note (2012) (Federal Management and Promotion of Electronic Government Services). This means the Decision will be available to anyone with access to the Internet. In accordance with Vaccine Rule 18(b), a party has 14 days to identify and move to delete medical or other information that satisfies the criteria in § 300aa-12(d)(4)(B). Further, consistent with the rule requirement, a motion for redaction must include a proposed redacted decision. If, upon review, the I agree that the identified material fits within the requirements of that provision, such material will be deleted from public access. 2 National Childhood Vaccine Injury Act of 1986, Pub L. No. 99-660, 100 Stat. 3755 (“the Vaccine Act” or “Act”). Hereinafter, for ease of citation, all “§” references to the Vaccine Act will be to the pertinent subparagraph of 42 U.S.C. § 300aa (2012). 3 Premature ovarian failure, also known as primary ovarian insufficiency, is the “absence or irregularity of menses lasting at least four months, with menopausal levels of serum gonadotrophins in an adolescent girl or woman under 40 years of age. It may be temporary or permanent.” Dorland’s Illustrated Medical Dictionary 1, 945 (32nd ed. 2012) [hereinafter “Dorland’s”]. I will refer to POF interchangeably with POI throughout this Decision. Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 2 of 42 presented a sufficient causation theory.” See Findings of Fact and Conclusions of Law (“Findings of Fact”) at 24, ECF No. 147; Brayboy v. Sec’y of Health & Hum. Servs., No. 15-183V, 2021 WL 4453146 (Fed. Cl. Spec. Mstr. Aug. 30, 2021). I found that the theory presented, “while not applicable to all of them, does survive Althen prong one, [i]n instances where a petitioner can establish by a preponderant standard that she suffers from autoimmune POI.” Findings of Fact at 24. Specifically, I found that the POI petitioners “have articulated a sound and reliable theory of how HPV vaccines could cause autoimmune POI via molecular mimicry.” Brayboy, 2021 WL 4453146, at *1. In order to succeed under this theory and the remaining prongs of Althen, I explained that each POI petitioner must show it is more likely than not that she suffers from POI with an autoimmune etiology. See id. at *19. A determination of whether Petitioner suffers from autoimmune POI and factual analysis pursuant to Althen prongs two and three is now ripe for consideration. After a careful review, Petitioner has failed to show by a preponderant standard that her POI is autoimmune in nature. As such, the record does not contain persuasive evidence that Petitioner’s injury was caused-in-fact by her HPV vaccination via the biological mechanism she has proposed pursuant to Althen prong one. Accordingly, Petitioner’s claim is hereby DISMISSED. I. Procedural History On May 22, 2013, Cristal Bello filed the first of the now-consolidated POI cases, alleging in her petition that the HPV vaccine she received on June 4, 2010, caused her to develop POI. Pet. at 1. She filed medical records, including an affidavit, on July 12, 2013, October 3, 2013, and December 13, 2013. Pet’r’s Exs. 1–9, ECF Nos. 8, 15, 23. Petitioner filed a statement of completion on January 27, 2014. ECF No. 31. On February 20, 2014, Respondent filed his Rule 4(c) report and denied that Petitioner was entitled to compensation. Resp’t’s Report at 7, ECF No. 35. Respondent argued that Petitioner had not satisfied her burden of proof under Althen, as “Petitioner ha[d] not submitted an expert report or any medical literature supporting the claim that the HPV vaccination caused her [POF].” Id. at 5–6 (citing Althen v. Sec’y of Dep’t of Health & Hum. Servs., 418 F.3d 1274, 1278–79 (Fed. Cir. 2005)). Additionally, “none of [P]etitioner’s treating physicians attributed her problem to the HPV vaccine.” Id. at 6. Respondent also generally contested numerous POI cases, including Petitioner’s, and alleged that they were barred by the statute of limitations. See ECF No. 53 at 1. The presiding special master ordered Petitioner to file an expert report in support of her claim. See ECF Nos. 36– 42. This matter was transferred to another special master on May 21, 2014. ECF Nos. 43–44. Petitioner filed additional medical records on July 16 and November 18, 2014. Pet’r’s Exs. 11–13, ECF Nos. 46, 52. On November 20, 2014, prior to the filing of Petitioner’s expert report, the presiding special master held a status conference and identified POI cases in which a finding regarding onset would be relevant to the statute of limitations or causation. ECF No. 53; Min. Entry, docketed Nov. 20, 2014. At the conclusion of the status conference, “the parties agreed that in all pending POI cases . . . an expert hearing would be held to address the question of what constitutes the first symptom or manifestation of POI onset recognized as such by the medical profession at large.” ECF No. 53 at 1; see also Culligan v. Sec’y of Health & Hum. Servs., No. 14- 2 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 3 of 42 318V, 2016 WL 3101981, at *3 (Fed. Cl. Spec. Mstr. June 2, 2016) (internal citations omitted). The presiding special master identified Petitioner’s case as one that did not have a statute of limitations issue, but that a finding regarding onset would be relevant to establishing causation. ECF No. 53 at 1. The special master therefore established that the Culligan case would serve as the test case, with all others trailing, including Petitioner’s. See id. The special master indicated that 1) “a timeliness determination would then be made based on the evidence presented at the Culligan hearing;” 2) all petitioners would consent to share their medical records; and 3) “similar hearings would not be conducted in other POI cases[.]” Culligan, 2016 WL 3101981, at *3–*4. In advance of the onset hearing, the presiding special master ordered the POI petitioners to file an expert report addressing several questions, including “what constitutes ‘the first symptom or manifestation of [POI/POF] onset[.]’” ECF No. 53 (citing Cloer v. Sec’y of Health & Hum. Servs., 654 F.3d 1322, 1340 (Fed. Cir. 2011)). Prior to the Culligan hearing, Petitioner filed a status report on December 17, 2014, consenting to the disclosure of her case information to other POI/POF petitioners. ECF No. 54. Petitioner filed medical records containing laboratory test results on February 18, 2015. Pet’r’s Ex. 14, ECF No. 58. On March 3, 2015, Petitioner filed expert reports from Drs. Yehuda Shoenfeld and Orit Pinhas-Hamiel, along with supporting medical literature on a compact disc on April 15, 2015. See Pet’r’s Exs. 15–18, 19 Tabs A1–A19, Tabs 1–95, 20 Tabs 1–14, ECF Nos. 59–62. A consolidated hearing regarding the issue of onset of POI was held on June 16–17, 2015, after which the presiding special master reiterated that Petitioner’s case could proceed consistent with the findings in Culligan. See Min. Entry, docketed June 18, 2015; see also No. 14-318V, ECF No. 79; Culligan, 2016 WL 3101981, at *5. Culligan was ultimately dismissed after the special master determined the case was time-barred. See Culligan, 2016 WL 3101981, at *11. On August 11, 2016, the presiding special master held a status conference with the parties and stated that while Petitioner’s case was not barred by the statute of limitations, Petitioner would need to undergo additional genetic and autoimmune testing in support of her claim. ECF No. 73 at 1. Petitioner’s counsel indicated that he would likely retain the same causation expert for all of the remaining POI cases, and Respondent indicated that his stance on further consolidation would depend on whether the POI petitioners presented the same theory of causation. See, e.g., ECF No. 73; see also No. 15-183V, ECF No. 15 at 1. On September 8, 2016, Petitioner filed a status report indicating “consent[] to the disclosure of her case information to other POI petitioners, including the POI petitioners whose petitions were filed after [Culligan].” ECF No. 73 at 2; ECF No. 76. Petitioner filed several status reports regarding the identity and progress of the POI petitioners’ experts. ECF Nos. 77–78. Petitioner submitted medical records on January 5, 2017. Pet’r’s Exs. 21–23, ECF No. 80. This case was reassigned to me on January 9, 2017. ECF Nos. 82–83. Petitioner filed additional medical records and a supplemental statement of completion on March 23, 2017. Pet’r’s Exs. 24–25, ECF Nos. 90–92. Following several extensions of time, on May 22, 2017, I sua sponte suspended Petitioner’s deadline for the filing of an expert report, in light of circumstances concerning her counsel. ECF No. 94. On June 14, 2017, Petitioner’s counsel filed a motion to substitute a new attorney in Petitioner’s case, which I granted the same day. ECF Nos. 95–96. The next day, I reinstated Petitioner’s deadline for the filing of her expert report. ECF No. 97; Non- PDF Order, docketed June 15, 2017. 3 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 4 of 42 On August 1, 2017, Petitioner submitted expert reports from Drs. Orit Pinhas-Hamiel, Felice Gersh, and Yehuda Shoenfeld. Pet’r’s Exs. 27–90, ECF Nos. 98, 100–06, 108. The expert report from Dr. Shoenfeld, Pet’r’s Ex. 31, was filed in each of the POI petitioners’ cases and did not discuss case-specific information. See, e.g., No. 15-183V, ECF No. 40. The reports from Drs. Pinhas-Hamiel and Gersh contained case-specific information. See Pet’r’s Exs. 27, 29, ECF No. 98. Following the submission of Petitioner’s expert reports, I held a status conference with the parties on August 15, 2017. ECF No. 99; Min. Entry, docketed Aug. 15, 2017. After some discussion, the parties agreed that Respondent should proceed with filing responsive expert reports addressing the first prong of Althen, as Petitioner’s theory was the same in each of the POI petitioners’ cases. See ECF No. 99. The parties agreed that consolidation remained appropriate. See No. 15-183V, ECF No. 41. Following several extensions of time, Respondent filed responsive expert reports on Althen prong one from Drs. Thomas Forsthuber, David Frankfurter, and Robert Yokel, along with supporting medical literature on May 14, 2018. Resp’t’s Exs. A, A.1–A.31, B–D, D Tabs 1–47, E, E Tabs 1–47, ECF Nos. 110–20. Petitioner filed supplemental expert reports on prong one from Drs. Pinhas-Hamiel and Shoenfeld on September 11, 2018. Pet’r’s Exs. 91–92, ECF No. 122. She filed medical literature on October 17, 2018. Pet’r’s Ex. 93, ECF No. 123. On November 12, 2018, Petitioner filed a consented motion to substitute a new attorney, which was granted. ECF No. 124. Respondent submitted supplemental expert reports from Drs. Forsthuber, Frankfurter, and Yokel on November 19, 2018. See Resp’t’s Exs. D Tabs 2–3, G, G Tabs 1–3, H, H Tabs 1–23, I, I Tabs 1–2, ECF Nos. 125, 127. On December 6, 2018, Petitioner filed another consented motion to substitute counsel and requested for one attorney to handle all the POI petitioners’ cases. ECF No. 126. I held a status conference with the parties on December 18, 2018, regarding Petitioner’s motion and whether counsel was prepared to handle the workload associated with these cases. ECF No. 128; Min. Entry, docketed Dec. 18, 2018. Following the conference and counsel’s representations, Mr. Mark Sadaka took over Petitioner’s claim on December 18, 2018. See ECF No. 128. I held a status conference with the parties on March 21, 2019, to discuss the parties’ arguments with respect to Althen prong one. See ECF Nos. 129–30, 132; Min. Entry, docketed Mar. 21, 2019. The same day, Respondent filed medical literature. Resp’t’s Ex. J, ECF No. 131. On May 6, 2019, Petitioner filed an additional supplemental expert report from Dr. Shoenfeld, with supporting medical literature. Pet’r’s Exs. 94–116, ECF Nos. 133–35. Respondent submitted supplemental reports from Drs. Forsthuber and Frankfurter, along with medical literature on September 27–30, 2019. Resp’t’s Exs. K, K Tabs 1–9, L, L Tabs 1–19, ECF Nos. 138–40. On October 1, 2019, Petitioner filed medical literature. Pet’r’s Exs. 117–18, ECF No. 141. The parties appeared for a status conference on December 6, 2019, during which I informed the parties that the best way to proceed would be for the parties to submit briefs on Althen prong one. See Min. Entry, docketed Dec. 6, 2019; see also No. 15-183V, ECF No. 80. The Brayboy case, No. 15-183V, was ultimately named as the lead case. ECF No. 80. The POI petitioners requested “the opportunity to use facts from [Brayboy] . . . to provide factual context to the parties’ arguments[]” related to prong one in their briefs. See id. I agreed and after numerous extensions of time, Petitioner accordingly filed a HIPAA waiver on May 1, 2020. See ECF Nos. 142–45. The 4 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 5 of 42 parties then filed their briefs on Althen prong one in the lead case on June 18, September 22, and November 20, 2020, respectively. See No. 15-183V, ECF Nos. 86, 88, 90.4 Following the submission of the parties’ briefs on Althen prong one, I issued a ruling on prong one only on August 30, 2021. ECF No. 147; Brayboy, 2021 WL 4453146, at *1. On December 14, 2021, consistent with my ruling, I held a status conference in this matter to discuss whether preponderant evidence has been submitted showing that Petitioner suffers from POI with an autoimmune etiology so that she may proceed under Althen prongs two and three. Sched. Order at 1, ECF No. 149. The parties agreed updated medical records would be needed and I awarded Petitioner sixty days to file such records. See id. On February 14, 2022, Petitioner filed an unopposed motion for an extension of time to file the requested information. ECF No. 150. I stayed Petitioner’s motion and ordered her to file 1) a status report indicating whether the case will proceed with expert reports on Althen prongs two and three or be dismissed; and/or 2) an explicit motion to supplement Petitioner’s request for sixty days to file medical records containing additional objective testing, including a timeline for the collection and submission of such filings. ECF No. 151. On March 15, 2022, Petitioner filed a supplemental motion for an extension of time alleging that she planned to undergo further antibody testing and providing a timeline. ECF No. 152. Respondent noted that he did not see the particular relevance to such testing when the last medical record in this matter was from 2017 and the onset of Petitioner’s symptoms was approximately twelve years ago. Id. at 2. In response to Petitioner’s status report, I held a status conference with the parties on April 12, 2022. Min. Entry, docketed Apr. 12, 2022. During the conference, the parties discussed the relevance of additional antibody testing, along with the additional factors set forth in my ruling on Althen prong one that will aid in my determination of vaccine causation. See ECF No. 153; see also Findings of Fact, ECF No. 147. I noted such test results are particularly unhelpful following prior negative results that were recorded closer in time to Petitioner’s initial symptom manifestation and diagnosis. ECF No. 153. Petitioner requested sixty days to file a status report or other filing identifying evidence regarding her basis to proceed, aside from any recent positive antibody results, and I granted her request. See id. Following one extension of time, on June 14, 2022, Petitioner filed updated antibody test results from April 8, 2022, along with an affidavit indicating she was still in the process of arranging to undergo ovarian antibody testing. Pet’r’s Exs. 121–22, ECF Nos. 156–57. Petitioner also filed a status report that cited to her positive antinuclear antibody (“ANA”)5 tests on July 27, 2011, and February 6, 2017, recurrent rashes "that could be psoriasis," and her treater’s note that says her POF "likely [has an] autoimmune etiology[,]" to support her claim. ECF No. 158 (citing Pet’r’s Ex. 5 at 6; Pet’r’s Ex. 2 at 41; Pet’r’s Ex. 9 at 76). Petitioner requested “additional time” to 4 As the Brayboy case was selected to be the lead case for the POI petitioners, the briefs in support of Althen prong one were filed in that case only but on behalf of all POI petitioners, including Petitioner. 5 Antinuclear antibodies are “antibodies directed against nuclear antigens; ones against a variety of different antigens are almost invariably found in systemic lupus erythematosus and are frequently found in rheumatoid arthritis, scleroderma (systemic sclerosis), Sjögren syndrome, and mixed connective tissue disease. Antinuclear antibodies may be detected by immunofluorescent staining. Serologic tests are also used to determine antibody titers against specific antigens.” Dorland’s at 101. 5 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 6 of 42 obtain antibody testing for anti-ovarian and/or anti-adrenal autoantibodies. See id. at 2. Petitioner maintained that her positive ANA tests, along with her clinical presentation are enough to allow her claim to continue pursuant to Althen prongs two and three. Id. On June 23, 2022, I denied Petitioner’s request for additional time to undergo further antibody testing. ECF No. 159 at 2. I cautioned Petitioner that “recent antibody tests are generally unhelpful in establishing POI etiology, particularly when there is a prior negative antibody test history. Without more, Petitioner will likely be unsuccessful in establishing the applicability of the [] biological mechanism.” See id. I ordered Petitioner to file an expert report on Althen prongs two and three, addressing the factors enumerated in my ruling on Althen prong one, aside from any recent positive antibody results if there have been years between such results and the onset of Petitioner’s symptoms, and/or prior negative results. Id.; see also ECF No. 162. Petitioner filed updated medical records on August 22, 2022. Pet’r’s Ex. 123, ECF No. 163. She also filed expert reports on Althen prongs two and three from Drs. David Axelrod and Orit Pinhas-Hamiel, along with supporting medical literature, on September 21, 2022. Pet’r’s Exs. 124–37, ECF Nos. 164–66. Petitioner submitted the literature cited in such reports on November 23, 2022. Pet’r’s Exs. 138–46, ECF No. 171. Following one extension, Respondent submitted responsive expert reports from Drs. Thomas Forsthuber and Corrine Welt, along with supporting medical literature on November 28, 2022. Resp’t’s Exs. M, M-1–M-9, N, N-1–N-19, O, ECF Nos. 167, 169, 172–73. With consideration of the factors enumerated in my ruling on Althen prong one, a determination of Petitioner’s vaccine causation pursuant to Althen prongs two and three is now ripe for consideration. II. Medical History Petitioner’s medical history is relevant for migraine headaches, depression and anxiety, bipolar disorder, asthma, sleep disorder, and two elective pregnancy terminations at ages 20 and 22. See Pet’r’s Ex. 4 at 3–4, ECF No. 8-5; Pet’r’s Ex. 5 at 6, ECF No. 8-6. Specifically, on September 19, 2006, Petitioner had a positive pregnancy test. Pet’r’s Ex. 8 at 7, 43, ECF No. 15- 2. She reported that her last two menstrual cycles began “on or about [July 19, 2006,]” and August 26, 2006, respectively. Id. at 43. Petitioner subsequently underwent a pregnancy termination on October 13, 2006. See id. at 8, 41. The same day, she reported that her last menstrual period was on August 28, 2006. Id. at 37. Petitioner noted Depo Provera injections6 as her current birth control method. Id. at 41. Petitioner’s Depo Provera injection record shows that she received only one dose of Depo Provera on October 13, 2006. Id. at 48. During a visit on April 26, 2007, Petitioner noted that her “last normal menstrual period” occurred during August of 2006, and she was “not sure” about the start dates of previous cycles. 6 Depo Provera is the trademark preparation of medroxyprogesterone acetate. Dorland’s at 492. Medroxyprogesterone acetate is used as an intramuscular, long-acting contraceptive. Id. at 1120. It is also a “progestin administered orally for treatment of secondary amenorrhea and dysfunctional uterine bleeding, induction of menses, prevention and treatment of endometrial hyperplasia in postmenopausal hormone replacement therapy, and testing for endogenous estrogen production; administered orally or intramuscularly as an antineoplastic in treatment of metastatic endometrial, breast, and renal carcinoma[.]” Id. 6 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 7 of 42 Id. at 43. Petitioner had a pregnancy test, which was negative, and her treater wrote that Petitioner “w[ould] return in [two] weeks if no menses [wa]s reported.” See id. Petitioner indicated that Depo Provera was her most recent form of birth control. Id. Five months later, on September 26, 2007, Petitioner returned and reported that her last normal menstrual period was on August 27, 2007, and again reported Depo Provera as her last method of birth control. Id. at 45. The record does not note that Petitioner’s cycle resumed at any point between August 2006 and August of 2007. See generally id. at 1–47. Later that year, on November 28, 2007, Petitioner was prescribed Ortho Tri- cyclen7 and her last menstrual period was noted as November 27, 2007. Id. at 20. The record does not note if Petitioner menstruated during the month of October in 2007. See id. Petitioner’s second positive pregnancy test occurred on May 7, 2008, following an ultrasound. Id. at 37. She noted that her last menstrual period was on March 10, 2008. Id. The records show this pregnancy was terminated but the exact date of this procedure is unclear.8 Id. at 13, 24–31, 33, 39. Petitioner’s medical records reflect she requested a prescription for hormonal contraception on March 20, 2009. Id. at 31. Petitioner was again prescribed oral contraceptives on May 25, 2010. Pet’r’s Ex. 2 at 61, ECF No. 8-3. Office notes on this date indicate that her last menstrual period was on May 23, 2010. Id. at 66. At age 23, Petitioner received the HPV vaccine in question on June 4, 2010. Id. at 64. On August 6, 2010, Petitioner presented to her gynecologist, Lana Selitsky, M.D., reporting complaints of hot flashes for the past two weeks. Id. at 59. She also complained of a three-pound weight loss, a “change in her energy status[,]” and vaginal dryness. Id. Dr. Selitsky ordered lab work, which showed post-menopausal levels of follicle stimulating hormone (“FSH”)9 (78.2, with 7 Ortho Tri-cyclen is the trademark preparation for therapeutic regimens of norgestimate and ethinyl estradiol. Dorland’s at 1339. Norgestimate is a synthetic progestational agent having little androgenic activity; used in combination with an estrogen component as an oral contraceptive. Id. at 1290. Ethinyl estradiol is “one of the most potent estrogens. It is used in combination with a progestational agent in oral contraceptives and contraceptive patches, and administered orally in hormone replacement therapy[.]” Id. at 651. 8 Petitioner’s record reflects that she underwent an ultrasound on May 7, 2008, revealing a pregnancy. Pet’r’s Ex. 8 at 37. On that date, she noted that her last menstrual period occurred on March 10, 2008. Id. Her records include an “abortion anesthesia record” dated March 20, 2009. See id. at 33. This record does not appear to relate to her May 7, 2008 pregnancy. Indeed, her records do not include documentation of a pregnancy termination in 2008. However, I must note that several of Petitioner’s records during this time period are undated, handwritten, and unclear. For example, the “preoperative exam” record containing a reference to Petitioner’s last menstrual period on March 10, 2008, (consistent with her May 7, 2008 ultrasound report), is undated or the date appears to have been inadvertently covered. See id. at 39. It also contains a notation that Petitioner’s pregnancy was 9–10 weeks along. Id. The evidence therefore shows Petitioner’s second pregnancy was likely terminated on May 7, 2008, but without additional context, I will not make such a determination by a preponderant standard. 9 The follicular stimulating hormone (“FSH”) is “an anterior pituitary [] hormone that is a gonadotropic hormone[] . . . that stimulates the growth and maturation of ovarian follicles, stimulates estrogen secretion, [and] promotes the endometrial changes characteristic of the first portion (proliferative phase) of the mammalian menstrual cycle . . . .” Dorland’s at 870. 7 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 8 of 42 post-menopausal range of 23–336)10 and luteinizing hormone (“LH”)11 (53.2, with post- menopausal range of 15–54).12 Id. at 50. Petitioner’s labs also showed low monocytes and a normal thyroid stimulating hormone (“TSH”). Id. at 50, 53. Petitioner underwent repeat labs on August 18, 2010, which showed a post-menopausal FSH level of 52.3. Pet’r’s Ex. 3 at 25, ECF No. 8-4. Approximately one month later, on September 22, 2010, Petitioner’s labs yielded normal FSH/LH levels of 14.4 and 14.2, respectively. Pet’r’s Ex. 2 at 48. On December 7, 2010, Petitioner faxed a note to gynecologist and reproductive endocrinologist Dov Goldstein, M.D. Pet’r’s Ex. 3 at 32. Petitioner reported that she began having hot flashes “[i]n the beginning of August [of 2010],” and “mentioned it to [her gynecologist,]” Dr. Selitsky. Id.; see also Pet’r’s Ex. 2 at 59 (wherein on August 6, 2010, Petitioner complained to Dr. Selitsky of hot flashes for the past two weeks). Petitioner continued that her gynecologist then ran tests, showing that Petitioner’s FSH levels had been “abnormally high.” Pet’r’s Ex. 3 at 32. Petitioner wrote to Dr. Goldstein that during said time in August of 2010, she had “missed [her] menstrual cycle for about [three] months[,]” so her gynecologist took her off birth control and continued to monitor her hormone levels for the next two months. Id. Petitioner indicated that her hot flashes then dissipated but they were now “back and worse than before.” Id. She complained of weight loss but that her appetite was increasing. Id. Petitioner also noted that her period was “again” two weeks late. Id. at 32–33. Among Dr. Goldstein’s visit notes is a handwritten examination note regarding Petitioner that is undated, unsigned, and without context.13 See id. at 7. It appears to reflect that Dr. Goldstein’s impression was once listed as “[rule out] premature ovarian failure.” Id. Dr. Goldstein started Petitioner on hormone replacement therapy with a Vivelle-Dot patch14 (estrogen) and Provera15 (a synthetic progestin) per this note, but the chronology is unknown.16 Id. 10 A normal FSH level for a woman still menstruating is 4.7 to 21.5 IU/L, although normal value ranges may vary slightly among different laboratories. See Follicle-stimulating hormone (FSH) blood test, MOUNT SINAI, https://www.mountsinai.org/health-library/tests/follicle-stimulating-hormone-fsh-blood-test (last visited Jan. 31, 2023). 11 The luteinizing hormone (“LH”) is an “anterior pituitary hormone that . . . acts with follicle-stimulating hormone to promote ovulation as well as secretion of androgens and progesterone. It instigates and maintains the second (secretory) portion of the mammalian estrus and menstrual cycle.” Dorland’s at 870. 12 A normal LH level for a woman prior to menopause is 5 to 25 IU/L, although normal value ranges may vary slightly among different laboratories. See Luteinizing hormone (LH) blood test, MOUNT SINAI, https://www.mountsinai.org/health-library/tests/luteinizing-hormone-lh-blood-test (last visited Jan. 31, 2023). 13 It is extremely difficult to decipher. See Pet’r’s Ex. 3 at 7. 14 The Vivelle-Dot patch is the trademark preparation for estradiol. Dorland’s at 2069. Estradiol is “1. the most potent naturally occurring ovarian and placental estrogen in mammals; it prepares the uterus for implantation of the fertilized oocyte and promotes the maturation and maintenance of the female accessory reproductive organs and secondary sex characters . . . 2. a preparation of this hormone used in estrogen replacement therapy[.]” Id. at 649. 15 See supra, note 6 (defining Depo Provera). 16 As this note is undated, the exact start date of Petitioner’s use of hormone replacement therapy is not clear. Her later records reflect that as of March 11, 2011, she had begun taking Provera. Pet’r’s Ex. 3 at 5. Her March 24, 2011 medical record seems to reflect that she stopped using the Vivelle-Dot patch because it was not helping her hot flashes. Id. By October 4, 2011, Dr. Goldstein wrote that Petitioner had “stopped” Vivelle and she was ordered to re-start the Vivelle-Dot patch and Provera. See id. at 2. On March 17, 2012, 8 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 9 of 42 Petitioner underwent repeat testing on December 16, 2010, revealing an elevated FSH and LH, and a negative ANA. See Pet’r’s Ex. 2 at 41–42. Her testing also revealed a normal rheumatoid factor17 and erythrocyte sedimentation rate (“ESR”).18 Id. Petitioner underwent a pelvic ultrasound on December 17, 2010, that showed a normal-sized right ovary with a follicle measuring 12 x 9 mm, but the left ovary was not clearly seen. Pet’r’s Ex. 3 at 13. A repeat pelvic ultrasound was performed on February 7, 2011, and was normal with one follicle on her right ovary measuring 5 x 4 mm, except the left ovary was again not clearly seen. Id. at 10–11. During this procedure, Dr. Goldstein noted that Petitioner’s last menstrual cycle was in November of 2010. Id. at 10. By March 1, 2011, Dr. Goldstein noted that Petitioner was still having “lots of” hot flashes. Id. at 5.19 On March 11, 2011, Dr. Goldstein recorded that Petitioner had “no hot flashes for [four to five] days]” and that she “[t]ook Provera.” Id. On March 24, 2011, Dr. Goldstein noted that Petitioner “stop[ped] the Vivelle[-Dot patch] but was still getting hot flashes[.]”20 Id. On July 27, 2011, Petitioner underwent additional lab testing that showed a positive ANA at 1:160. Pet’r’s Ex. 9 at 72, ECF No. 23-2. During this visit, Petitioner recounted her medical history of anxiety, asthma, depression, and type-2 diabetes mellitus.21 Id. at 7. Petitioner returned to Dr. Goldstein on October 4, 2011. Pet’r’s Ex. 3 at 2. He noted that Petitioner continued to experience fluctuating FSH levels and had discontinued her use of the Vivelle-Dot, due to a recurrence of her hot flashes. Id. Based on Petitioner’s history, Dr. Goldstein diagnosed her with amenorrhea22 and POF with hot flashes. Id. Dr. Goldstein ordered Petitioner to restart the Vivelle- Dot and Provera.23 Id. Dr. Gleicher noted that Petitioner had been taking hormone replacement therapy but she had stopped it one month prior to that appointment. Pet’r’s Ex. 5 at 6. It therefore appears that Petitioner was on hormone replacement therapy off and on from approximately March of 2011 through February of 2012. 17 Rheumatoid factor refers to “antibodies directed against antigenic determinants, i.e., Gm, in the Fc region of the IgG class of immunoglobulins; these are found in the serum of about 80 percent of persons with classical or definite rheumatoid arthritis but only about 20 percent of those with juvenile rheumatoid arthritis . . . Rheumatoid factors also occur in other connective tissue diseases and some infectious diseases.” Dorland’s at 676. 18 The erythrocyte sedimentation rate refers to “the rate at which erythrocytes precipitate out from a well- mixed specimen of venous blood . . . an increase in rate is usually due to elevated levels of plasma proteins, especially fibrinogen and immunoglobulins, which decrease the zeta potential on erythrocytes by dielectric shielding and thus promote rouleau formation. It is increased in monoclonal gammopathy, hypergammaglobulinemia due to inflammatory disease, hyperfibrinogenemia, active inflammatory disease, and anemia[.]” Dorland’s at 1594. An erythrocyte is a red blood cell. Id. at 644. 19 Such notations by Dr. Goldstein are likewise handwritten and extremely difficult to decipher. 20 This notation is handwritten and difficult to decipher. 21 Other than this self-reported diagnosis of type-2 diabetes mellitus, there is no other mention or diagnosis, of diabetes in Petitioner’s medical records. Petitioner’s own expert Dr. Axelrod highlighted this point. See Pet’r’s Ex. 124 at 2. Type-2 diabetes mellitus is “one of the two major types of diabetes mellitus, characterized by peak age of onset between 50 and 60 years, gradual onset with few symptoms of metabolic disturbance . . . and no need for exogenous insulin; dietary control with or without oral hypoglycemic is usually effective. Obesity and genetic factors may also be present. Diagnosis is based on laboratory tests indicating glucose intolerance.” Dorland’s at 506. 22 Amenorrhea is the absences of abnormal stoppage of the menses. Dorland’s at 59. 23 These notations are also handwritten and mostly illegible. 9 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 10 of 42 On March 17, 2012, Petitioner presented to gynecologist Norbert Gleicher, M.D. Pet’r’s Ex. 5 at 6. Dr. Gleicher wrote that Petitioner began menstruating at age 15, but that her periods had since ceased. Id. Petitioner reported that her last period was in October of 2010. Id. Dr. Gleicher noted that Petitioner had a positive ANA during “[July of 2011]” and that she was diagnosed with POF by Dr. Goldstein in 2010. Id. He also noted that Petitioner was on “[hormone replacement therapy], which she stopped [one] month ago[.]” Id. Dr. Gleicher wrote that Petitioner was “still allegedly producing mature follicles on [her ultrasound.]” Id. at 7. Dr. Gleicher’s impression was that her POF was “likely autoimmune[.]” Id. He ordered additional lab tests on March 17, 2012, which showed a negative ANA. Id. at 29. Such lab results were negative or normal for autoimmune serologies, including lupus anticoagulant,24 immunoglobulins,25 anti-cardiolipin antibody,26 beta-2 glycoprotein, thyroid antibodies, liver function testing, testosterone, dehydroepiandrosterone,27 anti-Müllerian hormone,28 anti-adrenal antibodies, anti-ovarian antibodies, thyrotropin receptor antibodies,29 and prolactin.30 Id. at 23–29, 33–36, 47. Her genetic testing for Fragile X mutation31 was also negative. Id. at 31, 34. Petitioner presented to another gynecologist on April 23, 2012, who noted her recent negative autoimmune workup. See id. at 4. Petitioner’s treater noted her family history of scleroderma32 and diabetes-mellitus. Pet’r’s Ex. 6 at 3–5, ECF No. 8-7; Pet’r’s Ex. 23 at 115, ECF No. 80-3. Petitioner underwent DNA testing on August 9, 2012, which was mostly normal. Pet’r’s Ex. 12 at 11, ECF No. 52-2. However, Petitioner’s anti-Müllerian hormone was abnormal at < 0.16 ng/mL (normal range for 25-year-old is 0.65–16.40 ng/mL). Pet’r’s Ex. 5 at 13. 24 Lupus anticoagulant is “a circulating anticoagulant that inhibits the conversion of prothrombin to thrombin, found in 5 to 10 per cent of patients with systemic lupus erythematosus, but also seen in other disorders.” Dorland’s at 102. 25 An immunoglobulin is an antibody used by the immune system to identify and neutralize foreign objects such as bacteria and viruses (antigens). Dorland’s at 919. 26 Anti-cardiolipin antibody is “an antibody directed against cardiolipin, seen with increased frequency in systemic lupus erythematosus; its presence correlates with increased risk for thrombotic events.” Dorland’s at 100. 27 Thyroid autoantibodies refer to those “against thyroid peroxidase, thyroglobulin, and thyroid-stimulating hormone receptors, seen in autoimmune thyroiditis.” Dorland’s at 180. 28 The anti-Müllerian hormone plays a role in the development of a fetus’s sex organs (primarily the uterine tubes and uterus in females and appendix testis and prostate in males) while in-utero. Dorland’s at 870. 29 Thyrotropin receptor antibodies are autoantibodies against “a glycoprotein anterior pituitary hormone (28,000 daltons) that promotes the growth of, sustains, and stimulates hormonal secretion of the thyroid gland. Called also thyroid-stimulating hormone.” Dorland’s at 1926. 30 Prolactin is an anterior pituitary hormone that stimulates the formation of milk in mammals and “has many other effects, including [providing] essential roles in the maintenance of immune system functions.” Dorland’s at 1524. 31 A Fragile X mutation is indicative of Fragile X syndrome. It is defined as “an X-linked syndrome associated with a fragile site at locus Xq27.3, characterized by intellectual disability, enlarged testes, high forehead, and enlarged jaw and ears in most males and mild intellectual disability in many heterozygous females.” Dorland’s at 1830. 32 Scleroderma is an autoimmune condition that involves the “chronic hardening and thickening of the skin[,]” and has two forms, localized and systemic scleroderma. Dorland’s at 1679. 10 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 11 of 42 On March 28, 2013, Petitioner presented to rheumatologist Soumya Reddy, M.D., for evaluation of her POF and a reported positive ANA “in 2011[.]”33 Pet’r’s Ex. 6 at 1. Petitioner reported she was experiencing hot flashes. Id. She also reported that she had developed a rash inside her ears in “mid 2012” that an ENT specialist thought was “maybe eczema34 or psoriasis[,]”35 and it improved with steroid cream. Id. Dr. Reddy wrote that Petitioner did not seek treatment with dermatology. Id. Petitioner stated she “gets [an] intermittent ‘bumpy rash’ [on her] back, stomach, and arm . . . [w]ith scaly/dry area[s]/redness[, m]ost severe [on her] scalp.” Id. Dr. Reddy recorded that Petitioner’s grandmother has scleroderma and that her sister has a “similar scalp rash/lesions.” Id. Upon exam, Dr. Reddy indicated that Petitioner had joint pain in her hands, hips, and knees (that was worse during winter), but no joint swelling. Id. Dr. Reddy also noted Petitioner had “mild flakiness at [her] hairline[] and inside [her left] ear,” but wrote there was “no obvious rash or psoriasis.” Id. at 3. Dr. Reddy did not find any evidence of an autoimmune rheumatologic disease in Petitioner, and assessed her with POF, positive ANA, and a rash. Id. In light of Petitioner’s family history of scleroderma and Petitioner’s reported positive ANA, Dr. Reddy ordered additional testing. Id. at 3–5. No labs from March of 2013 appear to be contained in the medical records. See Pet’r’s Ex. 24 at 4, ECF No. 90-1. Petitioner continued to receive treatment for her POF throughout 2013–2016. Petitioner underwent laboratory testing for adrenal autoantibodies on February 5, 2015, which was negative. Pet’r’s Ex. 14 at 1, ECF No. 58-2. On February 6, 2017, at the direction of Dr. Reddy, Petitioner underwent repeat testing that showed a positive ANA at a dilution of >1:80. Pet’r’s Ex. 24 at 38. Petitioner’s antibody testing, including for SCL-70 antibodies (used to test for scleroderma), was negative. Id. at 7–10. Testing for inflammatory markers, including ESR and c-reactive protein (“CRP”),36 was normal. Id. at 41. During a follow-up with Dr. Reddy on March 20, 2017, Dr. Reddy noted Petitioner’s positive ANA, POF, rash, unintentional weight change, and chronic fatigue under diagnoses. Id. at 1. On September 21, 2021, Petitioner presented to dermatologist Marisa Garshick, M.D., complaining of “multiple spots on the skin.” Pet’r’s Ex. 123 at 10, ECF No. 163-1. Dr. Garshick assessed Petitioner with acne and dermatofibroma,37 among other conditions acquired through chronic sun exposure, but did not diagnose her with psoriasis. Id. at 12–13. 33 The date of this positive ANA was July 27, 2011. Pet’r’s Ex. 9 at 72. 34 Eczema is “any of various pruritic, papulovesicular types of dermatitis occurring as reactions to endogenous or exogenous agents. In acute types there may be erythema, edema, inflammatory infiltrates in the dermis, vesiculation, crusting, and scaling. In chronic types there may be lichenification, skin thickening, signs of excoriation; and areas of hyperpigmentation or hypopigmentation.” Dorland’s at 592. 35 Psoriasis refers to “any of a group of common chronic, squamous dermatoses with variable symptoms and courses; some are inherited. Principal histologic findings are [] microabscesses and [] pustules; also seen are rounded, circumscribed, erythematous, dry, scaling patches of various sizes, covered by gray, silvery, or white, umbilicated, lamellar scales. The most common sites are extensor surfaces, nails, scalp, genitalia, and the lumbosacral region.” Dorland’s at 1547. 36 C-reactive protein refers to a protein made by the liver. Dorland’s at 1532. When elevated on a high sensitivity test, it reflects inflammation in the body. See id. 37 Dermatofibroma is “a benign, circumscribed, red to brown nodule in the dermis . . . . It is a form of benign fibrous histiocytoma, and the two terms are sometimes used synonymously . . . .” Dorland’s at 496. 11 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 12 of 42 In 2022, Petitioner underwent repeat antibody testing to attempt to establish an autoimmune etiology for her POF. On April 8, 2022, Petitioner’s labs showed negative 21- hydroxylase,38 thyroid peroxidase,39 and thyroglobulin antibodies. Pet’r’s Ex. 121 at 3, ECF No. 156-1. On August 19, 2022, Petitioner returned to dermatologist Dr. Garshick for her recurrent rashes. Pet’r’s Ex. 123 at 6. Petitioner reported her chief complaint as “psoriasis, new growth on skin[.]” Id. Petitioner also reported psoriasis in her ears, flares on her scalp, and that she was being monitored for “nevus on [the right] medial thigh[.]” Id. Petitioner explained that her psoriasis had been present for “years” in her ears and on her scalp but was now “worsening” with itchiness, bleeding, and scaling/flaking. Id. at 8. Dr. Garshick’s notations regarding the history of Petitioner’s present illness reflect that Petitioner was mainly concerned about her scalp and that her condition was “staying the same[.]” Id. at 9. Dr. Garshick’s assessment included psoriasis that was “established (worsening)[,]” and Petitioner was treated accordingly. Id. Petitioner’s relevant laboratory testing can be summarized as follows: 12/16/2010 7/27/2011 3/17/2012 2/5/2015 2/6/2017 4/8/2022 ANA Negative Positive Negative - Positive - (1:160) (>1:80) Anti- - - Negative Negative - Negative adrenal antibodies Anti- - - Negative - - - ovarian antibodies Thyroid - - Negative - - Negative peroxidase antibodies Anti- - - Negative - - Negative thyroid globulin See e.g., Pet’r’s Ex. 137 at 3. III. Expert Review40 A. Petitioner’s Expert, David Axelrod, M.D. 38 21-hydroxylase antibodies refer to markers of autoimmune Addison’s disease. Dorland’s at 882. Addison’s disease is “a chronic type of adrenocortical insufficiency, characterized by hypotension, weight loss, anorexia, weakness, and a bronzelike hyperpigmentation of the skin. It is due to tuberculosis- or autoimmune-induced destruction of the adrenal cortex, which results in deficiency of aldosterone and cortisol and is fatal in the absence of replacement therapy . . . . Called also chronic adrenocortical insufficiency and primary adrenal or primary adrenocortical insufficiency.” Id. at 528. 39 Thyroid peroxidase antibodies can be a sign of Hashimoto’s thyroiditis, which is an autoimmune disease and most common cause of hypothyroidism. Dorland’s at 102. 40 This Decision is limited to a discussion of Althen prongs two and three and the expert reports authored in support thereof. I therefore do not find it necessary to re-address the reports authored in support of Althen prong one, or the qualifications of the experts that opined on that factor only, unless the expert also authored reports on prongs two and three. See generally Findings of Fact, ECF No. 147. 12 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 13 of 42 Dr. Axelrod received his medical degree from the University of Michigan Medical School in 1974. Pet’r’s Ex. 125 at 1, ECF No. 164. Dr. Axelrod is a “[c]linical [i]mmunologist, trained at McGill University . . . and at the National Institutes of Health[.]” Id. The focus of his training at these institutions was in allergy and rheumatology. Id. He has held several academic appointments, including serving as the Academic Chief in the Division of Allergy, and later the Head of Clinical Research, at the Mount Carmel Mercy Hospital in Detroit, Michigan from 1984 to 1989, and then as an Associate Professor of Adult Rheumatology at the Medical College of Ohio until 1991. Id. at 2. He joined the faculty at New Jersey Medical School as an Associate Professor in the Division of Allergy, Immunology, and Rheumatology in 2007, and served as the Interim Director of the same division from 2009 until 2010. Id. During his clinical practice from 1991 until his retirement in 2018, he “was involved with the diagnosis and treatment of individuals with drug reactions (including to vaccines).” Id.; Pet’r’s Ex. 124 at 1. He holds memberships in numerous medical societies related to allergy, immunology, and rheumatology. Pet’r’s Ex. 125 at 2. His curriculum vitae contains approximately twenty-seven publications and abstracts of which he is a listed author. See id. at 3–4. B. Petitioner’s Expert, Orit Pinhas-Hamiel, M.D. Dr. Pinhas-Hamiel received her medical degree from the Sackler School of Medicine at Tel-Aviv University in Israel in 1986. Pet’r’s Ex. 18 at 1, ECF No. 59-6. She completed an internship and residency in pediatrics at Sheba Medical Center from 1985 to 1992. Pet’r’s Ex. 137 at 1. Dr. Pinhas-Hamiel then completed a fellowship in pediatric endocrinology at the Children’s Hospital in Cincinnati, Ohio in 1995. Id. She is board certified in pediatrics and pediatric endocrinology. Id. She has been Head of the National Juvenile Diabetes Center at Maccabi Health Care Services since 2000. Pet’r’s Ex. 18 at 4. Dr. Pinhas-Hamiel has also been Head of the Endocrine and Diabetes Unit at Edmond & Lily Safra Children’s Hospital, which is part of The Chaim Sheba Medical Center, in Israel since 2002. Id. She is the author or co-author of eighty- nine articles as well as numerous case reports, review articles, book chapters, and other works. Id. at 11–62. She has been a member of the editorial boards of Pediatric Diabetes and Frontiers in Endocrinology since 2011 and a member of the World Journal of Diabetes editorial board since 2014. Id. at 63. Dr. Pinhas-Hamiel noted that providing a “[w]ork-up diagnosis for amenorrhea . . . is a frequent problem [she] encounter[s] in [her] daily practice.” Pet’r’s Ex. 137 at 1. C. Respondent’s Expert, Thomas Forsthuber, M.D. Dr. Forsthuber received medical and doctoral degrees from the University of Tübingen in Germany between 1987 and 1989. Resp’t’s Ex. B at 2, ECF No. 56. He completed post-doctoral programs at the University of Mainz in Germany, the University of California at Los Angeles’s Department of Microbiology and Molecular Genetics, and Case Western Reserve University. Id. Dr. Forsthuber has been a Professor of Immunology in the University of Texas at San Antonio’s Department of Biology since 2005. Id. at 2–3. He is also an Adjunct Professor of Pathology and of Microbiology & Immunology at the UT Health Sciences Center. Id. He currently serves in editorial positions on multiple journals, including, for example, Clinical Immunology as well as Autoimmunity. Id. at 10. He is a listed author on eighty-five articles and four book chapters as well as numerous abstracts. Id. at 19–27, 32–40. Much of Dr. Forsthuber’s research is focused on autoimmunity and related topics. See id. 13 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 14 of 42 D. Respondent’s Expert, Corinne Welt, M.D. Dr. Welt received her medical degree from Cornell University Medical College in 1991. Resp’t’s Ex. O at 1, ECF No. 173-21. She completed post-doctoral training at the Brigham and Women’s Hospital in internal medicine from 1991 to 1994. Id. Dr. Welt then completed fellowships in endocrinology and reproductive endocrinology at Massachusetts General Hospital and Harvard Medical School in 1997. Id. From there, she served on the faculty at Massachusetts General Hospital in the Reproductive Endocrine Unit. Resp’t’s Ex. N at 1, ECF No. 173-1. Dr. Welt has been a Professor of Internal Medicine (Endocrinology and Metabolism) at the University of Utah since 2014. Resp’t’s Ex. O at 1. She has served as the Chief of the Endocrinology, Metabolism, and Diabetes Division at the same institution since 2019. Id. Dr. Welt has held several editorial and reviewer positions on journals regarding reproduction, endocrinology, and metabolism. Id. She is also a member of numerous professional organizations and scientific activities related to endocrinology, POF, and infertility. Id. at 4–6. Dr. Welt’s curriculum vitae lists over one hundred thirty-five articles, books, book chapters, and abstracts, of which she is a listed author. Id. at 9–25. Dr. Welt’s medical focus involves ovulatory disorders in women, including POI. Resp’t’s Ex. N at 1. She is currently a “key investigator [of POI,] coining the name change [from POF] . . . and leading [] research examining the etiology of POI and reviewing POI diagnostic criteria and treatment.” Id. She actively serves as a treating physician in the field of reproductive endocrinology in Salt Lake City, UT. Resp’t’s Ex. O at 2. She has seen “over 100 women with POI” and has “identified the cause of POI in multiple women[.]” Resp’t’s Ex. N at 1. IV. Expert Reports A. David Axelrod, M.D. Dr. Axelrod authored one written report in support of Petitioner’s claim regarding Althen prongs two and three. Pet’r’s Ex. 124. Dr. Axelrod did not dispute Petitioner’s POI diagnosis and deferred to the treater who made this evaluation. Id. at 4. Dr. Axelrod’s description of Petitioner’s history was generally consistent with her medical records.41 See id. at 1–4. He described the logical sequence of cause and effect in Petitioner’s case and argued that following Petitioner’s June 4, 2010 Gardasil vaccination, she “developed a protective immune response to the components of the [] vaccine[,]” causing her to develop autoimmune POI. Id. at 7. Specifically, Dr. Axelrod opined that given Petitioner’s family history of autoimmunity (scleroderma), her detectable positive ANAs, and her psoriasis diagnosis, “it is likely that [Petitioner’s] immune cells [] had escaped central selection and were held at bay by peripheral positive selection (regulation).” Id. He continued, “then with the Gardasil injection, she lost the positive selection (regulation) of her autoreactive immune cells that were then activated by the 41 Dr. Axelrod wrote that Petitioner had a positive ANA on July 31, 2011. Pet’r’s Ex. 124 at 2 (citing Pet’r’s Ex. 9 at 72–76). However, it appears Petitioner’s date of testing and positive ANA screening occurred on July 27, 2011. Pet’r’s Ex. 9 at 7. Additionally, Dr. Axelrod wrote that Petitioner had another positive ANA screening on October 14, 2011. Pet’r’s Ex. 124 at 3 (citing Pet’r’s Ex. 3 at 1). This notation seems to be a reiteration of Petitioner’s positive ANA on July 27, 2011. See Pet’r’s Ex. 3 at 1; Pet’r’s Ex. 9 at 72–76. 14 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 15 of 42 vaccine and attacked her ovaries,” resulting in POI. Id. Dr. Axelrod explained, consistent with my ruling on Althen prong one, that such activation occurred because of “similar amino acid sequences between the Gardasil vaccine components and [Petitioner’s] autoantigen targets of her ovaries.” Id. at 8. This degree of similarity “allow[ed] those cells to avoid her immune regulatory networks for the ovary directed immune cells.” Id. Dr. Axelrod argued that while such autoreactive immune cells typically “participate[] in the protective effects of the Gardasil vaccine,” they also “attacked and damaged” Petitioner’s ovaries, causing her autoimmune POI. Id. Dr. Axelrod “support[ed] the molecular mimicry [theory] outlined . . . by Dr. Shoenfeld [in the ruling on Althen prong one] that was shown to be sound and reliable[.]” Id. at 6. However, Dr. Axelrod added additional homologies “that [he argued] bolster the role of molecular mimicry and cross-reactivity in the development of [Petitioner’s POF].” Id. Specifically, Dr. Axelrod reiterated that the Gardasil vaccine Petitioner received contains the L1 protein from the following strains: HPV 6, 11, 16, 18. Id. Relying on the Tuohy and Altuntas42 review noting that MATER and α- enolase are the target antigens for autoimmune POI, Dr. Axelrod assessed and documented several “antigen peptide alignments[]” between such target antigens and strains within the HPV vaccine Petitioner received. Id. at 7 (citing Pet’r’s Exs. 133–36, ECF Nos. 165-8–165-11; Resp’t’s Ex. K, Tab 9, ECF No. 138-9). To arrive at such conclusion, Dr. Axelrod ran searches through a “clustal program” and noted that the L1 protein from HPV strain 6 and MATER “share amino acid sequences of 3–10 conserved similar conserved amino acids.” See id. Likewise, the same HPV strain compared to α-enolase share 3–7 amino acids. Id. Dr. Axelrod also compared the HPV 6 L1 peptide with α-enolase and keratin 17, the autoantigen thought to be targeted in psoriasis. Id.; see also Pet’r’s Ex. 126, ECF No. 165-1.43 He found 3 shared amino acids. Id. Dr. Axelrod found the same number of homologies in his comparison of the L1 protein of HPV 6, MATER, and keratin 17. Pet’r’s Ex. 124 at 7. Dr. Axelrod then argued that the methods used to measure α-enolase and/or MATER autoantibodies “are not currently used in clinical practice.” Id. at 5. He continued, “[t]herefore, even if [Petitioner] had antibodies or cells to these presumed target antigens in POF, they were not sought by her physicians.” Id. He addressed the lack of positive autoantibodies in Petitioner, aside from her positive ANA. Id. Dr. Axelrod argued that “it is unlikely that every subject with an autoimmune POF will have an associated autoimmune disorder or antibodies.” Id. Dr. Axelrod cited a review by La Marca et al.44 to argue that it is not significant that Petitioner did not “have detectable multiple autoantibodies.” Id. at 6 (citing Resp’t’s Ex. K, Tab 6 at 3–6, ECF No. 138-6). La Marca et al. tabulated the frequency of ovarian antibodies to certain “steroidogenic enzymes” in patients with POI. Resp’t’s Ex. K, Tab 6 at 3. The authors found that among their isolated POI patients, and their POI patients with a comorbid autoimmune disease who did not have adrenal insufficiency, antibodies to steroid-cell autoantibodies, were found in less than 5% of the patients. Id. However, they found that “more relevant” is the association between POI and autoimmune Addison’s disease, because “[a]pproximately 4–8% of women with POI are positive for circulating adrenal 42 V. Tuohy & C. Altuntas, Autoimmunity and premature ovarian failure, 19 CURR. OPIN. OBSTET. GYNECOL. 366–69 (2007). 43 Y. Liang et al., Psoriasis: A mixed autoimmune and autoinflammatory disease, 49 CURR. OPIN. IMMUNOL. 1–8 (2017). 44 A. La Marca et al., Primary ovarian insufficiency: autoimmune causes, 22 CURR. OPIN. OBSTET. GYNECOL. 277–82 (2010). 15 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 16 of 42 autoantibodies[.]” Id. at 2. The authors determined that ovarian autoantibodies against steroidogenic enzymes are present “almost exclusively in women with clinical or preclinical [autoimmune Addison’s disease].” Id. at 3. La Marca et al. wrote that the absence of such autoantibodies “does not exclude the possibility that other auto-antibodies may be present and other autoimmune mechanisms may be active[]” in the development of POI. Id. at 4. Dr. Axelrod therefore argued that while Petitioner did not have multiple, detectable autoantibodies, the La Marca et al. study says she would not have been expected to have “multiple” autoantibodies, “given that she did not have autoimmune adrenal insufficiency.” Pet’r’s Ex. 124 at 6. Dr. Axelrod described the accepted timeframe for a primary adaptive immune response to occur following vaccination. Id. at 8. He argued that such a response occurs within two weeks. Id. He cited a book chapter by Abbas et al.45 entitled “Properties and Overview of Immune Responses.” Id. (citing Pet’r’s Ex. 130, ECF No. 165-5). Dr. Axelrod relied on this overview to illustrate that a primary adaptive immune response “may peak by 14 days following an initial exposure to [an] antigen.” See id. He further relied on “an observational study [by Lawley et al.] of subjects with an autoimmune disorder[,]” serum sickness.46 Id. at 9 (citing Pet’r’s Ex. 131 at 1, ECF No. 165-6).47 Lawley et al. “prospectively evaluated the clinical and immunologic features of serum sickness” in twelve children. Pet’r’s Ex. 131 at 1. As part of their evaluation, the authors observed the time it took for child subjects to develop a primary adaptive immune response after being treated with horse anti-thymocyte globulin. Id. The authors noted that manifestations of a primary adaptive immune response occurred from ten to twenty-five days following exposure to the antigen. Id. at 2–4. The authors determined that symptoms of the disease occurred around the time of the peak immune response within this timeframe. See id. Regarding Petitioner, Dr. Axelrod noted that Petitioner received her first dose of the HPV vaccine on June 4, 2010, and argued that her menstrual cycle ceased after August 1, 2010. Pet’r’s Ex. 124 at 9 (citing Pet’r’s Ex. 12 at 2). He continued that by August 6, 2010, Petitioner exhibited FSH and LH levels in the postmenopausal range, and she had been experiencing hot flashes for the past two weeks. Id. (citing Pet’r’s Ex. 2 at 50–52, 59). Dr. Axelrod stated that “[t]his would put the onset of her symptoms that lead to her diagnosis of [POI] on or about July 23, 2010.” Id. However, Dr. Axelrod opined that “[i]t is likely that the disease process began sometime prior to July 23, 2010, to result in her symptoms[]” by that date. Id. He posited that if the damage did not begin closer in time to Petitioner’s June 4, 2010 HPV vaccine, her symptoms “could not have occurred” by July 23, 2010. Id. at 10. However, Dr. Axelrod did not identify the date of onset in more detail. See id. at 9. 45 ABUL K. ABBAS et al., CELLULAR & MOLECULAR IMMUNOLOGY 1–11 (Elsevier eds., 9th ed. 2018). 46 Serum sickness is “a hypersensitivity reaction to the administration of foreign serum or serum proteins characterized by fever, urticaria, arthralgia, edema, and lymphadenopathy. It is caused by the formation of circulating antigen-antibody complexes that are deposited in tissues and trigger tissue injury mediated by complement and polymorphonuclear leukocytes.” Dorland’s at 1707. 47 T. Lawley et al., A Prospective Clinical and Immunologic Analysis of Patients with Serum Sickness, 311:22 N. ENG. J. MED. 1407–14 (2011). 16 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 17 of 42 To explain the apparent inconsistency between the onset of Petitioner’s POI and the cited literature regarding an immune-mediated response, Dr. Axelrod relied on a study by Herrin et al.48 Id. at 10 (citing Pet’r’s Ex. 132, ECF No. 165-7). Herrin et al. observed the antibody response to two different trademarked HPV vaccinations (Gardasil and Cervarix), using data from the Vaccine Research Center. See Pet’r’s Ex. 132. The authors found that antibody levels following either HPV vaccine began to increase one month post vaccination, peaked around seven months post vaccination, and that antibodies were still present twenty-four months post vaccination. Id. at 3. They noted, however, that the patients they observed had received a second and third dose of the vaccine after one and six months, respectively. See id. Since Petitioner only received one dose of the vaccine, Dr. Axelrod insinuated that the peak immune response and manifestation of her POI would be expected to be less than the patients in the Herrin et al. study. Pet’r’s Ex. 124 at 10. Relying on the Herrin et al. study, he opined that the “time interval between [Petitioner’s] first Gardasil injection and the onset of her first symptom of what became her [POI] is consistent with a primary adaptive response to the [vaccine] that she received on June 4, 2010.” See id. Dr. Axelrod addressed a potential autoimmune comorbidity in Petitioner’s case and argued that Petitioner also suffers from psoriasis. Id. at 4. As support for Petitioner’s psoriasis diagnosis, Dr. Axelrod cited Petitioner’s visit notes with a dermatologist on August 19, 2022, which listed psoriasis as a diagnosis. Id. (citing Pet’r’s Ex. 123 at 9). He also cited to Dr. Reddy’s March 28, 2013 visit notes, made closer in time to Petitioner’s purported development of POI, wherein Dr. Reddy identified a differential diagnosis of either eczema or psoriasis. Id. (citing Pet’r’s Ex. 6 at 1–3). Dr. Axelrod submitted medical literature to show that psoriasis is thought to be an autoimmune disease. Id. He cited an article by Liang et al.,49 which “proposed that autoimmune and autoinflammatory processes contribute to the development of [p]soriasis.” See Pet’r’s Ex. 126 at 1. They noted this is because both adaptive immune responses and innate responses are involved in the development of varying types of psoriasis. Id. The authors wrote that “[t]he balance between the two dictate the clinical presentation of psoriasis with chronic plaque psoriasis having prominent adaptive/autoimmune responses[,] while pustular psoriasis is dominated by autoinflammatory immune responses.” Id. at 1, 3. Liang et al. found that peptides from keratin 17, “[t]he antimicrobial peptide LL-37[,]” and “the ADAMTS-like protein 5 []” are the autoantigens (targets) responsible for the development of psoriasis. Id. at 4. Dr. Axelrod used the authors’ findings to support his argument that psoriasis is an autoimmune disease and Petitioner therefore suffered from another autoimmune disorder. Pet’r’s Ex. 124 at 4 (citing Pet’r’s Ex. 126). He also cited an Indian Dermatology Online Journal study by Vashist et al.,50 which noted “[p]soriasis, an immune-mediated inflammatory dermatosis, . . . has been widely viewed as an autoimmune disease . . . triggered . . . by molecular mimicry.” Id. (citing Pet’r’s Ex. 127 at 1, ECF No. 165-2). Vashist et al. not only indicated that psoriasis itself is an autoimmune disease, they 48 D. Herrin et al., Comparison of adaptive and innate immune responses induced by licensed vaccines for Human Papillomavirus, 10:12 HUM. VACC. & IMMUNOTHERAPEUT. 3446–54 (2014). 49 Y. Liang et al., Psoriasis: A mixed autoimmune and autoinflammatory disease, 49 CURR. OPIN. IMMUNOL. 1–8 (2017). 50 S. Vashist et al., Association of Psoriasis with Autoimmune Disorders: Results of a Pilot Study, 11 INDIAN DERMATOL. ONLINE J. 753–59 (2020). 17 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 18 of 42 also investigated the association of psoriasis with other autoimmune disorders. Pet’r’s Ex. 127 at 1. The authors studied eighty psoriasis patients (fifty-seven males and twenty-three females), aged 13–75 years, for “concurrent autoimmune disorders.” Id. Of the eighty patients, thirty-seven of them (46.3%) “had clinical and/or sero-abnormality suggestive of autoimmune disorders[.]” Id. Specifically, they noted that 3.8% had vitiligo,51 1.3% had type-1 diabetes mellitus,52 and 6.3% had type-2 diabetes mellitus. Id. The authors also found that “[s]ero‑positivity reflecting subclinical autoimmunity was noted for anti‑CCP antibodies (in 2.5%), rheumatoid factor (in 2.5%), hypo‑ or hyper‑thyroidism (in 8.8%), anti‑TPO antibodies (in 5.0%), anti‑tTG antibody (in 1.3%), ANA (in 5.0%), anti‑dsDNA antibody (in 2.5%), and anti‑Ro antibody in 11.3% patients.” Id. They also found elevated fecal calprotectin levels suggestive of inflammatory bowel disease (“IBD”)53 in 11.2% of patients. Id. The authors determined that “psoriasis patients seem to have a predilection for other autoimmune disorders, particularly vitiligo, diabetes mellitus, autoimmune thyroiditis, rheumatoid arthritis (“RA”),54 and IBD. Id. However, they concluded that the “association between psoriasis and other autoimmune disorders at best remains tenuous for want of strong evidence.” Id. B. Orit Pinhas-Hamiel, M.D. Dr. Pinhas-Hamiel submitted one written report specifically on Althen prongs two and three, in addition to her earlier reports drafted generally in support of Petitioner’s claim. See Pet’r’s Ex. 17, ECF No. 59-5; Pet’r’s Ex. 27, ECF No. 98-2; Pet’r’s Ex. 91, ECF No. 122-1; Pet’r’s Ex. 137. Dr. Pinhas-Hamiel wrote “there is no doubt about the diagnosis of ovarian failure.” Pet’r’s Ex. 137 at 3. She posited that since there is no doubt about Petitioner’s POF diagnosis, “[t]he question is, what went wrong in a fully pubertal woman who had two spontaneous pregnancies?” Id. Dr. Pinhas-Hamiel attributed Petitioner’s POI to her June 4, 2010 HPV vaccination and opined that Petitioner’s POI is autoimmune in nature.55 Id. at 4. As support, Dr. Pinhas-Hamiel 51 Vitiligo is “1. a chronic, usually progressive, type of hypomelanosis in which melanocytes are destroyed, resulting in white patches on the skin that may be surrounded by a hyperpigmented border; there is an autosomal dominant predisposition to the condition, and the etiology is thought to be an autoimmune mechanism. 2. depigmentation.” Dorland’s at 2069. 52 Type-1 diabetes mellitus is “one of the two major types of diabetes mellitus: an autoimmune disease that results in the destruction of beta cells of the pancreas, leading to loss of the ability to secrete insulin. It is characterized by an abrupt onset of symptoms, insulinopenia, and dependence on exogenous insulin to sustain life; peak age of onset is 12 years, although onset can be at any age.” Dorland’s at 506. 53 Inflammatory bowel disease is “a general term for those inflammatory diseases of the intestines that have an unknown etiology, including Crohn disease and ulcerative colitis.” Dorland’s at 536. 54 Rheumatoid arthritis is “a chronic systemic disease primarily of the joints, usually polyarticular, marked by inflammatory changes in the synovial membranes and articular structures and by muscle atrophy and rarefaction of the bones. In late stages, deformity and ankylosis develop. The cause is unknown, but autoimmune mechanisms and virus infection have been postulated.” Dorland’s at 150. 55 I must note that Dr. Pinhas-Hamiel’s first expert report drafted in 2015 appears to be similar to her latest report drafted in 2022. See Pet’r’s Ex. 17; see also Pet’r’s Ex. 137. Yet, in Dr. Pinhas-Hamiel’s first report, she addressed autoimmunity as an etiology of POI generally, and in Petitioner’s case. Pet’r’s Ex. 17 at 5. She opined that there was no evidence of autoimmunity in Petitioner’s case because “[a]lthough [Petitioner 18 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 19 of 42 noted that Petitioner’s genetic testing was normal.56 Id. (citing Pet’r’s Ex. 13; Pet’r’s Ex. 5 at 52). She also noted that Petitioner had a positive ANA on July 27, 2011, approximately one year after her June 4, 2010 vaccination. Id. at 6. Dr. Pinhas-Hamiel opined that supplemental support for an autoimmune etiology is found in the fact that Petitioner experienced one additional positive ANA in 2017. Id. at 11. Additionally, Dr. Pinhas-Hamiel argued the timeframe for the onset of Petitioner’s pre- menopausal symptoms and bloodwork consistent with POI six weeks post Gardasil vaccination fits within the accepted timeframe for the onset of an autoimmune disease. Id. Dr. Pinhas-Hamiel wrote that although the onset of pre-menopausal symptoms can vary, “a few weeks is consistent with an immune mediated response and subsequent hormonal changes resulting in” autoimmune POI. Id. She therefore maintained that it is “more probable than not that the cause of [Petitioner’s POF] is secondary to [an] immune response secondary to the Gardasil vaccine.” Id. at 12. Dr. Pinhas-Hamiel argued that given the lack of evidence for any alternative cause for Petitioner’s POI, her vaccine must have been responsible for her ovarian failure. Id. at 9. She wrote that currently, “there is no proven sensitive and specific serum test to confirm that a woman has ovarian failure on an autoimmune basis.” Id. at 6 (citing Pet’r’s Exs. 138–39, ECF Nos. 171-1–171-2).57 However, Dr. Pinhas-Hamiel then wrote that “[a]utoantibodies are a hallmark of autoimmunity” and that autoantibodies like ANAs “have a central role” in identifying autoimmune etiology. Id. Dr. Pinhas-Hamiel argued that the presence of ANAs suggests the presence of autoimmune disease, specifically “systemic autoimmune rheumatic disease[s], such as systemic lupus erythematosus [(“SLE”)].58” Id. While Dr. Pinhas-Hamiel wrote that a positive ANA is associated with autoimmune disease, she admitted that “[s]ome individuals . . . may have a positive test for ANA and yet never develop any autoimmune disease.” Id. at 8. had] family history of . . . autoimmune disorder . . . there were no signs of autoimmune disorders such as hypo or hyperthyroidism, there were no antibodies to the thyroid gland, to the ovaries[,] or to the adrenals.” See id. Now, she argues there is evidence of autoimmunity in Petitioner’s case. Pet’r’s Ex. 137 at 4. 56 Dr. Pinhas-Hamiel wrote that Turner syndrome, or the lack of a second X chromosome, is the most common cause of POI. Pet’r’s Ex. 137 at 4. He posited that Petitioner’s karyotype results to test for Turner syndrome were pending as of September of 2022. Id. However, this appears to be inaccurate. Petitioner’s testing revealed a normal female karyotype on October 10, 2014. See Pet’r’s Ex. 13 at 2. Petitioner’s other expert, Dr. Axelrod, even noted this fact. See Pet’r’s Ex. 124 at 3. Petitioner’s records do not contain any evidence that she suffers from Turner syndrome. 57 J. Novosad et al., Ovarian antibodies as detected by indirect immunofluorescence are unreliable in the diagnosis of autoimmune premature ovarian failure: a controlled evaluation, 3:2 BMC WOMEN’S HEALTH 1–7 (2003); A. Szeliga et al., Autoimmune Diseases in Patients with Premature Ovarian Insufficiency – Our Current State of Knowledge, 22 INT. J. MOL. SCI. 1–11 (2021). 58 Systemic lupus erythematosus is “a chronic, inflammatory, often febrile multisystemic disorder of connective tissue that proceeds through remissions and relapses; it may be either acute or insidious in onset and is characterized principally by involvement of the skin . . . joints, kidneys, and serosal membranes. The etiology is unknown, but it may be a failure of regulatory mechanisms of the autoimmune system, since there are high levels of numerous autoantibodies against nuclear and cytoplasmic cellular components.” Dorland’s at 1080. 19 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 20 of 42 As support, she cited a study by Miyake et al.59 that “assess[ed] 20 women with secondary amenorrhea manifesting hormonal and clinical features of [POF] by different kinds of circulating autoantibodies[.]” Id. at 6 (citing Pet’r’s Ex. 146 at 1, ECF No. 171-9). The authors found that “35% had anti-thyroglobulin antibodies, 30% had anti-parietal cell antibodies, and 40% had [ANA].” See id. Dr. Pinhas-Hamiel pointed out that in some cases in the study, ANA was the only positive antibody. Pet’r’s Ex. 137 at 6. She argued that since anti-adrenal antibodies were negative in all patients, adrenal antibodies are not necessary for the diagnosis of POI, but rather a positive ANA is required. Id. She also cited a study by Ishizuka et al.60 that observed thirty-two women with POI with and without chromosomal abnormalities. Pet’r’s Ex. 140 at 1, ECF No. 171-3. The authors found a positive ANA in 77% of them; however, this statistic was based on a subset of the study (thirteen patients) who had normal karyotypes and developed amenorrhea at or under the age of 30. Id. The authors did not make the same finding in patients who developed amenorrhea later in life. Id. They concluded that their results “suggest that patients with [POF] and ANA are an aetiologically [sic] and clinically distinct group.” See id. A study by Cameron et al.61 relied upon by Dr. Pinhas-Hamiel found that among seventeen non-chromosomal, non-iatrogenic, adolescent POI patients, 41.1% were positive for ANAs. Pet’r’s Ex. 137 at 7 (citing Pet’r’s Ex. 141 at 1, ECF No. 171-4). The authors relied on this finding to argue that a positive ANA is evidence of autoimmunity in POI. Pet’r’s Ex. 141 at 2, 4. However, they noted that the “clinical significance of this [finding] is unknown because estimates of ANA positivity in healthy individuals range from 5 to 30% in adults . . . .” Id. at 4. They also indicated that low ANA titers (1:160 or less) are even less likely to be clinically significant and that only three patients in their study had “high ANA titers that may be associated with autoimmune disease.” Id. at 2. Such patients had titers greater than 1:1280. Id. Dr. Pinhas-Hamiel finally cited a study by Zhen et al.62 that examined ninety-six patients with POF compared to one hundred healthy controls. Pet’r’s Ex. 137 at 7 (citing Pet’r’s Ex. 142, ECF No. 171-5). The authors found that 19.8% and 14% of patients, respectively, had positive ANA titers. See id. However, the authors noted this finding “did not reach statistical significance.” Pet’r’s Ex. 142 at 4. Dr. Pinhas-Hamiel argued based on the medical literature that a positive ANA result “suggests the presence of autoimmune disease[.]” Pet’r’s Ex. 137 at 7. Dr. Pinhas-Hamiel discussed the difficulty in standardizing the ANA titer used between laboratories to address Petitioner’s fluctuating ANAs. Id. Dr. Pinhas-Hamiel noted that when patients’ samples are tested at a dilution of 1:40, “[t]his standardization makes the ANA test very sensitive for the diagnosis of autoimmune diseases but results in many false positive results.” Id. She explained that this is because “[i]mmunoassays [used to measure the presence of ANAs] are well known to be prone to interferences due to the complexity of antigen-antibody interaction and 59 T. Miyake et al., Implications of circulating autoantibodies and peripheral blood lymphocyte subsets for the genesis of premature ovarian failure, 12(3) J. REPROD. IMMUNOL. 163–71 (1987). 60 B. Ishizuka et al., Anti-nuclear antibodies in patients with premature ovarian failure, 14:1 HUM. REPROD. 70–75 (1999). 61 M. Cameron et al., Non-Chromosomal, Non-Iatrogenic Premature Ovarian Failure in an Adolescent Population: A Case Series, 21 J. PEDIATR. ADOLESC. GYNECOL. 3–8 (2008). 62 X. Zhen et al., Serologic autoimmunologic parameters in women with primary ovarian insufficiency, 15:11 BMC IMMUNOL. 1–6 (2014). 20 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 21 of 42 low concentration of an analyte.” Id. at 8. She noted false results can also be due to inconsistencies caused by using different labs. Id. Dr. Pinhas-Hamiel relied on the Pashnina et al.63 review of the role of positive ANAs in autoimmunity and wrote that at a dilution of 1:40, 20 to 30% of healthy patients have a positive ANA. Id. (citing Pet’r’s Ex. 143 at 9, ECF No. 171-6). She noted the authors’ findings showed that testing at a dilution of 1:80 reveals a positive ANA in 10 to 12% of healthy individuals. See id. She continued that a dilution of 1:160 shows a positive ANA in only 5% of healthy individuals. Id. Pashnina et al. wrote that studies have shown that “the positive predictive value of ANAs for the diagnosis of [autoimmune diseases] with the 1:160 cut-off titer was 11.6%.” Pet’r’s Ex. 143 at 11. The authors noted that even in the diagnosis of certain autoimmune diseases, such as SLE, that are known to have a higher significance of ANAs, the diagnostic value of ANAs still does not exceed 15%. Id. Pashnina et al. acknowledged that ANAs are known to be detected in systemic autoimmune diseases, including scleroderma, Sjögren’s syndrome,64 mixed connective tissue disease,65 RA, hepatitis, Hashimoto’s thyroiditis, immune thrombocytopenic purpura,66 idiopathic epilepsy, ischemic brain disease,67 and interstitial lung disease.68 Id. at 7. Dr. Pinhas-Hamiel relied on Pashnina et al.’s findings and argued that testing at a 1:160 dilution “increases the specificity of the ANA test for the diagnosis of autoimmune diseases” such as POI. Pet’r’s Ex. 137 at 7. She noted that Petitioner’s ANA testing showed a positive titer at 1:160. Id. at 8. She addressed the “fluctuation” in Petitioner’s antibody levels, specifically the fact that a positive ANA was not consistently detected in Petitioner. Id. Dr. Pinhas-Hamiel relied on the descriptions in the Pashnina et al. article and argued that patients with autoimmune diseases may show a “decrease in the level of certain autoantibodies and/or the strength of antibody-mediated bioeffects in comparison with healthy donors.” Id. (citing Pet’r’s Ex. 143 at 3). The authors noted 63 I. Pashnina et al., Antinuclear Autoantibodies in Health: Autoimmunity is Not a Synonym of Autoimmune Disease, 10 ANTIBODIES 1–26 (2021). 64 Sjögren’s syndrome is “a symptom complex of unknown etiology, usually occurring in middle-aged or older women, marked by the triad of keratoconjunctivitis sicca with or without lacrimal gland enlargement, xerostomia with or without salivary gland enlargement, and the presence of a connective tissue disease, usually rheumatoid arthritis but sometimes systemic lupus erythematosus, scleroderma, or polymyositis. An abnormal immune response has been implicated.” Dorland’s at 1848. 65 Mixed connective tissue disease is “a disorder combining features of scleroderma, myositis, systemic lupus erythematosus, and rheumatoid arthritis, and marked serologically by the presence of antibody against extractable nuclear antigen.” Dorland’s at 539. 66 Immune thrombocytopenic purpura is “any form of purpura in which the platelet count is decreased; it may be either primary or secondary.” Dorland’s at 1557. Purpura refers to “1. any of a group of conditions characterized by ecchymoses or other small hemorrhages in the skin, mucous membranes, or serosal surfaces; causes include blood disorders, vascular abnormalities, and trauma. 2. any of several conditions similar to the traditional purpura group, which may be caused by decreased platelet counts, platelet abnormalities, vascular defects, or reactions to drugs.” Id. 67 Ischemic brain disease, also called cerebral ischemia, is the “deficiency of blood in [the brain], usually due to functional constriction or actual obstruction of a blood vessel.” Dorland’s at 536. 68 Interstitial lung disease is “a heterogeneous group of noninfectious, nonmalignant disorders of the lower respiratory tract, affecting primarily the alveolar wall structures but also often involving the small airways and blood vessels of the lung parenchyma; slowly progressive loss of alveolar-capillary units may lead to respiratory insufficiency and death.” Dorland’s at 536. 21 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 22 of 42 that a growing number of studies show that the “level of autoantibodies decreases, rather than increases during exacerbations of some [autoimmune diseases]” described above. Pet’r’s Ex. 143 at 3. Pashnina et al. wrote that this fact is applicable to autoantibodies such as ANAs. Id. The authors analogized ANAs and antibodies relevant to endocrine disorders and noted that while “[t]raditionally, it was assumed . . . that the more autoantibodies [] a patient has, the more symptoms of the disease that will be present[,]” it has now been suggested that “not only an increase, but also a pathological decrease in the concentration of autoantibodies may reflect and even cause pathological processes in the body.” Id. However, the authors also acknowledged that “[a]ccording to the current opinion, ANAs . . . belong to the integral part of the normal functioning of the immune system.” Id. C. Thomas Forsthuber, M.D. Dr. Forsthuber authored one written report refuting Petitioner’s arguments regarding an autoimmune etiology for her POI. Resp’t’s Ex. M. Dr. Forsthuber deferred to Dr. Welt, Respondent’s second expert, on the diagnosis of Petitioner’s POI, but he opined that there is no reliable evidence for an autoimmune etiology. Id. at 6. As support, Dr. Forsthuber summarized Petitioner’s autoimmune laboratory testing and opined that when “[t]aken together, [Petitioner] does not have laboratory evidence of autoimmune POI.” Id. at 5. Specifically, he wrote that Petitioner was tested on several occasions post vaccination for ovarian, adrenal, and thyroid autoantibodies “and the results were consistently negative.” Id. Dr. Forsthuber also highlighted that Petitioner did not have other inflammatory markers, such as ESR and CRP, which, if abnormal, would show evidence of an autoimmune etiology. Id. at 19. Without such evidence, Dr. Forsthuber argued that Dr. Axelrod’s theory of cause and effect is “not logical.” Id. at 13. He pointed out Dr. Axelrod’s acknowledgement that Petitioner does not have autoantibodies found in autoimmune POI cases, but he “interpret[ed] that lack of these autoantibodies as evidence that her POI is ‘most likely of autoimmune origin.’” Id. (citing Pet’r’s Ex. 124 at 6). Dr. Forsthuber posited that “the most likely explanation” for Petitioner’s lack of autoantibodies, is that she does not have autoimmune POI. Id. (citing Pet’r’s Ex. 5 at 33). He also condemned Dr. Axelrod’s reliance on Petitioner’s treater Dr. Gleicher’s notation indicating that Petitioner “likely had autoimmune POF.” Id. at 6. Dr. Forsthuber argued that Dr. Gleicher did not have an account of Petitioner’s full condition when documenting this opinion. Id. Rather, only after noting his opinion regarding autoimmunity did Dr. Gleicher order a “battery of laboratory tests including a ‘full immunology’ screen[.]” Id. at 6–7. Dr. Forsthuber indicated that the autoimmune workup, once performed, showed that Petitioner did not have anti-ovarian, anti- adrenal, 21-hydroxylase, or thyroid autoantibodies. Id. at 7. She also did not have evidence of another autoimmune condition. Id. Based on such findings, Dr. Forsthuber opined that “it is highly unlikely that Dr. Gleicher would maintain an opinion of autoimmune POI after obtaining these lab tests.” Id. Dr. Forsthuber acknowledged that Petitioner had fluctuating positive and negative testing for ANAs, but he found such findings insignificant. Id. at 6. For example, Petitioner’s positive ANA test on February 6, 2017, was unsupported according to Dr. Forsthuber because all other 22 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 23 of 42 testing for autoimmune conditions performed that day was negative. Id. at 7. Dr. Forsthuber further argued that this finding is “of questionable relevance, especially in light of the fact that [Petitioner] had several ANA tests that were negative closer in time to [her June 4, 2010] vaccination[,]” including during December of 2010. Id. at 7, 19 (citing Pet’r’s Ex. 2 at 42). He also cited medical literature to support his opinion that Petitioner’s positive ANA results are insignificant. Bloch et al. wrote that approximately 5% of healthy individuals have a positive ANA at a dilution of 1:160. Id. at 7 (citing Resp’t’s Ex. M1, ECF No. 172-2).69 Bloch et al. noted that a positive ANA “may assist in the diagnosis of autoimmune diseases[]” and that a negative ANA decreases the likelihood that a patient’s symptoms are caused by an autoimmune condition. Resp’t’s Ex. M1 at 1–2. They went on to list autoimmune conditions where patients are known to test positive for ANAs, including SLE, scleroderma, Sjögren’s syndrome, mixed connective tissue disease, polymyositis, RA, thyroid diseases, gastrointestinal (“GI”) diseases such as IBD, and pulmonary diseases. Id. at 2–3. Having one or more relatives with an autoimmune disease has also been known to be associated with positive ANA tests. Id. at 3. However, the authors wrote that some individuals, even without a relative with an autoimmune disease, “may have a positive test for ANA and yet never develop any autoimmune disease.” Id. Bloch et al. issued a “word of caution” and indicated that a positive ANA “does not, by itself, indicate the presence of an autoimmune disease.” Id. at 4. Rather, “many normal individuals will have a positive test at low titers [and e]ven when detected at high titer, a positive ANA result,” in the absence of other symptoms or physical findings, “does not indicate that a patient has, or will develop, an autoimmune disease.” Id. Dr. Forsthuber argued that based on Petitioner’s history of negative ANAs and lack of other clinical evidence of autoimmunity, “it is highly likely” that her positive ANAs were false positives and therefore did not provide evidence of an autoimmune etiology. Resp’t’s Ex. M at 7. Next, Dr. Forsthuber disputed Dr. Axelrod’s explanation of molecular mimicry and argued that his proposed sequence homologies do not add support for an autoimmune etiology in Petitioner. See id. at 8. Specifically, Dr. Forsthuber argued that Dr. Axelrod “mistakes sequence homology with molecular mimicry.” Id. at 9. He opined that “[a]mino acid homologies between viral and bacterial proteins and human proteins is the rule, and not the exception.” Id. Furthermore, finding sequence homology between two random proteins can occur by “chance alone.” Id. at 14– 15. He continued that even if one finds a meaningful sequence homology, “this is not sufficient to claim that this sequence would be likely to induce autoimmune disease by way of molecular mimicry.” Id. at 9. Dr. Forsthuber argued that many additional steps and testing would be required to reach such a conclusion, including BLAST searches, which Dr. Axelrod did not use. Id. at 9, 16–18. Instead, Dr. Axelrod used clustal searches. See id. at 9. Dr. Forsthuber undertook a lengthy discussion70 of Dr. Axelrod’s “misconceptions about sequence alignments, [] fundamental mistakes in how to use the [c]lustal program, and [] 69 D. Bloch et al., Patient education: Antinuclear antibodies (ANA) (Beyond the Basics), UPTODATE, https://www.uptodate.com/contents/antinuclear-antibodies-ana-beyond-the-basics (last visited Jan. 31, 2023). 70 Throughout this discussion, Dr. Forsthuber attacked Dr. Axelrod’s accepted sequence length reflective of a molecular mimic. Resp’t’s Ex. M at 9. He cited medical literature attempting to refute that a short chain 23 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 24 of 42 misinterpretation of his clustal results[.]” Id. He criticized Dr. Axelrod’s misapplication of the clustal omega tool and wrote that it is “not recommended for comparing two proteins such as NALP5/MATER or ɑ-enolase with HPV L1 protein.” Id. at 14. Because this program is not meant for comparing only two proteins, Dr. Forsthuber argued that Dr. Axelrod’s conclusions are “unreliable.” Id. Due to Dr. Axelrod’s misuse and misinterpretation of the clustal tool, Dr. Forsthuber closely examined Dr. Axelrod’s provided printouts and determined that Dr. Axelrod did not find amino acid sequences of 3–10 or 3–7 conserved similar amino acids as he claimed. Id. at 14 (citing Pet’r’s Ex. 124 at 7; Pet’r’s Exs. 133–36). He even noted that Dr. Axelrod’s printouts “where he colored regions that he alleges to be similar,” did not include an interpretation of the clustal results from the clustal software itself. Id. at 18 (citing Pet’r’s Exs. 133–36). Instead, according to Dr. Forsthuber, Dr. Axelrod was responsible for coloring in the regions, based on “his misguided interpretation of the results.” See id. Out of all four exhibits, Dr. Forsthuber found only one region where three amino acids overlap and that was between HPV L1 and ɑ-enolase. Id. (citing Pet’r’s Ex. 134). Dr. Forsthuber acknowledged that where Dr. Axelrod used the software appropriately and compared three proteins (and not just two), he, at most, found one amino acid homology and that was between human keratin 17, NALP5/MATER, and HPV6 L1. Id. (citing Pet’r’s Exs. 135–36). Dr. Forsthuber argued that “it should be clear to anyone . . . that there is no meaningful overlap between NALP5/MATER, ɑ-enolase, and HPV L1 proteins.” Id. Dr. Forsthuber wrote that for Dr. Axelrod to claim that he found meaningful sequence homologies indicative of molecular mimicry is “baffl[ing]” because his searches “disprove[]” his claims. Id. at 18, 20. He therefore maintained that Dr. Axelrod’s clustal searches and alleged sequence similarities are “meaningless” and “do not provide evidence of molecular mimicry in [Petitioner’s] case or in POI in general.” Id. at 18. Further, Dr. Forsthuber indicated that there is no scientifically accepted method to substantiate whether a particular sequence homology would be evidence of molecular mimicry or “have any relationship to the development of a disease process in humans.” Id. He argued that the role of molecular mimicry in autoimmune conditions has not been established based on sequence homologies but found by “the presence of autoantibodies . . . that showed [evidence of] cross- reactivity between pathogens and human proteins.” Id. at 9–10 (citing Resp’t’s Ex. M4 at 6, ECF No. 172-5).71 Fourneau et al. sought to examine the role of mimicry in autoimmune diseases and stated that while sequencing was the traditional approach, the “identity of limited sequence stretches is not an indication of cross-reactive mimicry[.]” Resp’t’s Ex. M4 at 4. Dr. Forsthuber maintained that “there is no evidence for [molecular mimicry] in [Petitioner’s] case[.]” See Resp’t’s Ex. M at 9, 11, 13. of five to nine homologous amino acids is not sufficient to show molecular mimicry. Id. (citing Resp’t’s Ex. M5, ECF No. 172-6; Resp’t’s Ex. M8, ECF No. 172-9; Resp’t’s Ex. M9, ECF No. 172-10). Rather, he argued that the optimal length of a peptide for binding to major histocompatibility complex molecules is “approximately 18–20 amino acids.” Id. at 13 (citing Resp’t’s Ex. M7, ECF No. 172-8). Dr. Forsthuber argued that Dr. Axelrod’s alleged HPV molecular mimic of 3 amino acids is “dramatically shorter” than the optimal length. Id. Dr. Forsthuber also took issue with Dr. Shoenfeld’s proposed 5-amino acid sequence homologies. Id. at 13. However, after careful consideration, I have already credited Petitioner’s proposed minimum sequence length of 5 amino acids in my Ruling on Althen prong one. See Brayboy, 2021 WL 4453146, at *1. 71 J. Fourneau et al., The elusive case for a role of mimicry in autoimmune diseases, 40 MOL. IMMUNOL. 1095–102 (2004). 24 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 25 of 42 He addressed the lack of autoimmune comorbidity in Petitioner’s case. Dr. Forsthuber pointed out that Petitioner’s treating physicians did not feel that she suffered from an autoimmune condition. Id. at 5. He noted Petitioner’s 2022 psoriasis diagnosis and wrote that when Petitioner was seen by the same treating dermatologist in 2021, “no diagnosis of psoriasis was made.” Id. Dr. Forsthuber argued that Petitioner’s psoriasis was “[t]herefore . . . not evident until [twelve] years after the HPV vaccination and diagnosis of POI.” Id. He continued that regardless of the time gap, psoriasis is “frequently found in the population and [] is not associated with POI.” Id. at 6. He therefore opined that there is no reliable evidence of any autoimmune comorbidity in Petitioner’s case. Id. at 5. Dr. Forsthuber discussed the time of onset of Petitioner’s POI but did not provide an onset date. Rather, based on Petitioner’s medical records, Dr. Forsthuber argued that the onset of Petitioner’s amenorrhea is “unclear[.]” Id. at 6. He wrote that Petitioner’s petition indicates that her menstrual cycle stopped immediately following receipt of her HPV vaccine, while her medical records place the onset of amenorrhea in October of 2010. Id. He specifically noted that Petitioner’s medical records contain “conflicting reports as to the onset of hot flashes and menstrual cycle problems,” including both immediately post vaccination versus August or October of 2010. Id. at 19. As he could not make a determination, Dr. Forsthuber deferred to Dr. Welt regarding the onset of Petitioner’s POI. Id. at 6, 19. D. Corinne Welt, M.D. Dr. Welt agreed that Petitioner suffers from POI but disputed that her POI is autoimmune in nature. Resp’t’s Ex. N at 3, 5. As support, Dr. Welt pointed out that in her original report, Petitioner’s own expert Dr. Pinhas-Hamiel stated that the cause of Petitioner’s POI was not autoimmune. Id. at 5 (citing Pet’r’s Ex. 17 at 5–7; Pet’r’s Ex. 27 at 6–8). Dr. Welt criticized Dr. Pinhas-Hamiel’s reversal from her original contention, that no serum test can confirm that a woman has autoimmune POI, to her most recent assertion, that data shows a relationship with a positive ANA and autoimmune POI. Id. at 6 (citing Pet’r’s Ex. 17 at 5–7). Dr. Welt noted that Petitioner’s only positive antibody test results were two positive ANAs on “10/2011 and 11/2011.”72 Id. at 3–4. These results, Dr. Welt argued, “are not specific for POI.” Id. at 4 (citing Resp’t’s Ex. N10, ECF No. 173-11).73 As support for her argument that a positive ANA is not specific to autoimmune POI, Dr. Welt also discussed the medical literature Dr. Pinhas-Hamiel relied on. Id. at 6. Dr. Welt wrote that Dr. Pinhas-Hamiel “quot[ed] the rate of positive ANA tests in four small studies of women with POI and normal karyotype, and no additional testing for common causes of POI[,] including FMR1 premutations.” Id. (citing Pet’r’s Ex. 137 at 6–7). Dr. Welt noted that the Miyake et al. study that found positive ANAs in 40% of patients did not show that any patients had an autoimmune disease. Id. (citing Pet’r’s Ex. 146). Dr. Welt criticized the Ishizuka et al. study because the ANA test used was “created in house[,]” and the data was compared to women with fertility issues, not a healthy control group. Id. (citing Pet’r’s Ex. 140). Dr. Welt pointed out that none of the subjects had autoimmune diseases. She also pointed out that none of the subjects with 72 This notation seems to be incorrect. Petitioner’s positive ANA in 2011 occurred on July 27, 2011. 73 A. Hoek et al., Premature Ovarian Failure and Ovarian Autoimmunity, 18:1 ENDOCR. REV. 107–34 (1997). 25 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 26 of 42 a positive ANA titer had positive localized antibody testing, thus “failing to support the positive ANA test[.]” See id. (citing Pet’r’s Ex. 140). Dr. Welt attacked Dr. Pinhas-Hamiel’s reliance on the Zhen et al. article because the authors demonstrated that the rate of positive ANA tests was not different in women with POI and control women. Id. (citing Pet’r’s Ex. 142). Specifically, Zhen et al. found that the rate of positive ANAs in both groups did not reach statistical significance. See Pet’r’s Ex. 142. Dr. Welt noted that the Cameron et al. study found that among adolescent patients with POI, 41.1% (7/17) of subjects were found to have a positive ANA. Resp’t’s Ex. N at 6 (citing Pet’r’s Ex. 141 at 2). The authors wrote that of these subjects, 57.1% (4/7) had only “weakly positive titers of 1:160 or less.” Pet’r’s Ex. 141 at 2. The authors determined that the clinical significance of this rate is “unknown because estimates of ANA positivity in healthy individuals range from 5 to 30% in adults[.]” Id. at 4. They noted that “[o]nly three of [their] subjects had high ANA titers that may be associated with autoimmune disease.” Id. Dr. Welt relied on the authors’ notations and argued that their findings support her assertion that the rate of positive ANA in POI patients is similar to the rate of a positive ANAs in the normal population. Resp’t’s Ex. N at 6 (citing Pet’r’s Ex. 141; Resp’t’s Ex. N14, ECF No. 173-15; Resp’t’s Ex. N17, ECF No. 173-18).74 Tan et al. sought to determine the range of ANAs in healthy individuals compared to patients with autoimmune diseases, including SLE, scleroderma, Sjögren’s syndrome, and RA. Resp’t’s Ex. N14 at 1. The authors found that the frequency of a positive ANAs “did not differ significantly” between the two groups. Id. Based on their findings, the authors cautioned that ANA determinations “should not be used indiscriminately as a method to distinguish between normal individuals and patients in various disease groups.” Id. at 10. Wananukul et al. undertook to compare the positive ANA rate between healthy children and children with SLE. Resp’t’s Ex. N17 at 1. They examined two-hundred seven healthy children and fifty-two children with SLE and found 15% and 91%, respectively, had a positive ANA. Id. The authors determined the positive predictive value for a positive ANA and the development of an autoimmune condition was 57%, with a negative predictive value of 97%. Id. Based on this finding, the authors indicated that patients with a positive ANA are at “minimal risk” to develop an autoimmune disease. Id. at 4. Dr. Welt therefore argued that Dr. Pinhas-Hamiel’s references would not “support the assertion that a positive ANA at a titer of >1:160 would indicate an autoimmune cause of POI[]” in Petitioner. Resp’t’s Ex. N at 6. Dr. Welt provided additional context for the factors for autoimmune POI that I identified in my ruling on Althen prong one. She explained the importance of adrenal antibodies and/or oophoritis75 in establishing an autoimmune etiology for POI. See id. at 4 (citing Resp’t’s Ex. N3); see also Brayboy, 2021 WL 4453146, at *8. Dr. Welt argued that the presence (or absence) of adrenal antibodies “best discriminate autoimmune POI from POI of other etiologies.” Resp’t’s Ex. N at 4. Dr. Welt further described the connection between autoimmune oophoritis and POI. Id. She explained that oophoritis presents with amenorrhea in the presence of multiple, large follicles seen in a pelvic ultrasound, in conjunction with low levels of estradiol. Id. (citing Resp’t’s Ex. 74 E.M. Tan et al., Range of Antinuclear Antibodies in “Healthy” Individuals, 40:9 ARTHR. & RHEUMA. 1601–11 (1997); S. Wananukul et al., Prevalence of Positive Antinuclear Antibodies in Healthy Children, 23 ASIAN PAC. J. ALL. & IMMUNOL. 153–57 (2005). 75 Oophoritis is inflammation of the ovary. Dorland’s at 1323. 26 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 27 of 42 N19, ECF No. 173-20).76 Dr. Welt wrote that “POI is the clinical end stage for women with autoimmune oophoritis.” Id. (citing Resp’t’s Ex. N4, ECF No. 173-5; Resp’t’s Ex. N7, ECF No. 173-8).77 Regarding Petitioner, Dr. Welt opined that “there is no evidence of autoimmunity that would affect the ovary or the adrenal gland” indicative of autoimmune POI. Id. at 3. Dr. Welt maintained that while Petitioner had positive ANA tests over the years, she “remains negative for the majority of autoimmune factors tested[]” and had no evidence of “clinically documented autoimmune disease.” Id. at 6. Dr. Welt argued that “[m]ost importantly, [ P]etitioner had no evidence of autoimmunity to the adrenal gland with negative 21-hydroxylase antibodies documented in [April of 2022].” Id. at 4. She highlighted that Petitioner had negative adrenal antibodies at all other times when tested and presented no other evidence for adrenal insufficiency. Id. at 5 (citing Pet’r’s Ex. 14 at 121). Dr. Welt noted that Petitioner underwent pelvic ultrasounds “with no evidence of large follicles indicative of oophoritis.” Id. (citing Pet’r’s Ex. 3 at 11–13). Dr. Welt maintained that the absence of adrenal autoimmunity precludes autoimmunity as a cause of POI in Petitioner’s case. Id. at 8. Dr. Welt addressed the onset of Petitioner’s POI and opined that “it is difficult to determine the precise start date of her POI.” Id. at 3. Dr. Welt argued that the difficulty in pinpointing the onset of Petitioner’s POI is owed to the absence of “contemporaneous menstrual history in her medical records and her use of hormonal contraception on and off for several years[.]” Id. For instance, Dr. Welt indicated that the notes from Petitioner’s May 25, 2010 gynecology visit stated that her last menstrual period was May 23, 2010, but she highlighted that no “additional menstrual history was found in the note.” Id. She argued that without contemporaneous menstrual history in Petitioner’s medical records, normal menstruation pre vaccination “cannot be proven.” Id. at 4–5. Rather, “[o]n the contrary, there is some evidence that [Petitioner’s] menstrual cycles were not regular[,] and evaluation has been confounded by [use of] hormonal contraception” between 2006 and 2010. Id. at 5. She noted Petitioner’s history of birth control use and that “importantly, [it] will prevent hot flashes and mask underlying menstrual problems.” Id. at 3. Specifically, Dr. Welt indicated that Petitioner had been prescribed birth control “multiple times (Depot [sic] Provera 10/13/2006, Orthotricyclen [sic] 11/27/2007, [and] Orthrotricyclen [sic] after 3/20/2009).” Id. at 4. Dr. Welt noted that such contraceptive use could have blocked hot flashes or irregular menses during that time. Id. at 3 (citing Pet’r’s Ex. 8 at 32). She also noted that Petitioner was prescribed birth control pills as of May 25, 2010. Id. Dr. Welt argued that due to Petitioner’s documented use of hormonal contraceptives it is impossible to show that Petitioner had normal menstruation before her June 4, 2010 Gardasil vaccination. Id. at 4. 76 C. Welt et al., Selective Theca Cell Dysfunction in Autoimmune Oophoritis Results in Multifollicular Development, Decreased Estradiol, and Elevated Inhibin B Levels, 90(5) J. CLIN. ENDOCR. & METABOL. 3069–76 (2005). 77 P. Bannatyne et al., Autoimmune Oophoritis: A Clinicopathologic Assessment of 12 Cases, 9 INT. J. GYNECOL. PATH. 191–207 (1990); E. Gloor et al., Autoimmune Oophoriti, 81:1 AM. J. CLIN. PATH. 105– 09 (1984). 27 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 28 of 42 As additional support for her opinion that it is difficult to determine the onset of Petitioner’s POI, Dr. Welt discussed Petitioner’s earlier menstrual history and highlighted that Petitioner’s medical records show a potential period of amenorrhea prior to that at issue in 2010. Id. at 3. Specifically, during a visit on April 26, 2007, Petitioner’s last menstrual period was noted as “8/2006,” approximately eight months earlier. Id. Dr. Welt hypothesized that this period of amenorrhea could be due to a Depo Provera injection that Petitioner received on October 13, 2006. Id. However, she wrote that such birth control “lasts [three] months and would not explain continued amenorrhea for [eight] months.” Id. Dr. Welt acknowledged Petitioner’s two prior pregnancies during 2006 to 2009 but argued that such occurrences “would not rule out the diagnosis” of POI during that timeframe. Id. Dr. Welt wrote that “pregnancies do occur in women with POI.” Id. (citing Resp’t’s Ex. N1, ECF No. 173-2; Resp’t’s Ex. N15, ECF No. 173-16).78 Dr. Welt cited the Alper et al. study that discussed six women who were able to conceive after being diagnosed with POI. Resp’t’s Ex. N1 at 1. Two of the women conceived while receiving estrogen therapy; two while taking oral contraceptives; and two spontaneously. Id. Taylor et al. likewise found that women with POI still ovulate and can conceive. Resp’t’s Ex. N15 at 5. Although Dr. Welt was unable to determine the exact onset date of Petitioner’s POI, she generally discussed the time it takes for the development of autoimmune POI. Resp’t’s Ex. N at 4. Dr. Welt wrote that the lymphocytic infiltration and eventual ovarian destruction required for autoimmunity to be a cause of POI takes seventeen months to over two years to develop. Id. As support, Dr. Welt relied on a self-authored study. Id. (citing Resp’t’s Ex. N19).79 Welt et al. described the clinical course of three women with presumptive autoimmune oophoritis who went on to develop POF. Resp’t’s Ex. N19 at 1. Among their findings, the authors observed that all three subjects had adrenal antibodies, antibodies to 21-hydroxylase, and P450 side chain cleavage antibodies. Id. at 1, 5. They documented “follow up history” for the three patients and noted that patient 1 had a positive ANA titer two years after her initial presentation and three years later experienced complete ovarian destruction, with her FSH in the postmenopausal range. Id. at 5. Patient 2 had FSH levels in the postmenopausal range 1.5 years after her initial presentation, and patient 3 exhibited such levels 17 months after her initial presentation. Id. The authors did not address the trigger of POI in these patients. See id. The Taguchi et al.80 study, also cited by Dr. Welt, used mouse models of oophoritis induced after a thymectomy to identify early signs of lymphocyte infiltration and early oophoritis. Resp’t’s Ex. N at 8 (citing Resp’t’s Ex. N13, ECF No. 173-14). Taguchi et al. found that the first signs of 78 M. Alper et al., Pregnancies After Premature Ovarian Failure, 67:3 OBST. & GYNECOL. 59–63 (1986); A. Taylor et al., A Randomized, Controlled Trial of Estradiol Replacement Therapy in Women with Hypergonadotropic Amenorrhea, 81:10 J. CLIN. ENDOCR. & METABOL. 3615–23 (1996). 79 C. Welt et al., Selective Theca Cell Dysfunction in Autoimmune Oophoritis Results in Multifollicular Development, Decreased Estradiol, and Elevated Inhibin B Levels, 90(5) J. CLIN. ENDOCR. & METABOL. 3069–76 (2005). 80 O. Taguchi et al., Autoimmune oophoritis in thymectomized mice: detection of circulating antibodies against oocytes, 40 CLIN. EXP. IMMUNOL. 540–53 (1980). 28 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 29 of 42 oophoritis, or the appearance of autoantibodies against the ooplasma of oocytes,81 “was first demonstrated at day 30–40 in [the] sera of [] mice, whose ovaries showed a marked enhancement of follicular degeneration and the death of numerous oocytes . . . .” Resp’t’s Ex. N13 at 1. The titer levels of such autoantibodies increased at day 50–90 and diminished and eventually disappeared at day 150–360 “when no oocytes remained in the atrophic ovary.” Id. She further relied on a study by Altuntas et al.82 wherein the authors immunized female mice with peptides derived from mouse inhibin-ɑ activates CD4+ T cells and were able to induce autoimmune oophoritis followed by POF. Resp’t’s Ex. N at 6 (citing Resp’t’s Ex. N2 at 2, ECF No. 173-3). The authors found that ovaries from mice taken “early” after immunization showed hypertrophic ovaries with an increased number of follicles, overall consistent with continued ovulation. Resp’t’s Ex. N2 at 6. The authors found that “[i]n sharp contrast,” ovaries from mice taken 43 to 45 weeks post immunization “consistently appeared atrophic with few follicles[.]” Id. Altuntas et al. determined this latter “morphology” was consistent with POF, but the former was not. Id. Dr. Welt applied the findings in these studies and argued that according to her own research, the incitement of autoreactive immune cells resulting in total destruction of the ovaries “take[s] time.” Resp’t’s Ex. N at 7 (citing Resp’t’s Exs. N2, N13, N19). She further argued that the time between Petitioner’s vaccination inducing autoreactive cells and POI diagnosis is “inconsistent with [Petitioner’s] causal mechanism because an autoimmune process would take much longer to cause complete ovarian destruction[.]” Id. at 8. She argued “the destruction of the follicles in a human ovary would take more than two months after the trigger of an autoimmune process.” Id. at 4. In Petitioner’s case, however, Dr. Welt noted there were only two months between her Gardasil vaccination and manifestation of end stage POI with elevated FSH and low estradiol in August of 2010. Id. at 7 (citing Pet’r’s Ex. 2 at 50). Dr. Welt argued that Dr. Pinhas- Hamiel’s assertion that an immune-mediated response causing hormonal consequences would take only a few weeks is “very unlikely.” Id. She therefore opined that Petitioner’s June 4, 2010 HPV vaccine more likely than not did not cause Petitioner’s POI. Id. at 8. Additionally, Dr. Welt discounted Petitioner’s psoriasis diagnosis and argued that there is no evidence of a comorbid autoimmune disease in Petitioner. Id. Dr. Welt wrote that while one of Petitioner’s treaters “suggested” that she had psoriasis, “that is not an autoimmune disease associated with POI.” Id. at 5 (citing Resp’t’s Ex. N10).83 Hoek et al. listed autoimmune diseases associated with POI to some degree, including Addison’s disease, oophoritis, gastric abnormalities such as Crohn’s disease, thyroid abnormalities, Graves’ disease,84 Hashimoto’s disease, 81 An oocyte is “the immature female reproductive cell prior to fertilization, derived from an oogonium and occurring in two stages, primary and secondary oocytes.” Dorland’s at 1322. 82 C. Altuntas et al., Autoimmune Targeted Disruption of the Pituitary-Ovarian Axis Causes Premature Ovarian Failure, 177 J. IMMUNOL. 1988–96 (2006). 83 A. Hoek et al., Premature Ovarian Failure and Ovarian Autoimmunity, 18:1 ENDOCR. REV. 107–34 (1997). 84 Graves’ disease is “a syndrome of diffuse hyperplasia of the thyroid, with a female predominance; it usually has an autoimmune etiology and has been linked to autoimmune thyroiditis. Characteristics include hyperthyroidism . . . usually with goiter and ophthalmic symptoms[.] Most patients have circulating thyroid- 29 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 30 of 42 myasthenia gravis, positive ANAs, RA, SLE, and vitiligo. See Resp’t’s Ex. N10 at 12–15. This list did not include psoriasis. See id. Based on this list, Dr. Welt called Petitioner’s experts’ contention that Petitioner’s POI must be autoimmune since other autoimmune disorders are associated with POI, “tenuous.” Resp’t’s Ex. N at 5. V. Legal Standard The Vaccine Rules afford the special master discretion in choosing whether to hold a hearing, stating that he or she “may decide a case on the basis of written filings without an evidentiary hearing.” Vaccine Rule 8(d); see also Plummer v. Sec’y of Health & Hum. Servs., 24 Cl. Ct. 304, 307 (1991). Under the Vaccine Act, a petitioner may prevail in one of two ways. First, a petitioner may demonstrate that she suffered a “Table” injury—i.e., an injury listed on the Vaccine Injury Table that occurred within the time period provided in the Table. § 11(c)(1)(C)(i). “In such a case, causation is presumed.” Capizzano v. Sec’y of Health & Hum. Servs., 440 F.3d 1317, 1320 (Fed. Cir. 2006); see § 13(a)(1)(B). Second, where the alleged injury is not listed in the Vaccine Injury Table, a petitioner may demonstrate that she suffered an “off-Table” injury. § 11(c)(1)(C)(ii). Petitioner does not assert a Table claim in this case. In attempting to establish entitlement to a Vaccine Program award of compensation for an off-Table claim, a petitioner must satisfy all three of the elements established by the Federal Circuit in Althen. Althen requires that a petitioner establish by preponderant evidence that the vaccinations she received caused her injury “by providing: (1) a medical theory causally connecting the vaccination and the injury; (2) a logical sequence of cause and effect showing that the vaccination was the reason for the injury; and (3) a showing of a proximate temporal relationship between vaccination and injury.” 418 F.3d at 1278. Each of the Althen prongs requires a different showing. Under Althen prong one, petitioners must provide a “reputable medical theory,” demonstrating that the vaccine received can cause the type of injury alleged. Pafford v. Sec’y of Health & Hum. Servs., No. 01-165V, 2004 WL 1717359, at *4 (Fed. Cl. Spec. Mstr. July 16, 2004), aff’d, 64 Fed. Cl. 19 (2005), aff’d, 451 F.3d 1352 (Fed. Cir. 2006). To satisfy this prong, a petitioner’s theory must be based on a “sound and reliable medical or scientific explanation.” Knudsen v. Sec’y of Health & Hum. Servs., 35 F.3d 543, 548 (Fed. Cir. 1994). As indicated above, I have already determined that the petitioners in the consolidated POI cases have presented a persuasive medical theory pursuant to Althen prong one, describing the HPV vaccine’s role in the development of autoimmune POI. See Findings of Fact at 24, ECF No. 147; Brayboy, 2021 WL 4453146, at *1. Therefore, in order to succeed under the remaining prongs of Althen, Petitioner must now show by preponderant evidence that her POI is autoimmune in nature. The second Althen prong requires petitioners to demonstrate that the vaccine actually did cause the alleged injury. Althen, 418 F.3d at 1279; Pafford, 451 F.3d at 1352. This requires proof of a logical sequence of cause and effect, usually supported by facts derived from a petitioner’s medical records. Althen, 418 F.3d at 1278; Andreu v. Sec’y of Health & Hum. Servs., 569 F.3d 1367, 1375–77 (Fed. Cir. 2009). In Program cases, contemporaneous medical records and the stimulating immunoglobulins that cause excessive secretion of thyroid hormones by binding to TSH receptors on thyroid follicular cells.” Dorland’s at 534. 30 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 31 of 42 opinions of treating physicians are favored. Capizzano, 440 F.3d at 1319–20 (citing Althen, 418 F.3d at 1280). This is because “treating physicians are likely to be in the best position to determine whether ‘a logical sequence of cause and effect show[s] that the vaccination was the reason for the injury.’” Id. In addition, “[m]edical records, in general, warrant consideration as trustworthy evidence . . . [and] are generally contemporaneous to the medical events.” Cucuras v. Sec’y of Health & Hum. Servs., 993 F.2d 1525, 1528 (Fed. Cir. 1993). However, there is no presumption that medical records are accurate and complete as to all the patient’s physical conditions. Kirby v. Sec’y of Health & Hum. Servs., 997 F.3d 1378, 1383 (Fed. Cir. 2021). While a special master must consider these opinions and records, they are not “binding on the special master or court.” 42 U.S.C. § 300aa-13(b)(1). Rather, when “evaluating the weight to be afforded to any such . . . [evidence], the special master . . . shall consider the entire record . . . .” Id. The third Althen prong requires establishing a “proximate temporal relationship” between the vaccination and the injury alleged. Althen, 418 F.3d at 1281. This prong requires a petitioner to show that the timing of the injury fits with the causal theory. Id. at 1278. In other words, a petitioner must offer “preponderant proof that the onset of symptoms occurred within a timeframe which, given the medical understanding of the disorder’s etiology, it is medically acceptable to infer causation.” de Bazan v. Sec’y of Health & Hum. Servs., 539 F.3d 1347, 1352 (Fed. Cir. 2008); Shapiro v. Sec’y of Health & Hum. Servs., 101 Fed. Cl. 532, 542 (2011), recons. denied after remand on other grounds, 105 Fed. Cl. 353 (2012), aff’d without op., 503 F. App’x. 952 (Fed. Cir. 2013); Koehn v. Sec’y of Health & Hum. Servs., No. 11-355V, 2013 WL 3214877 (Fed. Cl. Spec. Mstr. May 30, 2013), mot. for review denied (Fed. Cl. 2013), aff’d, 773 F.3d 1239 (Fed. Cir. 2014). For example, if the petitioner’s theory involves a process that takes several days to develop after vaccination, an injury that occurred within a day of vaccination would not be temporally consistent with that theory. Conversely, if the theory is one that anticipates a rapid development of a reaction post vaccination, the development of the alleged injury weeks or months post vaccination would not be consistent with that theory. The special master cannot infer causation from temporal proximity alone. See Thibaudeau v. Sec'y of Health & Hum. Servs., 24 Cl. Ct. 400, 403–04 (1991); see also Grant v. Sec'y of Health & Hum. Servs., 956 F.2d 1144, 1148 (Fed. Cir. 1992). In this case, Petitioner must show an appropriate temporal relationship consistent with her accepted biological mechanism of molecular mimicry. VI. Analysis A. Experts Although special masters have the discretion to be informed by past rulings and experiences, case-specific filings and testimony are the most helpful types of evidence, given the fact-specific nature of each decision. See Doe v. Sec’y of Health & Hum. Servs., 76 Fed. Cl. 328, 338–39 (2007). To that end, experts are an essential piece of a petitioner’s claim and Respondent’s defense. Where both sides offer expert testimony, a special master’s decision may be “based on the credibility of the experts and the relative persuasiveness of their competing theories.” Broekelschen v. Sec’y of Health & Hum. Servs., 618 F.3d 1339, 1347 (Fed. Cir. 2010) (citing Lampe v. Sec’y of Health & Hum. Servs., 219 F.3d 1357, 1361 (Fed. Cir. 2000)). This case ultimately turns, not only on Petitioner’s medical history, but also the persuasiveness of the written reports and supporting documentation. I therefore must assess each expert’s opinion and assign 31 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 32 of 42 weight accordingly. This assessment will inform my analysis pursuant to each remaining prong of Althen. I cannot ignore that Dr. Welt is the only expert with any direct clinical experience diagnosing and treating patients with POF out of the four experts that presented opinion evidence in this case. More notably, Dr. Welt is among the leading clinical investigators in reproductive endocrinology and has personally treated “over 100” patients with POI. Resp’t’s Ex. N at 1. Through her care of such patients, she has acquired extensive knowledge and experience in determining, when possible, the underlying cause of POI in each of those patients. See id. Her academic research is also rooted in determining the etiology of POI and, in pursuit of that, she has authored numerous pieces of medical literature on the subject. Id. None of the remaining experts for either party has a comparable level of expertise in the alleged injury or field. The only other expert with any apparent familiarity with the alleged injury is Dr. Pinhas- Hamiel. However, Dr. Pinhas-Hamiel’s experience with POI is only tangentially related to the injury at issue because she admittedly only deals with providing the “[w]ork-up diagnosis for amenorrhea[.]” See Pet’r’s Ex. 137 at 1. Dr. Pinhas-Hamiel is an endocrinologist, and her relevant subspecialties are in pediatrics and diabetes. See, e.g., id. at 1–2. As Petitioner is an adult who does not suffer from diabetes, Dr. Pinhas-Hamiel’s knowledge and experience in pediatric endocrinology does not provide direct support for her opinion regarding an autoimmune etiology for Petitioner’s POF. When considering the parties’ arguments in relation to the immunologic response involved in Petitioner’s condition, Dr. Welt’s clinical experience therefore contributed significantly more to the value of her testimony than Dr. Pinhas-Hamiel’s. Similarly, Drs. Axelrod and Forsthuber primarily practice in the field of immunology. This subject-matter expertise would have been helpful support for a thorough discourse on the probability of an autoimmune etiology for Petitioner’s POI, pursuant to Althen prong two. Instead, both experts’ reports heavily focused on Althen prong one, general causation analysis. As I have noted, Petitioner’s biological mechanism has been litigated and established by preponderant evidence. Therefore, Drs. Axelrod’s and Forsthuber’s lengthy discussions were not helpful on that issue, nor for a determination of the etiology for Petitioner’s POI. In my previous ruling, I explicitly warned the parties that my findings related to Althen prong one would not be relitigated nor expanded, absent advances in the medical research. See Brayboy, 2021 WL 4453146, at *11. Still, the two experts spent a great deal of time rebranding previous arguments. Neither expert relied on advances in the medical literature. Respondent’s expert Dr. Forsthuber attacked the general acceptance of molecular mimicry, while Dr. Axelrod undercut the specificity and applicability of Petitioner’s original mechanism. I have already made detailed and informed findings regarding the parties’ arguments on Althen prong one. The experts’ current renewed arguments regarding molecular mimicry, the accepted sequence length of homologies, and the relevant autoantibodies found in autoimmune POI, have been litigated. My original findings apply and are summarized below for context for the prong two analysis. B. Althen Prong One As noted above, I found that the POI petitioners “have articulated a sound and reliable theory of how the HPV vaccines could cause autoimmune POI via molecular mimicry.” Brayboy, 32 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 33 of 42 2021 WL 4453146, at *1. Specifically, I indicated that the POI petitioners’ experts described how “autoantibodies can attack multiple short peptide chains contained within proteins needed for normal ovarian function, when said peptides are also contained within viral proteins identified by the immune system for destruction.” See id. In arriving at that conclusion, I already determined that the POI petitioners’ expert successfully identified, and Respondent’s experts failed to negate, specific points of potential cross-reactions between components of the vaccine and homologous proteins in the body that are directly responsible for the health and productivity of the ovary. See id. at *19. I specified that “[i]t is true that a penta-peptide chain is undisputedly short. However, given the multifactorial pathogenesis of POI, I f[ound] it logical that cross-reactions between multiple, short peptides within proteins relevant to oocyte function and in HPV vaccines may produce an ovary-specific autoimmune attack.” Id. In order to succeed under this theory and the remaining prongs of Althen, each POI petitioner must show it is more likely than not that she suffers from POI with an autoimmune etiology. See id. In cases where there is evidence of lymphocytic oophoritis, adrenal or ovarian autoantibodies, and comorbid autoimmune disorders, I will presume the POI is autoimmune in nature. Id. at *8–*11. If all three of these factors are not present, a petitioner may still be able to establish it more-likely-than-not that her POI is autoimmune, given her particular medical history. Id. If, for example, a petitioner has another autoimmune disorder associated with POI, such as Addison’s disease, along with anti-ovarian antibodies, that may be sufficient. Id. I cautioned the POI petitioners that if a petitioner’s clinical presentation is not at all consistent with a POI etiology, i.e., there is no evidence of oophoritis or anti-steroid antibodies, it is unlikely that she will be able to show how her POI could be characterized as autoimmune in nature. Id. I further warned that the presence of autoimmune co-morbidities without other factors will likely not be sufficient to establish an autoimmune etiology. Id. If all three of these enumerated factors are not present, a petitioner may still be able to establish it more-likely-than-not that her POI is autoimmune, given her medical history. For example, a petitioner that has other more common characteristics of a systemic immune reaction, such as inflammation, prolonged fever, and fatigue, may also be able to establish that her individual diagnosis is autoimmune in nature, when considered with other POI symptoms. See id. at *1. C. Althen Prong Two The parties do not dispute that Petitioner suffers from POI. However, they dispute that Petitioner suffers from POI with an autoimmune etiology. The evidence in the record does not support Petitioner’s contention that her POI is autoimmune by a preponderant standard. Petitioner is therefore unable to satisfy her burden under Althen prong two. i. Laboratory Testing for Autoantibodies Petitioner’s laboratory testing was consistently negative for the autoantibodies that have been associated with autoimmune POI. As noted in my ruling on Althen prong one, current medical literature identifies adrenal autoantibodies as the most significant marker of autoimmune POI. See Brayboy, 2021 WL 4453146, at *8 (indicating that markers of ovarian autoimmunity include “antibodies directed against steroid-producing cells of various endocrine glands such as adrenal cortex cells and theca cells of the ovary[.]”). Petitioner’s testing for adrenal autoantibodies was 33 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 34 of 42 consistently negative. For instance, her first post-vaccination laboratory testing for adrenal autoantibodies occurred on March 17, 2012, and was negative. Pet’r’s Ex. 5 at 23–29, 33–36, 47. Laboratory test results from February 5, 2015, and April 8, 2022, were also negative for adrenal autoantibodies. See Pet’r’s Ex. 121 at 3. While less specific to a determination of autoimmune POI, Petitioner’s laboratory testing for anti-ovarian antibodies was also negative on March 17, 2012, and she was not re-tested at any point after her POI diagnosis or during treatment. See Brayboy, 2021 WL 4453146, at *8 (“[I]n general, ‘[a]ntiovarian antibodies . . . are too nonspecific to be of use in identifying which patients have an autoimmune mechanism.”’); see also Pet’r’s Ex. 5 at 23–29, 33–36, 47. Petitioner’s negative laboratory testing for relevant autoimmune antibodies fails to provide any support for an autoimmune etiology for her POI. ii. Evidence of Adrenal Insufficiency The lack of positive testing for the relevant autoantibodies does not by itself preclude Petitioner from establishing an autoimmune etiology for her POI. In fact, medical literature referring specifically to atypical cases, shows that patients with POI may still have an autoimmune etiology even without the presence of adrenal autoantibodies. See Brayboy, 2021 WL 4453146, at *9 (indicating that typically, if a patient fails to have adrenal autoantibodies, she will also fail to show signs of autoimmune oophoritis on biopsy; but highlighting that there may be atypical cases that do not fit such a conclusion). To establish an autoimmune etiology for POI without the presence of adrenal autoantibodies, Petitioner may exhibit other symptoms or clinical manifestations of adrenal insufficiency, such as evidence of oophoritis. See id. at *11. Autoimmune lymphocytic oophoritis can be diagnosed via pelvic ultrasound or testing for 21- hydroxylase autoantibodies. See id. at *8; see also Resp’t’s Ex. N at 4; Resp’t’s Exs. N3, N19. Petitioner underwent two pelvic ultrasounds, on December 17, 2010, and February 7, 2011, following the onset of her POI symptoms. See Pet’r’s Ex. 3 at 12–13. Petitioner’s December 17, 2010 ultrasound revealed one follicle measuring 12 x 9 mm on her normal-sized right ovary. Id. at 13. Her February 7, 2011 ultrasound showed one follicle measuring 5 x 4 mm on her normal-sized right ovary. Id. at 11. During both of Petitioner’s pelvic ultrasound examinations, the technician searched for, but was unsuccessful in visualizing, her left ovary and noted that it “was not clearly seen.” See id. at 11, 13. The test’s inability to show the left ovary precluded the finding of follicles on said ovary. However, neither exam revealed the presence of multiple, large follicles consistent with oophoritis. See id. Dr. Welt credibly explained that the presence of a single follicle is inconsistent with the presence of multiple, large follicles, in conjunction with low levels of estradiol, and therefore does not meet the criteria for an autoimmune oophoritis diagnosis. See Resp’t’s Ex. N at 4. Petitioner did not present preponderant evidence that her ultrasound results support a finding of autoimmune oophoritis, nor did her expert make such an argument. Similarly, Petitioner’s laboratory testing for adrenal insufficiency, including for 21-hydroxylase antibodies on April 8, 2022, was negative. See Pet’r’s Ex. 121 at 3. Therefore, Petitioner has failed to establish proof of adrenal insufficiency by a preponderance of the evidence. iii. Anti-nuclear Antibodies (ANAs) Petitioner’s extensive and repeat laboratory testing and autoimmune workups yielded positive results for ANAs on July 27, 2011, and February 6, 2017. Pet’r’s Ex. 9 at 72; Pet’r’s Ex. 34 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 35 of 42 24 at 38. Petitioner relies on these results, in part, as evidence of molecular mimicry and to support an autoimmune etiology for her POI. Petitioner’s expert testimony, however, provided the best evidence against a relationship between ANAs and autoimmune POI. Dr. Pinhas-Hamiel conceded that “[s]ome individuals . . . may have a positive test for ANA and yet never develop any autoimmune disease.” Pet’r’s Ex. 137 at 8. Additionally, the medical literature submitted explains that a positive result for ANAs is not specific for the development of many autoimmune diseases, including autoimmune POI. This lack of specificity is illustrated by positive ANA tests in healthy patients. Cameron et al. indicated that a positive ANA can be found in 5 to 30% of healthy individuals. Pet’r’s Ex. 141 at 2, 4. Pashnina et al. likewise echoed Cameron et al.’s findings and found the same interval of positive ANAs in healthy patients. Pet’r’s Ex. 143 at 9–11. The authors went so far as to note that ANAs “belong to the integral part of the normal functioning of the immune system.” Id. at 3. Respondent’s submitted literature by Bloch et al. includes an explicit warning against relying on a positive ANA in the diagnosis of autoimmune disease. Resp’t’s Ex. M1 at 3. The authors also provided explanations for a positive ANA that do not implicate autoimmune etiology, such as when a patient has a family history of autoimmune disease. Id. Such consistent findings in the medical literature shows by a preponderance of evidence that a positive ANA test does not, without more, predict autoimmune disease. The same medical literature submitted by Petitioner shows that while a positive ANA is known to be associated with some systemic autoimmune diseases, POI is not one of them. Pashnina et al. extensively listed conditions wherein a positive ANA is known and, in some cases, used for diagnostic purposes. Pet’r’s Ex. 143 at 7. Before addressing this list in more detail, I must define association and diagnostic value. An association refers to “the occurrence together of two or more characteristics more often than would be expected by chance alone.”85 Diagnostic value refers to the importance of any symptom that provides evidence for making a specific diagnosis.86 These terms can be distinguished from each other. Pashnina et al. illustrated this point and how such principles can also overlap. The authors explained that positive ANAs may serve as one of many diagnostic tools in the case of autoimmune diseases known to be associated with positive ANAs. See id. Among Pashnina et al.’s list of autoimmune diseases associated with a positive ANA is scleroderma, Sjögren’s syndrome, mixed connective tissue disease, RA, autoimmune hepatitis, anemia associated with autoimmune atrophic gastritis, Hashimoto’s disease, ITP, and other conditions. See id. It is compelling that the authors took care to list approximately twenty autoimmune diseases (including some diseases which are not generally considered to be related to autoimmunity) wherein an association with positive ANAs is known and/or cited to as support for the diagnosis of such conditions, but that POI was not included. Id. Petitioner’s reliance on the Pashnina et al. article to explain her fluctuating positive and negative ANAs does not advance her case. See Pet’r’s Ex. 137 at 8. Petitioner merely cited the authors’ summary of findings in a growing number of un-filed studies that determined that the level of autoantibodies decreases (rather than increases) during exacerbations of some autoimmune diseases. See Pet’r’s Ex. 143 at 3. For example, the Pashnina et al. article cited to a publishing by Churilov et al. when discussing the argument that a decrease in autoantibodies could reflect or 85 M. Stöppler, Medical Definition of Association, MEDICINENET (March 29, 2021), https://www.medicinenet.com/association/definition.htm. 86 Diagnostic Value, COLLINS DICTIONARY https://www.collinsdictionary.com/dictionary/english/diagnostic-value (last visited Feb. 14, 2023). 35 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 36 of 42 even cause a pathological process in the body. Id. Assuming the authors’ conclusion is true, Pashnina et al. did not sufficiently elaborate on this summary, and Petitioner did not file the Churilov article for consideration. I will not speculate as to why Petitioner ultimately did not submit this article, but without it, I cannot consider it in more detail. More importantly, the authors did not discuss POI, and Petitioner did not relate the diseases mentioned in the article back to POI for analogy. Without more, I am unable to use the Pashnina et al. article to explain her fluctuating ANA levels. I am also persuaded by Respondent’s position that Petitioner’s positive ANA tests are irrelevant to a determination of an autoimmune etiology. As a result, Petitioner’s two positive ANAs do not provide preponderant evidence for an autoimmune etiology for her POI. iv. Autoimmune Comorbidity In my ruling on Althen prong one, I identified “comorbid autoimmune” disorders such as Addison’s disease, as a conjunctive factor in my determination of autoimmune etiology. Brayboy, 2021 WL 4453146, at *1. Petitioner argues that her psoriasis is a comorbid autoimmune disease that evinces her predisposition for autoimmune POI. Respondent’s expert Dr. Welt effectively critiqued Petitioner’s psoriasis diagnosis, and her argument is persuasive but not determinative. Petitioner visited her dermatologist, Dr. Garshick, in 2021, and she diagnosed Petitioner with only acne and dermatofibroma at that time. See Pet’r’s Ex. 123 at 10–13. When Petitioner returned on August 19, 2022, Dr. Garshick referred to Petitioner’s psoriasis as “established/worsening[.]” See id. at 6–9. Yet, a prior diagnosis of psoriasis does not appear in her record, either by Dr. Garshick or any other treater. Furthermore, a diagnosis of psoriasis does not appear in Petitioner’s medical record after August 19, 2022. Dr. Welt is correct that Dr. Garshick’s notation regarding Petitioner’s psoriasis diagnosis is ambiguous. In Program cases however, the opinions of treating physicians are favored. Capizzano, 440 F.3d at 1326 (citing Althen, 418 F.3d at 1280). Indeed, when reviewing the record, a special master must consider the opinions of treating physicians. Id. After a consideration of the entire treatment record, including Petitioner’s presentation and Dr. Garshick’s assessment, I will defer to Dr. Garshick’s opinion that Petitioner suffered from psoriasis. I must note that while Petitioner contends that evidence supports a psoriasis diagnosis as early as 2012 or 2013, this argument is contrary to the record. In fact, while Petitioner reported to rheumatologist Dr. Reddy that she received a differential diagnosis of eczema or psoriasis in mid- 2012, Dr. Reddy’s treatment notes from March 28, 2013, ruled out psoriasis. Pet’r’s Ex. 6 at 3. Dr. Reddy also recorded that Petitioner said her differential diagnosis in 2012 was made by an ENT. See id. at 1. Without contemporaneous medical records from a treating ENT who opined Petitioner suffered from psoriasis, I am unable to rely on her statement alone. Indeed, Petitioner’s statement to Dr. Reddy approximately one year later does not carry the same weight as would a medical record created contemporaneously to the event in question. Instead, Petitioner’s contemporaneous medical records refute a psoriasis diagnosis in 2013. Petitioner submitted literature that generally discusses how psoriasis is thought to be an autoimmune disease. See, e.g., Pet’r’s Exs. 126–27. It falls short of Respondent’s submitted literature that directly discusses autoimmune disorders that primarily involve adrenal or thyroid insufficiencies and are known to be associated with POI. See Resp’t’s Ex. N10 at 12–15. Of note, Hoek et al. listed Addison’s disease, oophoritis, gastric abnormalities such as Crohn’s disease, 36 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 37 of 42 thyroid abnormalities such as Graves’ disease, Hashimoto’s disease, myasthenia gravis, RA, SLE, and vitiligo as autoimmune diseases associated with POI. See id. This list did not include psoriasis. Lastly, Petitioner’s psoriasis, first noted in her medical record approximately twelve years post vaccination, does not have an appropriate temporal relationship to her POI symptom onset. After careful consideration of Petitioner’s psoriasis onset and diagnosis, the record fails to establish how this condition provides preponderant support for an autoimmune etiology of Petitioner’s POI. Petitioner also has a family history of autoimmunity, specifically a grandmother with scleroderma, a chronic autoimmune condition. Pet’r’s Ex. 6 at 1. Consequently, Petitioner underwent testing for scleroderma, specifically for the presence of SCL-70 antibodies on February 6, 2017, with negative results. Therefore, her family history is less persuasive evidence of a predisposition for Petitioner to develop an autoimmune disease. This is especially true because all of Petitioner’s clinical testing and symptomology directly contradicts signs of autoimmunity in her case. Petitioner has not shown it more likely that she had a predisposition for the development of an autoimmune disease based on autoimmune comorbidities. v. Systemic Immune Reaction Another avenue for the POI petitioners to support an autoimmune etiology of their POI is by showing symptoms of a systemic immune reaction in the medical record. This showing would need to include evidence of inflammation, prolonged fever, and fatigue, apart from POI symptomology. See Brayboy, 2021 WL 4453146, at *11. Petitioner underwent testing for signs of inflammatory factors on December 16, 2010, including ESR and rheumatoid factor, with negative results. Pet’r’s Ex. 2 at 41–42. Her testing for CRP, another inflammatory marker, was likewise negative on February 6, 2017. Pet’r’s Ex. 24 at 41. The results from these common clinical tests used to measure inflammation therefore provide significant evidence against autoimmunity and a systemic immune response in Petitioner. Likewise, Petitioner did not complain of, nor did her treaters document, a fever at any point during her diagnosis or treatment of POI. The only sign of a systemic immune reaction supported by Petitioner’s medical record is fatigue. For instance, during Petitioner’s first post vaccination visit with treaters on August 6, 2010, she complained of a “change in energy status[.]” Pet’r’s Ex. 2 at 59. By March 20, 2017, her treater listed “chronic fatigue” among her diagnoses. Pet’r’s Ex. 24 at 1. However, fatigue is a common, non-specific symptom. Without other signs of a systemic immune reaction, it is not sufficient to satisfy Petitioner’s burden by a preponderant standard. Therefore, Petitioner has failed to provide preponderant evidence of an autoimmune etiology for her POI. vi. Opinions Regarding Autoimmunity The record fails to support Petitioner’s treater Dr. Gleicher’s opinion on autoimmunity, relied upon by Petitioner. Although the opinions of treating physicians are to be favored in the Program, I must consider such notations in light of the entire record. Capizzano, 440 F.3d at 1319– 20 (citing Althen, 418 F.3d at 1280) (“In Program cases, contemporaneous medical records and the opinions of treating physicians are favored.”); see also 42 U.S.C. § 300aa-13(b)(1) (“While a special master must consider these opinions and records, they are not “binding on the special master or court.” Rather, when “evaluating the weight to be afforded to any such . . . [evidence], the special master . . . shall consider the entire record . . . .”). While Dr. Gleicher wrote on March 17, 2012, that he thought Petitioner’s POI was “likely autoimmune,” his notation is negated by the 37 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 38 of 42 rest of the record. See Pet’r’s Ex. 5 at 7. Indeed, he ordered and ran a battery of tests on Petitioner for autoimmune serologies, including autoantibodies and other inflammatory markers, and the results were all negative. See id. at 23–29, 33–36, 47. After such testing, Dr. Gleicher did not further note his opinion that Petitioner suffered from autoimmune POI. See generally id. at 1–55. As a result, I will not credit Dr. Gleicher’s March 17, 2012 notation as preponderant evidence of autoimmunity. I must also note that some of the evidence submitted by Petitioner in this case is contradictory. Petitioner’s expert, Dr. Pinhas-Hamiel, authored a report early on during the pendency of Petitioner’s case, and then a supplemental report following my ruling on Althen prong one. Her first report took the position that Petitioner’s POI was not autoimmune, because she did not have signs of autoimmune disorders, such as hypo or hyperthyroidism, and she did not have antibodies to the “thyroid gland, to the ovaries or to adrenals.” Pet’r’s Ex. 17 at 5. However, following my ruling regarding the factors necessary for establishing an autoimmune etiology, Dr. Pinhas-Hamiel reversed her opinion in her supplemental report, authored approximately seven years later, and argued that support for Petitioner’s autoimmune POI was found in her positive ANAs. Pet’r’s Ex. 137 at 7–8. Petitioner’s argument is undermined by the reversal with no explanation or acknowledgment of her expert’s prior position. Petitioner cannot have it both ways simply to meet new criteria. Overall, Petitioner has failed to present preponderant evidence that she suffers from lymphocytic oophoritis, has relevant autoantibodies, has a comorbid autoimmune disorder associated with POI, or that her clinical presentation was at all consistent with autoimmune POI. In light of the cumulative evidence discussed, pursuant to the factors enumerated in my ruling on prong one, Petitioner is unable to show it more likely than not that she suffers from POI with an autoimmune etiology. D. Althen Prong Three Petitioner has failed to meet her burden under Althen prong three. As previously discussed, early during the pendency of this case, the presiding special master held a hearing to determine the first symptom or manifestation of POI to assess whether this case was barred by the statute of limitations. See Culligan, 2016 WL 3101981, at *10. Indeed, the presiding special master determined that in women over 18 years of age, the development of menstrual irregularities that exceed “normal” variation, such as secondary amenorrhea and cycle and frequency irregularities, are the first symptoms or manifestation of POI, irrespective of the petitioner’s date of diagnosis. See id. at *7–*9. While the presiding special master found that Petitioner’s case was not time barred, such findings are now applicable to my Althen prong three analysis. Only two of the four experts in this case explicitly opined regarding the date of onset of Petitioner’s POI. While Dr. Welt applied the definition outlined in Culligan, that menstrual irregularities such as amenorrhea are the first manifestations of POI, the record does not provide preponderant support for Dr. Welt’s arguments on onset. Dr. Welt argued that the onset of Petitioner’s POI occurred sometime prior to her June 4, 2010 HPV vaccination, and as early as 2006. Resp’t’s Ex. N at 3. As support, she cited Petitioner’s use of hormonal contraceptives off and on from 2006 to 2010 and argued that she could have been having symptoms of POI during 38 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 39 of 42 that period, but such manifestations were blocked by the use of birth control.87 See id. Dr. Welt’s argument is not supported by Petitioner’s medical history pursuant to a preponderant standard. Indeed, Petitioner’s records show she was prescribed hormonal contraceptives approximately once per year, on October 13, 2006, November 27, 2007, March 20, 2009, and May 25, 2010. See Pet’r’s Ex. 8 at 20, 32, 41, 46, 48; Pet’r’s Ex. 2 at 61. However, Petitioner’s medical records do not establish that she was consistently using such medications as prescribed. In fact, Petitioner's 2006 and 2008 pregnancies are strong evidence that she was likely not using such contraceptives consistently. Pet’r’s Ex. 8 at 8, 38, 41. Therefore, Dr. Welt’s argument that birth control use blocked symptoms of Petitioner’s POI is speculative at best and does not provide preponderant evidence that Petitioner’s POI began pre vaccination. Dr. Welt reinforced her argument that the onset of Petitioner’s POI occurred between 2006 and 2007, based on medical records that note a potential period of amenorrhea prior to vaccination. Resp’t’s Ex. N at 3. She relied on Petitioner’s April 26, 2007 negative pregnancy test document, that listed her last menstrual period as August of 2006, as proof of amenorrhea for eight months from August of 2006 to April of 2007. See id. However, Dr. Welt could not say with certainty that Petitioner experienced amenorrhea during this time, opining that she “may have had” it prior to August of 2010. Petitioner’s medical records did not otherwise mention or discuss menstrual irregularities or periods of amenorrhea during 2006 and 2007. In fact, Dr. Welt pointed out that Petitioner’s medical records were notably and consistently lacking information regarding the dates of her last menstrual cycles, around that time and beyond. Without contemporaneous medical records or sufficient support from the record, Dr. Welt’s ambiguous and unsupported argument cannot be afforded much weight. Instead, Dr. Welt admitted that it is “difficult” to pinpoint the onset of Petitioner’s amenorrhea and POI symptoms and did not otherwise provide a specific onset date aside from saying it began pre vaccination. See id. Dr. Welt’s arguments therefore do not provide preponderant evidence for the onset of Petitioner’s POI. Indeed, as Dr. Welt correctly highlighted, Petitioner’s medical records are unclear regarding symptoms of menstrual irregularities, such as secondary amenorrhea and cycle infrequencies. This is due, in part, to the lack of pre-vaccination menstrual history generally contained in Petitioner’s medical records. It is also due to Petitioner’s failure to report and describe signs of amenorrhea as they allegedly occurred. For example, Petitioner presented to her gynecologist on August 6, 2010, and did not report any lack of menstruation or changes to her cycle. See Pet’r’s Ex. 2 at 59. She reported other gynecologically-related issues, as will be discussed in more detail below, but she did not mention menstrual infrequencies or amenorrhea at that time. See id. However, on December 7, 2010, approximately four months later, Petitioner told a different treater that by August of 2010, she had missed her cycle “for about [three] months[,]” or since roughly May of 2010, which prompted her gynecologist to take her off birth control and monitor her hormone levels. Pet’r’s Ex. 3 at 32. This is consistent with visit notes from Petitioner’s gynecologist on May 25, 2010, that noted the date of Petitioner’s last cycle on May 23, 2010. Pet’r’s Ex. 2 at 66. I will not speculate as to why Petitioner did not report menstrual irregularities or cycle infrequencies to her gynecologist on August 6, 2010. See, e.g., LaLonde v. Sec’y of Health & Hum. Servs., 110 Fed. Cl. 184, 203–04 (2013), aff’d, 746 F.3d 1334 (Fed. Cir. 2014) (outlining 87 I must note that while Culligan provided findings regarding how contraceptive use will impact conclusions regarding the onset of POI, such findings were applicable to statute of limitations issues, not Althen prong three. Culligan, 2016 WL 3101981, at *10. 39 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 40 of 42 four potential explanations for inconsistencies between contemporaneously created medical records and later testimony or accounts: “(1) a person’s failure to recount to the medical professional everything that happened during the relevant time period; (2) the medical professional’s failure to document everything reported to her or him; (3) a person’s faulty recollection of the events when presenting testimony; or (4) a person’s purposeful recounting of symptoms that did not exist.”); see also Matthews v. Sec’y of Health & Hum. Servs., No. 19-414V, 2021 WL 4190265, at *5 (Fed. Cl. Spec. Mstr. Aug. 19, 2021) (internal citations omitted) (acknowledging that “the absence of a reference to a condition or circumstance [in contemporaneous medical records] is much less significant than a reference which negates the existence of the condition or circumstance.”). Despite Petitioner’s August 6, 2010 record, I find her medical record from December 7, 2010, wherein she documented her history and described missing her cycle for three months prior to August of 2010, provides preponderant support for her menstrual irregularities and amenorrhea beginning in May of 2010. It is true that Petitioner’s subsequent medical records do not mention or discuss periods of amenorrhea, but they also do not consistently contain the date of her last menstrual cycle. They likewise do not reflect if the absence of a notation regarding the date of Petitioner’s last menstrual cycle is indicative of an irregularity or if such information simply was not sought. When the submitted records do reference the date of Petitioner’s last menstrual cycle, they seem to reflect that Petitioner did experience menstrual cycles during 2010. I do not have before me evidence to determine the precise regularity of her cycles, but there is some evidence in Petitioner’s medical record that she did not experience her cycle every month after May of 2010. For example, while Petitioner did note during her August 6, 2010 gynecology visit that she experienced a cycle on August 1, 2010, her record does not indicate if she experienced cycles in the preceding months of June or July. Therefore, this record does not contradict Petitioner’s account of irregular menstruation or amenorrhea beginning in May of 2010. See Pet’r’s Ex. 12 at 3. There is no indication in the record whether Petitioner’s cycle resumed in September of 2010. Subsequent records show she had menstrual cycles in October and November of 2010. Pet’r’s Ex. 3 at 10–12. In December of 2010, she reported that her cycle was “again” two weeks late, but she did not otherwise indicate when her last menstruation occurred. Id. at 32–33. Petitioner’s medical records from 2011 provide a bit more clarity and add context to Petitioner’s 2010 records. On February 7, 2011, Petitioner reported that her last cycle occurred in November of 2010. Id. at 10. This is consistent with Petitioner’s report on December 7, 2010, that her cycle was approximately two weeks late. Id. at 32–33. While it is not certain when Petitioner’s amenorrhea began, certainty is not the standard in the Program. There is preponderant evidence that Petitioner experienced menstrual irregularities and amenorrhea beginning in May of 2010. Consistent with Culligan, the onset of Petitioner’s POI was therefore more likely than not in May of 2010. The first symptom of Petitioner’s POI therefore began pre vaccination. As I have determined that Petitioner has not presented preponderant evidence that her condition began following her June 4, 2010 vaccination, and she has failed to establish an autoimmune etiology for her POI, it is impossible for me apply her biological mechanism and analyze her claim under Althen prong three. Indeed, Petitioner’s claim must fail under prong three because if a condition began before vaccination, it would be logically impossible to infer that Petitioner’s injury occurred “within a timeframe for which . . . it is medically acceptable to infer causation-in-fact.” See W.C. 40 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 41 of 42 v. Sec’y of Health & Hum. Servs., 704 F.3d 1352, 1360 (2013). Although my analysis could end there, for the sake of completeness, I will address the parties’ remaining arguments. The record does not provide preponderant evidence for Dr. Axelrod’s arguments on onset. Despite Culligan’s finding that the first symptom or manifestation of POI is menstrual irregularities, including secondary amenorrhea, Dr. Axelrod argued that Petitioner’s manifestation of POI occurred when she started experiencing hot flashes, “sometime” around or before July 23, 2010. See Pet’r’s Ex. 124 at 9–10. As support for this approximation, he relied on Petitioner’s report during her August 6, 2010 visit, with gynecologist Dr. Selitsky, that she had been having hot flashes “for the last two weeks.” Pet’r’s Ex. 2 at 59. As previously noted, while Culligan defined amenorrhea as the first symptom of POI, both Culligan and Brayboy account for and describe other clinical symptoms of POI, such as hot flashes. Culligan, 2016 WL 3101981, at *7; Brayboy, 2021 WL 4453146, at *7–*9. Thus, even if I accepted Dr. Axelrod’s argument that Petitioner’s hot flashes were the first manifestation of her POI, her claim still fails under Althen prong three because the onset of this symptom was far outside what is consistent with her biological mechanism. In arriving at this conclusion, I must first address the onset of Petitioner’s hot flashes. Her medical records show that she began experiencing hot flashes as early as the end of July of 2010, and by no later than the beginning of August of 2010. See Pet’r’s Ex. 2 at 59 (reporting hot flashes for the last two weeks on August 6, 2010); But see Pet’r’s Ex. 3 at 32 (reporting hot flashes beginning in August of 2010). While there is a slight distinction in these timeframes (end of July vs. beginning of August), I do not consider it to be consequential. The record establishes it more likely than not that Petitioner was experiencing hot flashes by approximately August 1, 2010. Assuming arguendo that Petitioner’s hot flashes on or around August 1, 2010, signaled the onset of her POI, the two-month timeframe between her June 4, 2010 vaccination and August 1, 2010 onset, is inconsistent with her biological mechanism. Indeed, this timeframe for the progression of Petitioner’s injury is beyond what is accepted for an immune-mediated response to trigger Petitioner’s mechanism of molecular mimicry. In fact, Petitioner’s submitted medical literature by Abbas et al. shows that an immune-mediated response following exposure to an antigen can be expected to take two weeks. Pet’r’s Ex. 130. Likewise, Petitioner’s submitted literature by Lawley et al. shows that an immune response occurs within ten to twenty-five days. Pet’r’s Ex. 131. A period of approximately two months is far greater than the ten to twenty-five day or two-week interval for an immune-mediated response to occur following exposure to an antigen as reported by Lawley et al. and Abbas et al. Notably, however, Petitioner’s submitted literature does not discuss POI generally, autoimmune POI, or POI triggered by the HPV vaccine. It merely provides a general overview of immune-mediated responses and/or addresses the development of serum sickness. Serum sickness is an acute or subacute hypersensitivity reaction. See, e.g., supra, note 46 (defining serum sickness as “a hypersensitivity reaction to the administration of foreign serum or serum proteins . . . caused by the formation of circulating antigen-antibody complexes that are deposited in tissues and trigger tissue injury mediated by complement and polymorphonuclear leukocytes.”). The acute or subacute onset of serum sickness is consistent with the mechanism of an immune-mediated response triggering molecular mimicry. See, e.g., Pet’r’s Ex. 131. An acute or subacute process 41 Case 1:13-vv-00349-SSS Document 175 Filed 03/10/23 Page 42 of 42 via molecular mimicry is commonly seen and accepted in Program cases alleging Guillain-Barré syndrome, transverse myelitis, and other vaccine-related demyelinating injuries petitioners successfully establish occurred via molecular mimicry. See, e.g., Tracy v. Sec’y of Health & Hum. Servs., No. 16-213V, 2022 WL 1125281, at *34 (Fed. Cl. Spec. Mstr. Mar. 30, 2022) (finding that the onset of transverse myelitis thirteen days following receipt of a Prevnar 13 vaccine was appropriate based on the petitioner’s mechanism of molecular mimicry). The acute or subacute nature of these diseases explains why a ten to twenty-five day or two-week onset following exposure to an antigen is appropriate. However, Petitioner failed to present any evidence to explain how the onset of serum sickness, an acute condition, is applicable to the onset of POI, a chronic condition, via her accepted biological mechanism of molecular mimicry. Consistent with prior successful Program cases alleging acute injuries via molecular mimicry, it stands to reason that if Petitioner had suffered an immune-mediated reaction triggering molecular mimicry in response to her June 4, 2010 HPV vaccination, she would have experienced a manifestation of her POI before August 1, 2010. Petitioner likewise did not provide persuasive evidence to explain how this two- month gap in onset is still consistent with her biological mechanism. Therefore, even applying Dr. Axelrod’s arguments on onset, Petitioner’s claim must still fail under Althen prong three. VII. Conclusion Petitioner has failed to establish by preponderant evidence that the HPV vaccine she received on June 4, 2010, was the cause-in-fact of her POI, as she cannot establish her POI is autoimmune and the onset is not consistent with her biological mechanism. While I am sympathetic towards Petitioner’s condition and acknowledge that she has suffered both physically and emotionally, the evidence in the record does not show entitlement to compensation by a preponderant standard. Accordingly, this case is hereby DISMISSED.88 IT IS SO ORDERED. s/Herbrina D. Sanders Herbrina D. Sanders Special Master 88 Pursuant to Vaccine Rule 11(a), entry of judgment is expedited by the parties’ joint filing of a notice renouncing the right to seek review. 42 ================================================================================ DOCUMENT 4: USCOURTS-cofc-1_13-vv-00349-4 Date issued/filed: 2023-09-12 Pages: 10 Docket text: JUDGE VACCINE REPORTED OPINION reissuing 183 Opinion and Order on Motion for Review. Signed by Judge Stephen S. Schwartz. (cmc) Service on parties made. -------------------------------------------------------------------------------- Case 1:13-vv-00349-SSS Document 185 Filed 09/12/23 Page 1 of 10 In the United States Court of Federal Claims No. 13-349V (Filed Under Seal: August 22, 2023) (Reissued: September 12, 2023) FOR PUBLICATION *************************************** CRISTAL BELLO, * * Petitioner, * * v. * * SECRETARY OF HEALTH AND * HUMAN SERVICES, * * Respondent. * * *************************************** Mark T. Sadaka, Sadaka Associates LLC, Englewood, NJ, for Petitioner. Kimberly S. Davey, Trial Attorney, Torts Branch, Civil Division, United States Department of Justice, Washington, D.C., for Respondent, United States. With her on briefs were Brian M. Boynton, Principal Deputy Assistant Attorney General, C. Salvatore D’Alessio, Director, Heather L. Pearlman, Deputy Director, and Lara A. Englund, Assistant Director, Torts Branch, Civil Division, United States Department of Justice, Washington, D.C. OPINION AND ORDER Petitioner Cristal Bello, who experienced premature ovarian failure after receiving the Gardasil vaccine, sought relief under the National Childhood Vaccine Injury Compensation Program. 42 U.S.C. §§ 300aa-10 to 34 (“Vaccine Act”). The Special Master found that Petitioner had not carried her burden to prove causation and denied recovery. See Entitlement Decision (ECF 174). Petitioner filed a motion for review, which has been fully briefed and argued.1 Although certain errors appear  This Opinion was issued under seal on August 22, 2023. The parties were directed to propose redactions by September 5, 2023. No proposed redactions were submitted. The Court hereby releases publicly the Opinion and Order of August 22 in full. 1 Petitioner’s Br. in Support of Motion for Review (“Pet. Br.) (ECF 176); Respondent’s Br. Opposing Motion for Review (“Resp. Br.”) (ECF 178); Tr. (ECF 182). Case 1:13-vv-00349-SSS Document 185 Filed 09/12/23 Page 2 of 10 in the record, the Special Master’s ultimate decision was not arbitrary and capricious, so the motion for review is DENIED.2 BACKGROUND I. The Vaccine Act To obtain compensation under the Vaccine Act, a petitioner must prove that a vaccine caused an injury. Althen v. Sec’y of Health & Hum. Servs., 418 F.3d 1274, 1278 (Fed. Cir. 2005). There are two ways to show causation: (1) through “a statutorily-prescribed presumption of causation upon a showing that the injury falls under the Vaccine Injury Table (‘Table injury’),” id. (citing 42 U.S.C. § 300aa-14(a)), or (2) by proof of causation in fact “where the complained-of injury is not listed in the Vaccine Injury Table (‘off-Table injury’),” id. (citing 42 U.S.C. §§ 300aa-13(a)(1), 300aa-11(c)(1)(C)(ii)(I)). For off-Table injuries, causation in fact has three elements: “(1) a medical theory causally connecting the vaccination and the injury; (2) a logical sequence of cause and effect showing that the vaccination was the reason for the injury; and (3) a showing of a proximate temporal relationship between vaccination and injury.” Id. A petitioner always must prove causation of off-Table injuries by preponderance of the evidence. See, e.g., Hibbard v. Sec’y of Health & Hum. Servs., 698 F.3d 1355, 1366 (Fed. Cir. 2012); Althen, 418 F.3d at 1278.3 Although the petitioner’s burden does not “require identification and proof of specific biological mechanisms,” Knudsen v. Sec’y of Health & Hum. Servs., 35 F.3d 543, 549 (Fed. Cir. 1994), “a ‘plausible’ or ‘possible’ causal theory” is not enough, see Boatmon v. Sec’y of Health & Hum. Servs., 941 F.3d 1351, 1360 (Fed. Cir. 2019) (quoting Moberly ex rel. Moberly v. Sec’y of Health & Hum. Servs., 592 F.3d 1315, 1322 (Fed. Cir. 2010)). Proof of causation requires “a reputable medical or scientific explanation that pertains specifically to the petitioner’s case.” See Broekelschen v. Sec’y of Health & Hum. Servs., 618 F.3d 1339, 1345 (Fed. Cir. 2010); Moberly, 592 F.3d at 1322; see also Knudsen, 35 F.3d at 549 (“[C]ausation can be found in vaccine cases based on epidemiological evidence and the clinical picture regarding the particular [patient] without detailed medical and scientific exposition on the biological mechanisms.”). A theory of causation must be supported by medical records or an expert’s opinion. Althen, 418 F.3d at 1279 (citing 42 U.S.C. § 300aa-13(a)(1)). 2 This Court has jurisdiction. See 42 U.S.C. §§ 300aa-11(c), 300aa-16(a). Petitioner timely moved for review. See 42 U.S.C. § 300aa-12(e)(1). 3 The government can rebut proof of causation by showing, “also by a preponderance of evidence, that the injury was in fact caused by factors unrelated to the vaccine.” Althen, 418 F.3d at 1278 (quoting Knudsen v. Sec’y of Health & Hum. Servs., 35 F.3d 543, 547 (Fed. Cir. 1994)); see 42 U.S.C § 300aa- 13(a)(1)(B). - 2 - Case 1:13-vv-00349-SSS Document 185 Filed 09/12/23 Page 3 of 10 II. Procedural and Factual History This is one of several cases alleging that the Gardasil vaccine — which is meant to prevent human papillomavirus infections — causes premature ovarian failure, an off-Table injury. See 42 U.S.C. § 300aa-14(a); 42 C.F.R. § 100.3(a)(XVI). The cases were consolidated before the Special Master, who held that the petitioners can satisfy Althen prong one when their ovarian failure is “autoimmune in nature.” See Ruling on Althen Prong One at 9 (ECF 147). Under that ruling — which is not challenged here — Petitioner must prove that she personally suffers from ovarian failure caused by autoimmunity and that there is a logical and proximate sequence under Althen prongs two and three. See id. at 24. The Special Master explained in detail how she would evaluate whether a petitioner has established autoimmune ovarian failure: In cases where there is evidence of lymphocytic oophoritis, adrenal or ovarian autoantibodies, and comorbid autoimmune disorders, I will presume the [ovarian failure] is autoimmune in nature. If all three of these factors are not present, a petitioner may still be able to establish it more-likely-than-not that her [ovarian failure] is autoimmune, given her particular medical history. Id. at 14; see also Entitlement Decision at 33. The most relevant facts concerning Petitioner are as follows. On May 25, 2010, when she was 23 years old, Petitioner visited a gynecologist. See Pet. Exh. 2 at 65 (ECF 8-3). She reported that her last menstrual period had begun two days earlier. Id. Her medical record suggests that the doctor observed a cervical abnormality, but it is not obvious from the notes what was the matter. Id. The doctor recommended that Petitioner receive the Gardasil vaccine, id., which was administered on June 4. Id. at 64. Aspects of Petitioner’s subsequent medical history are murky. On August 6, Petitioner reported to her doctor that she had been experiencing hot flashes and other symptoms for two weeks. Id. at 59. The doctor ordered laboratory tests, which showed post-menopausal (i.e., elevated) levels of certain hormones. Id. at 50; see also Pet. Exh. 3 at 24 (ECF 8-4). Those hormone levels were within the normal range a month later. Pet. Exh. 2 at 48. In December 2010, Petitioner faxed a message to a new gynecologist. She reported that she experienced hot flashes “[i]n the beginning of August” and had spoken to her doctor, who ran laboratory tests. See Pet. Exh. 2 at 32. She reported that she “missed [her] menstrual cycle for about 3 months so [the doctor] took [her] off birth control … and we monitored the levels for the next 2 months.” Id. The hot - 3 - Case 1:13-vv-00349-SSS Document 185 Filed 09/12/23 Page 4 of 10 flashes “went away,” but had come back, and she was “again … two weeks late on [her] cycle.” Id. at 32–33. Tests in December showed elevated hormone levels again. Pet. Exh. 2 at 41–42. The dates of Petitioner’s periods after May are not clear from the record. At a doctor’s appointment in December, after her fax message, she reported that her last period began in October 2010. See Pet. Exh. 3 at 12. In 2014, she reported a period in August 2010, Pet. Exh. 12 at 2 (ECF 52-2), though the parties agree that was likely error. Tr. at 10–13, 59. In February 2011 she reported a menstrual period as late as November 2010. See Pet. Exh. 3 at 10. But ultimately she was diagnosed with premature ovarian failure. See Entitlement Decision at 33 (“The parties do not dispute that Petitioner suffers from [premature ovarian failure].”). As mentioned, the Special Master’s Althen prong one ruling identified several conditions that, when appearing together, would lead her to presume that a petitioner’s ovarian failure was autoimmune in nature. Ruling on Althen Prong One at 9. Petitioner was never diagnosed with two of those conditions. Petitioner never had a positive test result for adrenal or anti-ovarian antibodies. See Entitlement Decision at 33–34; Pet. Exh. 5 at 23–29, 33–36, 47, 51 (ECF 8-6); Pet. Exh. 121 at 3 (ECF 156). She also showed no signs for oophoritis. See Entitlement Decision at 34; Pet. Exh. 3 at 11–13; Gov. Exh. N at 4 (ECF 173-1); Pet. Exh. 121 at 3. Instead, Petitioner had positive test results for antinuclear antibodies in 2011 and 2017, although she also had negative results in 2010 and 2012. See Entitlement Decision at 34–35, 9–10, 12; Pet. Exh. 9 at 72 (ECF 23-2); Pet. Exh. 24 at 38 (ECF 90- 1); Pet. Exh. 137 at 8 (ECF 166-1); Pet. Exh. 141 at 2 (ECF 171-4); Pet. Exh. 143 at 3, 9–11 (ECF 171-6). She also may have received a diagnosis of psoriasis. See Entitlement Decision at 36; Pet. Exh. 123 at 6–9, 10–13 (ECF 163-1); Pet. Exh. 126 (ECF 165-1); Pet. Exh. 127 (ECF 165-2); Gov. Exh. N10 at 12–16 (ECF 173-11). The parties dispute the significance of those two conditions, as discussed below. Petitioner and the government submitted medical literature and expert reports. The Special Master concluded that Petitioner had not established either (1) a logical sequence of cause and effect connecting her ovarian failure to her vaccine, or (2) that her ovarian failure was autoimmune in nature. Her reasoning was as follows. In her Althen prong three analysis, the Special Master found that Petitioner’s symptoms of ovarian failure began in May 2010. See Entitlement Decision at 40. Although Petitioner’s contemporaneous medical records mention a menstrual period beginning on May 23, the Special Master interpreted Petitioner’s December 7 fax as reporting three missed periods as of August 2010, i.e., Petitioner’s May, June, and July periods. Id. The fax, the Special Master wrote, provided “preponderant support - 4 - Case 1:13-vv-00349-SSS Document 185 Filed 09/12/23 Page 5 of 10 for [Petitioner’s] menstrual irregularities and amenorrhea beginning in May of 2010.” Id. The Special Master concluded on that basis that Petitioner’s June 2010 vaccination could not have caused her ovarian failure. Id. The Special Master reasoned in the alternative that if Petitioner’s hot flashes developed around August 1, 2010, her ovarian failure appeared too late to be consistent with an autoimmune response to the vaccination, which — depending on the study cited — typically appears within ten to 25 days. Id. at 41. In her Althen prong two analysis,4 Petitioner had argued that her positive tests for antinuclear antibodies predict autoimmune disease and that her psoriasis is an autoimmune condition comorbid with autoimmune ovarian failure. The Special Master appears to have assumed that Petitioner had both antinuclear antibodies and psoriasis. Id. at 34–35, 36–37. She found, rather — based on the medical literature and her evaluation of the parties’ expert reports — that those conditions are not associated with premature ovarian failure. “[T]he medical literature,” she wrote, “shows by a preponderance of evidence that a positive [antinuclear antibody] test does not, without more, predict autoimmune disease.” Id. at 35. In addition, “while a positive [test for antinuclear antibodies] is known to be associated with some systemic autoimmune diseases, [ovarian failure] is not one of them.” Id. That left Petitioner’s antinuclear antibody results “irrelevant to a determination of an autoimmune etiology” for her ovarian failure. Id. at 36. Although the Special Master found that psoriasis is autoimmune in nature, id., she wrote that it had been “ruled out” as to Petitioner in 2013, was not diagnosed until much later in her history, and was not one of the autoimmune conditions associated with ovarian failure. Id. at 36–37. DISCUSSION Petitioner argues that the Special Master erred by finding (1) that Petitioner’s ovarian failure predated her vaccine, and (2) that Petitioner failed to show that she has an autoimmune condition associated with ovarian failure. Pet. Br. at 1–2. This Court may set aside a special master’s factual conclusions as “arbitrary, capricious, an abuse of discretion, or otherwise not in accordance with law[.]” 42 U.S.C. § 300aa- 12(e)(2)(B). When the special master’s findings of fact are “supported by substantial evidence,” they must be upheld. Doe v. Sec’y of Health & Hum. Servs., 601 F.3d 1349, 1355 (Fed. Cir. 2010) (citing Whitecotton by Whitecotton v. Sec’y of Health & Human Servs., 81 F.3d 1099, 1105 (Fed. Cir. 1996)). That standard is “well understood to be 4 Although characterizing Petitioner’s ovarian failure overlaps with Althen prong one, the Federal Circuit has held that the question whether a given medical theory “accounted for” a Petitioner’s particular injuries is a prong two question. Hibbard, 698 F.3d at 1364. No party takes issue with the Special Master’s overall structuring of her analysis. - 5 - Case 1:13-vv-00349-SSS Document 185 Filed 09/12/23 Page 6 of 10 the most deferential possible.” Munn v. Sec’y of Dep’t of Health & Hum. Servs., 970 F.2d 863, 870 (Fed. Cir. 1992). I begin with the Special Master’s conclusion that Petitioner’s ovarian failure developed in May 2010, before Petitioner’s vaccination. That position is hard to understand or defend. On May 25, about a week before Petitioner received the Gardasil vaccine on June 4, her doctor wrote that Petitioner’s most recent menstrual period had begun two days earlier. Pet. Exh. 2 at 65. The Special Master did not identify anything in the record of that visit suggesting that Petitioner’s May period was late or otherwise unusual. Nor did she find that the medical records reporting Petitioner’s May period were inaccurate or incomplete in any way. The Special Master was not bound to credit the medical records. See Kirby v. Sec’y of Health & Hum. Servs., 997 F.3d 1378, 1382–83 (Fed. Cir. 2021). But standing alone, the contemporaneous medical records — which “in general[] warrant consideration as trustworthy evidence,” see Cucuras v. Sec’y of Dep’t of Health & Hum. Servs., 993 F.2d 1525, 1528 (Fed. Cir. 1993) — do not seem to rationally support the Special Master’s conclusion. Instead, the Special Master relied on Petitioner’s December 2010 fax saying that Petitioner “missed [her] menstrual cycle for about 3 months so [the doctor] took [her] off birth control[.]” Entitlement Decision at 40; see Pet. Exh. 3 at 32. According to the Special Master, Petitioner’s fax described menstrual abnormalities beginning in May, counting three months back from Petitioner’s August medical appointments. Entitlement Decision at 40. Yet the Special Master found that the fax was “consistent with” the notes for Petitioner’s May doctor visit. Id. at 39. That hardly makes rational sense either: If the fax does not contradict the May notes, then Petitioner must have had a period (without any abnormalities noted by the Special Master) in late May, just before receiving the Gardasil vaccine. Given that the Special Master did not find that the May medical record described any abnormalities in Petitioner’s menstrual cycle, the only way to reconcile the May records with the December fax is to say that Petitioner’s symptoms began after her May period. The government argues that the handwritten phrase “discharge clear,” appearing on Petitioner’s May 25 medical record, indicates that her menstrual discharge was abnormal. See Resp. Br. at 17–18 & n.22; Tr. at 58. The phrase might be preceded, though, by a circle with a line drawn through it, which medical professionals sometimes use when they do not observe something. In fact, it seems that is exactly what the doctor intended: She marked Petitioner’s breast exam as “normal” on the same medical record and handwrote the words “masses” and - 6 - Case 1:13-vv-00349-SSS Document 185 Filed 09/12/23 Page 7 of 10 “discharge” with the same symbol — meaning, presumably, that those abnormal breast conditions were not present. Pet. Exh. 2 at 65. The government also hypothesizes that if Petitioner had not missed her periods in May, June, and July, her doctors would not have ordered laboratory tests in August, Tr. at 60–62, though of course Petitioner was also experiencing hot flashes by then. Pet. Exh. 2 at 59. Regardless, the Special Master did not rely on those rationales to explain her decision, and the government cites no authority allowing this Court to affirm the Special Master based on speculative rationales developed here for the first time. Cf. Lemire v. Sec’y of Dep’t of Health & Hum. Servs., 60 Fed. Cl. 75, 79 (2004) (“This post- hoc justification had nothing to do with the special master’s explicit rationale.”). The Special Master’s alternative reasoning — that Petitioner’s symptoms appeared too late after the vaccine — is peculiar as well. The Special Master’s thinking seems to have been that Petitioner’s hot flashes began around the beginning of August. Entitlement Decision at 41. But the Special Master had also found that “secondary amenorrhea and cycle and frequency irregularities[] are the first symptoms or manifestation” of ovarian failure in patients like Petitioner. Id. at 38. Whenever Petitioner’s hot flashes began, she told her doctor in December that she had missed at least some periods by August. Pet. Exh. 2 at 32. The Special Master consistently credited Petitioner’s December account, and she found no evidence that Petitioner had a period in June or July. Entitlement Decision at 40. If the Special Master did not discount the December fax or find that Petitioner had periods in June or July, it is hard to understand how the Special Master could rationally have considered the hot flashes to be Petitioner’s first symptom rather than the missed periods beginning in mid- to late-June — roughly in the time frame the Special Master noted for the normal onset of autoimmune ovarian failure. Id. at 41. The Special Master also found no evidence that Petitioner’s ovarian failure was autoimmune in origin. Petitioner argues that her ovarian failure was caused by autoimmunity because it developed when she had psoriasis, a supposedly comorbid autoimmune condition, and antinuclear antibodies. Pet. Br. at 6. Yet no reference to a psoriasis diagnosis appears in Petitioner’s medical record until years later — in 2022 according to the Special Master, but at the earliest in a 2013 visit with a rheumatologist. Entitlement Decision at 36. The Special Master’s analysis of Petitioner’s psoriasis diagnosis is questionable too. She found that Petitioner’s medical literature does not associate psoriasis with ovarian failure, citing Petitioner’s exhibits 126 and 127. Entitlement Decision at 36– 37. But Petitioner claims that another one of the studies she presented to the Special Master could be read to do just that. See Pet. Exh. 128 (ECF 165-3); Tr. at 30–34; but see Tr. at 65–67 (government’s contrary reading of the study). One of Petitioner’s - 7 - Case 1:13-vv-00349-SSS Document 185 Filed 09/12/23 Page 8 of 10 experts described the study in those terms. See Pet. Exh. 124 at 4 (ECF 164-1) (Dr. David Axelrod, M.D.). The Special Master, at any rate, was “required to consider all relevant medical and scientific evidence of record … even if it [was] not explained by the testimony of an expert.” Moriarty by Moriarty v. Sec’y of Health & Hum. Servs., 844 F.3d 1322, 1330 (Fed. Cir. 2016).5 The Special Master’s omission suggests that she did not perform a complete review of the entire record as the Federal Circuit requires. The Special Master may also have erred in some of her conclusions about the onset of Petitioner’s psoriasis. The Special Master wrote that the notes of Petitioner’s 2013 rheumatology visit “ruled out” psoriasis. Entitlement Decision at 36. In fact, the doctor recorded that Petitioner had self-reported a possible eczema or psoriasis diagnosis from 2012, Pet. Exh. 6 at 1 (ECF 8-7), but that she did not observe any such condition herself, id. at 3, and recommended that Petitioner visit “dermatology for eval of psoriasis vs eczema,” id. It makes little sense to say that a doctor who recommends a follow-up for a patient to check for or distinguish between two conditions has “ruled out” either condition. Entitlement Decision at 36. Whatever weight the medical record might deserve,6 the government does not defend the plain terms of the Special Master’s reading. Tr. at 53–54. In short, several of the Special Master’s conclusions about Petitioner’s symptoms and medical condition lack rational support in the record. Ordinarily, such errors might well call for remand. But this Court and the Federal Circuit have ruled on a number of occasions that special master errors are not reversible unless the adverse party shows the error was prejudicial. See, e.g., Cedillo v. Sec’y of Health & Hum. Servs., 617 F.3d 1328, 1343 (Fed. Cir. 2010) (finding special master’s error harmless when “it did not affect the outcome of the proceeding”); Hines on Behalf of Sevier v. Sec’y of Dep’t of Health & Hum. Servs., 940 F.2d 1518, 1526–27 (Fed. Cir. 1991) (finding error harmless “because it did not change the outcome of the case”); see also A.Y. by J.Y. v. Sec’y of Health & Hum. Servs., 152 Fed. Cl. 588, 599 (2021); Johnson v. Sec’y of Health and Hum. Servs., 33 Fed. Cl. 712, 728–29 (1995); Cox v. Sec’y of Dept. of Health & Hum. 5 This Court presumes that a special master “considered the relevant record evidence even though he does not explicitly reference such evidence in his decision … [except] where a special master indicates otherwise.” Moriarty, 844 F.3d at 1328. Here, when the Special Master identified the evidence Petitioner meant to link psoriasis with ovarian failure, she left out the study that does so most directly. 6 The record might not be enough by itself to show that Petitioner had psoriasis in 2013, see Entitlement Decision at 36; Resp. Br. at 10, but all concerned seem to agree that Petitioner in fact was diagnosed with psoriasis eventually. The weight of record evidence is for the Special Master to determine, so long as her reading is not “arbitrary, capricious, an abuse of discretion, or otherwise not in accordance with law.” 42 U.S.C. § 300aa-12(e)(2)(B). - 8 - Case 1:13-vv-00349-SSS Document 185 Filed 09/12/23 Page 9 of 10 Servs., 30 Fed. Cl. 136, 142–45 (1993). Here, even if (1) Petitioner’s condition postdated her vaccine, (2) psoriasis were comorbid with ovarian failure, and (3) the Special Master misinterpreted evidence about when psoriasis first appeared in Petitioner’s record, Petitioner has not shown that it made any difference to the outcome. Assuming both that Petitioner’s ovarian failure postdated her vaccine and that psoriasis and ovarian failure are comorbid conditions, her theory still demands that the psoriasis and the ovarian failure existed closely enough in time to have something to do with each other. The Special Master found that Petitioner’s psoriasis diagnosis in 2022 “does not have an appropriate temporal relationship to her [ovarian failure] symptom onset.” Entitlement Decision at 37. At most Petitioner’s medical record brings her psoriasis back in time to 2012 or 2013. Petitioner does not explain why that makes any practical difference, let alone develop an argument about what an “appropriate temporal relationship” might be, or show evidence that ovarian failure could be connected to psoriasis that only manifests two or three years after the fact. Petitioner seeks to antedate her psoriasis by pointing to her positive tests for antinuclear antibodies.7 But Petitioner tested negative for antinuclear antibodies in 2010, when her symptoms began. Pet. Exh. 2 at 41; see Entitlement Decision at 12. Petitioner points to no evidence that a positive antibody test in 2011 could show that psoriasis appearing in 2012 or 2013 was actually developing at the time of a negative antibody test in 2010. Petitioner has no explanation for the absence of such evidence, and the proposed link between her ovarian failure and her psoriasis breaks down without it. Even if she had antinuclear antibodies around the time her ovarian failure developed — and no evidence suggests that she did — the Special Master also found that Petitioner had failed to prove that those antibodies are diagnostic of autoimmune disease generally or associated with autoimmune ovarian failure specifically. Entitlement Decision at 34–36. There is no causation without association, see Doles v. United States, 159 Fed. Cl. 241, 248 (2022), so the Special Master’s conclusion means that the mere presence of antinuclear antibodies at a given time could not imply that Petitioner had psoriasis or that her ovarian failure resulted from autoimmunity. Petitioner points to no evidence that the Special Master’s conclusion in that regard was arbitrary or capricious. 7 Petitioner might also frame the point in somewhat different terms: specifically, given that her ovarian failure began after her vaccine, when she had antinuclear antibodies, and that she was later diagnosed with an autoimmune condition, an inference of autoimmune ovarian failure makes the most sense. Tr. at 75. That phrasing ultimately does no more than obscure Petitioner’s burden to prove causal connections between different pieces of her medical record. - 9 - Case 1:13-vv-00349-SSS Document 185 Filed 09/12/23 Page 10 of 10 The narrow reed of harmless error is enough to hold up the Special Master’s decision. She appears to have erred as to the timing of Petitioner’s ovarian failure. She also appears to have erred as to the timing of Petitioner’s psoriasis and by overlooking evidence that the condition is associated with ovarian failure. But even assuming that Petitioner’s ovarian failure developed soon after her Gardasil vaccine in 2010, and further assuming that Petitioner later showed signs of a comorbid autoimmune condition, Petitioner points to no evidence that her ovarian failure and autoimmune condition could have been associated with each other. Because the gaps in Petitioner’s factual case are too wide to be bridged with lawyer argument alone, the Special Master’s decision must stand. CONCLUSION For the foregoing reasons, Petitioner’s motion for review is DENIED. The decision of the Special Master is SUSTAINED. The Clerk is directed to enter judgment accordingly. IT IS SO ORDERED. s/ Stephen S. Schwartz STEPHEN S. SCHWARTZ Judge - 10 -