VICP Registry Case Source Bundle Canonical URL: https://vicp-registry.org/case/USCOURTS-cofc-1_16-vv-00702 Package ID: USCOURTS-cofc-1_16-vv-00702 Petitioner: Grace Drummond Filed: 2016-06-16 Decided: 2023-04-21 Vaccine: HPV Vaccination date: 2013-07-22 Condition: Premature Ovarian Failure/Primary Ovarian Insufficiency (POF/POI) and Postural Orthostatic Tachycardia Syndrome (POTS) Outcome: denied Award amount USD: AI-assisted case summary: On June 16, 2016, Grace Drummond, who was 16 years old at the time of vaccination, filed a petition alleging that she developed Premature Ovarian Insufficiency (POI) and Postural Orthostatic Tachycardia Syndrome (POTS) as a result of receiving two doses of the human papillomavirus (HPV) vaccine on July 22, 2013, and October 23, 2013. She also received an influenza vaccine on October 23, 2013. Petitioner alleged that these vaccinations caused her POI and POTS. The case was litigated, and the Special Master issued a decision on April 21, 2023. Petitioner's medical history included irregular menses starting in August 2013 and stopping completely by October 2013, along with various other symptoms. Petitioner's experts, Dr. Felice Gersh and Dr. David Axelrod, argued that the HPV vaccine triggered an autoimmune response through molecular mimicry, leading to POI and POTS. Dr. Gersh hypothesized that Petitioner's prematurity led to an underdeveloped intestinal microbiome, which, when combined with the HPV vaccine, altered her immune system, resulting in POI. Dr. Axelrod supported the molecular mimicry theory, suggesting similarities between HPV vaccine peptides and ovarian proteins, and also linked Petitioner's POTS to the HPV vaccine via fibroblast growth factor receptor 3 homology. He also noted an association between POTS and Ehlers-Danlos Syndrome (EDS), a condition Petitioner also had. Respondent's experts, Dr. Corrine Welt, Dr. Thomas Forsthuber, and Dr. Amy Arnold, countered that Petitioner did not meet the diagnostic criteria for POI, citing normal hormone levels and the absence of clear autoimmune markers. Dr. Welt noted Petitioner's menstrual irregularities coincided with weight loss and that her hormone levels were normal. Dr. Forsthuber stated there was no reliable evidence for POI or an immune insult to Petitioner's ovaries, and he disputed the molecular mimicry theory's applicability. Dr. Arnold, an expert in POTS, concluded that Petitioner did not meet the diagnostic criteria for POTS, attributing her symptoms to EDS, and found no evidence linking POTS to autoimmunity or the HPV vaccine. The Special Master reviewed the evidence and expert testimony. Regarding POI, the Special Master found that Petitioner failed to present preponderant evidence that she suffered from POI, noting inconsistencies in her hormone levels and the lack of clear autoimmune indicators. The Special Master also found that Petitioner's expert, Dr. Axelrod, failed to establish a viable causation theory for POI, particularly concerning his new focus on AMH antibodies and the flu vaccine, and that his arguments were insufficient. Regarding POTS, the Special Master found that Petitioner did not establish a viable causation theory, noting the lack of a distinct biological mechanism for POTS separate from the POI theory and the inconsistent diagnoses from treating physicians. The Special Master also found that the temporal relationship between the vaccination and the alleged POTS onset was too remote. Ultimately, the Special Master dismissed the case, finding that Petitioner did not meet her burden of proof for entitlement to compensation for either POI or POTS. The decision was issued by Special Master Herbrina Sanders. Theory of causation field: Petitioner Grace Drummond, vaccinated with the HPV vaccine on July 22, 2013, and October 23, 2013, alleged that these vaccinations caused her to develop Premature Ovarian Insufficiency (POI) and Postural Orthostatic Tachycardia Syndrome (POTS). Petitioner's experts, Drs. Felice Gersh and David Axelrod, proposed an "off-Table" theory of causation based on molecular mimicry, suggesting that peptides in the HPV vaccine mimicked ovarian proteins, triggering an autoimmune response leading to POI. Dr. Axelrod also linked POTS to the HPV vaccine via molecular mimicry and noted an association with Petitioner's Ehlers-Danlos Syndrome (EDS). Respondent's experts, Drs. Corrine Welt, Thomas Forsthuber, and Amy Arnold, contested the diagnoses and causation theories, arguing against an autoimmune etiology for POI and POTS and questioning the molecular mimicry mechanism. The Special Master, Herbrina Sanders, found that Petitioner failed to establish by preponderant evidence that she suffered from POI, citing inconsistent hormone levels and lack of autoimmune indicators. The Special Master also found that Petitioner did not establish a viable causation theory for POTS, particularly regarding an autoimmune etiology or a proximate temporal relationship to the vaccination. Consequently, the case was dismissed for failure to meet the burden of proof for entitlement. Public staged source text: ================================================================================ DOCUMENT 1: USCOURTS-cofc-1_16-vv-00702-0 Date issued/filed: 2021-10-20 Pages: 24 Docket text: PUBLIC ORDER/RULING (Originally filed: 08/30/2021) regarding 86 Findings of Fact & Conclusions of Law. Signed by Special Master Herbrina Sanders. (rig) Service on parties made. -------------------------------------------------------------------------------- Case 1:16-vv-00702-UNJ Document 87 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 1:16-vv-00702-UNJ Document 87 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 1:16-vv-00702-UNJ Document 87 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 1:16-vv-00702-UNJ Document 87 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 1:16-vv-00702-UNJ Document 87 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 1:16-vv-00702-UNJ Document 87 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 1:16-vv-00702-UNJ Document 87 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 1:16-vv-00702-UNJ Document 87 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 1:16-vv-00702-UNJ Document 87 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 1:16-vv-00702-UNJ Document 87 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 1:16-vv-00702-UNJ Document 87 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 1:16-vv-00702-UNJ Document 87 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 1:16-vv-00702-UNJ Document 87 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 1:16-vv-00702-UNJ Document 87 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 1:16-vv-00702-UNJ Document 87 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 1:16-vv-00702-UNJ Document 87 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 1:16-vv-00702-UNJ Document 87 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 1:16-vv-00702-UNJ Document 87 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 1:16-vv-00702-UNJ Document 87 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 1:16-vv-00702-UNJ Document 87 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 1:16-vv-00702-UNJ Document 87 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 1:16-vv-00702-UNJ Document 87 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 1:16-vv-00702-UNJ Document 87 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 1:16-vv-00702-UNJ Document 87 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 2: USCOURTS-cofc-1_16-vv-00702-1 Date issued/filed: 2023-04-21 Pages: 47 Docket text: PUBLIC DECISION (Originally filed: 03/31/2023) regarding 111 DECISION of Special Master. Signed by Special Master Herbrina Sanders. (arm) Service on parties made. -------------------------------------------------------------------------------- Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 1 of 47 In the United States Court of Federal Claims OFFICE OF SPECIAL MASTERS Filed: March 31, 2023 * * * * * * * * * * * * * * * * * * GRACE DRUMMOND, * No. 16-702v * Petitioner, * Special Master Sanders * v. * Denial of Entitlement; Human * Papillomavirus (“HPV” or “Gardasil”) SECRETARY OF HEALTH * Vaccine; Premature Ovarian Failure/ AND HUMAN SERVICES, * Primary Ovarian Insufficiency (“POF/ * POI”); Postural Orthostatic Tachycardia Respondent. * Syndrome (“POTS”) * * * * * * * * * * * * * * * * * * Mark T. Sadaka, Law Offices of Sadaka Associates, LLC, Englewood, NJ, for Petitioner. Jennifer A. Shah, United States Department of Justice, Washington, DC, for Respondent. DECISION ON ENTITLEMENT1 On June 16, 2016, Grace Drummond (“Petitioner”) filed a petition pursuant to the National Vaccine Injury Compensation Program (“Program” or “Vaccine Program”).2 42 U.S.C. § 300aa- 10 to 34 (2012). Pet. at 1, ECF No. 1. Petitioner alleges that she received human papillomavirus (“HPV” or “Gardasil”) vaccinations on July 22, 2013, and October 23, 2013, and that these vaccines resulted in “postural orthostatic tachycardia syndrome (“POTS”),3 and diminishing ovarian failure/insufficiency,4 which were caused-in-fact by the above-stated vaccinations.” Id. 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 redact 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, I agree that the identified material fits within the requirements of that provision, such material will be withheld from public access. 2 National Childhood Vaccine Injury Act of 1986, Pub.L. No. 99–660, 100 Stat. 3755. 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 Postural orthostatic tachycardia syndrome (“POTS”) is “a group of symptoms (not including hypotension) that sometimes occur when a person assumes an upright position, including tachycardia, tremulousness, lightheadedness, sweating, and hyperventilation; this is seen more often in women than in men, and the etiology is uncertain.” Dorland’s Illustrated Medical Dictionary 1, 1844 (32nd ed. 2012) [hereinafter “Dorland’s”]. 4 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 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 2 of 47 On August 30, 2021, I issued a Ruling for this case and seven other petitioners who had “consolidated their claims for the purpose of determining whether they have presented a sufficient causation theory,” pursuant to Althen prong one. See Findings of Fact and Conclusions of Law (“Findings of Fact”) at 24, ECF No. 86; 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. On September 21, 2022, Petitioner filed a supplemental expert report that “provided a theory of causation, based on molecular mimicry for [Petitioner’s] amenorrhea, [POI,] and [POTS], related to her vaccinations of July 22, 2013, and October 23, 2013.” Pet’r’s Ex. 126 at 22, ECF No. 103-1. Respondent responded with three expert reports filed on November 27, 2022, and November 28, 2022. Resp’t’s Exs. M, N, P, ECF Nos. 107–08, 110. Petitioner’s specific entitlement claim, in light of my August 30, 2021 Ruling, and the evidence submitted pursuant to Althen prongs two and three, is now ripe for consideration. For the reasons stated below, Petitioner’s case is hereby DISMISSED. I. Procedural History Petitioner was among a group over the past several years that have filed claims alleging that they suffered POI due to HPV vaccinations. See, e.g., 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). Those cases were all contested by Respondent, who argued that many of the claims were barred from entitlement because the statute of limitations had run. Culligan, 2016 WL 3101981, at *3. The special master presiding over the cases at that time determined that case timeliness would depend on the onset of each petitioner’s POI symptoms. Id. Prior to the filing of this case, “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.” Id. A consolidated hearing regarding the issue of onset of POI was held in June of 2015. Id. at *5. The lead case, Culligan, was dismissed as untimely, but many trailing cases were allowed to continue. See id. On June 16, 2016, Petitioner filed her petition. Pet. at 1. She filed medical records on July 11, 2016. Pet’r’s Exs. 1–5, 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 filed additional medical records on September 28, October 6, and November 21, 2016. Pet’r’s Exs. 6–15, ECF Nos. 15–16, 19. The presiding special master held a status conference on December 1, 2016, regarding how to proceed with the remaining consolidated and newly filed POI cases. Min. Entry, docketed Dec. 1, 2016. Following the conference, in addition to agreeing that all of the POI petitioners would submit outstanding medical records, the parties agreed that they would file expert reports. Sched. Order, ECF No. 22. The parties also indicated that they would explore how to further proceed once expert reports were filed. Id. or woman under 40 years of age. It may be temporary or permanent.” Dorland’s at 945. I will refer to POF and POI interchangeably throughout this Decision. 2 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 3 of 47 Petitioner submitted additional medical records on December 15 and 20, 2016. Pet’r’s Exs. 16–19, ECF Nos. 23–24. This case was reassigned to me on January 9, 2017. ECF No. 27. Petitioner filed medical records and a statement of completion on January 24, 2017. Pet’r’s Exs. 20–21, ECF Nos. 28–29. On June 14, 2017, Petitioner filed, and I granted, a motion to substitute in a new attorney. ECF Nos. 34–35. On August 2, 2017, Petitioner filed expert reports from Drs. Felice Gersh and Yehuda Shoenfeld. See Pet’r’s Exs. 22–25, ECF No. 37. On September 26, 2017, and January 3, 2018, Petitioner filed supporting medical literature. Pet’r’s Exs. 26–84, ECF Nos. 39–45, 47. The expert report authored by Dr. Shoenfeld was filed in support of each of the POI petitioners’ cases and did not discuss case-specific information. See Pet’r’s Ex. 25, ECF No. 37-4. Dr. Gersh’s report was case-specific. See Pet’r’s Ex. 23, ECF No. 37-2. 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 POI petitioners presented the same causation theory in each of the consolidated cases. Min. Entry, docketed Aug. 15, 2017; Sched. Order, ECF No. 38. I ordered Respondent to produce an expert report in accordance with his suggestion. Sched. Order at 1. Respondent filed expert reports and curricula vitae from Drs. Thomas Forsthuber, David Frankfurter, and Robert Yokel, as well as accompanying medical literature, on May 14, 2018. Resp’t’s Exs. A, A.1–A.31, B–F, ECF Nos. 50–55. Respondent filed additional medical literature on compact discs on June 18, 2018. Resp’t’s Exs. D, D Tabs 1–47, E Tabs 1–47, ECF Nos. 56–57. On September 11, 2018, Petitioner filed responsive supplemental expert reports from Drs. Pinhas-Hamiel and Shoenfeld. Pet’r’s Exs. 85–86, ECF No. 59. Petitioner filed an additional piece of medical literature on October 17, 2018. Pet’r’s Ex. 87, ECF No. 60. On November 12, 2018, Petitioner filed a motion to substitute in a new attorney, which I granted on November 13, 2018. See ECF No. 61. Respondent filed responsive supplemental expert reports from Drs. Forsthuber, Frankfurter, and Yokel on November 19, 2018. Resp’t’s Exs. G–I, ECF No. 62. On December 6, 2018, Petitioner filed a motion to substitute in Petitioner’s current attorney, which I granted following a status conference on December 18, 2018. See ECF No. 63; see also Min. Entry, docketed Dec. 18, 2018. Respondent filed additional medical literature on a compact disc on December 10, 2018. Resp’t’s Exs. D Tabs 2–3, G Tabs 1–3, H Tabs 1–23, I Tabs 1–2, ECF No. 64. On March 21, 2019, Respondent submitted an additional piece of medical literature. Resp’t’s Ex. J, ECF No. 69. Petitioner filed an additional expert report from Dr. Shoenfeld on May 6, 2019, and medical literature the next day. Pet’r’s Exs. 88–110, ECF Nos. 70–71. Respondent then filed medical literature on September 27, 2019. Resp’t’s Exs. K Tabs 1–9, ECF No. 75. The next day, Respondent filed an additional expert report from Dr. Frankfurter, along with medical literature. Resp’t’s Exs. L, L Tabs 1–19, ECF No. 77. Petitioner submitted additional medical literature on October 1, 2019. Pet’r’s Exs. 111–112, ECF No. 78. Respondent filed a corrected version of Dr. Forsthuber’s supplemental report on October 8, 2019. Resp’t’s Ex. K, ECF No. 81. I held a status conference with the parties in the remaining eight consolidated POI cases on December 6, 2019. Min. Entry, docketed Dec. 6, 2019; Sched. Order at 1, ECF No. 82. Although 3 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 4 of 47 the facts in each case varied, the causation theory asserted was the same, and the same experts were used. Sched. Order at 1. Consequently, I proceeded to evaluate the “viability of the causation mechanism [that had been submitted in] all of these claims,” pursuant to Althen prong one. Id. There was no objection from any of the parties. Id. The parties also agreed that the facts from one case could be used for context. Id. The Brayboy case, No. 15-183V, was ultimately selected as the lead case. See id. To that end, the POI petitioners again agreed to file HIPPA waivers and share medical records. Id. Petitioner filed her health information disclosure authorization on February 28, 2020. Pet’r’s Ex. 113, ECF No. 84. On August 30, 2021, I issued a Ruling on Althen prong one in all eight consolidated cases, including Petitioner’s. Findings of Fact, ECF No. 86. During a status conference held on December 14, 2021, Petitioner asserted her belief that she would be able to satisfy the factors outlined in my August 30, 2021 Ruling. See Min. Entry, docketed Dec. 14, 2021; see also Sched. Order at 1, ECF No. 88. She expressed her intention to continue the prosecution of her case and file additional medical records. Sched. Order at 1. Petitioner filed an additional medical record and a status report reiterating her intention to proceed on March 15, 2022. Pet’r’s Ex. 114, ECF Nos. 91–92. She submitted medical records on April 11, 2022, and August 22, 2022. Pet’r’s Exs. 115–125, ECF Nos. 93, 102. Approximately one month later, Petitioner filed an expert report from Dr. David Axelrod regarding Althen prongs two and three and additional medical literature. Pet’r’s Exs. 126– 164, ECF Nos. 103–04. Respondent filed two responsive expert reports from Drs. Corrine Welt and Thomas Forsthuber, curricula vitae, and accompanying literature on November 27, 2022. Resp’t’s Exs. M, M Tabs 1–13, O, O Tabs 1–9, N, ECF Nos. 107–09. The following day, Respondent submitted a third report from Dr. Amy Arnold, with an accompanying curriculum vitae and literature. Resp’t’s Exs. P, P Tabs 1–17, Q, ECF No. 110. II. Evidence a. Medical History Petitioner is a fraternal twin, born premature at 34 weeks and 3 days on September 16, 1997. See, e.g., Pet’r’s Ex. 23 at 1. Her relevant pre-vaccination history includes headaches, rashes, and musculoskeletal symptoms since 2009. Pet’r’s Ex. 3a at 2–5, ECF No. 7-7. Her musculoskeletal symptoms included joint pain and stiffness, a left elbow injury, and multiple joint hypermobility. Pet’r’s Ex. 8b at 914–15, ECF No. 19-2. A medical record dated June 24, 2010, notes an adverse skin reaction (urticaria)5 to the varicella vaccine and an amoxicillin allergy. Id. at 915. Petitioner was thirteen years old at the time she began menstruating. See, e.g., Resp’t’s Ex. M at 6, ECF No. 107-1. Petitioner was seen on February 19, 2013, for symptoms of fatigue, intermittent petechiae,6 and elevated anti-nuclear antibodies (“ANAs”).7 Pet’r’s Ex. 3a at 64. Her 5 Urticaria is “a vascular reaction in the upper dermis, usually transient, consisting of localized edema caused by dilatation and increased capillary permeability . . . called also hives.” Dorland’s at 2011. 6 A petechia is “a pinpoint, nonraised, perfectly round, purplish red spot caused by intradermal or submucous hemorrhage.” Dorland’s at 1422. 7 Anti-nuclear 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 4 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 5 of 47 family history is significant for adverse vaccine reactions by her twin brother. See, e.g., Pet’r’s Ex. 4b at 137, ECF No. 8-3. He suffered from joint swelling, syncope,8 bradycardia,9 and hypotension.10 Id. Petitioner’s mother also reported adverse reactions to vaccines and hypermobile joints. Pet’r’s Ex. 11 at 3, ECF No. 19-5. At approximately age sixteen, Petitioner received her first HPV vaccination on July 22, 2013, and her second dose on October 23, 2013, along with an influenza (“flu”) vaccine. Pet’r’s Ex. 3a at 1.11 On October 29, 2013, Petitioner was seen by her dermatologist with complaints of “scaly depigmented patches on [her] arm and face[.]” Pet’r’s Ex. 2a at 5, ECF No. 7-2. The patches were first reported by Petitioner’s mother via email in MyChart on October 15, 2013. Id. at 2. By November 23, 2013, Petitioner was experiencing irregular menses. Pet’r’s Ex. 3c at 238, ECF No. 7-9. Labs from that date showed normal follicular stimulating hormone (“FSH”)12 and luteinizing hormone (“LH”)13 levels. Pet’r’s Ex. 3a at 90. Petitioner’s Anti-Müllerian Hormone (“AMH”)14 was within normal range, but low, and her thyroid peroxidase and thyroglobulin antibody levels were normal. Id. Labs also showed normal estradiol and estrogen 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. 8 Syncope is “a temporary suspension of consciousness due to generalized cerebral ischemia; called also faint[ing].” Dorland’s at 1818. 9 Bradycardia is “slowness of the heartbeat, as evidenced by slowing of the pulse rate to less than 60.” Dorland’s at 245. 10 Hypotension is an “abnormally low blood pressure; seen in shock but not necessarily indicative of it.” Dorland’s at 906. 11 Petitioner also received a flu vaccine on February 7, 2013, before her first and second doses of HPV. Pet’r’s Ex. 3a at 2. 12 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. A normal FSH level for a woman still menstruating is approximately 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 Mar. 7, 2023). 13 LH levels were not measured as consistently as FSH, AMH, and estradiol (“E2”). On November 23, 2013, her levels measured within normal range at 5.9 IU/mL. Pet’r’s Ex. 3c at 46. 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. 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 Mar. 7, 2023). 14 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. 5 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 6 of 47 levels. Pet’r’s Ex. 2a at 82. Petitioner’s 21-hydroxylase antibodies15 were negative/undetectable. Id. Her treater’s impressions by December 6, 2013, included joint mobility consistent with Ehlers- Danlos type III (“EDS”)16 and post-HPV amenorrhea,17 for which Petitioner was “undergoing further evaluation.” Pet’r’s Ex. 3a at 91. Petitioner tested negative for ANAs and anti-ovarian antibodies on December 7, 2013. Pet’r’s Ex. 3c at 82–83, 88. Her C3 levels18 were low. Id. at 84. A pelvic ultrasound on December 11, 2013, yielded normal results. Pet’r’s Ex. 3d at 74, ECF No. 8-1. On December 30, 2013, Petitioner had a follow-up regarding “coloring/duskiness” and splotches on her face. Pet’r’s Ex. 2a at 9. The record from that visit also noted her brother’s “recent joint swelling [and antistreptolysin O titer (“ASO”)]19 of 800.” Id. Petitioner’s ASO screen and Lyme disease20 titers were negative. Id. Petitioner also described stomach pains. Pet’r’s Ex. 3a at 94. Petitioner’s treater Dr. Joanne Taylor noted concerns that since Petitioner’s first HPV vaccine, she “has had no further menses.” Id. at 96. Dr. Taylor noted Petitioner’s history of “significant reactions to vaccines in the past[,] as has her twin.” Id. Petitioner was referred to “Dr. [Christine] Virnig for [an] immunology work[-]up secondary to concerns of [an] immune process or auto immune [sic] process being a factor in causing [Petitioner’s] amenorrhea and possible ovarian failure.” Id. On December 24, 2013, Petitioner engaged in a phone consultation for potential patients with the Colorado Center for Reproductive Medicine. Pet’r’s Ex. 16 at 27, ECF No. 23-1. She reported that “[a]fter her vaccine, she had a light period in August [of 2013], spotting in September [of 2013], with subsequently only one to two days of spotting in October and November [of 2013]. 15 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. 16 Ehlers-Danlos type III or Ehlers-Danlos syndrome is “a group of inherited disorders of connective tissue; formerly subdivided into ten numbered types, they have been reclassified into six descriptive types. Prominent manifestations include hyperextensible skin and joints, easy bruisability, and friability of tissues with bleeding and poor wound healing, with additional symptoms specific for individual types.” Dorland’s at 1828. 17 Amenorrhea is the absence or abnormal stoppage of the menses. Dorland’s at 59. 18 C3 proteins are part of the complement system, which is part of the immune system, and protect the body from infection and illness. Dorland’s at 393. Low levels of C3 in the blood can be signs of an autoimmune disease or a recurring bacterial infection. See id.; see also C3 Complement Blood Test, CLEVELAND CLINIC https://my.clevelandclinic.org/health/diagnostics/22138-c3-complement-blood-test (last visited Mar. 7, 2023). 19 An antistreptolysin O titer (“ASO”) is “an antibody that inhibits streptolysin.” Dorland’s at 109. Streptolysin is “an exotoxin produced by certain strains of streptococci[.]” Id. at 1783. 20 Lyme disease is “a recurrent, multisystemic disorder caused by the spirochete Borrelia burgdorferi; vectors for human infection are the ticks Ixodes scapularis and I. pacificus. It begins in most cases with erythema chronicum migrans (at least 5 cm in diameter), often accompanied by fatigue, malaise, chills, fever, headache, and regional lymphadenopathy, followed after several weeks or months by highly variable manifestations that may include musculoskeletal pain, involvement of the heart and the nervous system, and conjunctivitis and other eye abnormalities. Persistent infection, which may last for months or years, is characterized by arthritis of large joints and, in some cases, neurologic manifestations, including chronic axonal polyneuropathy, ataxia, and spastic paraparesis.” Dorland’s at 538. 6 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 7 of 47 Her last full menses was in July [of 2013].” Id. at 28. Petitioner was concerned about premature ovarian failure and wanted to “explore future fertility preservation through oocyte vitrification.” Id. at 27. Petitioner was cautioned that the phone consultation “[wa]s in no way to be considered medical care or the dispersion of medical advice.” Id. Petitioner was assessed with POI, and a possible association with the HPV vaccines was noted. Id. at 28. Petitioner was seen by Dr. Joanne Kriege on January 17, 2014, who noted that Petitioner “had post[-]HPV amenorrhea.” Pet’r’s Ex. 3a at 99. Dr. Kriege also recorded “joint hypermobility consistent with Ehlers-Danlos type III[ but noted Petitioner] does not have signs on exam or on lab of a systemic autoimmune disease.” Id. During a phone called placed on January 27, 2014, Petitioner’s mother reported to Dr. Taylor concerns that Petitioner “has [symptoms] related to vaccines she got in 2013[, including headache], weight loss, paresthesias, fingers turning blue, difficulty thinking[, worsening grades], fatigue and increased sleeping[,] and decreased [blood pressure].” Pet’r’s Ex. 2a at 11. Neurologist Dr. Meredith Schultz subsequently examined Petitioner on February 7, 2014, for complaints of difficulties concentrating, headaches, and tingling in her extremities. Pet’r’s Ex. 3b at 105, ECF No. 7-8. Dr. Schultz noted “several episodes of parasthesias [sic] in her feet and also a Reynaud [sic] type21 reaction in her hands and feet,” but Dr. Schultz did not suspect “that there is any underlying neurologic damage related to vaccines.” Id. at 108. A pelvic ultrasound on February 10, 2014, showed that Petitioner’s right ovary measured 2.2 cm x 1.3 cm x 1.9 cm and her left ovary measured 3.1 cm x 1.9 cm x. 2.9 cm, both within normal range. Id. at 144. There were multiple follicles seen within both ovaries with no suspicious growths or significant fluid accumulation. Id. On February 26, 2014, Dr. Christine Seroogy from the Pediatric Immunology Clinic examined Petitioner “to see if a unifying diagnosis or insight into her medical problems can be provided from an immunologic perspective.” Pet’r’s Ex. 15 at 27, ECF No. 19-9. Dr. Seroogy noted Petitioner’s “[h]istory of reactions to vaccinations[.]” Id. at 29. She noted that Petitioner “has amenorrhea that temporally is correlated with receiving HPV and the influenza vaccine[; h]owever, the underlying mechanism of this remains unclear.” Id. Dr. Seroogy continued that Petitioner’s “estrogen levels ha[d] been normal and follicles were visualized on [her] transabdominal ultrasound.” Id. Additionally, Petitioner “has no clinical or laboratory evidence of autoimmune-mediated ovarian failure or other autoimmune endocrine problems.” Id. at 30. Dr. Seroogy referenced Petitioner’s negative testing for anti-21 hydroxylase antibodies, thyroid antigen autoantibodies, and normal LH, FSH, and estradiol levels. Id. at 28. She opined that “[t]here is no medical evidence to support a causal relationship between vaccinations and POI,” and she found none in Petitioner’s case. Id. at 29. Petitioner was seen by Dr. Gisela Chelimsky at the Children’s Hospital of Wisconsin Autonomic Reflex Laboratory on May 12, 2014. Pet’r’s Ex. 4a at 26, ECF No. 8-2. The listed history recorded “Ehlers-[D]anlos with recent development of multiple medical issues/sympttoms [sic].” Id. Dr. G. Chelimsky noted that Petitioner’s mother believed Petitioner’s amenorrhea stemmed from the HPV vaccine. Id. Dr. G. Chelimsky documented symptoms of dysautonomia in Petitioner’s record from this visit, including instances “where her heart rate will drop very low for 21 Raynaud’s phenomenon is “intermittent bilateral ischemia of the fingers, toes, and sometimes ears and nose, with severe pallor and often paresthesias and pain[.]” Dorland’s at 1430. 7 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 8 of 47 several hours[,]” randomly dilated pupils, and brain fog. Id. Petitioner underwent a tilt test,22 which was mildly abnormal. Id. at 28–31. Dr. G. Chelimsky recorded, “1) a pre-syncopal episode; 2) no evidence of postural tachycardia syndrome; 3) normal cardiac sympathetic and parasympathetic function; [and] 4) no evidence of an autonomic neuropathy.” Id. at 31. Dr. Thomas Chelimsky, also with Children’s Hospital of Wisconsin’s Autonomic Reflex Laboratory, saw Petitioner on August 5, 2014. Id. at 83. Dr. T. Chelimsky noted Petitioner’s past diagnoses including hypermobility syndrome, dizziness, elbow dysplasia, and chronic constipation. Id. at 85. He wrote that Petitioner presented with “post HPV vaccine near syncope and migraine with POTS by [autonomic nervous system (“ANS”)] testing.” Id. at 86. Dr. T. Chelimsky found that “[t]he salient feature of her presentation appears to be excessive lability of many vegetative processes, including heart rate, estrogen levels (by history)[,] and weight.” Id. He noted his impression that this was “some type of central autonomic instability[, but he was n]ot sure if this [wa]s lesion[-]based or perhaps an auto-immune [sic] process?” Id. Petitioner was diagnosed with POTS, syncope, and variant migraines. Id. A note from a telephone encounter between Petitioner’s mother and both Drs. G. and T. Chelimsky from August 11, 2014, showed Petitioner “had several unusual symptoms this past week, including [approximately] 48 [hours] of twitching of her right arm, left eyelid[,] and lower lip,” as well as a “severe restless legs” feeling in her entire body, which “kept her awake for most of the night.” Pet’r’s Ex. 4b at 137. Petitioner’s mother continued that “[t]wo days later[,]” she had “a more pronounced episode of pallor, duskiness of [her] face, lips, and hands, [and] dizziness,” followed by feeling “out of it[,]” cold in 70–80 degree Fahrenheit weather, sensitivity to sound and light, brain fog, fatigue, and increased irritability. Id. Dr. Paul Reber performed an endocrinology evaluation on August 26, 2014, due to Petitioner’s reduction in menses, orthostasis,23 and 17-pound weight loss from May to December of 2013. Pet’r’s Ex. 3b at 142. An anti-ovarian antibody test was negative. Id. at 143. Petitioner reported suffering from headaches, lightheadedness, and nausea. Id. at 142. An assessment included “reduced menses, orthostatic hypotension, and unintentional weight loss [in a 16-year- old] with a history of joint hypermobility/possible Ehlers[-]Danlos type III.” Id. at 145. Dr. Reber noted “that [Petitioner] ha[d] regained her weight,” but indicated a “till [sic] table test [was] consistent with autonomic dysfunction/POTS.” Id. at 144–45. Petitioner continued to complain of dysautonomia symptoms through 2014 and 2015, including an irregular heartrate, Pet’r’s Ex. 2b at 2, ECF No. 7-3; bradycardia with a drop in blood pressure, Pet’r’s Ex. 4b at 192; and “dizziness, pallor/duskiness, [and] simultaneous low pulse and [blood pressure].” Pet’r’s Ex. 2c at 194, ECF No. 7-4. On May 29, 2015, Petitioner returned to Dr. Kriege for a follow-up. Pet’r’s Ex. 3b at 168. She noted Petitioner had “post-HPV amenorrhea – now improved.” Id. Dr. Kriege indicated that 22 A tilt test is the “measurement of various bodily responses while the patient is tilted to different angles on a tilt table, usually head up, such as monitoring of circulatory, cardiac, and neurologic responses.” Dorland’s at 1901. 23 Orthostasis or orthostatic hypotension refers to “a fall in blood pressure associated with dizziness, blurred vision, and sometimes syncope, occurring upon standing or when standing motionless in a fixed position; it can be acquired or idiopathic, transient or chronic, and may occur alone or secondary to a disorder of the central nervous system.” Dorland’s at 906. 8 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 9 of 47 Petitioner was experiencing regular menses with low AMH levels, subject to monitoring. Id. at 169. Dr. Kriege did not see “signs on exam or lab of a systemic autoimmune disease.” Id. Petitioner’s labs from June 1, 2015, showed that “all antibody labs ha[d] returned negative (including anti-ovarian), which [sic] exception of mildly elevated ANA (very nonspecific).” Pet’r’s Ex. 2d at 36, ECF No. 7-5. Her growth hormone and thyroid labs were normal. Id. Petitioner’s AMH was normal at 1.4, along with her T4 Free, thyroid stimulating hormone, and complete blood count levels. Pet’r’s Ex. 3d at 48–51. Her 21-hydroxylase, thyroid peroxidase, and thyroglobulin antibodies were also negative. Id. at 58, 63–64. A pelvic ultrasound performed the same day showed Petitioner’s right ovary measured 2.1 x 1.5 x 1.8 cm and her left ovary measured 2.0 x 1.8 x 1.6 cm. Pet’r’s Ex. 3b at 73. A June 3, 2015 note from Petitioner’s mother to Dr. Reber reports that Petitioner had a “weakly positive [ANA] (1.5), which we know is nonspecific.” Pet’r’s Ex. 2c at 58, 61; Pet’r’s Ex. 3d at 54. Reproductive specialist Dr. David Olive wrote a letter, dated June 19, 2015, expressing “considerable concern that [Petitioner’s decreased ovarian reserve] may progress to primary ovarian insufficiency.” Pet’r’s Ex. 7 at 1, ECF No. 16-1. Petitioner had sought out Dr. Olive for information regarding egg retrieval. Id. A July 14, 2015 medical record, signed by Dr. Minjarez from the Colorado Center for Reproductive Medicine, stated that Petitioner had progressed to POI. Pet’r’s Ex. 16 at 20. The record also noted, however, that Petitioner’s 2013 AMH levels had improved over the last two years, and as of June 11, 2015, Petitioner’s “cycles ha[d] returned regularly, every 26–27 days.” Id. at 21, 25. The record continued that Petitioner “ha[d] been evaluated by neurology, rheumatology, and hematology with no definitive diagnosis.” Id. at 25. Petitioner continued regular testing for evidence of autoimmune disease throughout 2015 and 2016. Testing for anti-adrenal antibodies was negative on January 4, 2016. Pet’r’s Ex. 6 at 1, ECF No. 15-1. On July 18, 2016, Petitioner was seen by Dr. Don Bukstein for her “extraordinarily complex history revolving around reactions to multiple vaccines,” and “immediate concerns [of] symptoms and objective testing suggesting ovarian failure following an HPV vaccine.” Pet’r’s Ex. 19 at 1, ECF No. 24-2. Dr. Bukstein stated his belief that Petitioner’s easy bruising and petechia is a “blood vessel problem[,] secondary to a type of metabolic connective tissue disease, possible Ehlers-Danlos syndrome, type 3, rather than immunologically mediated.” Id. He did not rule out an autoimmune etiology for her ovarian problem and noted an ongoing investigation into “the possibility of ovarian antibodies or other antibodies in signaling or even causing this disorder.” Id. Dr. Bukstein advised that, “for the near future[,]” Petitioner “should NOT receive any vaccines of any sort.” Id. (emphasis in original). Approximately two years later, on June 18, 2018, Petitioner presented to St. Mary’s Hospital with complaints of vertigo24 with ataxia.25 Pet’r’s Ex. 121 at 294, ECF No. 102-6. An MRI “revealed a left cerebellar peduncle lesion (small)[,] which generated concern for [a] possible demyelinating process [versus] a small ischemic26 workup.” Id. at 296. Anticardiolipin, lupus 24 Vertigo is “an illusory sense that either the environment or one's own body is revolving; it may result from diseases of the internal ear or may be due to disturbances of the vestibular centers or pathways in the central nervous system.” Dorland’s at 2051. 25 Ataxia is “failure of muscular coordination; irregularity of muscular action.” Dorland’s at 170. 26 Ischemia generally refers to the “deficiency of blood in a part, usually due to functional constriction or actual obstruction of a blood vessel.” Dorland’s at 961. 9 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 10 of 47 anticoagulant, and beta-2 glycoprotein testing yielded negative results; and her ANA, ANCA, and complement levels were normal. Id. Neuroimmunologist Dr. Paul Robelia recommended against inpatient admission because “she did not meet criteria,” based on her improving symptoms, but he referred Petitioner to an outpatient neuroimmunology clinic for follow up. Id. Laboratory testing done on June 29, 2018, revealed anti-α-1-adrenergic and anti-muscarinic cholinergic receptor 3 antibodies. Pet’r’s Ex. 114 at 1–2, ECF No. 91-1. On June 20, 2019, Petitioner was seen for a follow-up by Dr. Matthew Raday. Pet’r’s Ex. 121 at 508. He reviewed Petitioner’s MRI images and found them to be “most consistent with an acute ischemic stroke.”27 Id. On August 28, 2019, Dr. Mary Hintermeyer at Children’s Hospital of Wisconsin evaluated Petitioner for recurrent infections. Pet’r’s Ex. 119 at 1, ECF No. 102-4. She did “not feel that [Petitioner] has an underlying immune deficiency disorder.” Id. at 10. Dr. Hintermeyer assessed Petitioner with POTS, prior Epstein-Barr virus infection,28 rhinitis,29 GERD,30 and constipation. Id. Petitioner underwent extensive lab testing on March 14, 2022, that showed she was “at risk” for anti-AT1R antibodies and anti-ETAR antibodies. Pet’r’s Ex. 115 at 1, ECF No. 93-1. Petitioner was also positive for anti-ɑ-1-adrenergic antibodies, anti-ß-1 and anti-ß-2-adrenergic antibodies, anti-muscarinic cholinergic receptor-3 and 4 antibodies, anti-TSHDS-IgM-antibodies, anti-ACE-2-antibodies, and anti-MAS1-antibodies. See id. An ovarian assessment report dated August 2, 2022, revealed normal AMH, FSH, LH, and estradiol levels, and a “good” egg retrieval score. Pet’r’s Ex. 125 at 1, ECF No. 102-10. Petitioner has not filed additional medical records. b. Petitioner’s Hormone Tests Results31 DATE FSH AMH Estradiol (reference 3.0-14.4 IU/L .7-3.5 ng/mL <84 pg/mL range)32 11.23.2013 4.9 IU/L 1.5 ng/mL 97 pg/mL 12.07.2013 1.43 ng/mL 12.27.2013 246 pg/mL 01.01.2014 1.42 ng/mL 01.13.2014 10 IU/L 82 pg/mL 02.01.2014 4.2 IU/L 1.72 ng/mL 62 pg/mL 27 An ischemic stroke is stroke syndrome caused by ischemia of an area of the brain. Dorland’s at 1786. Stroke syndrome is “a condition with sudden onset caused by acute vascular lesions of the brain, such as infarction from hemorrhage, embolism, or thrombosis, or rupturing aneurysm. It may be marked by any of a variety of symptoms reflecting the focus of infarction or hemorrhage, including hemiparesis, vertigo, numbness, aphasia, and dysarthria; it is often followed by permanent neurologic damage.” Id. at 1849. 28 Epstein-Barr is “a virus of the genus Lymphocryptovirus that causes infectious mononucleosis[.]” Dorland’s at 2061. 29 Rhinitis is “inflammation of the mucous membrane of the nose.” Dorland’s at 1639. 30 GERD (gastroesophageal reflux disease) is “any condition noted clinically or histopathologically that results from gastroesophageal reflux, ranging in seriousness from mild to life-threatening; principal characteristics are heartburn and regurgitation.” Dorland’s at 533. 31 These labs were all drawn after Petitioner’s second HPV vaccine and flu vaccine administered on October 23, 2013. 32 See Pet’r’s Ex. 7 at 6. 10 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 11 of 47 02.21.2014 4.7 IU/L 1.8 ng/mL 109 pg/mL 05.16.2014 2.6 ng/mL 11.26.2014 2.8 ng/mL 05.23.2014 1.0 ng/mL 06.01.2015 4.5 IU/L 1.4 ng/mL 31 pg/mL 06.29.2015 4.75 IU/L 1.1 ng/mL 53 pg/mL 07.14.2015 1.9 ng/mL 08.02.2022 8.49 IU/L 1.58 ng/mL 45.8 pg/mL c. Petitioner’s Status Reports On March 15, 2022, Petitioner filed a status report that indicated her intention to rely on her clinical presentation along with positive antibody testing to establish an autoimmune etiology for her POI. ECF No. 92. A June 15, 2022 status report specified that on June 29, 2018, Petitioner tested positive for anti-α-1-adrenergic and anti-muscarinic cholinergic receptor 3 antibodies. ECF No. 97 (citing Pet’r’s Ex. 114). It further specified that on March 14, 2022, Petitioner underwent additional testing, which showed positive results for eight different types of autoantibodies. Id. (citing Pet’r’s Ex. 115). III. Expert Review33 A. Petitioner’s Expert, Felice Gersh, M.D. Dr. Gersh received her medical degree from the University of Southern California School of Medicine in 1977. Pet’r’s Ex. 22 at 1, ECF No. 37-1. She completed her internship and residency in obstetrics and gynecology at Kaiser Hospital in Hollywood, California in 1981. Id. Dr. Gersh then completed a fellowship in integrative medicine at the University of Arizona in 2012. Id. She has worked in private practice and as the medical director for the Integrative Medical Group of Irvine since 1981. Id. at 2. Her prior experience also includes serving as an assistant clinical professor at the University of Southern California. Id. at 3. Dr. Gersh is board certified in obstetrics and gynecology. Id. at 1. Her areas of expertise include polycystic ovary syndrome, endometriosis, uterine fibroids, menstrual irregularity, and the effects of environmental toxins on female reproductive and gynecological health. Id. B. Petitioner’s Expert, David Axelrod, M.D. Dr. Axelrod received his medical degree from the University of Michigan Medical School in 1974. Pet’r’s Ex. 126 at 1, ECF No. 103-1. 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 33 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. 86. 11 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 12 of 47 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. He holds memberships in numerous medical societies related to allergy, immunology, and rheumatology. Pet’r’s Ex. 127 at 2, ECF No. 103-2. His curriculum vitae contains approximately twenty-seven publications and abstracts of which he is a listed author. See id. at 3–4. 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 1, ECF No. 53-3. 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. at 3. Dr. Forsthuber has been a professor of immunology in the University of Texas (“UT”) at San Antonio’s department of biology since 2005. Id. He is also an adjunct professor of pathology and of microbiology and 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 approximately eighty-five articles and four book chapters as well as numerous abstracts. Id. at 19–27, 32–41. Much of Dr. Forsthuber’s research is focused on autoimmunity and related topics. See id. 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. M at 1. 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 until 1997. Id. From there, she served on the faculty at Massachusetts General Hospital in the reproductive endocrine unit. Id. Dr. Welt has been a professor of internal medicine (endocrinology and metabolism) at the University of Utah since 2014. Id. She has served as the chief of the endocrinology, metabolism, and diabetes division at the same institution since 2019. Resp’t’s Ex. N at 1, ECF No. 109-1. Dr. Welt has held several editorial and reviewer positions on journals regarding reproduction, endocrinology, and metabolism. Id. at 2. 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 135 articles, books, book chapters, and abstracts, of which she is a listed author. Id. at 9–30. Dr. Welt’s medical focus involves ovulatory disorders in women, including POI. Resp’t’s Ex. M 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. N at 1. She has seen “over 100 women with POI” and has “identified the cause of POI in multiple women[.]” Resp’t’s Ex. M at 1. 12 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 13 of 47 E. Respondent’s Expert, Amy Arnold, Ph.D. Dr. Arnold received her doctorate degree in physiology and pharmacology from Wake Forest University in 2009. Resp’t’s Ex. Q at 1, ECF No. 110-19. She later received a master of science degree in clinical investigation from Vanderbilt University in 2014. Id. Dr. Arnold completed a fellowship at the Vanderbilt Autonomic Dysfunction Center. Resp’t’s Ex. P at 1, ECF No. 110-1. She currently serves as an associate professor in the department of neural and behavioral sciences at the Pennsylvania State University College of Medicine. Id. Dr. Arnold has published seventy-four peer-reviewed manuscripts, of which, over thirty are related to the diagnosis, pathophysiology, and treatment of cardiovascular autonomic disorders, including POTS, orthostatic hypotension, and primary autonomic failure. Id. She is on the editorial boards for Clinical Autonomic Research, Hypertension, and Autonomic Neuroscience: Basic and Clinical. Id. at 2. She has also participated in a national working group that created the 2020 Report to the National Institute of Health entitled: “Postural Orthostatic Tachycardia Syndrome: State of the Science, Clinical Care, and Research.” Id. at 1. Dr. Arnold has also received research grants to understand the prevalence of hypermobile EDS in POTS. Id. IV. Petitioner’s Expert Reports34 A. Dr. Felice Gersh Dr. Gersh provided a very brief summary of Petitioner’s medical history, which she described as “quite complicated.” Pet’r’s Ex. 23 at 1. She noted Petitioner’s EDS diagnosis, “numerous issue [sic] with her joints,” skin conditions, and numerous infections. See id. Dr. Gersh also referenced Petitioner’s family history of adverse vaccine reactions, as well as her mother’s fertility difficulties and menstrual dysfunction. Id. Despite this family history, Dr. Gersh opined that Petitioner’s ovarian dysfunction is tied to her HPV vaccination. See id. at 1–2. Post vaccination, Petitioner’s estrogen levels were measured regularly, but “varied from a high to a relatively low level.” Id. at 1. Dr. Gersh asserted that Petitioner’s AMH level was borderline low initially, [and] ultimately [became] significantly low,” as well as her antral follicle count, “indicat[ing] the development of [POI].” Id. Dr. Gersh explained that because Petitioner was born premature, she was “prone to developing abnormal microbiomes of [her] intestinal tract, which predispose[d her] to a myriad of risks involving [her] developing immune system[].” Id. at 2. Dr. Gersh concluded it is “very medically probable that the development of the ovarian insufficiency was strongly connected to the poorly developed intestinal microbiome placing her at an increased risk, with the HPV vaccine functioning as the final link in altering the immune system . . . resulting in [POI].” Id. B. Dr. David Axelrod 34 Petitioner filed expert reports authored by Drs. Yehuda Shoenfeld and Orit Pinhas-Hamiel, outlining her proposed general causation theory. Pet’r’s Exs. 23, 25. These reports were filed in eight cases consolidated for the purpose of determining whether the POI petitioners presented a sufficient causation theory pursuant to Althen prong one. My determination, contained in a Ruling issued on August 30, 2021, discussed these reports in detail. I will not re-litigate those resolved issues here, although the reports may be referenced as necessary. This Decision is specific to this Petitioner’s case and applies my findings from the general causation Ruling to the evidence presented herein on Althen prongs two and three. 13 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 14 of 47 Dr. Axelrod began his report with a list of relevant notations in Petitioner’s medical history. Pet’r’s Ex. 126 at 1–2. He noted that pre vaccination, on January 11, 2013, Petitioner “had a weakly positive [ANA]” test result. Id. at 2. He noted that on November 8, 2013 (approximately two weeks after Petitioner’s second HPV vaccine), Petitioner’s mother reported that her daughter’s menstrual cycles had become irregular in August of 2013 (the month after Petitioner’s first HPV vaccination). Id. at 3. She further reported that Petitioner’s cycles had stopped completely in October, immediately following the second HPV vaccination. Id. Dr. Axelrod acknowledged that Petitioner’s cycles began again in 2014; however, he noted her mother’s report that “they were now anovulatory.” Id. at 4 (citing Pet’r’s Ex. 3b at 105–08). He also referenced Dr. Schultz’s neurology report that indicated Petitioner’s treaters were concerned that Petitioner had EDS. Id. at 1–2. Dr. Axelrod expanded on Petitioner’s causation theory for POI. See id. at 13–16. He provided a general explanation of molecular mimicry supported by filed literature.35 Id. at 13 (citing Pet’r’s Exs. 128, 140–41, ECF Nos. 104-1, 104-13–104-14).36 He wrote that he “support[s] the molecular mimicry theory outlined therein by Dr. Shoenfeld that was shown to be sound and reliable by the Court. However, in this case, [Petitioner] has multiple positive autoantibodies and a condition, [EDS,] that deserve further comment and analysis.” Id. Dr. Axelrod acknowledged that “the optimal length for peptides to [cross-react during a molecular mimicry process] may be 8–12 amino acids,” but he argued that “Hemmer et al.37 showed that even small peptides (3–5 amino acids in length) could result in [autoimmune] responses.” Id. at 14 (citing Pet’r’s Ex. 145 at 1, ECF No. 104-18). The Hemmer et al. article aimed to examine and challenge minimal peptide length requirements “for activation of CD4+ HLA class II restricted T cells.” Pet’r’s Ex. 145 at 1. The study revealed that “shorter peptides may be sufficient in certain instances, although at much higher concentrations.” Id. at 2. The authors suggested that the study may have implications for our understanding of “the potential for cross- reactivity in the immune system.” Id. at 1. The Frankild et al.38 article was also referenced by Dr. Axelrod to argue that “amino acid similarity, not identity, is a predictive measure of cross-reactivity.” Pet’r’s Ex. 126 at 14 (citing Pet’r’s Ex. 146, ECF No. 104-19). This article is a study of cytotoxic T cell cross-reactivity, and the authors found that “seemingly distinct T cell epitopes, i.e., ones with low sequence identity, 35 A detailed review of the general mechanics of molecular mimicry will not be included in this Decision. The parties have already presented detailed arguments on the merits of molecular mimicry generally, and in these cases alleging HPV vaccine-caused POI. As I have repeatedly admonished, I will not continue to relitigate the merits of my findings on Althen prong one. I have included an abbreviated recitation of any additional arguments that the parties have presented and my consideration and analysis of said arguments where appropriate herein. 36 See, e.g., ABUL K. ABBAS et al., CELLULAR & MOLECULAR IMMUNOLOGY 1–11 (Elsevier eds., 9th ed. 2018); D. Kanduc et al., Massive peptide sharing between viral and human proteomes, 29 PEPTIDES 1755– 66 (2008); B. Trost et al., Bacterial peptides are intensively present throughout the human proteome, 1:1 SELF/NONSELF 71–74 (2010). 37 B. Hemmer et al., Minimal peptide length requirements for CD4+ T cell clones – implications for molecular mimicry and T cell survival, 12(3) INT. IMMUNOL. 375–83 (2000). 38 S. Frankild et al., Amino Acid Similarity Accounts for T Cell Cross-Reactivity and for “Holes” in the T Cell Repertoire, 3(3) PLoS ONE 1831–39 (2008). 14 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 15 of 47 are in fact more biochemically similar than expected.” Pet’r’s Ex. 146 at 1. Furthermore, the authors noted that cytotoxic T cells “have the tendency to respond mostly to peptides that do not resemble self-antigens.” Id. Dr. Axelrod opined that Petitioner “developed a protective immune reaction to her Gardasil [and flu] injections.” Pet’r’s Ex. 126 at 15. She “developed an inflammatory response consistent with both a primary adaptive immune response and a secondary adaptive immune response . . . with a clinical picture of irregular periods,” followed by amenorrhea after the second Gardasil injection. Id. This immune response was the catalyst for a molecular mimicry process that caused her to develop “blocking antibodies to her [AMH] to account for her clinical picture.” Id. at 15– 16. Dr. Axelrod focused on Petitioner’s AMH levels because AMH “regulates the number of growing follicles and their selection for ovulation.” Id. at 8. He asserted that “[AMH] levels are considered a predictor of [POI],” and “[l]ow [AMH] levels [in] women result[] in a lower number of retrievable oocytes, irrespective of [] FSH levels.” Id. In support, he filed several articles that discuss AMH in reproductive health. See id. (citing Pet’r’s Exs. 130–31, ECF Nos. 104-3–104- 4).39 The Bedenk et al.40 article, for example, is a review of the value of AMH as a predictor “in assessing the ovarian reserve, which can lead to a better efficiency of in vitro fertilization [“IVF”)] procedures.” Pet’r’s Ex. 129 at 1, ECF No. 104-2. The Xu et al.41 study focused on the “role of AMH during follicular development in vivo in nonhuman primates.” Pet’r’s Ex. 132 at 8, ECF No. 104-5. Researchers concluded that “follicle growth patterns and corresponding steroid hormone production were altered by AMH protein supplementation or [by] blocking endogenous AMH action.” Id. Dr. Axelrod identified a series of amino acid sequences in the Gardasil and influenza vaccines that contain one or more peptides found in AMH strain, P03971. Pet’r’s Ex. 126 at 14. He noted that the Tuohy and Altuntas42 article “suggest[s] that MATER [protein] and [alpha]- enolase [enzyme] are target antigens for autoimmune [POI].” Id. (citing Resp’t’s Ex. K, Tab 9 at 1, ECF No. 75-9). Dr. Axelrod also identified similarities in amino acid sequences of 3–7 conserved amino acids between these two antigens and components of Gardasil. Id. at 16. He argued that this homology is sufficient to incite a molecular mimicry cross-reaction capable of causing the development of POI. Id. at 16–17. 39 See, e.g., L. Moolhuijsen et al., Anti-Müllerian Hormone and Ovarian Reserve: Update on Assessing Ovarian Function, 105:11 J. CLIN. ENDOCRIN. & METABOL. 3361–73 (2020); A. La Marca et al., Anti- Müllerian hormone (AMH) in female reproduction: is measurement of circulating AMH a useful tool?, 64 CLIN. ENDOCRIN. 603–10 (2006). 40 J. Bedenk et al., The role of anti-Müllerian hormone (AMH) in ovarian disease and infertility, 37 J. ASSISTED REPRODUCT. & GEN. 89–100 (2020). 41 F. Xu et al., Stage-dependent actions of antimüllerian hormone in regulating granulosa cell proliferation and follicular function in the primate ovary, 1(2) F. S. SCI. 161–71 (2021). 42 V. Tuohy & C. Altuntas, Autoimmune and premature ovarian failure, 19 CURR. OPIN. OBSTET. GYNECOL. 366–69 (2007). 15 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 16 of 47 Petitioner eventually “developed a number of antibodies with reactivity to auto-antigens,” including fibroblast growth factor,43 which Dr. Axelrod asserted is associated with POTS. Id. at 12. He asserted that there is similar amino acid sequencing between fibroblast growth factor receptor 3 peptides and the L1 protein from HPV strain 6 within the Gardasil vaccine. Id. This homology is also sufficient, according to Dr. Axelrod, for a cross-reaction leading to the development of POTS. Id. at 17. After identifying homology within the peptide sequences, Dr. Axelrod applied his theory of molecular mimicry to Petitioner’s case. He argued that Petitioner “had within her immune system lymphocytes capable of reacting to her [AMH].” Id. at 16–17. He continued that Petitioner “eventually developed antibodies to autoantigens related to autoimmune [POI] and [POTS], indicating that her immune system lymphocytes are capable of reacting to her ovaries and autonomic myelinated and unmyelinated neurons.” Id. at 17. This production of antibodies “prevent[ed] her [AMH] from its physiologic function of providing ovarian follicular reserve.” Id. Citing the Kirshenbaum et al.44 article, Dr. Axelrod discussed the clinical presentation of POI and noted that “while follicular depletion might be the consequence of non-autoimmune causes, it may also be the final stage of an autoimmune disease.” Id. at 10 (citing Pet’r’s Ex. 136, ECF No. 104-9). Kirshenbaum et al. stated “that autoimmune causes of [POI] should be suspected in the presence of anti-ovarian antibodies, lymphocytic oophoritis or any associated autoimmune disorder.” Pet’r’s Ex. 136 at 2. Dr. Axelrod also cited the Komorowska45 article that cautioned, “[b]y the time a woman is diagnosed [with POI], she has [often] exhausted her follicular supply and, presumably, also the target antigen for the autoimmune attack on her ovary.” Pet’r’s Ex. 137 at 2, ECF No. 104-10. Komorowska concluded, “[t]hus, the autoimmunity causal of POI can be difficult to detect retrospectively.” Id. Dr. Axelrod argued that in these POI cases, “anti-ovarian antibodies cannot be found,” despite an autoimmune etiology. Pet’r’s Ex. 126 at 10. The Jankowska46 article relied upon by Dr. Axelrod identifies vaccination as a potential cause of POI and noted that these patients “showed low levels of [estradiol] and increased FSH and LH and specific auto-antibodies (antiovarian and antithyroid), suggesting that the HPV vaccine triggered an autoimmune response.” Pet’r’s Ex. 135 at 3, ECF No. 104-8. Dr. Axelrod referenced Petitioner’s March 17, 2022 positive antibody results, but noted that “she did not have evidence of any of the diseases associated with these autoantibodies.” Pet’r’s Ex. 126 at 10–11. He noted her consistently normal FSH, LH, and estradiol levels. Id. at 11. He also noted her progesterone levels and normal inhibin B levels. Id. He stated that “she did not suffer from hot flashes, night sweats, excessive sweating or hair loss.” Id. Dr. Axelrod opined that “it is not clear that [Petitioner] suffered from [POI].” Id. He continued, “[h]owever, given the transient loss of her menstrual periods following her first Gardasil injection, [and a sustained] loss of her menstrual 43 Fibroblast growth factor is “a family of structurally related polypeptides that act as signaling molecules [that] are involved in a wide range of biological functions, regulating cellular proliferation, survival, migration, and differentiation. Usually mitogens, they also have regulatory, morphologic, and endocrine effects.” Dorland’s at 870. 44 M. Kirshenbaum & R. Orvieto, Premature ovarian insufficiency (POI) and autoimmunity – an update appraisal, 36 J. ASSISTED REPRODUCT. & GEN. 2207–15 (2019). 45 B. Komorowska, Autoimmune premature ovarian failure, 15(4) MENOPAUSE REV. 210–14 (2016). 46 K. Jankowska, Premature Ovarian Failure, 16(2) MENOPAUSE REV. 51–56 (2017). 16 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 17 of 47 periods following her second Gardasil injection, as well as the low complement C3 level, in the face of a normal complement C4 level,”47 he argued this “suggests an immune cause to her [amenorrhea].” Id. Ultimately, Dr. Axelrod reasoned that the HPV vaccines “activated [Petitioner’s] lymphocytes, specific for her [AMH], with the production of antibodies to her [AMH], which resulted in the loss of early growing follicles and the loss of her ability to ovulate and have normal menses.” Id. at 9. He further opined that the antibodies, “blocked the interaction of [AMH] with its receptor [Anti-Müllerian Hormone receptor type 2 (“AMHRII”)] and interfered with its detection in the blood.” Id. However, the blocking antibodies “did not fix[,] complement or direct cytotoxic cells . . . to cause inflammatory damage to [Petitioner’s] ovaries.” Id. The 2018 and 2022 autoantibody results indicate to Dr. Axelrod that Petitioner “has lymphocytes with receptors to these proteins that have escaped central thymic [and potentially] peripheral selection (regulation), perhaps through exposure to peptides with similar conserved amino acids, such as the Gardasil and [i]nfluenza vaccines.” Id. at 12. Despite his initial equivocation, Dr. Axelrod ultimately found support for an autoimmune POI diagnosis in Petitioner. Id. He noted the proximity of Petitioner’s ovarian problems to, what he considered, “both a challenge and rechallenge to the Gardasil vaccinations, and given that she received an influenza vaccination ([with a likely history of exposure to influenza]), with evidence of complement activation.” Id. In Dr. Axelrod’s opinion, Petitioner’s EDS made it more likely that she suffered from POTS. Id. Dr. Axelrod noted Petitioner’s autonomic symptoms began after her first HPV vaccine. Id. He then cited the Brooks et al.48 study’s finding that not only were EDS subjects more likely than controls to suffer from autonomic dysfunction, “they were more likely to suffer from [POTS] than their controls.” Id. (citing Pet’r’s Ex. 139, ECF No. 104-12). Dr. Axelrod acknowledged that this correlation “does not prove that either [EDS] or [POTS] are autoimmune.” Id. The appropriate timeframes, identified by Dr. Axelrod, for the primary adaptive immune response and secondary adaptive response that evolves into molecular mimicry is 2–3 days and 14 days, respectively. Id. at 18 (citing Pet’r’s Ex. 128, ECF No. 104-1).49 Dr. Axelrod cited to Lawley et al.’s50 study of serum sickness, which noted that “serum sickness has long been presumed to be mediated by the formation of circulating immune complexes composed of host antibody and foreign antigenic proteins.” Pet’r’s Ex. 147 at 4–5, ECF No. 104-20. Researchers documented the 47 Complement C4 is “a key molecule in the complement system that is one of chief constituents of innate immunity for immediate recognition and elimination of invading microbes . . . . Complement C4 is the most polymorphic protein in complement system. A plethora of research data demonstrated that individuals with C4 deficiency are prone to microbial infections and autoimmune disorders.” H. Wang & M. Liu, Complement C4, Infections, and Autoimmune Disease, 12 FRONT IMMUNOL. 1–15 (2021). 48 R. Brooks et al., Prevalence of gastrointestinal, cardiovascular, autonomic and allergic manifestations in hospitalized patients with Ehlers-Danlos syndrome: a case-control study, 60 RHEUMATOL. 4272–80 (2021). 49 ABUL K. ABBAS et al., CELLULAR & MOLECULAR IMMUNOLOGY 1–11 (Elsevier eds., 9th ed. 2018). 50 T. Lawley et al., A Prospective Clinical and Immunologic Analysis of Patients with Serum Sickness, 311:22 N. ENG. J. MED. 1407–14 (2011). 17 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 18 of 47 onset of clinical signs and symptoms within 2 weeks, but as early as 8 days. Id. at 2–3. This is consistent, according to Dr. Axelrod, with the onset of Petitioner’s amenorrhea within a month of her second Gardasil injection. Pet’r’s Ex. 126 at 21. Dr. Axelrod explained that “[d]epending upon the actual time interval between the vaccination and the onset of [Petitioner’s] amenorrhea, this timing is consistent with a secondary adaptive immune response, or even a primary adaptive immune response, if she had not developed immune memory after the first Gardasil injection.” Id. Dr. Axelrod concluded by noting that his theory accounts for her amenorrhea, POI, and POTS by way of HPV and flu vaccines. Id. at 22. V. Respondent’s Expert Reports51 A. Dr. Corrine Welt Dr. Welt noted that Petitioner “had three normal FSH and estradiol levels in the [same] time frame [as her] documented irregular menses and amenorrhea.” Resp’t’s Ex. M at 6. Based on these findings, she concluded that Petitioner does not meet “the classic definition” of “4–6 months of amenorrhea with elevated FSH in the menopausal range and low estradiol[]” to meet the diagnostic criteria for POI. Id. Dr. Welt noted that Petitioner’s “medical records document that [she] had menarche at age 13 years, but do not provide information about menstrual cycle regularity in contemporaneous doctor [sic] visits.” Id. at 5. The irregularity of Petitioner’s cycles from August of 2013 through November of 2014 appears in the record “by recall, and the mother state[d] that [P]etitioner had irregular menstrual cycles starting in [August of 2013], with amenorrhea starting [in October of 2013].” Id. (citing Pet’r’s Ex. 3 at 89, 95, 108, 111). During this time, however, Dr. Welt noticed there was also weight loss documented in the medical record. Id. at 6. Dr. Welt reasoned that Petitioner’s weight fluctuations could be the cause of her menstrual irregularity.52 Id. In his report, Dr. Axelrod offered the timing of the irregularity of Petitioner’s cycles in relation to her second HPV vaccine in October of 2013 as evidence that she acquired POI post vaccination. Id. at 7 (citing Pet’r’s Ex. 126). However, Dr. Welt noted that “documentation [i]n [August of 2013] indicate[d Petitioner’s] cycles were already irregular by recall. Then, regular menstrual cycles were documented at medical visits after [February 17, 2015].” Id. Dr. Welt 51 Respondent likewise filed expert reports in the eight consolidated cases in contemplation of Althen prong one from Drs. Thomas Forsthuber, David Frankfurter, and Robert Yokel. Those reports will not be recounted herein, though they may be referenced as necessary. 52 Dr. Welt relied on several notations in the medical record that noted Petitioner’s weight fluctuations. Resp’t’s Ex. M at 6. For instance, at menarche in 2013, Petitioner’s weight was 141 lbs. On May 22, 2013, her height was listed as 5’7” and her weight was 143 lbs., making her BMI 22 kg/m2. See id. Dr. Welt then noted that there was a “dip in [Petitioner’s] weight” between ages 16 and 17, when her menstrual irregularities began. Pet’r’s Ex. 18 at 24–25. Specifically, her medical records note on January 27, 2014, that Petitioner had experienced a ten-pound weight loss, weighing 132 lbs., and her BMI was 20.5 kg/m2. Pet’r’s Ex. 16 at 26. By May of 2014, Petitioner weighed 138 lbs. and her BMI was 21.4 kg/m2. Pet’r’s Ex. 15 at 58. Dr. Welt noted that by the time her menstrual cycles returned to normal in 2015, Petitioner’s weight was increasing. Resp’t’s Ex. M at 6. Petitioner weighed 159 lbs. on July 17, 2015, and 152 lbs. on August 5, 2015. Id. (citing Pet’r’s Ex. 15 at 151, 172). Dr. Welt observed that Petitioner’s menstrual cycles were present when her BMI was > 22 kg/m2. Id. 18 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 19 of 47 contended that Dr. Axelrod’s assertions that “[Petitioner’s] disorder was acquired[] and that she developed amenorrhea after her [second] Gardasil injection ‘without resolution’ are incorrect.” Id. Dr. Welt bolstered Dr. Axelrod’s statement that “it is not clear that [Petitioner] suffered from [POI].” Id. Dr. Axelrod cited Dr. Olive’s concerns that Petitioner’s AMH levels in the lower end of the normal range meant she would progress toward POI, but Dr. Welt also noted Dr. Baker’s conclusions that “healthy girls have AMH levels in the range of [ P]etitioner[ and] that [AMH] is not used for the diagnosis of POI.” Id. Ultimately, Dr. Welt concluded that Petitioner’s “transient irregular menses and amenorrhea approximately one year [post] vaccinations,” were “coincident with weight loss.” Id. at 8. She ruled out POI due to Petitioner’s normal relevant hormone levels. Id. She opined that Petitioner’s “autoimmunity profile is not needed in the absence of a POI diagnosis, but nonetheless there is no evidence of autoimmune POI.” Id. B. Dr. Thomas G. Forsthuber Respondent filed a second report from Dr. Forsthuber that focused on the autoimmune etiology of Petitioner’s condition. See Resp’t’s Ex. O. He began with a summary of Petitioner’s medical records, including diagnoses pre and post vaccination, laboratory testing, ovarian functionality, and CellTrend assays. Id. at 1–7. Dr. Forsthuber acknowledged his “defer[ence] to the clinical expert Dr. Welt on [Petitioner’s] diagnosis of POI,” but he then noted that “[e]very antibody test for POI, adrenal, thyroid, or other autoimmune condition was negative.” Id. at 10. Dr. Forsthuber identified several points that Dr. Axelrod made in his reports for discussion. See id. He agreed with Dr. Axelrod’s recount of Petitioner’s labs and Dr. Axelrod’s “acknowledg[ment] that her inflammatory markers (i.e.[,] [C-reactive protein]) were normal.” Id. Dr. Forsthuber concluded that, “[t]aken together, Dr. Axelrod acknowledge[d] that [Petitioner] did not have laboratory[-]supported evidence of autoimmune POI or other autoimmune or inflammatory conditions.” Id. at 11. Dr. Forsthuber addressed Dr. Axelrod’s opinion that Petitioner suffered from complement activation, which “suggests an immune insult to her ovulatory physiology.” Id. at 12. Dr. Forsthuber strongly disagreed with this assessment. Id. He noted that Petitioner’s “complement of C4 was normal on [December 6, 2013,] (18 mg/dL; ref. range 15–57 mg/dL), and her complement C3 was minimally lower at 80 mg/dL (ref. range 83–193 mg/dL).” Id. Dr. Forsthuber again noted Petitioner’s negative autoantibody testing, normal erythrocyte sedimentation rate (“ESR”),53 and normal hormone levels in December of 2013. Id. He concluded that “there is absolutely no reliable evidence for POI and, even less so, for an ‘immune insult’ to [Petitioner’s] ovaries.” Id. In response to Dr. Axelrod’s reliance on AMH antibodies as evidence of autoimmune POI in Petitioner’s case, Dr. Forsthuber first noted that he had been unable to find any articles that “have reported on the presence of autoantibodies against AMH or AMH receptors in POI/POF.” 53 ESR refers to “the rate at which erythrocytes precipitate out from a well-mixed specimen of venous blood, measured by the distance the top of the column of erythrocytes falls in a given time interval under specified conditions; 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. 19 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 20 of 47 Id. at 13. He then explained that even if viable, Dr. Axelrod’s theory is inapplicable to Petitioner’s case “because [her] AMH levels [] did not correspond to her menstrual cycle irregularities.” Id. For example, Petitioner’s AMH levels tested throughout 2014, (in February (1.7 ng/ml), May (2.6 ng/ml), November (2.8 ng/ml), and December (1.8 ng/ml)), were all within the normal range of 0.9 to 9.5 ng/ml. Id. at 13–14. However, Dr. Forsthuber acknowledged that Petitioner reported breakthrough bleeding without menses and cycle irregularities in late summer and fall of 2014. Id. at 14. Dr. Forsthuber also discussed the Komorowska article54 and Dr. Axelrod’s contention that in POI patients, “the follicular supply is exhausted, including the target antigen for the autoimmune attack on the ovary.” Id. (citing Pet’r’s Ex. 137). This, Dr. Forsthuber contended, is also inconsistent with Petitioner’s presentation. Id. Petitioner’s ultrasound, “on several occasions revealed ovarian follicles. Thus, there is no evidence that an autoimmune attack on the ovaries exhausted the follicular supply.” Id. Dr. Forsthuber asserted that, as illustrated by Petitioner’s clinical presentation, “Dr. Axelrod’s own references disprove his claims.” Id. According to Dr. Forsthuber, Petitioner’s March 17, 2022 antibody testing revealed positive results, but Petitioner “did not have evidence of any of the specific diseases associated with these autoantibodies.” Id. at 15. Regarding Petitioner’s EDS diagnosis, Drs. Axelrod and Forsthuber disagreed on the significance of this condition. Id. Dr. Axelrod noted a higher prevalence of autonomic dysfunction, specifically POTS, in patients with EDS and argued that this could be evidence of Petitioner’s POTS diagnosis. Id. (citing Pet’r’s Ex. 126 at 12). Dr. Forsthuber opined that because “EDS is not an autoimmune but a genetic condition,” this diagnosis in Petitioner may be evidence of POTS with a non-autoimmune etiology. Id. Like Dr. Axelrod, Dr. Forsthuber argued the merits of a molecular mimicry mechanism for vaccine-caused POI, despite my previous Ruling. Id. at 16. He acknowledged that “Dr. Shoenfeld’s earlier-expressed causation theory has been accepted by the Court.” Id. However, he also addressed “Dr. Axelrod’s additional contentions.” Id. Dr. Forsthuber wrote that “[t]here is no evidence that rare similarities of 3-amino acid peptides that [Dr. Axelrod] alleges with his [homology] searches induced immune responses after infection with viruses or bacteria, or in particular, after [the] HPV vaccination.” Id. Dr. Forsthuber cited the Kanduc et al.55 article as evidence that “suggests that peptide motif sharing is a constant property of the viral proteomes, exclusively depending on the viral proteome length and with no relationship to other structural and/or pathogenic viral features.” Resp’t’s Ex. O, Tab 3 at 7, ECF No. 108-4. Likewise, the Trost et al.56 article noted that “about 50,000 perfect sequences, each 9 amino acids long, are shared between the 40 bacterial proteomes described [therein] and about one third of the human proteome.” Resp’t’s Ex. O, Tab 9 at 1, ECF No. 108-10. The article continued, “past and present data tend to exclude a causal mechanistic role for molecular mimicry in the genesis of autoimmunity.” Id. at 3. The authors opined that “it is difficult to reconcile the enormous number of viral and bacterial peptides disseminated throughout the human proteins with a fundamental 54 B. Komorowska, Autoimmune premature ovarian failure, 15(4) MENOPAUSE REV. 210–14 (2016). 55 D. Kanduc et al., Massive peptide sharing between viral and human proteomes, 29 PEPTIDES 1755–66 (2008). 56 B. Trost et al., Bacterial peptides are intensively present throughout the human proteome, 1:1 SELF/NONSELF 71–74 (2010). 20 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 21 of 47 role for molecular mimicry in the etiology of certain autoimmune conditions.” Id. They alternatively proposed “that the high number of bacterial sequences that are also found in the human proteome, but are not clinically relevant in terms of inducing autoimmune diseases, offers a mechanistic basis for an additional microbial immune evasion strategy.” Id. Dr. Forsthuber concluded that the significant difference in length between two of the proteins Dr. Axelrod identified as potential mimics made it “extremely unlikely that processing of these proteins would generate exactly this region of 3 amino acids for the proteins that Dr. Axelrod claims as [a] ‘molecular mimic.’” Resp’t’s Ex. O at 20. Likewise, Dr. Forsthuber argued that “it is highly unlikely that the sequences would line up exactly the same way in the MHC peptide-binding pocket and that T cells induced by the HPV L1 vaccine could induce [autoantibodies].” Id. Even in cases where similarity could be established, Dr. Forsthuber rebutted Dr. Axelrod’s assertion that “amino acid similarity, not identity, is a predictive measure of crossreactivity [sic].” Id. The Frankild et al.57 article that Dr. Axelrod cited in support of this contention is referenced by Dr. Forsthuber, who argued that “the authors show that the greater the similarity is between the viral epitopes and self-antigen epitopes, the less immunogenic these epitopes are.” Id. (citing Pet’r’s Ex. 146). Dr. Forsthuber undertook a lengthy discussion58 of Dr. Axelrod’s “misconceptions about sequence alignments, [] fundamental mistakes in how to use [the sequencing search] program, and [] misinterpretation of his [search] results[.]” See id. at 21–26. He criticized Dr. Axelrod’s misapplication of the search tool for use to compare only two proteins. Id. at 21. Dr. Forsthuber argued that Dr. Axelrod’s conclusions are “unreliable.” Id. at 26. He examined Dr. Axelrod’s evidence 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 22 (citing Pet’r’s Exs. 151–64, ECF Nos. 104- 24–104-37). “By [Dr. Forsthuber’s] count, for all except HPV18[, Dr. Axelrod] f[ound] only one region across the entire protein where three amino acids [] overlap[.]” Id. 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 26. C. Dr. Amy Arnold Dr. Arnold’s report “focus[ed] on the POTS pathophysiology and diagnosis” and ultimately concluded that “while it is clear [ P]etitioner has experienced a constellation of symptoms, both before and after her HPV vaccinations, she does not meet the diagnostic criteria 57 S. Frankild et al., Amino Acid Similarity Accounts for T Cell Cross-Reactivity and for “Holes” in the T Cell Repertoire, 3(3) PLoS ONE 1831–39 (2008). 58 Throughout this discussion, Dr. Forsthuber attacked Dr. Axelrod’s accepted sequence length reflective of a molecular mimic. Resp’t’s Ex. O at 16. He cited medical literature attempting to refute that a short chain of five to nine homologous amino acids is not sufficient to show molecular mimicry. Id. (citing Resp’t’s Ex. O, Tab 3; Resp’t’s Ex. O, Tab 9). 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 19 (citing Resp’t’s Ex. O, Tab 7, ECF No. 108-8). Dr. Forsthuber argued that Dr. Axelrod’s alleged HPV molecular mimic of 3 amino acids is “dramatically shorter” than the optimal length. Id. at 19–20. Dr. Forsthuber also took issue with Dr. Shoenfeld’s proposed 5-amino acid sequence homologies. Id. at 19. 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. 21 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 22 of 47 for POTS.” Resp’t’s Ex. P at 6. Dr. Arnold described POTS as “a heterogenous clinical disorder that is characterized by excessive increases in heart rate upon standing, in the absence of low blood pressure, and with chronic symptoms of orthostatic intolerance that are relieved by lying down.” Id. (citing Resp’t’s Ex. P, Tab 2, ECF No. 110-3; Resp’t’s Ex. P, Tab 16, ECF No. 110-17).59 She identified current consensus diagnostic criteria, including sustained heart rate increases, symptoms of orthostatic intolerance, absence of orthostatic hypotension, and absence of overt causes for sinus tachycardia.60 Id. (citing Resp’t’s Ex. P, Tab 2 at 2). Dr. Arnold noted Petitioner’s post-vaccination reports as follows: Report Date of Complaint Cite Decreased blood pressure January 2014 Pet’r’s Ex. 2a at 12 Decreased heart rate April 2014 Pet’r’s Ex. 3b at 115 Echocardiograms (normal) August 2014 Pet’r’s Ex. 121 at 39, 103, January 2016 164, 261 November 2016 August 2017 Home-based monitoring April 2014 Pet’r’s Ex. 3 at 389 (normal) August 2018 Pet’r’s Ex. 121 at 391 October 2018 Pet’r’s Ex. 119 at 12 EKGs with low and high November 2016 Pet’r’s Ex. 121 at 165, 262, heart rate September 2017 544 June 2019 According to Dr. Arnold, these are all inconsistent with a POTS diagnosis. Resp’t’s Ex. P at 6. Furthermore, Dr. Arnold asserted that Petitioner’s “autonomic function tests and orthostatic vital signs were normal post vaccination and showed no evidence of autonomic issues, including POTS.”61 Id. at 7. In support of her assessment, Dr. Arnold cited a record of autonomic testing done by Dr. G. Chelimsky on August 14, 2017, which showed “no evidence of POTS.” Id. (citing Pet’r’s Ex. 119 at 27). While acknowledging suggestions in the medical community that POTS may have an autoimmune phenotype, Dr. Arnold opined that “current scientific evidence [] does not establish the likelihood that autoimmunity is actually involved in the pathophysiology of POTS.” Id. at 8. Studies on the presence of autoantibodies to diagnose POTS have been inconsistent, with some finding elevated antibodies against adrenergic receptors, and some finding no difference between 59 A. Arnold et al., Postural tachycardia syndrome – Diagnosis, physiology, and prognosis, 215 AUTONOM. NEUROSC. 3–11 (2018); R. Sheldon et al., 2015 Heart Rhythm Society Expert Consensus Statement on the Diagnosis and Treatment of Postural Tachycardia Syndrome, Inappropriate Sinus Tachycardia, and Vasovagal Syncope, 12:6 HEART RHYTHM 41–64 (2015). 60 Sinus tachycardia is the “excessive rapidity in the action of the heart (in the sinus node); the term is usually applied to a heart rate above 100 beats per minute in an adult[.]” Dorland’s at 1867. 61 Dr. Arnold notes “[t]he only occasion on which [ P]etitioner actually met heart rate criteria for POTS was in August [of] 2018, about five years after her HPV vaccinations, and shortly after she was reported to suffer from an ischemic stroke event.” Resp’t’s Ex. P at 7. Petitioner’s vital signs returned to normal range when measured during a follow-up visit, approximately six months later. Id. 22 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 23 of 47 autoantibody concentrations in diagnosed patients and healthy controls. Id. Dr. Arnold quoted the Miglis et al.62 article in support: “adrenergic, muscarinic[,] and angiotensin receptor antibodies have not been proven to be causative or useful in confirming a diagnosis of POTS.” Id. (citing Resp’t’s Ex. P, Tab 12 at 1, ECF No. 110-13). The article questioned if “these autoantibodies, which seem ubiquitous in the serum of POTS patients, [are] a mechanistic cause of disease or rather a bystander effect of the disease process.” Resp’t’s Ex. P, Tab 12 at 1. The authors also questioned, “[i]f the autoantibodies are causative, should we expect evidence of autonomic failure due to tissue destruction at some point in the natural history of POTS, as we see in autoimmune autonomic ganglionopathy?” Id. at 2. Miglis et al. concluded that “at this time, [such antibodies] have not been proven to be causative or useful in confirming a diagnosis of POTS.” Id. at 3. POTS is Dr. Arnold’s area of expertise, but she noted “there is no evidence supporting a connection between POTS and POI.” Resp’t’s Ex. P at 8. She could not find a study that suggested such an association. See id. However, she cited the Peggs et al.63 study of gynecologic disorders in POTS patients, which noted the potential for the patients’ recall bias for other symptoms. Id. (citing Resp’t’s Ex. P, Tab 13 at 6, ECF No. 110-14). For example, POTS patients reported on a questionnaire, symptoms including increased lightheadedness during the menstrual cycle, a higher incidence of secondary amenorrhea, and a higher incidence of gynecologic abnormalities, but none of the patients had POI. See Resp’t’s Ex. P, Tab 13 at 6. Petitioner’s EDS diagnosis is not disputed by any of the experts, and Dr. Arnold hypothesized that “the constellation of symptoms described throughout [ P]etitioner’s medical records are consistent with hypermobile [EDS].” Resp’t’s Ex. P at 9. This assertion is consistent with Dr. T. Chelimsky’s statement that “[EDS] probably contributes to POTS[,]” referring to both Petitioner’s POTS and POTS in general. Id. at 10 (citing Pet’r’s Ex. 122 at 16). Dr. Arnold also cited Petitioner’s genetic counselor who, considering Petitioner’s “complex health history and maternal family history of similar features,” believed many of Petitioner’s “symptoms clinically overlap with hypermobile [EDS].” Id. (citing Pet’r’s Ex. 121 at 824). Dr. Arnold noted that EDS is a hereditary connective tissue disorder that “can also be accompanied by cardiovascular complications such as low blood pressure, vasovagal syncope, and orthostatic intolerance, including POTS.” Id. at 9 (citing Resp’t’s Ex. P, Tab 8, ECF No. 110-9).64 She wrote that causes for this comorbidity include, abnormal blood vessel physiology, “neuropathy, connective tissue laxity, adrenergic receptor hyper-responsiveness, and the use of vasoactive medications.” Id. Dr. Arnold identified several large-scale assessments of an increased incidence of POTS following the HPV vaccine when compared to unvaccinated adolescents. Id. at 10–11 (citing Resp’t’s Exs. P, Tabs 1, 3, 5, 14, ECF Nos. 110-2, 110-4, 110-6, 110-15).65 None of these authors 62 M. Miglis et al., Is postural tachycardia syndrome an autoimmune disorder? And other updates on recent autonomic research, 30 CLIN. AUTONOM. RES. 3–5 (2020). 63 K. Peggs et al., Gynecologic disorders and menstrual cycle lightheadedness in postural tachycardia syndrome, 118(3) INT. J. GYNECOL. OBSTET. 242–46 (2013). 64 A. Hakim et al., Cardiovascular Autonomic Dysfunction in Ehlers-Danlos Syndrome – Hypermobile Type, 175C AM. J. MED. GEN. 168–74 (2017). 65 J. Arana et al., Reports of Postural Orthostatic Tachycardia Syndrome After Human Papillomavirus Vaccination in the Vaccine Adverse Event Reporting System, 61 J. ADOLESC. HEALTH 577–82 (2017); A. 23 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 24 of 47 found a higher incidence of POTS in adolescents who had received the HPV vaccination. See id. The American Autonomic Society went further and asserted that the identified studies offering a dissenting opinion only show weak temporal associations, and “the small sample sizes, inherent selection biases, and lack of control populations preclude drawing any scientifically valid conclusions of causality.” See Resp’t’s Ex. P, Tab 3 at 3. There were several of Dr. Axelrod’s contentions that Dr. Arnold responded to directly in her report. Resp’t’s Ex. P at 12. Dr. Arnold attacked Dr. Axelrod’s reliance on Petitioner’s treater’s notations regarding POTS. Id. She questioned why, after finding Petitioner did not meet the diagnostic criteria for POTS on May 12, 2014, Dr. G. Chelimsky reversed course after re- evaluation on August 4, 2014, and diagnosed Petitioner with POTS. Id. Dr. Arnold opined there was “no basis for [Dr. G. Chelimsky’s] change in diagnosis, as [Petitioner’s] orthostatic vitals taken during standing at re-evaluation . . . still showed that heart rate changes did not meet diagnostic criteria for POTS at this visit.” Id. In support of her opinion, Dr. Arnold referenced Petitioner’s cardiologist Dr. McDonnell, who “indicated in 2016 that, ‘[h]er current episodes are not consistent with POTS. There is not a postural component.”’ Id. (citing Pet’r’s Ex. 121 at 40). Dr. Arnold also questioned the relevance of Dr. Axelrod’s identification of “two shared sequences between HPV strains and fibroblast growth factor receptor 3,” because Petitioner “had negative results for anti-fibroblast growth factor receptor 3 antibodies in 2018 and 2022.” Id. (citing Pet’r’s Exs. 114–15). Lastly, Dr. Arnold took issue with the proximate temporal relationship between the vaccination and the injury as outlined by Dr. Axelrod. Id. at 13. Dr. Arnold noted that Petitioner’s “cardiovascular-related symptoms were already present prior to vaccination,” and “all reports immediately following vaccination suggested . . . decreased blood pressure and heart rate . . . , which is not consistent with the increase in heart rate upon standing that clinically defines POTS.” Id. VI. Applicable Law I am resolving Petitioner’s claim on the filed record. The Vaccine Act and Rules not only contemplate but encourage special masters to decide petitions on the papers where, in the exercise of their discretion, they conclude that doing so will properly and fairly resolve the case. See 42 U.S.C. § 12(d)(2)(D); Vaccine Rule 8(d). The decision to rule on the record in lieu of hearing has been affirmed on appeal. Kreizenbeck v. Sec’y of Health & Hum. Servs., 945 F.3d 1362, 1366 (Fed. Cir. 2020); see also Hooker v. Sec’y of Health & Hum. Servs., No. 02-472V, 2016 WL 3456435, at *21 n.19 (Fed. Cl. Spec. Mstr. May 19, 2016) (citing numerous cases where special masters decided cases on the papers in lieu of hearing and those decisions were upheld). I am simply not required to hold a hearing in every case, no matter the preferences of the parties. Hovey v. Sec’y of Health & Hum. Servs., 38 Fed. Cl. 397, 402–03 (1997) (determining that the special master acted Barboi et al., Human papillomavirus (HPV) vaccine and autonomic disorders: a position statement from the American Autonomic Society, 223 AUTONOM. NEUROSC. 1–5 (2020); B. Butts et al., Human Papillomavirus Vaccine and Postural Orthostatic Tachycardia Syndrome: A Review of Current Literature, X J. CHILD NEUROL. 1–10 (2017); A. Phillips et al., Safety of Human Papillomavirus Vaccines: An Updated Review, 41 DRUG SAF. 329–46 (2018). 24 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 25 of 47 within his discretion in denying an evidentiary hearing); Burns v. Sec’y of Health & Hum. Servs., 3 F.3d 415, 417 (Fed. Cir. 1993); Murphy v. Sec’y of Health & Hum. Servs., No. 90-882V, 1991 WL 71500, at *2 (Fed. Cl. Spec. Mstr. Apr. 19, 1991). To receive compensation under the Vaccine Act, a petitioner must demonstrate either that: (1) the petitioner suffered a “Table injury” by receiving a covered vaccine and subsequently developing a listed injury within the time frame prescribed by the Vaccine Injury Table set forth at 42 U.S.C. § 300aa-14, as amended by 42 C.F.R. § 100.3; or (2) the petitioner suffered an “off- Table injury,” one not listed on the Table, as a result of his receiving a covered vaccine. See 42 U.S.C. §§ 300aa-11(c)(1)(C); Moberly v. Sec’y of Health & Hum. Servs., 592 F.3d 1315, 1321 (Fed. Cir. 2010); Capizzano v. Sec’y of Health & Hum. Servs., 440 F.3d 1317, 1319–20 (Fed. Cir. 2006). Petitioner does not allege a Table injury in this case; thus, she must prove that her injury was caused-in-fact by a Table vaccine. It is each petitioner’s burden to demonstrate by a preponderant standard that the subject of the claim actually suffers from the injury alleged to have been caused by the identified 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). Petitioner’s diagnoses are in dispute not only between the parties, but also between Petitioner’s treaters and her own experts. Although the various conditions asserted by medical professionals in this case may “present with many of the same symptoms, their underlying causes are different and require different treatments.” See Broekelschen, 618 F.3d at 1344. To decide if Petitioner is entitled to damages, “it [i]s appropriate in this case–where virtually all of the evidence on causation [i]s dependent on the diagnosis [and etiology of Petitioner’s] condition–for [me] to determine the proper diagnosis before applying the Althen test.” Id.; Althen v. Sec’y of Health & Hum. Servs., 418 F.3d 1274, 1278–79 (Fed. Cir. 2005). In the seminal case of Althen, the Federal Circuit set forth a three-pronged test used to determine whether a petitioner has established a causal link between a vaccine and the claimed injury. See 418 F.3d at 1278–79. The Althen test requires petitioners to set forth: “(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. at 1278. Each Althen prong requires a different showing. Under the first prong, a petitioner 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, 1355– 56 (Fed. Cir. 2006). To satisfy this prong, a petitioner’s “theory of causation must be supported by a ‘reputable medical or scientific explanation.’” Knudsen v. Sec’y of Health & Hum. Servs., 35 F.3d 543, 548 (Fed. Cir. 1994). This theory need only be “legally probable, not medically or scientifically certain.” Knudsen, 35 F.3d at 548. Nevertheless, “petitioners [must] proffer trustworthy testimony from experts who can find support for their theories in medical literature.” LaLonde v. Sec’y of Health & Hum. Servs., 746 F.3d 1334, 1341 (Fed. Cir. 2014). 25 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 26 of 47 The second Althen prong 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. In Program cases, contemporaneous medical records and the 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. That term has been equated to the phrase “medically-acceptable temporal relationship.” Id. 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). The explanation for what is a medically acceptable timeframe must also coincide with the theory of how the relevant vaccine can cause an injury (Althen prong one’s requirement). de Bazan, 539 F.3d at 1352; Shapiro v. Sec’y of Health & Hum. Servs., 101 Fed. Cl. 532, 542 (2011), recons. den’d 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 den’d (Fed. Cl. Dec. 3, 2013), aff’d, 773 F.3d 1239 (Fed. Cir. 2014). A petitioner who satisfies all three prongs of the Althen test has established a prima facie showing of causation. Hammitt v. Sec’y of Health & Hum. Servs., 98 Fed. Cl. 719, 726 (2011). When and if a petitioner establishes a prima facie case, the burden then shifts to the government to prove that an alternative cause, unrelated to the administration of the vaccine, was the “sole substantial factor” in causing the alleged injury. de Bazan, 539 F.3d at 1354; see also Hammitt, 98 Fed. Cl. at 726 (explaining that the respondent’s burden is to show that the “factor unrelated” was the “sole substantial factor” in causing the injury). Additionally, a factor unrelated “may not include ‘any idiopathic, unexplained, unknown, hypothetical, or undocumentable cause, factor, injury, illness or condition.’” 42 U.S.C. § 300aa-13(a)(2). VII. Analysis A. Expert Reports My August 30, 2021 Ruling was based on the proposed biological mechanism and the expert reports submitted up to that time. See generally Findings of Fact; Brayboy, 2021 WL 4453146. I found that “[the POI p]etitioners have articulated a sound and reliable theory of how HPV vaccines could cause autoimmune POI via molecular mimicry” and met their burden with 26 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 27 of 47 respect to Althen prong one. See Findings of Fact. More specifically, 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.” Id. at 2. Pursuant to my Ruling, in order for this theory to be applicable to any individual POI petitioner for Althen prong two analysis, she must be able to establish by preponderant evidence that she suffers from autoimmune POI. I indicated that an autoimmune etiology will not be presumed for any claim and will be determined by each POI petitioner’s individual medical history. I found that “[a] petitioner whose condition does not present evidence of an autoimmune etiology, such as lymphocytic oophoritis, adrenal or ovarian autoantibodies, and comorbid autoimmune disorders”66 will likely be unable to establish the applicability of the theory. Id. at 24. I further cautioned that “[t]here 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.” Id. In the present case, Petitioner’s latest expert presents evidence that both deviates from the causation theory originally presented and contravenes my instruction that the “[p]etitioners should proceed with the prosecution of claims in accordance with [my August 30, 2021] Ruling.” See id. Dr. Axelrod attempted to mitigate this noncompliance by noting that he “support[s] the molecular mimicry theory outlined therein by Dr. Shoenfeld.” Pet’r’s Ex. 126 at 13. However, Dr. Axelrod’s extensive explanation of molecular mimicry is a direct violation of not only my August 30, 2021 Ruling, but also my December 14, 2021 Order, that any subsequent expert reports should address Althen prongs two and three. Findings of Fact; ECF No. 88 at 1. Dr. Axelrod identified several additional short peptide chains found within the various strains of HPV that are included in the Gardasil vaccine. See Pet’r’s Ex. 126 at 13–16. He then asserted their relevance in a potential pathological molecular mimicry process, causing POI. Notably, he spent much of this section of his report discussing the mechanics of molecular mimicry generally and in the context of a tetanus, diphtheria, and/or pertussis infection. See id. at 14. Given the nature of the Program and the specific procedural history of this case, Dr. Axelrod’s foundational discussion of molecular mimicry, with references to the Kanduc and Trost studies, was as unhelpful as it was unnecessary. Id. at 13 (citing Pet’r’s Exs. 140–41). Further explanation by way of an analogy to tetanus, diphtheria, and/or pertussis was likewise ineffectual. In the context of Petitioner’s vaccinations and their relationship to POI, Dr. Axelrod listed a string of seven or eight proteins in the flu and HPV vaccines that contain three amino acids also found in AMH. Id. at 15. He then devoted a significant part of his report to AMH and its role in reproductive development. AMH levels are used in evaluating ovarian reserve for IVF. See Pet’r’s Ex. 129 at 1. However, that AMH levels may be undetectable in POI patients does not make AMH levels a predictor of POI. Dr. Axelrod presented no medical literature to support such a conclusion. He referenced a study by Xu et al. on “the effect of blocking antibody to [AMH] upon granulosa cells and ovarian follicles.” Pet’r’s Ex. 126 at 9 (citing Pet’r’s Ex. 132). He then opined that Petitioner “has circulating lymphocytes with specificity to [AMH that] upon exposure to the components of the Gardasil [vaccine], [were activated] with the production of antibodies to her [AMH].” Id. Petitioner’s medical record did not indicate the presence of AMH antibodies, nor did 66 Diseases, including autoimmune polyendocrine syndromes and Addison’s disease, were identified by Respondent’s expert Dr. Forsthuber, as effective predictors of autoimmune POI. Findings of Fact at 11. 27 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 28 of 47 her treaters note such antibodies during the entirety of Petitioner’s POI testing. Dr. Axelrod asserted that this process further “resulted in the loss of early growing follicles and the loss of her ability to ovulate and have normal menses.” Id. This assertion is contrary to the results of Petitioner’s February 10, 2014 ultrasound, which revealed multiple follicles within both ovaries. Pet’r’s Ex. 3b at 144. Through his focus on AMH, Dr. Axelrod attempted to identify a potential, additional point of cross-reaction, but he did not submit persuasive evidence that it is more likely to occur than Dr. Shoenfeld’s originally named proteins, or that it is likely to occur at all. He did not provide any literature or other evidence that specifically links molecular mimicry, vaccines, or autoimmune POI to AMH autoantibodies. While medical literature is not required, Dr. Axelrod offers only speculation, without any supporting evidence, of any causal association between AMH antibodies and POI. Indeed, the Moolhuijsen et al. study that Petitioner filed to discuss the role of AMH in reproductive health, noted that “recent studies suggest that the relationship between autoimmune diseases and diminished [functional ovarian reserve], as assessed by AMH, remains inconsistent.” Pet’r’s Ex. 130 at 9. The authors added that “well-controlled studies are needed to analyze the impact of disease onset, duration, and therapy on AMH levels.” Id. Petitioner had already submitted a valid causation theory that explains the cross reaction “between L1 proteins contained in Gardasil and proteins essential to proper ovarian function.” Findings of Fact at 19. This theory involves “an enzyme that helps a cell repair DNA damage” and “has been associated with the development of POI.” Id. at 20–21. Although I specifically instructed Petitioner not to relitigate the viability of a biological mechanism for vaccine-induced POI, she filed an expert report that reiterates previously made points without additional preponderant evidence. Dr. Axelrod also noted “a protective immune reaction to [Petitioner’s] influenza vaccination,” but he did not explain how the flu vaccine fits within the previously asserted theory or his new theory. The biological mechanism that was previously litigated for use in this case does not contemplate a flu vaccine. I will not allow Petitioner to make substantial, but ineffectual, changes to her argument six years into litigation, in an attempt to address facts that existed at the time her claim was filed. Frankly, Dr. Axelrod’s vague mention of a flu vaccine is insufficient to explain how this additional immune system trigger would change the molecular mimicry mechanism already presented. Lastly, Dr. Axelrod added that Petitioner has “a condition, [EDS], that deserve[s] further comment and analysis.” Pet’r’s Ex. 126 at 13. The case consolidation that includes Petitioner’s claim was premised on the shared, identified injury of POI. EDS is a condition that Dorland’s defines as “a group of inherited disorders of connective tissue.”67 EDS is not an autoimmune condition, nor is it associated with POI. Dr. Axelrod does not claim as much. Like his mention of Petitioner’s flu vaccine, it is unclear how this diagnosis affects any claim of HPV vaccine-caused POI. Dr. Axelrod’s recent additions to Petitioner’s biological mechanism do not amount to preponderant evidence applicable to Althen prongs one, two, or three. Respondent’s expert Dr. Forsthuber also devoted a significant portion of his most recent expert report to renewed objections to the molecular mimicry causation theory. See Resp’t’s Ex. O. He, like Dr. Axelrod, noted an “understanding that Dr. Shoenfeld’s earlier-expressed causation 67 See supra, note 16 (defining Ehlers-Danlos Syndrome). 28 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 29 of 47 theory has been accepted by the Court.” Id. at 16. Nevertheless, Dr. Forsthuber felt it necessary to rebut Dr. Axelrod’s new evidence and asserted that “this massive amount of sequence sharing of peptides between proteins from bacteria/viruses and humans does not support their role in human disease processes via molecular mimicry.” Id. As I did not find Dr. Axelrod’s newly submitted evidence in support of molecular mimicry probative, I will not spend additional time addressing Respondent’s rebuttal. Such arguments are untimely and, to a degree, moot. As explained below, Petitioner is unable to establish that she has the injury alleged or that her vaccinations resulted in an autoimmune pathogenic process. Therefore, the theory proposed, and any additional supporting or refuting evidence with respect to Althen prong one, is of no further consequence in this case. B. POI Diagnosis Before deciding whether the evidence supports an autoimmune etiology for Petitioner’s condition, I must first assess the evidence of her diagnosis. See Broekelschen, 618 F.3d at 1344 (“[I]t [i]s appropriate in this case–where virtually all of the evidence on causation [i]s dependent on the diagnosis [and etiology of a petitioner’s] condition–for [the special master] to determine the proper diagnosis before applying the Althen test.”). Dorland’s defines POI as the “absence or irregularity of menses lasting at least four months, with menopausal levels of serum gonadotropins, in an adolescent girl or woman under 40 years of age.”68 In my August 30, 2021 Ruling, I relied on the filed medical literature and expert consensus and defined POI as amenorrhea lasting for more than four months in a woman younger than 40 years of age. See Findings of Fact at 9–10; Brayboy, 2021 WL 4453146, at *7. The amenorrhea must be accompanied by FSH levels greater than 40 IU/mL on two occasions. See Findings of Fact at 9–10. I also noted that clinical symptoms such as hot flashes and night sweats, sleep disturbances, and dyspareunia69 may be supportive evidence. Id. Petitioner’s expert questioned whether Petitioner actually suffered from POI. Dr. Axelrod detailed Petitioner’s normal laboratory results following her HPV vaccinations and noted that “[s]he did not suffer from hot flashes, night sweats, excessive sweating or hair loss.” Pet’r’s Ex. 126 at 11. Indeed, Petitioner’s FSH levels tested normal on January 13, 2014, February 1, 2014, June 1, 2015, and as recently as September 21, 2022. Pet’r’s Ex. 7 at 7, 16, 26; Pet’r’s Ex. 120 at 6, ECF No. 102-5. Dr. Axelrod then stated, “it is not clear that she suffered from [POI].” Pet’r’s Ex. 126 at 11. His plain application of the diagnostic criteria to Petitioner’s medical record does not support a finding by a preponderant standard that Petitioner developed POI. Dr. Axelrod is not a reproductive specialist, however. In support of his argument that Petitioner developed POI, Dr. Axelrod referenced a July 14, 2015 medical record, signed by Dr. Minjarez from the Colorado Center for Reproductive Medicine, that stated Petitioner had progressed to POI. Pet’r’s Ex. 16 at 20. The record listed POI as an assessment but noted that Petitioner’s 2013 AMH levels had improved over the last two years with “resumption of her regular cycles.” Id. at 21. The record continued that Petitioner “ha[d] been evaluated by neurology, rheumatology, and hematology with no definitive diagnosis.” Id. Dr. Minjarez wrote that as of June 11, 2015, Petitioner’s “cycles ha[d] returned regularly, every 26–27 days.” Id. at 25. Dr. Minjarez did not identify medical records that document amenorrhea, accompanied by increased 68 See supra, note 4 (defining POI). 69 Dyspareunia is “difficult or painful sexual intercourse.” Dorland’s at 579. 29 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 30 of 47 FSH levels, to support this POI assessment. Dr. Axelrod, likewise, did not cite to a clinical presentation of symptoms in Petitioner’s medical record that further supports Dr. Minjarez’s POI diagnosis. Dr. Gersh is Petitioner’s reproductive expert, and she also noted that Petitioner’s medical record “indicated the development of [POI].” Pet’r’s Ex. 23 at 1. In her brief report, Dr. Gersh admitted that Petitioner’s FSH levels remained normal, but Dr. Gersh instead relied on Petitioner’s fluctuating estrogen levels, a low antral follicle count, and “most importantly,” low AMH levels to support a POI diagnosis. Dr. Gersh did not explain the significance of a low antral follicle count or AMH levels in the context of a patient with normal FSH levels, to diagnose POI. She did not cite to or provide any medical literature that includes low AMH levels as part of the diagnostic criteria for POI. Dr. Gersh then hypothesized that Petitioner’s prematurity caused her “poorly developed intestinal microbiome” to react somehow to the HPV vaccine and lead to the manifestation of POI. Id. She similarly did not cite to or provide any medical literature that explains how the intestinal microbiome is related to POI. She did not include in her report a logical sequence of cause and effect from the HPV vaccine to an intestinal immune reaction that culminates in the development of POI. I must also note that despite Dr. Gersh’s expertise in reproductive health, she does not identify POI as an area of specialty. Furthermore, her curriculum vitae does not list any training, experience, or expertise in prematurity complications or intestinal conditions. See generally Pet’r’s Ex. 22. Without additional context from her or support in the medical literature, Dr. Gersh’s opinion is conclusory and insufficient to meet the preponderant standard. Indeed, nothing requires the acceptance of an expert's conclusion “connected to existing data only by the ipse dixit of the expert,” especially if “there is simply too great an analytical gap between the data and the opinion proffered.” Snyder v. Sec’y of Health & Hum. Servs., 88 Fed. Cl. 706, 743 (2009) (quoting Gen. Elec. Co. v. Joiner, 522 U.S. 136, 146 (1997)); see also Isaac v. Sec'y of Health & Hum. Servs., No. 08-601V, 2012 WL 3609993, at *17 (Fed. Cl. Spec. Mstr. July 30, 2012), mot. for review den'd, 108 Fed. Cl. 743 (2013), aff'd, 540 F. App’x. 999 (Fed. Cir. 2013). Furthermore, I find it notable that Petitioner’s initial POI diagnosis in December of 2013 was made via phone consultation in contemplation of egg preservation. Pet’r’s Ex. 16 at 28. This diagnosis was not supported by any follow up lab reports or testing. The aggregate of: (1) Dr. Minjarez’s assessment unsupported by diagnostics; (2) Dr. Axelrod’s concurrence despite contradictory analysis; and (3) Dr. Gersh’s conclusion short of explanation does not meet the preponderant standard for establishing diagnosis when each opinion is carefully examined. Alternatively, Respondent’s expert Dr. Welt is a reproductive specialist with experience researching, diagnosing, and treating POI. In her report, she evaluated Petitioner’s medical record, focusing specifically on the patterns of amenorrhea and hormone levels. Dr. Welt showed that, while Petitioner did have some abnormal testing and amenorrhea, her records do not reflect amenorrhea coupled with the menopausal levels of serum gonadotropins needed to diagnose POI. Dr. Welt also noted that Petitioner did not suffer the clinical symptoms of menopause that are commonly seen in POI patients. She agreed with Dr. Axelrod’s reading of Petitioner’s medical record, which did not reveal POI symptoms, and remained unequivocal in her opinion. Dr. Welt concluded that Petitioner’s condition did not meet the clinical or diagnostic criteria for POI. 30 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 31 of 47 After a consideration of the medical record, Petitioner has not presented preponderant evidence that she suffered from POI. Her symptoms are not consistent with the clinical presentation, and her hormone levels were not in the appropriate range at the time of her amenorrhea. Further, Petitioner did not present persuasive evidence that AMH levels are, or should be, used as a diagnostic factor for POI. She also did not present persuasive evidence that an irregular intestinal microbiome is relevant to the development of POI. Because Petitioner is unable to establish it more likely than not that she had POI, she cannot establish it more likely than not that she suffered from POI that is autoimmune in origin and caused by her vaccinations. Nonetheless, I will address the parties’ arguments regarding autoimmune etiology. C. Autoimmune POI a. Althen Prong Two Although Petitioner has not presented preponderant evidence that she suffered from POI, some of Petitioner’s treaters noted “post[-]HPV amenorrhea.” Pet’r’s Ex. 3a at 99. While Dr. Kriege was one of those treaters, she “emphasize[d]” her lack of expertise in autoimmune reproductive issues. Id. As noted above, in Program cases, the opinions of treating physicians are favored and must be considered. Capizzano, 440 F.3d at 1326 (citing Althen, 418 F.3d at 1280). However, while a special master must consider these opinions and records, they are not “binding on the special master or court[,]” and I must consider the entire record. 42 U.S.C. § 300aa-13(b)(1). Indeed, as a result of the suspicions of some of her treaters, Petitioner was routinely tested for evidence of autoimmune disease, generally, and autoimmune POI, specifically. Petitioner’s most recently filed medical literature echoed her previously filed articles that articulate the evidence for an autoimmune etiology in POI patients. The Komorowska article identified “the presence of lymphocytic oophoritis, association with other autoimmune disorders, and autoantibodies to ovarian antigen” as factors “clearly documented in numerous studies.” Pet’r’s Ex. 137 at 2. I enumerated these same factors in my August 30, 2021 Ruling, and accordingly, will apply them to Petitioner’s medical history to determine if she has presented preponderant evidence of autoimmune POI. See Findings of Fact at 24. The Jankowska article filed by Petitioner, discussed POI caused by “an autoimmune process consisting of the production of anti-ovarian antibodies.” Pet’r’s Ex. 135 at 3. The Kirshenbaum et al. article, also filed by Petitioner, acknowledged that “[w]hile a specific noninvasive reliable diagnostic test for the diagnosis of an autoimmune etiology is lacking, nowadays, patients should be screened for the most common autoantibodies.” Pet’r’s Ex. 136 at 5. Dr. Axelrod conceded that Petitioner “did not have detectable anti-ovarian antibod[ies],” but he immediately asserted that “the presence or absence of this antibody does not prove or disprove an autoimmune cause for [POI].” Pet’r’s Ex. 126 at 11. Despite his equivocation on Petitioner’s diagnosis and Petitioner’s lack of anti-ovarian antibodies, Dr. Axelrod ultimately identified her “low complement C3 level” and “detectable levels of antibodies, [including] to anti-adrenergic receptor antibodies and anti-muscarinic cholinergic receptor antibodies” in testing done on June 29, 2018, and March 14, 2022, as evidence of her autoimmune POI. Id. at 5. Petitioner received her HPV vaccines on July 22, 2013, and October 23, 2013. Pet. at 1. She underwent antibody testing on November 23, 2013 (Pet’r’s Ex. 3a at 91), December 7, 2013 (Pet’r’s Ex. 3c at 83), 31 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 32 of 47 August 26, 2014 (Pet’r’s Ex. 3b at 143), June 1, 2015 (Pet’r’s Ex. 2d at 36), and January 4, 2016 (Pet’r’s Ex. 6 at 1). The June 1, 2015 record noted, “all antibody labs have returned negative (including anti-ovarian), which [sic] exception of mildly elevated ANA (very nonspecific).” Pet’r’s Ex. 2d at 36. The 2016 labs were likewise negative. Pet’r’s Ex. 6 at 1. Dr. Axelrod placed a premium on Petitioner’s positive test results beginning in 2018. He did not explain the negative results over the several years following vaccination, even when Petitioner’s negative results continued after POI was initially suspected as early as December of 2013. For example, Dr. Kriege diagnosed Petitioner with post-HPV amenorrhea in January of 2014, but she wrote there were no signs on exam or on lab of a systemic autoimmune disease. Pet’r’s Ex. 3a at 99. She reiterated that position in May of 2015, despite Petitioner’s low AMH levels, and noted that Petitioner’s post-HPV amenorrhea was improving. Id. at 168. Dr. Seroogy noted in February of 2014 that Petitioner had “no clinical or laboratory evidence of autoimmune- mediated ovarian failure or other autoimmune endocrine problems.” Pet’r’s Ex. 15 at 30. In light of such notations, Dr. Axelrod’s reliance on positive test results obtained in 2018 and 2022 is tenuous, if not irrelevant, to Petitioner’s vaccinations received approximately five years prior. The weight of the evidence is further lessened by interim, negative tests, despite the alleged progression of Petitioner’s POI during that time. Furthermore, Petitioner tested positive for antibodies in 2018. However, based on lab work on March 14, 2022, Petitioner had normal AMH, FSH, LH, and estradiol levels, with a good egg retrieval score. Pet’r’s Ex. 125 at 1. This is wholly inconsistent with a POI diagnosis, with or without an autoimmune etiology. Petitioner’s comprehensive antibody testing therefore does not provide preponderant evidence of an autoimmune etiology. Dr. Axelrod further noted that Petitioner did not develop adrenal insufficiency, diabetes, or thyroiditis. Pet’r’s Ex. 126 at 12. Indeed, he did not suggest that Petitioner suffered from any autoimmune comorbidity. He stated only that she is at “risk for the development of an autoimmune disorder.” Id. Given the amount of time that has elapsed since her vaccination, the failure of any such disorder to manifest nullifies the probative value of Dr. Axelrod’s purported risk. While Petitioner’s medical record documents an extensive history of adverse vaccine reactions and rashes, these manifestations were similar in their locality and acute onset, unlike autoimmune polyendocrine syndromes,70 Addison’s disease,71 or other autoimmune conditions that are chronic in nature and associated or comorbid with POI. See Findings of Fact at 24. In fact, Petitioner’s medical record dated May 29, 2015, noted that no autoimmune diagnosis had been made to date. Pet’r’s Ex. 2c at 36. Petitioner did not suffer from any comorbid autoimmune disease that could provide preponderant evidence of autoimmune POI. Lastly, it is undisputed that Petitioner did not exhibit any signs of lymphocytic oophoritis. After a thorough examination of Petitioner’s medical record, Petitioner has not presented preponderant evidence that any of the enumerated factors used to identify autoimmune POI are 70 Autoimmune polyendocrine syndromes, or polyendocrine autoimmune syndromes, are “syndromes comprising combinations of endocrine and nonendocrine autoimmune diseases.” Dorland’s at 1844. It is characterized by the presence of two of three major clinical symptoms: candidiasis, hypoparathyroidism, and adrenal insufficiency. Id. 71 See supra, note 15 (defining Addison’s disease). 32 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 33 of 47 present in her case. Therefore, the causation theory based on molecular mimicry presented by Dr. Shoenfeld and credited in my Ruling, is inapplicable. Petitioner has failed to meet her burden under Althen prong two. b. Althen Prong Three Petitioner has not met her burden pursuant to Althen prong two. However, in the interest of completeness, I will complete the third Althen prong analysis that requires Petitioner establish a “proximate temporal relationship” between the vaccination and the injury alleged. Althen, 418 F.3d at 1281. Dr. Axelrod argued that Petitioner’s menstrual cycle became irregular within one month of her first HPV vaccination on July 22, 2013, and stopped completely within one month of her second HPV vaccination on October 23, 2013. He also noted an influenza vaccination Petitioner received on October 23, 2013, that produced “either a secondary or primary adaptive response,” within a month. Pet’r’s Ex. 126 at 21. This timeframe is consistent with the Lawley et al. article referenced in Dr. Axelrod’s report that revealed the “manifestation of a primary adaptive immune response, which resulted in the production of complement fixing immune complexes, occurred from 10 to 25 days following the initial exposure to the antigen.” Pet’r’s Ex. 126 at 19 (citing Pet’r’s Ex. 147). Furthermore, one month has previously been accepted in the Program as an appropriate timeframe for the manifestation of autoimmune diseases from vaccine-initiated molecular mimicry. See, e.g., Stewart v. Sec’y of Health & Hum. Servs., No. 06-777V, 2011 WL 3241585, at *16 (Fed. Cl. Spec. Mstr. July 8, 2011) (finding the petitioner satisfied Althen prong three because the onset of the injury, Guillain-Barré syndrome (“GBS”), occurred within four weeks of a flu vaccine via molecular mimicry). This timeframe, however, is usually applied to acute diseases with a shorter progression than POI, such as GBS. See, e.g., id. POI onset determination is further complicated by the measurement of hormone levels on two occasions over several months. Because Petitioner did not present preponderant evidence that she suffers from POI, I cannot apply the onset of her condition (whether based on hormone levels or amenorrhea) to any proposed temporal relationship. Petitioner has therefore failed to meet her burden pursuant to Althen prong three. D. POTS In the present case, Petitioner has also alleged that her HPV vaccines caused her to develop POTS. In order to be successful on that claim, Petitioner must establish vaccine-causation pursuant to all three Althen prongs for that injury. a. Althen Prong One Petitioner did not present a separate causation theory for POTS. Instead, Dr. Axelrod identified potential, limited, sequence homology between components of the HPV vaccine and fibroblast growth factor receptor 3. Pet’r’s Ex. 126 at 16. This brief mention is vague, however, given the relevance of fibroblast growth factor to numerous processes and systems in the body. Dr. Axelrod did not explain how this protein, a signaling molecule that regulates cell activity, is relevant to the autonomic system or POTS, specifically. Dr. Axelrod did not explain why a pathogenic cross-reaction would be more likely to occur following an HPV vaccine and target 33 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 34 of 47 fibroblast growth factor receptors in such a way that would lead to the development of POTS. Alternatively, Dr. Axelrod presented evidence of an association between POTS and the hereditary condition, EDS. Dr. Axelrod stated in this report that EDS patients were more likely to also suffer from POTS, but he then acknowledged that “this does not prove that either [EDS] or [POTS] are autoimmune disorder [sic].” Id. at 12. Respondent’s expert agreed with this association and noted there was no evidence of an autoimmune etiology for POTS or EDS. See Resp’t’s Ex. P at 8. Dr. Axelrod stated that Petitioner “developed antibodies to autoantigens related to autoimmune [POI] and [POTS], indicating that her immune system lymphocytes are capable of reacting to her ovaries and autonomic myelinated and unmyelinated neurons.” Pet’r’s Ex. 126 at 17. He described the mechanism with respect to POI. Id. He detailed the production of AMH antibodies and hypothesized that the “immune response to her autoantigens related to her ovaries, as well as her autonomic neurons[,] then caused damage to her autonomic nervous system, with the development of [POTS] and autoimmune [POI], which progressed over time.” Id. While he devoted much time and analysis to relitigating the POI mechanism, he did not develop an independent theory for POTS. Indeed, POTS is essentially relegated to an afterthought, tacked on to arguments clearly developed for POI. As such, there is no meaningful and distinct identification or explanation of a biological mechanism to apply to Petitioner’s clinical presentation of autonomic dysfunction. Petitioner has asserted a molecular mimicry theory with respect to her POI claim. As the two injuries were inextricably linked together in Dr. Axelrod’s report, it stands to reason that a molecular mimicry process would also be the basis of her POTS causation theory. Although Petitioner has not claimed as much, I will address this potential argument based on the record as a whole. Petitioner has failed to present evidence that her proposed theory of molecular mimicry would apply to POTS. See W.C. v. Sec’y of Health & Hum. Servs., 704 F.3d 1352, 1360 (2013) (finding that a petitioner cannot prevail by simply invoking the term ‘molecular mimicry,’ or by showing that molecular mimicry is a valid theory to explain how other triggers may have induced other diseases and determining that a petitioner must produce additional evidence that molecular mimicry can cause the flu vaccine to cause POTS). If I accepted Petitioner’s implication that molecular mimicry could be used to demonstrate an association between any combination of antigens and autoimmune injuries, Althen prong one “would be rendered meaningless.” See Caves v. Sec’y of Health & Hum. Servs., 100 Fed. Cl. 119, 135 (2011), aff’d, 463 F. App’x. 932 (2012); see also McKown v. Sec’y of Health & Hum. Servs., No. 15-1451, 2019 WL 4072113, *50 (Fed. Cl. Spec. Mstr. July 15, 2019) (“[M]erely chanting the words ‘molecular mimicry’ in a Vaccine Act case does not render a causation theory scientifically reliable, absent additional evidence specifically tying the mechanism to the injury and/or the vaccine in question.”). Lastly, I cannot ignore the fact that to date, no claim has succeeded in the Program that alleged vaccine-caused POTS. Indeed, that pertains to all covered vaccines in the Program. See, e.g., Hibbard v. Sec’y of Health & Hum. Servs., 698 F.3d 1355 (Fed. Cir. 2012) (affirming the special master’s dismissal of a case alleging that the flu vaccine caused POTS); America v. Sec’y of Health & Hum. Servs., No. 17-542V, 2022 WL 278151, at *27 (Fed. Cl. Spec. Mstr. Jan. 4, 2022) (ruling against the petitioner’s argument that the HPV vaccine can interfere with the nervous system sufficient to cause POTS, autonomic dysfunction or generalized dysautonomia, or vasovagal syncope); L.P. v. Sec’y of Health & Hum. Servs., No. 16-1278V, 2021 WL 2373863, at 34 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 35 of 47 *29 (Fed. Cl. Spec. Mstr. Apr. 26, 2021) (rejecting the petitioner’s claim that the flu vaccine can cause POTS via the induction of antiphospholipid antibodies); Hughes v. Sec’y of Health & Hum. Servs., No. 16-930V, 2021 WL 839092, at *30 (Fed. Cl. Spec. Mstr. Jan. 4, 2021) (denying compensation for a claim involving the HPV vaccine and POTS); E.S. v. Sec’y of Health & Hum. Servs., No. 17-480V, 2020 WL 9076620, at *49–51 (Fed. Cl. Spec. Mstr. Nov. 13, 2020); Balasco v. Sec’y of Health & Hum. Servs., No. 17-215V, 2020 WL 1240917, at *33–34 (Fed. Cl. Spec. Mstr. Feb. 14, 2020); Yalacki v. Sec’y of Health & Hum. Servs., No. 14-278V, 2019 WL 1061429, at *34 (Fed. Cl. Spec. Mstr. Jan. 31, 2019), mot. for review den’d, 146 Fed. Cl. 80 (2019) (finding that the evidence presented to show POTS is autoimmune was thin and that the petitioner failed to show a HPV vaccine likely causes “the production of antibodies associated with autonomic damage or interference sufficient to cause POTS”); Johnson v. Sec’y of Health & Hum. Servs., No. 14-254V, 2018 WL 2051760, at *1 (Fed. Cl. Spec. Mstr. Mar. 23, 2018) (ruling against the petitioner in a case alleging that the HPV vaccine caused POTS and noting that the medical literature suggesting that POTS “might be autoimmune appears [to be] extremely limited”); L.A.M. v. Sec’y of Health & Hum. Servs., No. 11-852V, 2017 WL 527576, at *63 (Fed. Cl. Spec. Mstr. Jan. 31, 2017) (finding that most cases of POTS do not have an autoimmune etiology and that the petitioner’s claim that the HPV vaccine caused POTS must fail because she did not provide corroborating evidence of an autoimmune process); Combs v. Sec’y of Health & Hum. Servs., No. 14-878V, 2018 WL 1581672 (Fed. Cl. Spec. Mstr. Jan. 31, 2017); Turkopolis v. Sec’y of Health & Hum. Servs., No. 10-351V, 2014 WL 2872215 (Fed. Cl. Spec. Mstr. May 30, 2014). This is not to say that a future case alleging vaccine-caused POTS cannot and will not succeed in the Program based on the evolving understanding of the post-vaccination pathogenesis of the condition. However, Petitioner’s claim is not one of those cases. Therefore, Petitioner has failed to satisfy the first prong of Althen by a preponderance of the evidence for her alleged POTS injury. b. Althen Prong Two Petitioner presented evidence that multiple treaters assessed her with POTS. Dr. T. Chelimsky diagnosed Petitioner with POTS on August 5, 2014. Pet’r’s Ex. 4a at 86. Dr. Reber assessed Petitioner with POTS on August 26, 2014. Pet’r’s Ex. 3b at 145. And yet, despite a formal diagnosis from Dr. T. Chelimsky, Respondent’s expert Dr. Arnold contended that Petitioner does not have POTS. Resp’t’s Ex. P at 7. Dr. Arnold asserted that despite what Petitioner’s treaters believed, Petitioner did not meet the diagnostic criteria for POTS. Dr. Arnold noted Dr. G. Chelimsky’s determination in May of 2014, that there was “no evidence of POTS[,]” was based on Petitioner’s tilt table test results, despite the presence of autonomic symptoms, including instances “where her heart rate will drop very low for several hours[,]” randomly dilated pupils, and brain fog. See Pet’r’s Ex. 4a at 26. Indeed, Dr. T. Chelimsky did not rely on filed tilt table test results to support his disagreement with Dr. G. Chelimsky and to formally diagnose Petitioner with POTS in August of 2014. Dr. T. Chelimsky instead relied on Petitioner’s symptoms of near syncope, migraines, and other “salient feature[s]” including the “excessive lability of many vegetative processes, including heart rate, estrogen levels (by history)[,] and weight[.]” See id. at 86. Drs. G. and T. Chelimsky both examined and assessed Petitioner over a relatively short period but reached opposite conclusions. There is no indication that Petitioner’s clinical presentation changed, or that she had additional test results to explain the different diagnoses. I 35 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 36 of 47 find the difference in diagnoses puzzling and will address this unique circumstance in more detail.72 Dr. G. Chelimsky is the chief of pediatric gastroenterology for the Children’s Hospital of Richmond at Virginia Commonwealth University (“VCU”).73 She is board certified in autonomic disorders and a prior director of the pediatric autonomic disorders program, Rainbow Babies at the Children’s Hospital at the University of Cleveland.74 Dr. G. Chelimsky is a leading authority on autonomic disorders and has co-authored several papers on POTS, including Adolescent fatigue, POTS, and recovery, a guide for clinicians, and with Dr. T. Chelimsky, Comorbidities in pediatric patients with postural orthostatic tachycardia syndrome.75 Dr. T. Chelimsky is a professor of neurology and the director of the autonomic laboratory at VCU.76 He is a past president of the American Autonomic Society and is also seen as a leading expert on autonomic disorders, such as POTS.77 At the time of Petitioner’s treatment, Drs. G. and T. Chelimsky were employed by the same medical facility, Wisconsin Children’s Hospital Autonomic Reflex Laboratory, in the same area of medicine. See, e.g., Pet’r’s Ex. 4a at 26. Certainly, it is reasonable that Dr. T. Chelimsky would have had access to Dr. G. Chelimsky’s earlier notes and opinions with respect to Petitioner prior to diagnosing her. It is unknown why Dr. T. Chelimsky would disregard those notes and overrule the expertise of Dr. G. Chelimsky without direct explanation. Dr. G. Chelimsky’s opinion in May of 2014 was unequivocal, as was Dr. T. Chelimsky’s diagnosis in August of the same year. Neither should be disregarded, nor do they cancel each other out. The level of expertise of both treaters warrants careful consideration of their respective diagnoses and rationale. I will consider both assessments in the context of Petitioner’s entire medical record. Additionally, two years later in 2016, Petitioner’s cardiologist noted that Petitioner did not have symptoms consistent with POTS. Petitioner did not submit medical literature or an expert discussion of a POTS clinical presentation similar to hers. I am not a physician, and it is not my role to diagnose Petitioner. She had at least two treaters who found her symptoms indicative of POTS and at least two that did not. I find that there is some reasonable disagreement among the medical professionals in this case concerning Petitioner’s POTS diagnosis. The Program places a premium on the opinions of real- time treaters, and I will do the same. I find that Petitioner has presented preponderant evidence that she suffered from some variation of POTS. 72 To that end, to provide background information on the treaters and context for my in-depth analysis of and reliance on their respective diagnoses, I reference publicly available biographical information in this Decision. The source material for such information is included in this Decision as attachments. See Appendices A–C. 73 Introducing our new chief of pediatric gastroenterology: Q & A with Dr. Gisela Chelimsky, CHILDREN’S HOSPITAL OF RICHMOND AT VCU (Mar. 7, 2022), https://www.chrichmond.org/blog/introducing-our-new-chief-of-pediatric-gastroenterology-qa-with-dr- gisela-chelimsky. 74 Gisela G. Chelimsky, MD, MEDICAL HOME PORTAL, https://www.medicalhomeportal.org/author/286 (last visited Mar. 31, 2023). 75 See id. 76 VCU Department of Neurology Welcomes Dr. Thomas Chelimsky, VCU (Mar. 22, 2022), https://neurology.vcu.edu/news/department-of-neurology-welcomes-dr-thomas- chelimsky/#:~:text=Thomas%20C.,of%20neurology%20and%20department%20chair. 77 See id. 36 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 37 of 47 Her burden does not end there, however. Petitioner must still apply her biological mechanism for vaccine causation to her alleged injury. Petitioner did not present preponderant evidence of a biological mechanism pursuant to prong one. She did not present preponderant evidence that POTS can be autoimmune in nature or that her POTS was autoimmune. Without a logical sequence of cause and effect applying a biological mechanism to Petitioner’s condition, Petitioner has not presented preponderant evidence to meet her burden pursuant to Althen prong two with respect to her POTS injury. c. Althen Prong Three As Petitioner did not present preponderant evidence of a biological mechanism for vaccine- caused POTS, there is no identified timeline to assess what would be an appropriate symptom progression. Dr. Axelrod did not identify an appropriate temporal relationship for vaccine-caused POTS, aside from the timeframe he argued was applicable to Petitioner’s POI claim. Therefore, I am left only able to apply the same timeframe for both injuries. Petitioner was first diagnosed with POTS by Dr. T. Chelimsky in August of 2014. It is notable that when Dr. G. Chelimsky first assessed Petitioner in May of the same year, Dr. G. Chelimsky wrote Petitioner’s objective testing did not show evidence of POTS. Pet’r’s Ex. 4a at 31. In diagnosing Petitioner with POTS in August of 2014, Dr. T. Chelimsky did not describe any change in Petitioner’s clinical presentation since Dr. G. Chelimsky’s prior determination in May of 2014 that Petitioner showed no evidence of POTS. See id. at 31, 86. Instead, Dr. T. Chelimsky noted Petitioner’s changes in heart rate, estrogen levels, and weight. However, these fluctuations were also present prior to May of 2014, and to some extent, were explicitly noted by Dr. G. Chelimsky in May of 2014. See Pet’r’s Ex. 4a at 26 (a May 12, 2014 medical record noted that Petitioner’s heart rate would drop very low for several hours). Dr. T. Chelimsky also did not detail the addition of any autonomic symptoms or rely on any objective testing from May of 2014 to August of 2014 that could establish the onset of Petitioner’s POTS or explain his diagnosis. Dr. G. Chelimsky’s notes from Petitioner’s exams through May of 2014 make it clear, however, that Petitioner’s treaters did not see persuasive evidence of POTS at least up to that point. Given that, I find that it is more likely than not that in diagnosing Petitioner with POTS in August of 2014, Dr. T. Chelimsky relied on some factor that Dr. G. Chelimsky did not previously see or consider in Petitioner during her May 2014 exam. This material change in symptoms likely emerged sometime after Petitioner’s May 12, 2014 exam with Dr. G. Chelimsky and sometime before her formal diagnosis on August 5, 2014, by Dr. T. Chelimsky. At the approximate point of this change, there is preponderant evidence that Petitioner was manifesting evidence of POTS. Even assuming that this change in Petitioner’s presentation of POTS symptoms started immediately in mid to late May following her May 12, 2014 visit with Dr. G. Chelimsky, a seven- month lapse between Petitioner’s October 2013 vaccination and symptom onset is too remote in time to be attributable to either of the HPV vaccines at issue. The interim negative tilt table testing in May of 2014 provides the most persuasive support that Petitioner’s ultimate diagnosis in August of 2014 is not a timely result of molecular mimicry. Therefore, Petitioner has failed to present preponderant evidence to meet her burden pursuant to Althen prong three for her POTS claim. VIII. Conclusion 37 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 38 of 47 Petitioner has failed to establish by preponderant evidence that the HPV vaccines she received on July 22, 2013, and October 23, 2013, caused her to develop POI or POTS, as she cannot establish it more likely that she suffers from POI or that her POTS has an autoimmune etiology. 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.78 IT IS SO ORDERED. s/Herbrina D. Sanders Herbrina D. Sanders Special Master 78 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. 38 Introducing our new chief of pediatric gastroenterology: Q&A with Dr... https://www.chrichmond.org/blog/introducing-our-new-chief-of-pediat... Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 39 of 47 1 of 5 3/31/2023, 12:35 PM Introducing our new chief of pediatric gastroenterology: Q&A with Dr... https://www.chrichmond.org/blog/introducing-our-new-chief-of-pediat... Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 40 of 47 2 of 5 3/31/2023, 12:35 PM Introducing our new chief of pediatric gastroenterology: Q&A with Dr... https://www.chrichmond.org/blog/introducing-our-new-chief-of-pediat... Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 41 of 47 3 of 5 3/31/2023, 12:35 PM Introducing our new chief of pediatric gastroenterology: Q&A with Dr... https://www.chrichmond.org/blog/introducing-our-new-chief-of-pediat... Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 42 of 47 4 of 5 3/31/2023, 12:35 PM Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 43 of 47 Medical Home Portal - Gisela G. Chelimsky, MD https://wwwmedicalhomeportal.org/author/286 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 44 of 47 1 of 2 3/31/2023, 12:37 PM Medical Home Portal - Gisela G. Chelimsky, MD https://wwwmedicalhomeportal.org/author/286 Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 45 of 47 2 of 2 3/31/2023, 12:37 PM Firefox https://neurologyvcuedu/news/department-of-neurology-welcomes-dr-thomas-chelimsky/#:~:text Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 46 of 47 Department of Neurology > News > Department of Neurology Welcomes Dr. Thomas Chelimsky VCU Department of Neurology Welcomes Dr. Thomas Chelimsky By Shea Wright SHARE THIS STORY Neurology March 22, 2022 The VCU Department of Neurology welcomes Dr. Thomas C. Chelimsky, a professor of Neurology and the Director of VCU’s Autonomic Laboratory. Dr. Chelimsky joined VCU on February 1, 2022, from the Medical College of Wisconsin where he held positions of tenured professor of neurology and department chair. In a previous appointment at Case Western Reserve University in 1993 he opened the second autonomic lab in the country. He also directed the Case Pain Center from 1994 to 2004, which led to founding and becoming CEO of PainSTakers, an educational company currently dedicated to training doctors, physical therapists, and behaviorists in the non-pharmacological approach to chronic pain management. Dr. Chelimsky, is an early pioneer in the field of functional autonomic disorders such as POTS (postural tachycardia syndrome), and pediatric functional gastrointestinal disorders and has published over 85 peer-reviewed articles. He has received continuous funding by NIH since 2009 to study the interface between pelvic pain and autonomic dysfunction and is past-president of the American Autonomic Society (AAS) where he held multiple positions, and past chair of both the American Academy of Neurology’s (AAN) Pain and Autonomic Sections. He has been instrumental in fellow board certification and fellowship accreditation in Autonomic Disorders through the United Council for Neurologic Subspecialties (UCNS) where he chaired the first examination committee. In his new role, Dr. Chelimsky’s interests and enthusiasm will focus on a rich collaboration with VCU faculty members over many disciplines to develop an autonomic program that crosses traditional boundaries to include both children and adults, to offer both interdisciplinary diagnostic services and an on-site interdisciplinary treatment program, and to foster robust clinical, research and educational components. 1 of 2 3/31/2023, 3:51 PM Firefox https://neurologyvcuedu/news/department-of-neurology-welcomes-dr-thomas-chelimsky/#:~:text Case 1:16-vv-00702-UNJ Document 112 Filed 04/21/23 Page 47 of 47 As a child Dr. Chelimsky had a small role in the movie Charade with Audrey Hepburn and Cary Grant, but ultimately chose medicine as his field of choice. Dr. Chelimsky graduated from Washington University Medical School in St. Louis, MO, and completed his residencies at Mayo Clinic in both internal medicine and neurology, where he was their first fellow in autonomic disorders. 2 of 2 3/31/2023, 3:51 PM