VICP Registry Case Source Bundle Canonical URL: https://vicp-registry.org/case/USCOURTS-cofc-1_13-vv-00675 Package ID: USCOURTS-cofc-1_13-vv-00675 Petitioner: Rhone DePena Filed: 2013-09-12 Decided: 2017-08-25 Vaccine: MMR Vaccination date: 2010-09-15 Condition: severe pneumonia Outcome: denied Award amount USD: AI-assisted case summary: On September 12, 2013, Bo and Natalie DePena, as legal representatives of their minor son Rhone DePena, filed a petition for compensation under the National Childhood Vaccine Injury Act of 1986. They alleged that Rhone, who was seven years old, developed severe pneumonia caused by pneumococcus as a result of receiving a second dose of the Measles-Mumps-Rubella (MMR) vaccine on September 15, 2010. The petitioners' theory, supported by pediatric pulmonologist Dr. Boris Lokshin, was that the MMR vaccine weakened Rhone's immune system, specifically by suppressing T cells, making him susceptible to the pneumococcal infection. The respondent, the Secretary of Health and Human Services, disagreed, presenting the views of pediatric immunologist Dr. Neil D. Romberg. Dr. Romberg argued that the MMR vaccine does not affect the part of the immune system responsible for responding to pneumococcal infections and that T cells are not essential for fighting such infections. Following an evidentiary hearing and post-hearing submissions, Special Master Christian J. Moran issued a decision on February 22, 2017, denying compensation. The Special Master found Dr. Romberg to be the more persuasive expert, citing his stronger qualifications in immunology, the established scientific principles supporting his opinions, and the rebuttal of Dr. Lokshin's reliance on mouse models. The Special Master concluded that the petitioners failed to establish a credible medical theory connecting the MMR vaccine to Rhone's pneumonia, thus not meeting the first prong of the Althen test for causation. The court affirmed the Special Master's decision on August 25, 2017, finding no error in the Special Master's consideration of the evidence, expert qualifications, and application of the Althen test. The petition was denied. Theory of causation field: Petitioners alleged that the MMR vaccine administered on September 15, 2010, to seven-year-old Rhone DePena caused severe pneumococcal pneumonia by weakening his immune system and suppressing T cells, making him vulnerable to infection. Petitioners' expert, Dr. Boris Lokshin (pediatric pulmonologist), theorized that the MMR vaccine suppressed T cells, which he argued were crucial for fighting pneumococcal infections. Respondent's expert, Dr. Neil D. Romberg (pediatric immunologist), countered that the MMR vaccine does not affect the immune response to pneumococcus and that T cells are not essential for combating this infection, as the primary immune response involves antibodies produced by B cells and the innate immune system. The Special Master found Dr. Romberg's expertise and reasoning more persuasive, noting that pneumococcus is a T cell-independent antigen and that established immunology principles do not support a significant role for T cells in fighting pneumococcal infections. The Special Master also found Dr. Lokshin's reliance on mouse studies unconvincing due to the lack of demonstrated applicability to humans and his limited depth in immunology. The court affirmed the Special Master's denial of compensation, agreeing that petitioners failed to establish a credible medical theory connecting the MMR vaccine to the injury under the first prong of the Althen test. The case was denied. Attorneys for petitioners were Michael Baseluos and for respondent Heather L. Pearlman. Special Master was Christian J. Moran. Judge Margaret M. Sweeney reviewed the decision. Public staged source text: ================================================================================ DOCUMENT 1: USCOURTS-cofc-1_13-vv-00675-0 Date issued/filed: 2017-03-22 Pages: 28 Docket text: PUBLIC DECISION (Originally filed: 2/22/17) regarding 87 DECISION of Special Master. Signed by Special Master Christian J. Moran. (dh) Copy to parties. -------------------------------------------------------------------------------- Case 1:13-vv-00675-MMS Document 90 Filed 03/22/17 Page 1 of 28 In the United States Court of Federal Claims OFFICE OF SPECIAL MASTERS * * * * * * * * * * * * * * * * * * * * * BO DEPENA and NATALIE * DEPENA, legal representatives of a * No. 13-675V minor child, RHONE DEPENA , * Special Master Christian J. Moran * Petitioners, * Filed: February 22, 2017 * v. * Entitlement, MMR vaccine, * pneumococcal pneumonia, SECRETARY OF HEALTH * animal models AND HUMAN SERVICES, * * Respondent. * * * * * * * * * * * * * * * * * * * * * * Michael Baseluos, Baseluos Law Firm, San Antonio, TX, for petitioners; Heather L. Pearlman, United States Dep’t of Justice, Washington, DC, for respondent. PUBLISHED DECISION DENYING COMPENSATION1 Rhone DePena, the son of the petitioners Bo and Natalie DePena, received a dose of the measles-mumps-rubella (MMR) vaccine when he was seven years old. Within a few weeks, he developed a severe pneumonia for which he was hospitalized for many weeks. During this time, the treating doctors determined that a bacteria, known as pneumococcus, infected his lungs and caused the pneumonia. The DePenas claim that the MMR vaccine caused Rhone’s pneumonia. Through an expert with a background in pediatric pulmonology, Boris Lokshin, they allege that the MMR vaccine weakened a portion of Rhone’s immune system 1 The E-Government Act, 44 § 3501 note (2012) (Federal Management and Promotion of Electronic Government Services), requires that the Court post this decision on its website. Pursuant to Vaccine Rule 18(b), the parties have 14 days to file a motion proposing redaction of medical information or other information described in 42 U.S.C. § 300aa-12(d)(4). Any redactions ordered by the special master will appear in the document posted on the website. Case 1:13-vv-00675-MMS Document 90 Filed 03/22/17 Page 2 of 28 and, in his debilitated state, Rhone could not resist the pneumococcus infection. The Secretary has disagreed with this argument and presented the views of an expert with a background in pediatric immunology, Neil D. Romberg. In Dr. Romberg’s view, the MMR vaccine does not affect the part of a human being’s immune system that responds to pneumococcus infections. Between the two experts, the Secretary’s expert was more persuasive. First, Dr. Romberg has a stronger background in the relevant field, immunology. Second, the Secretary established that his expert’s opinions are grounded in immunologic principles that have been established and accepted for decades. Indeed, even Dr. Lokshin did not seriously contest much of Dr. Romberg’s opinion. Third, to the extent that Dr. Lokshin presented an innovative theory based on relatively recent mouse models, the Secretary effectively rebutted that evidence by showing that mice do not model what happens to human beings facing a pneumococcal infection. For these reasons, the DePenas have failed to meet their burden of proof. Procedural History The course of litigation has been relatively routine. The DePenas filed the petition on September 12, 2013. Within approximately two months, they submitted Rhone’s medical records. On May 28, 2014, the Secretary submitted his report, filed pursuant to Vaccine Rule 4. After a review of the medical records, the Secretary recommended that compensation be denied because the DePenas had not presented any evidence in the form of a medical record from a treating doctor or a medical opinion to demonstrate that a vaccine caused Rhone’s pneumonia. Resp’t’s Rep. at 11. The DePenas retained Dr. Lokshin. As mentioned previously, Dr. Lokshin’s specialty is pediatric pulmonology. Exhibit 19 (curriculum vitae). Before the hearing, they submitted four reports from him. Exhibits 21 (Feb. 28, 2015), 22 (May 31, 2015),2 23 (Aug. 5, 2015), and 25 (Dec. 15, 2015). The literature on which Dr. Lokshin relied was appended to his reports as numbered tabs. The undersigned has reviewed all these articles. In response to Dr. Lokshin, the Secretary retained Dr. Romberg, a pediatric immunologist. See exhibit B (curriculum vitae). Dr. Romberg authored three 2 Dr. Lokshin’s May 31, 2015 report largely, but not entirely, repeats the material in the February 28, 2015 report. 2 Case 1:13-vv-00675-MMS Document 90 Filed 03/22/17 Page 3 of 28 reports: exhibits A (May 5, 2015), P (June 30, 2015), and FF (Jan. 27, 2016). The Secretary filed the literature on which Dr. Romberg relied as separate exhibits marked with consecutively assigned letters. The undersigned has reviewed all these articles as well. After unsuccessful efforts to resolve the case informally, it was set for a hearing. Before the hearing, the parties submitted briefs, which narrowed the issues. For example, the Secretary conceded that the Rhone developed pneumonia within a time after vaccination for which it is appropriate to infer causation. Resp’t’s Preh’g Br., filed Jan. 27, 2016, at 23. A hearing was held in San Antonio, Texas on February 11, 2016. Both Mr. and Ms. DePena testified about Rhone’s health before and after the September 15, 2010 MMR vaccination. The DePenas also called Dr. Lokshin. The Secretary’s witness was Dr. Romberg. For various reasons, the hearing did not proceed as expeditiously as anticipated, and the hearing did not conclude despite continuing until the early evening. After the first session of the hearing ended, the DePenas submitted additional information responding to issues that arose during the February 11, 2016 hearing. Another hearing was held on April 12, 2016, during which the attorneys and the witnesses appeared by videoconferencing. Following the hearing, the parties made additional submissions. The DePenas filed another report from Dr. Lokshin. Exhibit 30.3 The Secretary filed one brief. With the submission of the DePenas’s reply brief and another report from Dr. Lokshin, the case is ready for adjudication. Facts The parties’ disagreement in this case concerns whether Rhone’s MMR vaccination weakened a relevant portion of his immune system, making him more susceptible to pneumococcus. The facts outlined below which underlie that disagreement, however, are largely undisputed. This section outlines Rhone’s early health, the operation of pneumococcus, the general operation of the MMR vaccine, Rhone’s health following the MMR vaccination, and the overall operation 3 Filing an unrequested expert report was a mistake. Rather than filing more evidence, the DePenas should have filed a brief in which they marshalled the already admitted evidence in support of their claim. Nevertheless, the DePenas’s recent submissions, including the attached medical articles, have been considered. 3 Case 1:13-vv-00675-MMS Document 90 Filed 03/22/17 Page 4 of 28 of the immune system. These facts are the foundation for the subsequent evidentiary analysis. 1. Rhone’s Early Health Rhone was born in 2003. Exhibit 9 ¶ 1. Until he was seven years old, Rhone’s health was normal. See exhibit 5 (records from Northeast Pediatric Associates) passim. He participated in typical activities such as swimming, biking, playing tennis, and playing basketball. Exhibit 9 ¶ 2; Tr. 16, 54. In his periodic visits to his pediatrician, Rhone received vaccinations, although not on the typically recommended schedule. See exhibit 1. In August 2004, Rhone received the first dose of the MMR vaccine. Exhibit 1 at 1.4 On November 11, 2003, March 30, 2004, and June 22, 2005, Rhone received doses of the pneumococcal conjugate vaccine. Exhibit 1 at 1.5 2. Pneumococcus6 Pneumococcus is a type of bacterium. Dorland’s Illustrated Medical Dictionary 1470, 1782-83 (32d ed. 2012). There are more than 90 strains of pneumococcus and the numerous strains contribute to the difficulty in developing an effective vaccine. Exhibit 21.10 (Test ID: PN23 Streptococcus pneumoniae IgG Antibodies, 23 Serotypes, Serum, Mayo Clinic (undated), http://www.mayomedicallaboratories.com/test- catalog/Clinical+and+Interpretive/83640); see also Tr. 274, 331. The outside capsule of pneumococcus is comprised of polysaccharides. Tr. 231. Polysaccharides are carbohydrates, like sugars. Tr. 268; Dorland’s at 1493 4 Early in the litigation, the DePenas contended that Rhone broke out in an extensive rash shortly after receiving MMR at age two. Exhibit 8 (statement from Ms. DePena) at 1; see also exhibit 6 at 9-11 (record from Dr. Infante, dated April 13, 2011); Suppl. Pet. No. 1, filed Nov. 11, 2013 ¶ 6. However, the evidence showed that Ms. DePena’s recollection was incorrect. While Rhone did have a widespread rash in September 2005, see Tr. 40-41, exhibit 11, this rash occurred more than one year after the first MMR vaccination. Tr. 38. 5 The pneumococcal conjugate vaccine is often referred to by its brand name: Prevnar. The pneumococcal conjugate vaccine given to Rhone between 2003 and 2005 protected against seven strains of the pneumococcal bacteria. Exhibit 21.11 (Pneumococcal Vaccination: Who Needs It?, Centers for Disease Control and Prevention (Jan. 25, 2015), http://www.cdc.gov/vaccines/vpd-vac/pneumo/vacc-in-short.htm. 6 A more formal name for pneumococcus is streptococcus pneumoniae. Tr. 268. For consistency, this decision uses the term “pneumococcus.” 4 Case 1:13-vv-00675-MMS Document 90 Filed 03/22/17 Page 5 of 28 (defining polysaccharide). When faced with a polysaccharide invader, the body’s adaptive immune system responds by producing antibodies, which come from B cells, and the body does not produce T cells in response. Tr. 216-17. Consequently, pneumococcus has been categorized as a type II T cell-independent antigen. Tr. 217. The body’s encounter with pneumococcus is unusual in the sense that the first step is colonization. Tr. 110. Colonization means that a strain of pneumococcus is living in a person’s nose and throat. Tr. 186; cf. Dorland’s at 387. This nasopharyngeal colonization is extremely common with estimates exceeding 25 percent. Exhibit S (Jeremy S. Brown et al., The classical pathway is the dominant complement pathway required for innate immunity to Streptococcus pneumoniae infection in mice, 99(26) Proc. of Nat’l Acad. of Sci. of the U.S. 16969 (2002)) at 16969; exhibit 23, tab 4 (Jeffrey Pido-Lopez et al., Acquisition of Pneumococci Specific Effector and Regulatory Cd4+ T Cells Localising within Human Upper Respiratory-Tract Mucosal Lymphoid Tissue, 7(12) PLoS Pathogens e1002396 (2011)) at e1002396; exhibit 25, tab 2 (R Wilson et al., Protection against Streptococcus pneumoniae lung infection after nasopharyngeal colonization requires both humoral and cellular immune responses, 8(3) Mucosal Immunology 627 (2015)) at 628 (“almost universal”); Tr. 144 (Dr. Lokshin: pneumococcus is so common, “we cannot really avoid it”); see also Tr. 122 (Dr. Lokshin reading from Wilson article). Colonization, which is also known as carriage, is especially frequent in the very young and the very old. Tr. 272, 329- 30. During colonization of the mucosal surfaces of the nose and throat, the body’s adaptive immune system produces an antibody known as immunoglobulin A. Tr. 344; exhibit 25, tab 12 (Jason W. Rosch et al., A live-attenuated pneumococcal vaccine elicits CD4 T-cell dependent class switching and provides serotype independent protection against acute otitis media, 6(1) EMBO Molecular Med. 141 (2013)) at 142; see also Dorland’s at 919-20 (immunoglobulin secretory i. A). On some occasions, and in some people, a colonization resolves without a worsening of symptoms. Tr. 219-20; Resp’t’s Posth’g Br., filed July 27, 2016, at 2 (citing exhibit OO (Barry M. Gray et al., Epidemiologic Studies of Streptococcus pneumoniae in Infants: Acquisition, Carriage, and Infection during the First 24 Months of Life, 142(6) J. Infect. Dis. 923 (1980)) at 928, fig. 5). However, pneumococcus can also migrate from the nasopharynx to other portions of the body. Although the petitioners describe the T cells’ role in the change from colonization to infection as a “critical” issue in this case (Pet’rs’ Preh’g Br., filed Dec. 15, 2015, at 8), relatively little is known about how this 5 Case 1:13-vv-00675-MMS Document 90 Filed 03/22/17 Page 6 of 28 change occurs. See Tr. 111, 343. When pneumococcus moves to the ears and sinuses, it causes otitis media and sinusitis. Tr. 237-38, 270; exhibit OO. These types of infections are both relatively common and mild. Tr. 202-03. It is much more alarming when pneumococcus infects the lungs, causing a condition called pneumococcal pneumoniae. Dorland’s at 1474. In the United States in 2015, more than one million people suffered from pneumococcal pneumoniae. Tr. 270 (Dr. Romberg); see exhibit 21.10 (Mayo Clinic); see also exhibit 25, tab11 (Marianne W. Mureithi et al., T Cell Memory Response to Pneumococcal Protein Antigens in an Area of High Pneumococcal Carriage and Disease, 200 J. Infect. Dis. 783 (2009)). As previously mentioned, the body’s response to a pneumococcal infection is to produce antibodies. For more than 100 years, scientists have believed that antibodies (not T cells) are the way the adaptive immune system responds to pneumococcus. Exhibit 23, tab 4 (Pido-Lopez); Tr. 439, 506.7 According to Dr. Lokshin, it is likely that Rhone had pneumococcus in his nasopharynx before receiving the MMR vaccination. Tr. 203. 3. MMR Vaccination At an appointment with his pediatrician, Frederick Rhame, on September 15, 2010, Rhone received a series of vaccinations. Exhibit 1; exhibit 5 at 6, 15. For this case, the relevant vaccine is the measles-mumps-rubella vaccine. The MMR vaccine is an attenuated vaccine, that is, the vaccine contains a weakened form of the live measles virus. In its wild (or natural) state, the measles virus is extremely virulent. Measles causes the death of thousands of unvaccinated people each year. The people who survive measles infection are more vulnerable to infection from other pathogens for 1-4 weeks. Scientists have recently theorized that the measles virus destroys the memory aspect of the survivor’s immune system. Without this memory in their immune system, survivors of the measles virus may be unable to fight off infection and may contract diseases. Exhibit Y (Michael J. Mina et al., Long-term measles-induced immunomodulation increases overall childhood infectious disease mortality, 348(6235) Science 694 (2015)) at 694. 7 As discussed more extensively below, the petitioners, by contrast, are advancing a theory in which the body’s response to pneumococcus requires T cells. 6 Case 1:13-vv-00675-MMS Document 90 Filed 03/22/17 Page 7 of 28 Dr. Romberg, the Secretary’s expert, conceded that the MMR vaccine can have the same consequence as the wild measles virus: a suppression of some parts of the adaptive immune system. Dr. Romberg’s concession on this point simplified the litigation.8 4. Rhone’s Medical History Immediately Following MMR Vaccination (September 2010 through October 2010) As just stated, when he was vaccinated, Rhone encountered a weakened form of the measles virus on September 15, 2010. Two days later, Rhone’s mother called to report that he had a “bad reaction to shots” and requested a “steroid cream.” Exhibit 5 at 31; see also Tr. 17. Although the nurse’s note does not verbally describe the nature of the reaction, the pediatrician’s record includes a photograph showing raised dots on his thigh. Exhibit 5 at 38; see also exhibit 11; Tr. 17, 41, 56, 264, 372. On Saturday, September 25, 2010, Rhone’s parents brought him to the emergency room at Methodist Children’s Hospital because he was having lower back pain. Rhone also had been coughing for two days and his temperature, according to his mother, was “high for him.” Exhibit 7 at 32; exhibit 8 at 1. The doctors diagnosed him as having an acute viral syndrome. Exhibit 7 at 35; see also Tr. 21. Rhone’s health did not improve over the next few days. On Tuesday, September 28, 2010, Rhone’s mother took him to Dr. Rhame’s office because of a high fever, greyish color, and grunting sounds when he was breathing. Tr. 22. Dr. Rhame sent him for testing, including a chest X-ray. Exhibit 5 at 46; exhibit 8 at 1. The chest X-ray showed bilateral pneumonia. Exhibit 5 at 46. Rhone’s pneumonia was severe. He remained at Methodist Children’s Hospital for 21 days. Exhibit 7 at 62. His mother described the frightening details in her statement, although the course of how the doctors treated Rhone is not 8 In addition to the Mina article (exhibit Y), other articles relevant to how the measles virus and the measles vaccine may suppress the immune system include exhibit 21, tab 1 (Philip Fireman et al., Effect of Measles Vaccine on Immunologic Responsiveness, 43(2) Pediatrics 264 (1968)), and exhibit 21, tab 3 (Christopher L. Karp et al., Mechanism of Suppression of Cell- Mediated Immunity by Measles Virus, 273 Science 228 (1996)). 7 Case 1:13-vv-00675-MMS Document 90 Filed 03/22/17 Page 8 of 28 relevant to determining whether the MMR vaccine contributed to the pneumonia. See exhibit 8 at 2-3; Tr. 23-27. The doctors determined that Rhone was infected with pneumococcus. Exhibit 7 at 63, 91, 112, 171. There is no doubt that the pneumococcus caused Rhone’s pneumonia. Tr. 203. The only question raised in this litigation is whether the MMR vaccine contributed to it. Near the end of Rhone’s hospitalization, the doctors tested Rhone’s blood for the presence of titers against 14 serotypes of pneumococcus. For three strands, Rhone had levels of antibodies that exceeded 1.3 μg/mL, which is considered the threshold for protective levels. See exhibit 7 at 501 (results dated October 11, 2010); Tr. 97, 327, 334-36 (explaining protective level). One strand was 1.15 μg/mL. Rhone’s titers for the remaining antibodies were less than 1.0 μg/mL. Exhibit 7 at 501. After recovering in the hospital, Rhone was discharged on October 18, 2010. Exhibit 7 at 62-64; see also Tr. 27-28, 58. 5. Medical History after October 2010 Rhone’s pulmonologist, Amanda M. Dove, followed his case for several months. Exhibit 3 at 8-17. In June 2013, Dr. Dove assessed Rhone as having mild reactive airway disease. Exhibit 3 at 2. She prescribes medication for an inhaler. Tr. 46. In August 2015, a CT scan of Rhone’s chest was normal, except for some slight scarring. Exhibit 24 at 1. A spirometry test was also normal. Id. at 6; see also Tr. 193. Prompted by questions that arose in this litigation, the DePenas obtained additional information about Rhone’s antibody levels in 2016. This testing indicated that Rhone’s antibody levels were low to 13 serotypes of pneumococcus. Exhibit 27; Tr. 455, 489. At the time of the first hearing, Rhone had improved. He sometimes had problems breathing and ran slower than his peers. Tr. 35-35, 60. The DePenas emphasize that after Rhone’s 2010 pneumonia, which followed the MMR vaccination, Rhone has not had another episode of pneumonia. Tr. 34, 59, 168. 8 Case 1:13-vv-00675-MMS Document 90 Filed 03/22/17 Page 9 of 28 6. Operation of the Immune System A body’s responses to foreign invaders, often called antigens or pathogens, are controlled by the immune system. See Dorland’s at 1861. Immunologists generally divide the immune system into two branches: the innate immune system and the adaptive immune system. Tr. 266. Innate Immune System. The innate immune system is relatively primitive. The innate immune system generally recognizes foreign invaders. Tr. 266. Components of the innate immune system include cytokines, natural killer cells, and complement. Tr. 214, 225-26. According to Dr. Romberg, the innate immune system contributes to how the body responds when pneumococcus becomes infectious. Exhibit P (Dr. Romberg report) at 3 (citing exhibit S (Brown), exhibit T (Carolyn Mold et al., Protection from Streptococcus pneumoniae Infection by C-Reactive Protein and Natural Antibody Requires Complement But Not Fcγ Receptors, 168 J. of Immunology 6375 (2002))); Tr. 326-27. Dr. Lokshin stated that Dr. Romberg’s report nicely described the innate immune system. Tr. 117. Dr. Lokshin also acknowledged that the “Innate immune system clearly has a very big role in killing pneumococcus. That’s not in question.” Tr. 467. Adaptive Immune System. In comparison to the innate immune system, the adaptive immune system is more advanced. The adaptive immune system recognizes specific antigens. Tr. 266. The adaptive immune system contains two types of cells: B cells and T cells. See Dorland’s at 1084 (defining lymphocyte). Dr. Lokshin and Dr. Romberg appear to agree about the primacy of B cells in responding to pneumococcus.9 B cells. B cells make antibodies. Tr. 267. Antibodies, in turn, can be classified into different types of immunoglobulin. See Dorland’s at 100. Antibodies recognize polysaccharides (or sugars). Tr. 269, 461. Antibodies’ ability to respond to polysaccharides is one trait that distinguishes them from T cells. 9 The dispute is over the role of T cells in the body’s response to a pneumococcus infection. 9 Case 1:13-vv-00675-MMS Document 90 Filed 03/22/17 Page 10 of 28 T cells. The other part of the adaptive immune system is T cells. T cells derive their name from the thymus, where they mature. Tr. 302; Dorland’s at 1925 (thymus). T cells are further classified. The basic division is into two groups, known as cytotoxic T cells and helper T cells. Cytotoxic T cells, which are also known as CD8+ cells, kill cells that are infected by viruses. Tr. 267, 358. For example, when the body is infected by cytomegalovirus (“CMV”), cytotoxic T cells respond. Tr. 435.10 There are multiple types of helper T cells, also known as CD4+ cells. Th1 cells help cytotoxic T cells kill cells infected with infectious agents, especially viruses.11 Tr. 267, 296. Th2 cells help B cells. Tr. 268, 297. Th17 cells help cells at the mucosal level respond to infections by generating interleukin (“IL”) 17.12 354. Another type of helper T cell makes sure that the immune system does not overrespond. These helper T cells are known as T regulatory cells. Tr. 137, 268. Adopting a simile that Dr. Lokshin proposed, Dr. Romberg described helper T cells as the conductor of an orchestra in that they help other cells do their job. Tr. 267; see also Tr. 102-04. The crux of the disagreement between Dr. Lokshin and Dr. Romberg concerns whether T cells contribute to the body’s response to a pneumococcal infection. Dr. Lokshin opines that T cells have a role in the immune system’s response. In contrast, Dr. Romberg opines that T cells are expendable. The following sections are reasons why Dr. Romberg’s opinion is more persuasive. Standards for Adjudication In the analysis section below, evidence in this case will be analyzed according to the following standards of adjudication. 10 In this context, Dr. Romberg was asked hypothetically, if a person developed a CMV infection within three weeks of an MMR vaccination, could the suppression of the immune system by MMR contribute to the CMV infection? Dr. Romberg responded that this “mechanism makes biologic sense.” Tr. 436. Dr. Romberg’s willingness to recognize the potential adverse consequences to vaccination enhanced his credibility. 11 Without contradiction, Dr. Romberg stated that the measles vaccine can suppress Th1 cells, not Th2 cells. Tr. 421. 12 Interleukins are types of cytokines. Dorland’s at 949. Cytokines, in turn, are proteins by which cells of the immune system communicate. Id. at 466. 10 Case 1:13-vv-00675-MMS Document 90 Filed 03/22/17 Page 11 of 28 Petitioners are required to establish their case by a preponderance of the evidence. 42 U.S.C. § 300aa–13(1)(a). The preponderance of the evidence standard requires a “trier of fact to believe that the existence of a fact is more probable than its nonexistence before [he] may find in favor of the party who has the burden to persuade the judge of the fact’s existence.” Moberly v. Sec’y of Health & Human Servs., 592 F.3d 1315, 1322 n.2 (Fed. Cir. 2010) (citations omitted). Proof of medical certainty is not required. Bunting v. Sec’y of Health & Human Servs., 931 F.2d 867, 873 (Fed. Cir. 1991). Distinguishing between “preponderant evidence” and “medical certainty” is important because a special master should not impose an evidentiary burden that is too high. Andreu v. Sec’y of Health & Human Servs., 569 F.3d 1367, 1379-80 (Fed. Cir. 2009) (reversing special master’s decision that petitioners were not entitled to compensation); see also Lampe v. Sec’y of Health & Human Servs., 219 F.3d 1357 (Fed. Cir. 2000); Hodges v. Sec’y of Health & Human Servs., 9 F.3d 958, 961 (Fed. Cir. 1993) (disagreeing with dissenting judge’s contention that the special master confused preponderance of the evidence with medical certainty). Special masters are fact finders that use their accumulated expertise to judge the individual merits of claims. See Hodges, 9 F.3d at 961; Munn v. Sec’y of Health & Human Servs., 970 F.2d 863, 871(Fed. Cir. 1992). Thus, the probative value of the evidence, the credibility of the witnesses, and the relative persuasiveness of the competing medical theories of the case, are within their purview. Moberly, 592 F.3d at 1326 (“Finders of fact are entitled-indeed, expected-to make determinations as to the reliability of the evidence presented to them and, if appropriate, as to the credibility of the persons presenting that evidence.”); Lampe, 219 F.3d at 1361-62. Special masters may use the Daubert framework for analyzing the admissibility of scientific, technical, or other specialized knowledge, and the rules of evidence require the testimony to have a reliable basis in the relevant discipline. Terran v. Sec’y of Health & Human Servs., 195 F.3d 1302, 1316 (Fed. Cir. 1999). The elements of the DePenas’ case are set forth in the often cited passage from the Federal Circuit’s decision in Althen: “(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.” Althen v. Sec’y of Health & Human Servs., 418 F.3d 1274, 1278 (Fed. Cir. 2005). 11 Case 1:13-vv-00675-MMS Document 90 Filed 03/22/17 Page 12 of 28 Analysis To analyze the petitioners’ T cell-centered immunology theory requires both an understanding of both the parties’ experts’ qualifications and basic principles of immunology. The analysis below first focuses on the experts’ qualifications, and second reviews widely accepted principles of immunology related to pneumococcal infection. With the experts’ qualifications and the basic principles of immunology as foundations, the analysis goes on to assess the reliability of the petitioners’ new immunologic theory. 1. Expert Qualifications In considering the value of opinion testimony, special masters may consider the offeror’s expertise. See Snyder v. Sec’y of Health & Human Servs., 553 F. App'x 994, 1000–02 (Fed. Cir. 2014) (special master's finding that respondent's experts were more persuasive due in part to their current practice in neurology compared to petitioner’s expert who had no recent practice was not arbitrary or capricious); see also Copenhaver v. Sec'y of Health & Human Servs., 129 Fed. Cl. 176, 183 (2016) (rejecting argument that special master erred in evaluating the qualifications of the experts); Tompkins v. Sec’y of Health & Human Servs., 117 Fed. Cl. 713, 719 (2014) (noting special master reasonably articulated one expert’s relative lack of training and experience as a basis for not crediting the witness); Holmes v. Sec’y of Health & Human Servs., 115 Fed. Cl. 469, 490 (2014) (stating the special master was reasonable in considering a testifying expert’s “research credentials in the field”); Locane v. Sec’y of Health & Human Servs., 99 Fed. Cl. 715, 727 (2011) (finding special master rationally credited an expert with specialization in the disease in determining when the petitioner’s disease began), aff’d, 685 F.3d 1375, 1380 (Fed. Cir. 2012). Here, the primary question is how the body responds to pneumococcal colonization or infection. This question is about human immunology. Therefore, the qualifications of the experts are reviewed with an emphasis on immunology. A. Dr. Lokshin Dr. Lokshin graduated from medical school and completed a pediatric internship in Russia. He completed a second pediatric internship in California, where he also had a pathology residency and a pediatric residency. Exhibit 19 (curriculum vitae). 12 Case 1:13-vv-00675-MMS Document 90 Filed 03/22/17 Page 13 of 28 From 1988-90, Dr. Lokshin had a joint fellowship in allergy / immunology and pediatric pulmonology at the University of Iowa. In describing his expertise in immunology, Dr. Lokshin emphasized this stage of his medical career. Tr. 64. After his Iowa fellowship ended, Dr. Lokshin completed another residency in pediatrics and then completed another fellowship, this time in pediatric pulmonology. Both of these fellowships were through the University of Missouri- Columbia School of Medicine, where he also served as an assistant professor in pediatric pulmonology from 1991 through 1993. Exhibit 19. In 1993, the most recent of five articles written by Dr. Lokshin was published. Id.; see also Tr. 72. Dr. Lokshin’s next teaching position was in Connecticut at the Yale-New Haven School of Medicine. During this time (1993-95), he also served in the pediatric pulmonology / allergy division within the department of pediatrics at Danbury Hospital. He first became board certified in pediatric pulmonology in 1996, when he was living in Nevada. Exhibit 19; see also Tr. 62. For some time after May 1996, Dr. Lokshin taught allergy to medical students in large lecture classes at the University of Nevada, Reno. Exhibit 19; Tr. 73. Dr. Lokshin’s current teaching involves working with a single student for a few weeks in his office. Tr. 74. His current employment, which started in 1995, is working in a practice consisting of two doctors, called Allergy and Asthma Associates. Exhibit 19; Tr. 63. He usually sees one patient or two patients with pneumococcal pneumonia each year. Tr. 70. After the petitioners offered Dr. Lokshin as an expert in the relationship between “T cells and invasive pneumococcal disease,” the Secretary objected. Tr. 68. The ensuing voir dire brought out that Dr. Lokshin is not board certified in immunology. He has not received any special training on T cells. Tr. 73. He was not performing any research. Tr. 72. His work in treating patients with allergies draws upon his knowledge of immunology because allergy is a subtype of immunology. Tr. 75-79. Ultimately, he was recognized as an expert in pediatric pulmonology. He possesses the minimum qualifications to testify about immunologic concepts because of his training and experience. However, his testimony on immunologic topics was presented with the risk of being given less weight because of his relative lack of experience in immunology. Tr. 80-81. Dr. Lokshin’s lack of specialized training in immunology affected the quality of his testimony. When Dr. Lokshin presented the articles on which he 13 Case 1:13-vv-00675-MMS Document 90 Filed 03/22/17 Page 14 of 28 relied, he frequently stated that he was not presenting his opinion, he was simply presenting a view someone else expressed. Tr. 77, 84, 85, 100, 130, 213. While it is hornbook law that a testifying expert may rely upon the work of another expert if the testifying expert would normally rely upon the second expert’s work, see Summit 6, LLC v. Samsung Electronics Co., Ltd., 802 F.3d 1283, 1299 (Fed. Cir. 2015), Dr. Lokshin often left the impression that he did not have the depth of experience in immunology necessary to evaluate and render an opinion on immunologic topics. For example, when asked to explain the components of the innate immune system, Dr. Lokshin provided a brief answer, but added that if more information were needed, he would need to research the topic separately. Tr. 214. As another example, Dr. Lokshin used terminology about the immune system that was at least unusual, and possibly incorrect.13 He talked about the “three pillars of the immune system,” referring to the innate immune system, B cells, and T cells. Tr. 115. Traditionally, however, immunologists divide the immune system into the innate immune system and the adaptive immune system. See Tr. 266. The adaptive immune system is further divided into B cells and T cells.14 Id. Similarly, Dr. Lokshin’s presentation of articles was extremely cursory. Despite the undersigned’s recommendation that the petitioners and Dr. Lokshin discuss a smaller number of articles with a deep level of analysis, petitioners and Dr. Lokshin more often skimmed the surface of many articles. The petitioners and Dr. Lokshin would have been better served to focus on fewer articles but discuss their complicated immunology more thoroughly. Although the undersigned has reviewed all the articles, more in depth testimony from Dr. Lokshin about the significance of the articles could have promoted the petitioners’ case. The intent of these examples is not to catch Dr. Lokshin in small errors, but explain why he did not appear fluent in the language of immunology. This lack of fluency, again, gave the impression that Dr. Lokshin had limited experience on 13 Similarly, the petitioners’ briefs sometimes contain phrasing that lacks precision. For example, petitioners asserted “The immune systems contains two (2) lines of defenses: T cell lymphocytes (cell mediated immunity) and B cell dependent specific antibodies (humoral immunity).” Pet’rs’ Preh’g Br. at 5. This statement overlooks the innate immune system. The petitioners also asserted that “CD4 is a synonym for T cells.” Id. at 9 n.9. Actually, CD4 cells are a type of T cells. Tr. 358. As explained above, some T cells are not CD4 cells. 14 The way Dr. Lokshin described the immune system is akin to saying that the federal government of the United States is divided into four components: the Executive Branch, the Judicial Branch, the Senate, and the House of Representatives. 14 Case 1:13-vv-00675-MMS Document 90 Filed 03/22/17 Page 15 of 28 which to base his opinions. This impression, in turn, diminished the overall value of Dr. Lokshin’s testimony. See Snyder, 553 F. App'x at 1000–02 (noting the special master did not find persuasive the testimony of expert who read literature to support his opinion but did not actually treat patients with the relevant disease); Daubert v. Merrell Dow Pharm., Inc., 43 F.3d 1311, 1317 (9th Cir. 1995) (“[o]ne very significant fact to consider is whether the experts are proposing to testify about matters growing naturally and directly out of research they have conducted independent of the litigation, or whether they have developed their opinions expressly for purposes of testifying”). B. Dr. Romberg Dr. Romberg graduated from Pennsylvania State College of Medicine in 2004. He was a resident in pediatrics at New York University School of Medicine from 2004 to 2008, with the last year as pediatric chief resident. He completed a fellowship in allergy and clinical immunology at Yale University from 2008-11. Tr. 257-59; exhibit GG.15 In 2011, Dr. Romberg began his teaching career at Yale. He remained at Yale with various titles and responsibilities until 2015. During this time, he obtained his board certification in allergy and immunology. He also wrote at least six papers about immunology, which were published in peer reviewed journals. Some of the papers focus on B cells. Exhibit GG at 3-5. Through grants, the National Institute of Health funded his research on human immunology. Tr. 259. In 2015, he was appointed to the Jeffrey Modell Chair of Pediatric Immunology Research at Children’s Hospital of Philadelphia. Dr. Romberg explained that this position gives him indefinite funding for his research on deficiencies in the immune system. Tr. 260. Although Dr. Romberg’s primary vocation is research, Tr. 259, he also treats children whose immune systems are missing parts. Tr. 275. He estimated that he has treated 40-60 patients with pneumonia, although he did not specify whether the patients with pneumonia also had defective immune systems and did not specify whether pneumococcus caused the pneumonia. Tr. 401. Overall, Dr. Romberg’s knowledge about immunology was impressive. His demeanor and the content of this testimony demonstrated that he understood how the human immune system functions to a level of great detail. He took care to be 15 Exhibit GG is an updated version of Dr. Romberg’s curriculum vitae. The previous curriculum vitae was filed as exhibit B. 15 Case 1:13-vv-00675-MMS Document 90 Filed 03/22/17 Page 16 of 28 precise in his wording. See Tr. 358. On immunologic topics, Dr. Romberg was, simply, a much stronger witness than Dr. Lokshin. See Moberly, 592 F.3d at 1326 (recognizing that special masters are obligated to evaluate the evidence, including the experts, before them).16 2. Principles of Immunology Related to Pneumococcal Infection Because the petitioners maintain that the MMR vaccine impaired Rhone’s ability to create T cells and the ensuing lack of T cells created a vulnerability to a pneumococcal infection, their case depends on T cells preventing a pneumococcal infection in a human being. As expert testimony unfolded, there was little dispute about the principles underlying the immune system’s response to pneumococcal infection. Dr. Lokshin agreed with Dr. Romberg about multiple things that undermine a primary role for T cells in fighting pneumococcal infection. As outlined below, both Dr. Lokshin and Dr. Romberg agreed that an effective response to pneumococcal infection requires both the innate immune system and antibodies from the adaptive immune system. Additionally, Dr. Lokshin did not dispute that T cells do not respond directly to pneumococcal infection (most likely because the external surface of pneumococcus is primarily composed of polysaccharides). Further, Dr. Lokshin did not dispute Dr. Romberg’s observations regarding humans suffering from X-linked agammaglobulinemia and severe combined immune deficiency (SCID), which strongly support the argument that T cells are expendable in the body’s response to pneumococcal infection. In short, the following concessions by Dr. Lokshin undermine his ability to maintain that T cells have a significant role in fighting pneumococcal infection in human beings. 16 As mentioned earlier, the theory that the DePenas and Dr. Lokshin advanced involved immunology. Therefore, the qualifications of the respective experts in immunology are paramount. In saying that Dr. Lokshin was not as persuasive on immunology, the undersigned does not intend to denigrate Dr. Lokshin’s qualifications as a pediatric pulmonologist. 16 Case 1:13-vv-00675-MMS Document 90 Filed 03/22/17 Page 17 of 28 A. An Effective Response to Pneumococcal Infection requires both the Innate Immune System and Antibodies from the Adaptive Immune System Throughout this litigation, Dr. Romberg has maintained that in response to pneumococcal infections, T cells are expendable. In his first report, Dr. Romberg wrote: It has been known for more than 6 decades that serum soluble factors like complement components, C-reactive protein and immunoglobulins form the basis of human immunity to Streptococcus Pneumonia. These serum proteins target the capsular polysaccharide residues that cover pneumococcus and it is the presence of pneumo[co]ccal-specific IgG antibodies especially which confer meaningful protection to blood borne and lung infections. Exhibit A at 3. He continued this position in a subsequent report and in his testimony. Exhibit P at 3; Tr. 273, 418, 439-40. On the other hand, Dr. Lokshin’s reports and testimony focused on the role of T cells. E.g., Tr. 215, 485. He attempted to explain that T cells are a part of the body’s response to a pneumococcal infection. Near the end of the second hearing day, Dr. Lokshin presented his views on the value of antibodies. He stated: antibodies “are highly effective. I don’t think anybody disagree[s] with that, and that’s a pretty old finding that is well established, and there is absolutely no disagreement about that.” Tr. 460. Later still in his testimony, Dr. Lokshin also agreed that the innate immune system also “has [a] very big role in killing pneumococcus. That’s not in question.” Tr. 467. With these two passages, Dr. Lokshin has essentially agreed with Dr. Romberg that an effective response to a pneumococcal infection can come from the innate immune system and antibodies. The only remaining question is whether T cells contribute to this response. B. T Cells Do Not Respond Directly to a Pneumococcal Infection On a very simple level, antibodies respond to polysaccharides, and T cells respond to proteins. The capsule of pneumococcus is (mostly) comprised of 17 Case 1:13-vv-00675-MMS Document 90 Filed 03/22/17 Page 18 of 28 polysaccharides. See Tr. 216-17 (Dr. Lokshin). Therefore, antibodies (and not T cells) respond to pneumococcus. Although the connection between antibodies and polysaccharides and the lack of connection between T cells and polysaccharides was generally not disputed, Dr. Romberg explained some of the highly technical experiments underlying these postulates. For example, he discussed an article reporting on competitive affinity experiments that demonstrated that T cells cannot see polysaccharides.17 Tr. 299-302, 421-24 (both discussing exhibit W (Clifford V. Harding et al., Effects of pH and polysaccharides on peptide binding to class II major histocompatibility complex molecules, 88 Proc. of Nat’l Acad. of Sci. of the United States of America 2740 (1991))). According to the abstract, the Harding article shows “T-cell independence of polysaccharide antigens.” Exhibit W at 2740. T cell independence was another way in which the disagreement between Dr. Lokshin and Dr. Romberg was manifest, particularly in regard to exhibit X (James J. Mond et al., T Cell-Independent Antigens Type 2, 13 Annual Review Immunology 655 (1995)). Dr. Lokshin quoted a portion of this article that states: “All of these studies demonstrated that responses to TI [T cell independent] antigens could be T cell regulated and/or T cell dependent, despite their inability to stimulate MHC class II-dependent T cell help; thus their classification as T cell- independent is not entirely accurate.” Tr. 147 (quoting exhibit X at 663). From this basis, Dr. Lokshin asserted that T cell independence is a relative term. Tr. 149-50. When asked about this passage, Dr. Romberg stated that T cells can help B cells make antibodies but producing antibodies that depend on T cells takes four to six weeks. Tr. 306; Cf. Tr. 419 (Dr. Romberg stating that he had not reviewed the underlying studies and, therefore, he could not comment on this portion of the Mond article). On the other hand, the same Mond article also discussed pneumococcus specifically. Mond stated: “Early studies with Pneumococcus and other encapsulated and nonencapsulated organisms established the T cell-independence of the antibody response to the polysaccharide component.” Exhibit X at 679. After citing Mond and Harding in his second expert report, Dr. Romberg asserted: “Carbohydrate antigens like those on pneumococcus belong to the category named type II T-cell independent antigens.” Exhibit P at 3. When asked in the first hearing about Dr. Romberg’s classifying pneumococcus as a T cell independent 17 More technically, for a T cell to respond to a foreign invader, an antigen presenting cell must interact with the invader. Tr. 525; see also Tr. 422-23. 18 Case 1:13-vv-00675-MMS Document 90 Filed 03/22/17 Page 19 of 28 antigen, Dr. Lokshin agreed. Tr. 217-18. Dr. Lokshin’s admission that pneumococcus is a T cell independent antigen undermines much of his opinion.18 Prior to the second hearing, however, petitioners submitted additional exhibits to further support the possibility that T cells can respond directly to pneumococcus. See Tr. 466; exhibits 25, tab 7 (Qibo Zhang et al., Low CD4 T Cell Immunity to Pneumolysin Is Associated with Nasopharyngeal Carriage of Pneumococci in Children, 195 J. Infect. Dis. 1194 (2007)); exhibit 25, tab 10 (Adam K. A. Wright, Experimental Human Pneumococcal Carriage Augments IL- 17A-dependent T-cell Defence of the Lung, 9(3) PLOS Pathogens 1 (2013)); exhibit 25, tab 11 (Mureithi); Pet’rs’ Posth’g Br. Reply, filed Aug. 26, 2016, at 1-4 (discussing the exhibits submitted between the first and second hearing). In support of a direct T cell response, petitioners argued T cells can respond to proteins, and that many capsular proteins have been isolated on the pneumococcal capsule, thus allowing T cells to see the pneumococcal capsule and respond. Tr. 441-42, 461. This argument, however, led to a nuanced discussion of how T cells function, a discussion which further highlighted Dr. Romberg’s more thorough understanding of the human immune system when compared to Dr. Lokshin. Dr. Romberg did not dispute the presence of proteins outside the pneumococcal capsule, but did draw on important distinctions that undermined petitioners’ response theory. See Tr. 443. He noted that the proteins outside of the pneumococcal capsule are not part of the capsule, that although proteins may be present they are not necessarily targetable by the immune system, and that T cells cannot see proteins directly, but only interact with them through an antigen- presenting cell. See Tr. 443, 524-525. Despite the additional articles providing some evidence to the contrary, Dr. Lokshin conceded that T cells do not respond directly to pneumococcal infection. He emphasized that the T cells’ alternate role in attacking pneumococcus, testifying: “It’s important I think for us because it is not necessarily the T-cells themselves have [sic] to kill something. They may influence other parts of immune [sic] system that will do the job; specifically, innate [sic] immune system.” Tr. 466. 18 On redirect, the petitioners’ attorney attempted to “clarify” this testimony. However, the exchange between counsel and Dr. Lokshin was confusing and did not provide a persuasive reason for rescinding Dr. Lokshin’s earlier statement that pneumococcus is a T cell independent antigen. See Tr. 244-50. 19 Case 1:13-vv-00675-MMS Document 90 Filed 03/22/17 Page 20 of 28 C. Human Beings’ Experience with Diseases is Consistent with the Distinction between T Cells and B Cells In addition to the persuasive immunological studies cited by Dr. Romberg, his experience treating people with dysfunctional immune systems allowed him to add insights about the significance of the difference between T cells and B cells in preventing diseases. Some people do not produce B cells and they suffer from a disease known as X-linked agammaglobulinemia. Tr. 275-76. These people without B cells are vulnerable to pneumococcal infections, which they get repeatedly unless they receive antibodies. Exhibit J (Ogden C. Bruton, Agammaglobulinemia, 9 Pediatrics 722 (1952)). Dr. Romberg interpreted the Bruton article as showing that T cells alone do not prevent pneumococcal infections. If T cells alone were effective, then the child reported in the Bruton article would not have suffered multiple pneumococcal infections. The boy’s improvement after receiving antibodies is further evidence that the reason for the repeated pneumococcal infections was due to a problem in the B cells. Tr. 275-76. When asked about this article, Dr. Lokshin agreed that “If somebody gets antibodies, they will stop getting sick [with pneumococcal infections].” Tr. 505. A different situation occurs with people suffering from severe combined immune deficiency (SCID). People with SCID lack T cells and have either no B cells or defective B cells. When untreated, they get many infections, including fungal, viral, parasitic, and pneumococcal infections. After they receive antibodies, people with SCID do not develop pneumococcal infections, although they continue to develop other types of infections. Tr. 276-77. Again, Dr. Lokshin did not disagree with Dr. Romberg on this point, although Dr. Lokshin noted that the effectiveness of antibodies in responding to pneumococcus does not provide any information about the effectiveness of T cells. Tr. 460. 3. Petitioners’ New Immunology Theory Related to Pneumococcal Infection Against this background of well-established and generally accepted precepts of immunology, Dr. Lokshin proposes a new idea. In Dr. Lokshin’s opinion, a human being’s response to a pneumococcal infection includes a role for T cells. Tr. 105, 114-16, 181-82.19 To support this opinion, Dr. Lokshin initially relied upon murine (mouse) studies and later added articles based on human beings. 19 This step links the MMR vaccine, which can rarely depress the production of T cells, to a pneumococcal infection. 20 Case 1:13-vv-00675-MMS Document 90 Filed 03/22/17 Page 21 of 28 Before examining the support provided by Dr. Lokshin, it bears repeating that he seems ill-equipped to topple established immunologic ideas, such as T cells do not respond to polysaccharides. Dr. Lokshin does not routinely treat patients with immunologic disorders, he does not teach classes of medical school students in immunology, he does not have any advanced certifications in immunology, and he does not currently author articles on immunology. In short, when the topic is cutting-edge immunology, Dr. Lokshin has less qualifications to present new ideas persuasively. A. Mouse Studies In Dr. Lokshin’s initial reports, he cited several articles that reported on experiments using mice. In these tests, the researchers discovered that mice do produce T cells in response to a pneumococcal infection. At hearing, Dr. Romberg agreed that mice respond to pneumococcus infection by having a particular type of T helper cell, which is known as Th17, produce IL17. Tr. 284, 354, 516.20 Dr. Lokshin attempted to argue that what happens in mice is what happens in human beings. Tr. 135. The Federal Judicial Center (“FJC”) has published a series of guides designed to “assist judges ... in reaching an informed and reasoned assessment concerning the basis of expert evidence.” Jerome P. Kassirer & Gladys Kessler, Preface to Reference Manual on Scientific Evidence, at xv (Federal Judicial Center, 3d ed. 2011). With respect to animal studies, the FJC offered the following guidance: “The expert should review similarities and differences in the animal species in which the compound has been tested and in humans. This analysis should form the basis of the expert’s opinion as to whether extrapolation from animals to humans is warranted.” Bernard D. Goldstein and Mary Sue Henifin, “Reference Guide on Toxicology,” in Reference Manual on Scientific Evidence (3d ed. 2011) at 661. In considering the usefulness of animal studies, a starting point is that “there is an overwhelming similarity in the biology of all living things and a particularly strong similarity among mammals.” Id. at 662. However, this is not an iron-clad rule as “laboratory animals differ from humans in many ways.” Id. 20 IL 17 is an interleukin type of cytokine. See Dorland’s at 949. Cytokines, in turn, are proteins by which cells of the immune system communicate. Id. at 466. 21 Case 1:13-vv-00675-MMS Document 90 Filed 03/22/17 Page 22 of 28 In this case, although Dr. Lokshin wanted to extrapolate from mice to humans, he did not review the similarities and differences between mice and humans. This leads to a gap in his opinion.21 Moreover, Dr. Romberg disagreed with Dr. Lokshin’s comparison, stating that with respect to the response to pneumococcal infections, mice differ from people. Tr. 285-86; see also Tr. 120 (Dr. Lokshin: “mice are not identical to humans”), 281 (Dr. Lokshin: “Mouse immunology is not human immunology.”). Literature supports this differentiation. One article stated that “mice lacking the Ill7a and Ill7ra genes or, to a lesser extent, the Ill7f gene, are susceptible to a broad range of infections with bacterial and fungal pathogens at the mucosal surface. In contrast, human patients lacking a component of IL-17 immunity due to a genetic defect, have a narrower spectrum of pathogen susceptibility.” Exhibit KK (Sophie Cypowyj et al., Immunity to infection in IL-17-deficient mice and humans, 42(9) Eur. J. Immunol. 2246 (2012)) at 2247; see also Tr. 286-87 (Dr. Romberg’s discussion of Cypowyj). An editorial presented a similar point, using less complex language. The authors wrote: “Translation of many other important findings from murine models to humans has been rather disappointing. This is best exemplified by models of autoimmunity and cancer immunotherapy where numerous studies showing promising outcomes in murine models have achieved limited success in a human setting.” Exhibit NN (Rajiv Khanna and Scott R. Burrows, Human immunology: a case for the ascent of non-furry immunology, 89 Immunol. and Cell Biology 330 (2011)) at 330. These authors continued: “Confidence in these model systems has eroded, as we now know that there are significant differences in human physiology and the immune regulatory pathways from these animal models.” Id. This evidence has undermined the assumption that Dr. Lokshin appears to have made about the transferability of mouse studies on pneumococcus to human beings. Without some reliable showing that an extrapolation from mice to people is appropriate, the studies based upon mice are not useful. B. Human Studies In addition to studies on mice, Dr. Lokshin relied upon human studies to show that a person’s response to a pneumococcal infection involves T cells. One 21 Dr. Lokshin sometimes suggested that an extrapolation from mice to humans must be appropriate because otherwise scientists would not conduct experiments on mice. Tr. 135-36; 138. This suggestion is illogical and not persuasive. See Tr. 281. 22 Case 1:13-vv-00675-MMS Document 90 Filed 03/22/17 Page 23 of 28 person exploring this possible connection is Richard Malley, a researcher at Harvard Medical School and Boston Children’s Hospital. Dr. Malley is attempting to develop a vaccine against pneumococcus that stimulates the production of T cells. One advantage to this type of vaccine is that one dose of the vaccine could lead to immunity from many (possibly all) strains of pneumococcus. There is no doubt that some research is being done in the field. For example, petitioners submitted an excerpt showing that the National Institutes of Health has funded research into a T cell based vaccine against pneumococcus. Exhibit 25, tab 8 (Kristin Leigh Moffitt, Innate and acquired immune responses to novel pneumococcal T cell antigens, Grantome (January 27, 2017), http://grantome.com/grant/NIH/K08-AI095352-04); see also Tr. 447-48. Dr. Lokshin is “optimistic” about this research. Tr. 502. Petitioners also submitted a press release in which a manufacturing company, Genocea, touted its progression to “phase 2” for “a novel T cell vaccine” against pneumococcal colonization. Exhibit 25, tab 9 (GEN-004 for Pneumococcus, Genocea Biosciences (Feb. 28, 2016), http://www.genocea.com/pipeline/gen004-for-pneumococcus/). Under some circumstances, this undergirding could reinforce Dr. Lokshin’s opinion. However, the company’s phase 2 trials did not show any statistically significant improvement. Thus, the company suspended further development of the vaccine. Exhibit 25, tab 9 (Genocea Biosciences); see also Tr. 437-40. This failure suggests, although one failure does not absolutely prove, that the theory needs reexamination. See Daubert, 509 U.S. at 593 (recognizing whether a theory has been tested as one factor that may be considered in evaluating an expert’s opinion); Terran, 195 F.3d at 1316 (endorsing a special master’s use of Daubert in the Vaccine Program). Dr. Lokshin acknowledged that research into a T cell based vaccine is “just too early” and “not moving as fast as we want.” Tr. 501-02; accord Tr. 472-73 (Dr. Lokshin’s testimony that the Genocea article does not constitute definitive proof of the effectiveness of a pneumococcus vaccine based on T cells). Despite the lack of success in developing a T cell based vaccine against pneumococcus, Dr. Lokshin relied upon several other articles either written with Dr. Malley or based upon his work. The goal of developing a T cell based vaccine is certainly laudatory – a successful T cell based vaccine could protect against many (maybe all) strains of pneumococcus. The potential benefits, especially in the regions of the world with less access to medical care, could be immense. 23 Case 1:13-vv-00675-MMS Document 90 Filed 03/22/17 Page 24 of 28 However, the worthiness of the pursuit does not automatically make any of Dr. Malley’s studies a reliable basis for an expert’s opinion. As previously mentioned, Dr. Lokshin relied upon several articles from Dr. Malley or Dr. Malley’s associates. The undersigned reviewed this material multiple times and has considered the testimony from both Dr. Lokshin and Dr. Romberg about those articles. 22 The articles did not present a persuasive basis for toppling the generally accepted principle in immunology that a human being’s response to a pneumococcal infection does not involve T cells. Althen Analysis The previous section explains why Dr. Romberg’s opinion was more persuasive than Dr. Lokshin’s opinion. These reasons include Dr. Romberg’s superior qualifications in immunology, the well accepted and well demonstrated idea that T cells cannot recognize polysaccharides, and the undeveloped effort to overturn immunologic dogma. The remaining task is to place these findings in the context of the Althen criteria. To review, the Federal Circuit set forth the petitioner’s burden regarding causation in off-Table cases as “(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.” Althen, 418 F.3d at 1278. 1. Prong 3: Timing The third prong of Althen requires “a showing of a proximate temporal relationship between vaccination and injury.” Id. As part of their case-in-chief, the petitioners bear the burden of establishing that the onset of their child’s disease 22 Petitioners noted multiple articles showing relationships between the quantity of T cells and pneumococcal infection to support the concept that T cells influence other parts of the immune system to respond to pneumococcus. See exhibits 25 tab 7 (Zhang), 25 tab 10 (Wright), 25 tab 11 (Mureithi); see, e.g., Tr. 475 (discussing exhibit 25 tab 10). For example, Wright states that “increased rates of pneumococcal carriage in children and clinical cases of pneumonia in adults were associated with a reduction in circulating . . . T-cells.” Dr. Romberg agreed that there is likely a relationship, but explained the relationship by stating that T cells probably affect pneumococcal infection by helping B cells to secrete antibodies – an idea inconsistent with petitioners’ theory because it highlights the significance of B cells, vice T cells, in responding to pneumococcal, and creates a timing issue. See Tr. 306 (Dr. Romberg stating that T cells can help B cells make antibodies, however producing antibodies that depend on T cells takes four to six weeks); 446, 515. 24 Case 1:13-vv-00675-MMS Document 90 Filed 03/22/17 Page 25 of 28 occurred within an acceptable time. Bazan v. Sec’y of Health & Human Servs., 539 F.3d 1347, 1352 (Fed. Cir. 2008). This formulation implies that the third prong from Althen actually contains two parts. First, there must be a showing that a range of time is “acceptable” to infer causation. Second, there must be a showing that the vaccinee’s disease arose in this acceptable time. Shapiro v. Sec’y of Health & Human Servs., 101 Fed. Cl. 532, 542–43 (2011), recons. denied after remand on other grounds, 105 Fed. Cl. 353 (2012), aff’d per curiam, 503 F. App’x 952 (Fed. Cir. 2013). Before the hearing, the Secretary conceded that Rhone’s pneumococcal infection developed within a “medically acceptable timeframe.” Resp’t’s Preh’g Br., filed Jan. 27, 2016, at 23. Thus, the DePenas have met their burden of proof on this prong. However, a finding in a petitioner’s favor on prong 3, by itself, does not mean that the petitioner is entitled to compensation. Hibbard v. Sec’y of Health & Human Servs., 698 F.3d 1355, 1364 (Fed. Cir. 2012) (holding that the special master did not err in resolving case based upon the second prong of the Althen test); Grant v. Sec’y of Health & Human Servs., 956 F.2d 1144, 1148 (Fed. Cir. 1992) (“Temporal association is not sufficient, however, to establish causation in fact.”). The petitioners are required to establish the first and second Althen prongs, which is where their case falters. 2. Prong 1: Theory The first prong from Althen requires the petitioners to establish “a medical theory causally connecting the vaccination and the injury.” Althen, 418 F.3d at 1278. The Court of Federal Claims has interpreted this portion of Althen as requiring not simply the presentation of a theory, but the presentation of a persuasive theory. M.S.B. by Bast v. Sec’y of Health & Human Servs., 117 Fed. Cl. 104, 123 (2014), appeal dismissed, 579 F. App’x 1001 (Fed. Cir. 2014); Taylor v. Sec’y of Health & Human Servs., 108 Fed. Cl. 807, 819 (2013). For the reasons previously set forth, Dr. Lokshin has failed to establish the reliability of his theory that T cells have a substantive role in a human being’s response to a pneumococcal infection. The theory Dr. Lokshin advanced seems contrary to what science knows about the immune system of human beings. It is not persuasive. Therefore, the petitioners have not met their burden regarding prong 1. 25 Case 1:13-vv-00675-MMS Document 90 Filed 03/22/17 Page 26 of 28 3. Prong 2: Logical Sequence of Cause and Effect Given that the DePenas have failed to establish prong 1, it follows that they have also failed to establish prong 2. See Caves v. Sec’y of Health & Human Servs., 100 Fed. Cl. 119, 134 (2011) (discussing the logical connections between prongs 1 and 2). Nevertheless, to demonstrate that the entire record has been reviewed, the following factors have also been considered. Treating Doctors. In connection with prong 2, the Federal Circuit has instructed special masters to consider carefully the views of treating doctors. Capizzano v. Sec’y of Health & Human Servs., 440 F.3d 1317, 1326 (Fed. Cir. 2006). The DePenas conceded that they are “unaware of any statements expressed by treating doctors that indicate the MMR vaccine caused [Rhone] DePena’s vulnerability to pneumococcal infection.” Pet’rs’ Preh’g Br., filed Dec. 15, 2016, at 19. An independent review of the record has also not located any suggestions that treating doctors linked Rhone’s receipt of the MMR vaccine to his pneumococcal pneumonia. Thus, this factor does not weigh in the petitioners’ favor. Challenge-Rechallenge. The Federal Circuit defined a rechallenge event as one in which “a patient who had an adverse reaction to a vaccine suffers worsened symptoms after an additional injection of the vaccine.” Capizzano, 440 F.3d at 1322. Here, Dr. Lokshin initially indicated that Rhone’s case fell into the challenge-rechallenge paradigm. A foundation for this opinion was an assumption that Rhone developed a rash shortly after receiving his first dose of the MMR vaccine. See exhibit 21 (Dr. Lokshin report) at 3; exhibit 8 (Ms. DePena’s Detailed Statement) at 1. However, further development of the evidence eliminated this foundation because Rhone’s rash developed approximately one year after the MMR vaccine. On cross-examination, Dr. Lokshin graciously recognized that Rhone did not manifest challenge-rechallenge. Tr. 196. Removing one of the beams of support for Dr. Lokshin’s opinion results in a slight weakening of his opinion. Titer levels after the vaccine and more recently. Before the first hearing, the DePenas submitted the results of testing conducted on October 11, 2010. This testing, which was conducted after Rhone developed pneumonia, showed that his IgG antibody titers were below the level to confer immunity for several strains. Exhibit 7 at 501; see also Tr. 168, 327, 334. Rhone’s parents testified that he has 26 Case 1:13-vv-00675-MMS Document 90 Filed 03/22/17 Page 27 of 28 not developed pneumonia after he was hospitalized for pneumonia in 2010. Tr. 34, 59. From these two facts, Dr. Lokshin drew the inference that the only difference between Rhone in 2010 and Rhone in the ensuing five years was that Rhone received the MMR vaccine in 2010. This exposure to the MMR vaccine, according to Dr. Lokshin’s theory, created a vulnerability in Rhone that was not present in other times of his life. Tr. 144-45. Dr. Romberg’s response included an observation that Rhone’s current levels were not known. Tr. 333-34. Therefore, between the first hearing and the second hearing, the DePenas had Rhone tested. His antibody levels from 2016 remained below protective levels for several strains. Exhibit 27; see also Tr. 455, 489. To Dr. Lokshin, this finding reinforced his conclusion that antibodies cannot be the only way to prevent infection because if antibodies were the only way to prevent infection, Rhone would have become infected again. Tr. 489-90, 502-03; see also exhibit 30 (Dr. Lokshin’s post-hearing expert report) at 7-9; Pet’rs’ Posth’g Reply, filed Aug. 26, 2016, at 9. This reasoning is not persuasive. First, the process from colonization to infection is not understood. Some people develop pneumococcal pneumonia entirely apart from an MMR vaccination. The factor (or factors) that permitted pneumococcal infections in those cases could have been present in Rhone. To isolate the MMR vaccination and consequent decrease in T cells as the reason for Rhone’s pneumococcal pneumonia seems to overlook many other potentially contributory factors. For example, the particular bacteria that infected Rhone in 2010 could have been especially virulent and Rhone could have encountered more mild bacteria since then. See Tr. 251; exhibit I (E. Alonso DeVelasco et al., Streptococcus pneumoniae: Virulence Factors, Pathogenesis, and Vaccines, 59(4) Microbiological Reviews 591 (1995)); exhibit 23 (Dr. Lokshin’s report) at 2. The variability in type of pneumococcal infection, ranging from relatively mild cases of ear infections, to full blown pneumonia, further suggests that process from colonization to infection is complicated. Second, Dr. Lokshin appears to misunderstand Dr. Romberg’s opinion. Dr. Lokshin asserted that “The ‘titers’ are the antibody levels that, according to Dr. Romberg's theory, is the one and only protection from the pneumococcal infection.” Exhibit 31 at 1. Actually, Dr. Romberg listed parts of the innate immune system, such as complement, as contributing to the protection against pneumococcal infection. Exhibit A at 3; exhibit P at 3; Tr. 326-27. These parts of 27 Case 1:13-vv-00675-MMS Document 90 Filed 03/22/17 Page 28 of 28 Rhone’s innate immune system could have protected him from further pneumococcal infection in the past six years.23 Conclusion Rhone’s pneumococcal pneumonia inflicted a toll on him and his parents. His parents demonstrated their concern for Rhone’s well-being during their testimony and have reached the belief that the MMR vaccine caused the pneumonia. However, the evidence does not rise to a “more likely than not” level. The more persuasive evidence is consistent with a finding that the MMR vaccine did not alter the effectiveness of Rhone’s innate immune system or his ability to produce antibodies in response to pneumococcus. Thus, the DePenas have not established that the MMR vaccine contributed to Rhone’s pneumococcus infection. The DePenas are not entitled to compensation. The Clerk’s Office is instructed to issue judgment in accord with this decision. IT IS SO ORDERED. S/ Christian J. Moran Christian J. Moran Special Master 23 More generally, Dr. Lokshin contended that human beings’ response to pneumococcus cannot depend on antibodies because the lag in producing antibodies would permit pneumococcus to flourish and to kill the host. See Tr. 110-11. The innate immune system is a partial response to Dr. Lokshin. The other part of the response is that pneumococcus unfortunately has killed many people over the millennia. See Tr. 156-57, 329. The advent of antibiotics prevents many deaths from pneumococcus. See exhibit 31 (Dr. Lokshin’s second post-hearing report) at 2; Tr. 218. 28 ================================================================================ DOCUMENT 2: USCOURTS-cofc-1_13-vv-00675-2 Date issued/filed: 2017-08-25 Pages: 17 Docket text: JUDGE VACCINE REPORTED OPINION reissuing 103 Judge Vaccine Order/Opinion. Signed by Judge Margaret M. Sweeney. (kb1) -------------------------------------------------------------------------------- Case 1:13-vv-00675-MMS Document 105 Filed 08/25/17 Page 1 of 17 In the United States Court of Federal Claims No. 13-675V (Filed Under Seal: August 9, 2017) (Reissued for Publication: August 25, 2017)1 ************************************* BO DEPENA and NATALIE DEPENA, * legal representatives of a minor child, R.D., * * Petitioners, * Vaccine Act; Motion for Review; MMR * Vaccine; Severe Pneumonia; Althen; v. * Causation-in-Fact; Consideration of Medical * Literature; Expert Credibility SECRETARY OF HEALTH AND * HUMAN SERVICES, * * Respondent. * ************************************* Michael Baseluos, San Antonio, TX, for petitioners. Heather L. Pearlman, United States Department of Justice, Washington, DC, for respondent. OPINION AND ORDER SWEENEY, Judge Petitioners Bo and Natalie DePena seek compensation under the National Childhood Vaccine Injury Act of 1986 (“Vaccine Act”), 42 U.S.C. §§ 300aa-1 to -34 (2012), alleging that their son, R.D.,2 developed severe pneumonia as a result of a Measles-Mumps-Rubella (“MMR”) vaccination. In a February 22, 2017 decision, the special master denied petitioners’ request for compensation. Before the court is petitioners’ motion for review of the special master’s decision. For the reasons set forth below, the court denies petitioners’ motion and sustains the decision of the special master. 1 Vaccine Rule 18(b), contained in Appendix B of the Rules of the United States Court of Federal Claims (“RCFC”), affords each party fourteen days in which to object to the disclosure of (1) trade secrets or commercial or financial information that is privileged or confidential or (2) medical information that would constitute “a clearly unwarranted invasion of privacy.” Neither party objected to the public disclosure of any information contained in this opinion. 2 Because R.D. is a minor, the court will refer to him by his initials. See RCFC 5.2(a). Case 1:13-vv-00675-MMS Document 105 Filed 08/25/17 Page 2 of 17 I. BACKGROUND A. R.D.’s Medical History R.D.’s medical history, which is undisputed by the parties, can be briefly summarized.3 R.D. was born in 2003. He received his first MMR vaccination in August 2004. He also received three pneumococcal conjugate vaccinations–which protected against seven strains of Streptococcus pneumoniae (“pneumococcus”)–in November 2003, March 2004, and June 2005. On September 15, 2010, during an appointment with his pediatrician, R.D. received several vaccinations, including a second MMR vaccination. Two days later, R.D.’s mother reported that R.D. had a bad reaction to the vaccinations, and there is photographic evidence of raised dots on R.D.’s thigh. Then, on September 25, 2010, petitioners took R.D. to the emergency room because he was experiencing lower back pain; R.D. also had a two-day history of cough and a higher-than-normal temperature. The emergency room doctors diagnosed an acute viral syndrome. Because R.D.’s health did not improve, his mother took him to his pediatrician on September 28, 2010. R.D. had a high fever, his skin had a grayish color, and he made grunting sounds when breathing. A chest x-ray revealed bilateral pneumonia. R.D. was admitted to the hospital. During the hospitalization, R.D.’s physicians determined that pneumococcus was the cause of R.D.’s pneumonia. They further determined, after testing R.D.’s blood for the presence of antibodies against fourteen serotypes (i.e., strains) of pneumococcus, that R.D. had protective levels of antibodies for only three serotypes. Due to the severity of his pneumonia, R.D. remained hospitalized for twenty-one days, and ultimately was discharged on October 18, 2010. In the years following his discharge from the hospital, R.D. was diagnosed with mild reactive airway disease and prescribed an inhaler, a CT scan revealed slight scarring in R.D.’s chest, and a spirometry test was normal. By 2016, R.D.’s condition had improved. Moreover, even though testing conducted in 2016 revealed that R.D. did not have protective levels of antibodies for thirteen serotypes of pneumococcus, he had not suffered from any episodes of pneumonia since his 2010 hospitalization. B. Medical and Scientific Background In their motion for review, petitioners contend that the special master erred by rejecting their theory that R.D.’s September 15, 2010 MMR vaccination caused R.D.’s severe pneumonia. However, neither they nor respondent contests much of the medical and scientific background 3 The court derives this information from the special master’s decision. See generally DePena v. Sec’y of HHS, No. 13-675V, 2017 WL 1075101, at *2-6 (Fed. Cl. Spec. Mstr. Feb. 22, 2017). -2- Case 1:13-vv-00675-MMS Document 105 Filed 08/25/17 Page 3 of 17 information contained in the special master’s decision. Because this information provides context for the arguments set forth in petitioners’ motion for review, the court briefly recounts it. 1. Operation of the Immune System As an initial matter, the special master provided a basic explanation of the immune system: A body’s responses to foreign invaders, often called antigens or pathogens, are controlled by the immune system. Immunologists generally divide the immune system into two branches: the innate immune system and the adaptive immune system. Innate Immune System. The innate immune system is relatively primitive. The innate immune system generally recognizes foreign invaders. Components of the innate immune system include cytokines, natural killer cells, and complement. . . . . Adaptive Immune System. In comparison to the innate immune system, the adaptive immune system is more advanced. The adaptive immune system recognizes specific antigens. The adaptive immune system contains two types of cells: B cells and T cells. . . . B cells. B cells make antibodies. Antibodies, in turn, can be classified into different types of immunoglobulin. Antibodies recognize polysaccharides (or sugars). Antibodies’ ability to respond to polysaccharides is one trait that distinguishes them from T cells. T cells. The other part of the adaptive immune system is T cells. T cells derive their name from the thymus, where they mature. T cells are further classified. The basic division is into two groups, known as cytotoxic T cells and helper T cells. Cytotoxic T cells, which are also known as CD8+ cells, kill cells that are infected by viruses. . . . There are multiple types of helper T cells, also known as CD4+ cells. Th1 cells help cytotoxic T cells kill cells infected with infectious agents, especially viruses. Th2 cells help B cells. Th17 cells help cells at the mucosal level respond to infections . . . . Another type of helper T cell makes sure that the immune -3- Case 1:13-vv-00675-MMS Document 105 Filed 08/25/17 Page 4 of 17 system does not overrespond. These helper T cells are known as T regulatory cells. DePena, 2017 WL 1075101, at *5-6 (footnotes and citations omitted). 2. The MMR Vaccine and the Measles Virus The special master also provided information regarding the MMR vaccine and the measles virus: The MMR vaccine is an attenuated vaccine, that is, the vaccine contains a weakened form of the live measles virus. In its wild (or natural) state, the measles virus is extremely virulent. Measles causes the death of thousands of unvaccinated people each year. The people who survive measles infection are more vulnerable to infection from other pathogens for 1-4 weeks. Scientists have recently theorized that the measles virus destroys the memory aspect of the survivor’s immune system. Without this memory in their immune system, survivors of the measles virus may be unable to fight off infection and may contract diseases. Id. at *4. He further explained “that the MMR vaccine can have the same consequence as the wild measles virus: a suppression of some parts of the adaptive immune system.” Id. 3. Pneumococcus Finally, the special master described pneumococcus and how the body can react to it: Pneumococcus is a type of bacterium. There are more than 90 strains of pneumococcus and the numerous strains contribute to the difficulty in developing an effective vaccine. The outside capsule of pneumococcus is comprised of polysaccharides. Polysaccharides are carbohydrates, like sugars. When faced with a polysaccharide invader, the body’s adaptive immune system responds by producing antibodies, which come from B cells, and the body does not produce T cells in response. Consequently, pneumococcus has been categorized as a type II T cell-independent antigen. The body’s encounter with pneumococcus is unusual in the sense that the first step is colonization. Colonization means that a strain of pneumococcus is living in a person’s nose and throat. This nasopharyngeal colonization is extremely common with estimates exceeding 25 percent. Colonization, which is also known as carriage, is especially frequent in the very young and the very old. -4- Case 1:13-vv-00675-MMS Document 105 Filed 08/25/17 Page 5 of 17 During colonization of the mucosal surfaces of the nose and throat, the body’s adaptive immune system produces an antibody known as immunoglobulin A. On some occasions, and in some people, a colonization resolves without a worsening of symptoms. However, pneumococcus can also migrate from the nasopharynx to other portions of the body. . . . [R]elatively little is known about how this change occurs. When pneumococcus moves to the ears and sinuses, it causes otitis media and sinusitis. These types of infections are both relatively common and mild. It is much more alarming when pneumococcus infects the lungs, causing a condition called pneumococcal pneumoniae. In the United States in 2015, more than one million people suffered from pneumococcal pneumoniae. Id. at *3 (citations omitted). He further noted that “the innate immune system contributes to how the body responds when pneumococcus becomes infectious.” Id. at *5. II. PROCEDURAL HISTORY Petitioners filed a petition for compensation under the Vaccine Act on September 12, 2013. Upon reviewing R.D.’s medical records, respondent recommended that the special master deny petitioners compensation. Thereafter, the parties submitted expert reports. Petitioners ultimately provided the special master with six submissions–five reports and a response to a legal brief–from pediatric pulmonologist Boris M. Lokshin, M.D., and respondent provided three reports from pediatric immunologist Neil D. Romberg, M.D. The special master convened an evidentiary hearing,4 during which he heard the testimony of Dr. Lokshin and Dr. Romberg. The parties offered posthearing submissions, and the special master issued a decision on February 22, 2017. In his decision, the special master noted that there was no dispute that R.D. developed severe pneumonia caused by pneumococcus. Rather, the parties disputed whether R.D.’s September 15, 2010 MMR vaccination caused the pneumonia. Petitioners argued, based on the opinion of Dr. Lokshin, that the MMR vaccination impaired R.D.’s immune system’s ability to produce T cells, and that the lack of T cells rendered R.D.’s body unable to resist the pneumococcal infection. Respondent countered, based on the opinion of Dr. Romberg, that the MMR vaccination did not affect the parts of R.D.’s immune system responsible for responding to pneumococcal infections and, as a result, the MMR vaccination could not have led to R.D.’s severe pneumonia. In short, the parties disagreed regarding the role that T cells play in responding to a pneumococcal infection; petitioners contended that T cells play a role, while respondent contended that T cells are expendable. 4 The hearing occurred over two days–February 11, 2016, and April 12, 2016. -5- Case 1:13-vv-00675-MMS Document 105 Filed 08/25/17 Page 6 of 17 After identifying the parties’ dispute, the special master analyzed the viability of petitioners’ theory of causation. First, he compared the qualifications of the parties’ experts. Dr. Lokshin, the special master noted, was not board certified in immunology, did not have any training in T cells, and was not performing research. The special master qualified Dr. Lokshin as an expert in pediatric pulmonology and declared that Dr. Lokshin “possesse[d] the minimum qualifications to testify about immunologic concepts because of his training and experience.” Id. at *8. However, the special master continued: Dr. Lokshin’s lack of specialized training in immunology affected the quality of his testimony. When Dr. Lokshin presented the articles on which he relied, he frequently stated that he was not presenting his opinion, he was simply presenting a view someone else expressed. While it is hornbook law that a testifying expert may rely upon the work of another expert if the testifying expert would normally rely upon the second expert’s work, Dr. Lokshin often left the impression that he did not have the depth of experience in immunology necessary to evaluate and render an opinion on immunologic topics. . . . . . . . [H]e did not appear fluent in the language of immunology. This lack of fluency, again, gave the impression that Dr. Lokshin had limited experience on which to base his opinions. This impression, in turn, diminished the overall value of Dr. Lokshin’s testimony. Id. at *8-9 (footnote and citations omitted); see also id. at *13 (“Dr. Lokshin . . . seems ill-equipped to topple established immunologic ideas . . . . Dr. Lokshin does not routinely treat patients with immunologic disorders, he does not teach classes of medical school students in immunology, he does not have any advanced certifications in immunology, and he does not currently author articles on immunology. In short, when the topic is cutting-edge immunology, Dr. Lokshin has [fewer] qualifications to present new ideas persuasively.”). In contrast, the special master credited Dr. Romberg’s education and experience in pediatric immunology, and remarked: “Overall, Dr. Romberg’s knowledge about immunology was impressive. His demeanor and the content of this testimony demonstrated that he understood how the human immune system functions to a level of great detail. He took care to be precise in his wording.” Id. at *10. The special master concluded that “[o]n immunologic topics, Dr. Romberg was, simply, a much stronger witness than Dr. Lokshin.” Id. After evaluating the experts’ credentials, the special master discussed three immunological principles related to pneumococcal infections that, he asserted, were not in dispute: (1) “an effective response to pneumococcal infection requires both the innate immune system and antibodies from the adaptive immune system,” id.; (2) “T cells do not respond directly to pneumococcal infection,” id.; and (3) individuals whose immune systems produce no -6- Case 1:13-vv-00675-MMS Document 105 Filed 08/25/17 Page 7 of 17 B cells or produce defective B cells “do not develop pneumococcal infections” when they receive antibodies, regardless of whether T cells are also present, id. at *13. The special master then evaluated the proposition at the heart of petitioners’ theory of causation–that a human’s response to pneumococcal infection involves T cells–and the medical literature that petitioners submitted in support of that proposition. Several of the submitted articles described mouse studies, and revealed that mice produce T cells in response to pneumococcal infections. Dr. Lokshin argued that the results of these studies supported a conclusion that humans also produce T cells in response to pneumococcal infections. The special master noted, however, that Dr. Lokshin did not explain the similarities between mice and humans that would support extrapolating the results of the studies from mice to humans, and that Dr. Romberg testified–and provided supporting evidence–that “with respect to the response to pneumococcal infections, mice differ from people.” Id. at *14. The special master concluded that “[w]ithout some reliable showing that an extrapolation from mice to people is appropriate, the studies based upon mice are not useful.” Id. Petitioners also submitted articles that described studies in humans, as well as other related documents, in support of their proposition that T cells are involved in a human’s response to pneumococcal infection. This evidence reveals that researchers and at least one company are “attempting to develop a vaccine against pneumococcus that stimulates the production of T cells,” and “that the National Institutes of Health has funded research into a T cell based vaccine against pneumococcus.” Id. However, the evidence also reveals that the company suspended development of the vaccine because it was not obtaining statistically significant results; indeed, Dr. Lokshin testified that “research into a T cell based vaccine is ‘just too early’ and ‘not moving as fast’” as desired. Id. at *15. The special master noted: The goal of developing a T cell based vaccine is certainly laudatory–a successful T cell based vaccine could protect against many (maybe all) strains of pneumococcus. The potential benefits, especially in the regions of the world with less access to medical care, could be immense. However, the worthiness of the pursuit does not automatically make any of [the human] studies a reliable basis for an expert’s opinion. Id. He therefore concluded that “[t]he articles did not present a persuasive basis for toppling the generally accepted principle in immunology that a human being’s response to a pneumococcal infection does not involve T cells.” Id. At the close of his decision–after noting that “Dr. Romberg’s opinion was more persuasive than Dr. Lokshin’s opinion” because of “Dr. Romberg’s superior qualifications in immunology, the well accepted and well demonstrated idea that T cells cannot recognize polysaccharides, and the undeveloped effort to overturn immunologic dogma,” id. at *16–the special master analyzed petitioners’ case under the test for causation set forth in Althen v. Secretary of HHS, 418 F.3d 1274 (Fed. Cir. 2005). In Althen, the United States Court of -7- Case 1:13-vv-00675-MMS Document 105 Filed 08/25/17 Page 8 of 17 Appeals for the Federal Circuit (“Federal Circuit”) articulated a three-part test, based on prior precedent, explaining what a petitioner must show to prove causation under the Vaccine Act: [Petitioner]’s burden is to show by preponderant evidence that the vaccination brought about [the] injury by providing: (1) a medical theory causally connecting the vaccination and the injury; (2) a logical sequence of cause and effect showing that the vaccination was the reason for the injury; and (3) a showing of a proximate temporal relationship between vaccination and injury. Id. at 1278. The special master concluded that petitioners had not established either of the first two prongs of the Althen test, explaining that petitioners had not reliably shown “that T cells have a substantive role in a human being’s response to a pneumococcal infection.”5 DePena, 2017 WL 1075101, at *16. Moreover, with respect to the second prong of the Althen test, the special master further noted that none of R.D.’s treating physicians posited that R.D.’s severe pneumonia was the result of his September 15, 2010 MMR vaccination; that R.D.’s case did not fit within the challenge-rechallenge paradigm (when an individual who reacts to the administration of a vaccine exhibits a more severe reaction to a second administration of that vaccine); and that R.D.’s persistent low levels of antibodies protective against pneumococcal infection and concomitant failure to develop a second pneumococcal infection did not mean that R.D.’s September 15, 2010 MMR vaccination–which triggered a decrease in T cells–was the only event that could have caused R.D.’s severe pneumonia because “isolat[ing] the MMR vaccination and consequent decrease in T cells as the reason for [R.D.’s] pneumococcal pneumonia seem[ed] to overlook many other potentially contributory factors.” Id. at *18. He therefore denied petitioners’ request for compensation. Petitioners, alleging error, seek review of the special master’s decision, which respondent opposes. Upon reviewing the record that was before the special master and hearing the parties’ arguments, the court is prepared to rule. III. DISCUSSION The United States Court of Federal Claims (“Court of Federal Claims”) has jurisdiction to review the record of the proceedings before a special master, and upon such review, may: (A) uphold the findings of fact and conclusions of law of the special master and sustain the special master’s decision, (B) set aside any findings of fact or conclusion of law of the special master found to be arbitrary, capricious, an abuse of discretion, or otherwise not in accordance with law and issue its own findings of fact and conclusions of law, or (C) remand the petition to the special master for further action in accordance with the court’s direction. 5 Respondent conceded that the third prong of the Althen test had been satisfied. -8- Case 1:13-vv-00675-MMS Document 105 Filed 08/25/17 Page 9 of 17 42 U.S.C. § 300aa-12(e)(2). The standards set forth in section 12(e)(2)(B) “vary in application as well as degree of deference. . . . Fact findings are reviewed . . . under the arbitrary and capricious standard; legal questions under the ‘not in accordance with law’ standard; and discretionary rulings under the abuse of discretion standard.” Munn v. Sec’y of HHS, 970 F.2d 863, 870 n.10 (Fed. Cir. 1992). In the instant case, petitioners enumerate, pursuant to Vaccine Rule 24, three objections to the special master’s decision. First, petitioners contend that the special master failed to seriously consider the medical literature supporting their theory of causation. Second, petitioners assert that the special master improperly relied solely on an assessment of expert credibility in rejecting their theory of causation, impermissibly raising their burden of proof. Third, petitioners aver that the special master erroneously determined that they could not causally link R.D.’s September 15, 2010 MMR vaccination to his severe pneumonia. In short, petitioners believe that they have established a prima facie case of causation under the Vaccine Act. A. Proving Causation Under the Vaccine Act Pursuant to 42 U.S.C. § 300aa-13(a)(1), the court shall award compensation if a petitioner proves, by a preponderance of evidence, all of the elements set forth in 42 U.S.C. § 300aa- 11(c)(1),6 and if there is not a preponderance of evidence that the illness is due to factors unrelated to the administration of the vaccine. A petitioner can recover in one of two ways: either by proving an injury listed on the Table or by proving causation-in-fact. See 42 U.S.C. §§ 300aa-11(c)(1)(C), -13(a)(1). Under the first method of recovery, a petitioner must demonstrate that the injury was sustained within the time frame set forth in the Table. Id. § 300aa-11(c)(1)(C)(I), -14(a). “If petitioner can make such a showing, causation is presumed and petitioner is deemed to have made out a prima facie case of entitlement to compensation under the Act.” Whitecotton v. Sec’y of HHS, 81 F.3d 1099, 1102 (Fed. Cir. 1996). To establish a prima facie case when proceeding on a causation-in-fact theory, as petitioners attempted to do in this case, a petitioner must “prove, by a preponderance of the evidence, that the vaccine was not only a but-for cause of the injury but also a substantial factor in bringing about the injury.” Shyface v. Sec’y of HHS, 165 F.3d 1344, 1352 (Fed. Cir. 1999). 6 Subsection (c)(1) requires, among other things, that the following elements be satisfied: (1) that the vaccine in question is set forth in the Vaccine Injury Table (“Table”); (2) that the vaccine was received in the United States or in its trust territories; (3) that the injured person either sustained an injury as a result of the administration of a Table-designated vaccine for a period of more than six months after the administration of the vaccine, suffered illness, disability, injury, or condition from the vaccine that resulted in inpatient hospitalization and surgical intervention, or died from the administration of the vaccine; and (4) that the petitioner has not previously collected an award or settlement of a civil action for damages arising from the alleged vaccine-related injury or death. 42 U.S.C. § 300aa-11(c)(1). -9- Case 1:13-vv-00675-MMS Document 105 Filed 08/25/17 Page 10 of 17 “[T]o show that the vaccine was a substantial factor in bringing about the injury, the petitioner must show ‘a medical theory causally connecting the vaccination and the injury.’” Id. at 1352-53 (quoting Grant v. Sec’y of HHS, 956 F.2d 1144, 1148 (Fed. Cir. 1992) (per curiam)). In other words, “[t]here must be a ‘logical sequence of cause and effect showing that the vaccination was the reason for the injury,’” id. at 1353 (quoting Grant, 956 F.2d at 1148), and “[t]his ‘logical sequence of cause and effect’ must be supported by a sound and reliable medical or scientific explanation,” Knudsen v. Sec’y of HHS, 35 F.3d 543, 548 (Fed. Cir. 1994) (citing Daubert v. Merrell Dow Pharms., Inc., 509 U.S. 579 (1993); Jay v. Sec’y of HHS, 998 F.2d 979, 984 (Fed. Cir. 1993)); accord Grant, 956 F.2d at 1148 (“A reputable medical or scientific explanation must support this logical sequence of cause and effect.”); see also 42 U.S.C. § 300aa-13(a)(1) (“The special master or court may not make such a finding based on the claims of a petitioner alone, unsubstantiated by medical records or by medical opinion.”). However, medical or scientific certainty is not required. Knudsen, 35 F.3d at 548-49; Bunting v. Sec’y of HHS, 931 F.2d 867, 873 (Fed. Cir. 1991). As noted above, the Federal Circuit, in Althen, distilled this prior precedent into a three- part test, holding that to prove causation-in-fact, a petitioner must provide “(1) a medical theory causally connecting the vaccination and the injury; (2) a logical sequence of cause and effect showing that the vaccination was the reason for the injury; and (3) a showing of a proximate temporal relationship between vaccination and injury.” 418 F.3d at 1278. All three prongs “must cumulatively show that the vaccination was a ‘but-for’ cause of the harm, rather than just an insubstantial contributor in, or one among several possible causes of, the harm.” Pafford v. Sec’y of HHS, 451 F.3d 1352, 1355 (Fed. Cir. 2006). The Federal Circuit also explained in Althen that causation-in-fact can be established with circumstantial evidence–in other words, with medical records or medical opinion. 418 F.3d at 1279-80 (citing 42 U.S.C. § 300aa-13(a)(1)). A petitioner “need not produce medical literature or epidemiological evidence to establish causation,” but “where such evidence is submitted, the special master can consider it in reaching an informed judgment as to whether a particular vaccination likely caused a particular injury.” Andreu v. Sec’y of HHS, 569 F.3d 1367, 1379 (Fed. Cir. 2009); see also id. at 1380 (remarking that a special master may assess “the relevant scientific data” when determining whether a petitioner has offered a reputable and reliable explanation supporting his theory of causation); Capizzano v. Sec’y of HHS, 440 F.3d 1317, 1325 (Fed. Cir. 2006) (“[R]equiring either epidemiologic studies, rechallenge, the presence of pathological markers or genetic disposition, or general acceptance in the scientific or medical communities to establish a logical sequence of cause and effect is contrary to what we said in Althen[, and] impermissibly raises a claimant’s burden under the Vaccine Act . . . .”). But see LaLonde v. Sec’y of HHS, 746 F.3d 1334, 1341 (Fed. Cir. 2014) (“In Vaccine Act cases, petitioners must proffer trustworthy testimony from experts who can find support for their theories in medical literature in order to show causation under the preponderance of the evidence standard. The level of specificity of such support may vary from circumstance to circumstance.”). -10- Case 1:13-vv-00675-MMS Document 105 Filed 08/25/17 Page 11 of 17 Once a petitioner has established a prima facie case, the burden shifts to the respondent to show, by a preponderance of the evidence, that the injury was caused by a factor unrelated to the vaccine. 42 U.S.C. § 300aa-13(a)(1)(B); Shalala v. Whitecotton, 514 U.S. 268, 270-71 (1995); Deribeaux v. Sec’y of HHS, 717 F.3d 1363, 1367 (Fed. Cir. 2013). However, if a petitioner fails to establish a prima facie case, the burden does not shift. Bradley v. Sec’y of HHS, 991 F.2d 1570, 1575 (Fed. Cir. 1993). Regardless of whether the burden ever shifts to the respondent, the special master may consider the evidence presented by the respondent in determining whether the petitioner has established a prima facie case. See Stone v. Sec’y of HHS, 676 F.3d 1373, 1379 (Fed. Cir. 2012) (“[E]vidence of other possible sources of injury can be relevant not only to the ‘factors unrelated’ defense, but also to whether a prima facie showing has been made that the vaccine was a substantial factor in causing the injury in question.”); de Bazan v. Sec’y of HHS, 539 F.3d 1347, 1352 (Fed. Cir. 2008) (“The government, like any defendant, is permitted to offer evidence to demonstrate the inadequacy of the petitioner’s evidence on a requisite element of the petitioner’s case-in-chief.”). B. Petitioners Have Not Established That the Special Master Erred in Considering the Medical Literature That They Submitted In their motion for review, petitioners first challenge the special master’s consideration of the submitted medical literature. In particular, they argue that a “cursory review,” Mot. 9, of a sample of fifteen of the articles they submitted supports their theory that “the absence of [the] protection provided by antibodies” does not automatically result in the development of a pneumococcal infection and that “[n]atural protection from pneumococcal infection in those without ready to use specific antibodies is very much T cell dependent,” id. at 8. See also id. at 12 (“The articles cited by Petitioners, even under the most cursory of reviews, reasonably stand for the proposition that T cells play a substantial role in the modulation and prevention of invasive pneumococcal disease.”). By failing to properly consider this evidence, petitioners argue, the special master “impermissibly raised [their] burden under Althen prong one from a reputable medical theory in which T cell suppression from MMR vaccine can substantially play a role in the development of [invasive pneumococcal disease] to one of medical and scientific certainty.” Id. at 12. Respondent, in contrast, contends that the special master’s decision reflects that the special master reviewed all of the medical literature in the record, including the medical literature submitted by petitioners, and properly determined that the medical literature did not support petitioners’ theory of causation. Under the Vaccine Act, “a special master, reviewing the entire record of the case before him, must consider all relevant medical and scientific evidence contained in the record,” and “‘shall’ consider the entire record, which includes this relevant evidence, when assigning the weight given to particular evidence.” Moriarty v. Sec’y of HHS, 844 F.3d 1322, 1327-28 (Fed. Cir. 2016). Moreover, reviewing courts generally presume that a special master has considered all of the material in the record, regardless of whether it is mentioned in his or her decision. Id. at 1328; Hazlehurst v. Sec’y of HHS, 604 F.3d 1343, 1352 (Fed. Cir. 2010). In his decision, the special master referenced and discussed many of the articles submitted by the parties by name. -11- Case 1:13-vv-00675-MMS Document 105 Filed 08/25/17 Page 12 of 17 See DePena, 2017 WL 1075101 passim. He also specifically declared that he had reviewed all of the submitted medical literature. See id. at *1 (“The undersigned has reviewed all [of petitioners’] articles. . . . The undersigned has reviewed all [of respondent’s] articles as well.”), *9 (“[T]he undersigned has reviewed all the articles . . . .”). Thus, petitioners do not attempt to rebut the presumption that the special master considered all of the submitted medical literature. Rather, their argument is focused on the weight that the special master assigned to the articles that they submitted. Special masters “have very wide discretion” in determining what evidence to consider and “the weight to be assigned that evidence.” Whitecotton, 81 F.3d at 1108; accord Koehn v. Sec’y of HHS, 773 F.3d 1239, 1244 (Fed. Cir. 2014) (remarking “that it is within the Special Master’s discretion to weigh the relevant evidence”). Consequently, the court accords deference to the special master’s factual findings and fact-based conclusions, Hodges v. Sec’y of HHS, 9 F.3d 958, 961 (Fed. Cir. 1993), and may not reweigh the evidence, id. (holding that “on review, the Court of Federal Claims is not to second guess the Special Master[’]s fact-intensive conclusions”); Hines v. Sec’y of HHS, 940 F.2d 1518, 1527 (Fed. Cir. 1991) (“[A]rguments as to the weighing of evidence . . . do not demonstrate reversible error.”); see also Lampe v. Sec’y of HHS, 209 F.3d 1357, 1363 (Fed. Cir. 2000) (“[W]e do not sit to reweigh the evidence.”); Munn, 970 F.2d at 871 (“[I]t is not then the role of this court to reweigh the factual evidence, or to assess whether the special master correctly evaluated the evidence.”). Indeed, “reversible error is ‘extremely difficult to demonstrate’ if the special master ‘has considered the relevant evidence of record, drawn plausible inferences and articulated a rational basis for the decision.’” Lampe, 219 F.3d at 1360 (quoting Hines, 940 F.2d at 1528); accord Hibbard v. Sec’y of HHS, 698 F.3d 1355, 1363 (Fed. Cir. 2012). According to petitioners, had the special master properly evaluated the medical literature they submitted, he would have concluded that their theory of causation was supported by the necessary “‘indicia of reliability,’” Mot. 12 (quoting Moberly v. Sec’y of HHS, 592 F.3d 1315, 1324 (Fed. Cir. 2010)), and that they had satisfied the first prong of the Althen test. Petitioners’ contention is problematic for two reasons. First, as reflected in his decision, the special master considered the articles submitted by petitioners, but concluded that those articles were outweighed by other evidence in the record. See, e.g., DePena, 2017 WL 1075101, at *12 (“Despite the additional articles providing some evidence to the contrary, Dr. Lokshin conceded that T cells do not respond directly to pneumococcal infection.”), *13-14 (noting that Dr. Lokshin “cited several articles that reported on experiments using mice” but did not make “a reliable showing that an extrapolation from mice to people is appropriate”), *14 (“Dr. Lokshin relied upon human studies to show that a person’s response to a pneumococcal infection involves T cells. . . . The undersigned reviewed this material multiple times and has considered the testimony from both Dr. Lokshin and Dr. Romberg about those articles. The articles did not present a persuasive basis for toppling the generally accepted principle in immunology that a human being’s response to a pneumococcal infection does not involve T cells.”). In other words, the special master considered the relevant evidence, drew plausible inferences, and articulated a rational basis for his conclusion. Second, petitioners’ contention that the special master -12- Case 1:13-vv-00675-MMS Document 105 Filed 08/25/17 Page 13 of 17 improperly considered the evidence in the record amounts to a request that this court reevaluate that evidence. However, the court is not empowered to undertake such a task unless it first concludes that the special master’s fact-based conclusions were arbitrary and capricious–and it has not so concluded. In sum, petitioners have not established that the special master failed to properly consider the articles they submitted. C. Petitioners Have Not Established That the Special Master Solely Relied on an Assessment of Expert Credibility In their second objection to the special master’s decision, petitioners contend that the special master relied solely on his assessment of the credibility of the testimony of the parties’ experts in rejecting their theory of causation, and as a result disregarded the evidence in the record, impermissibly raising their burden of proof. Specifically, petitioners contend that the special master (1) “refus[ed] to apply the results of mouse studies to human studies,” Mot. 13; (2) “essentially disregard[ed] any evidence that T cells respond to pneumococcus,” id. at 15; (3) ignored a “weakness” with Dr. Romberg’s proposition that R.D.’s severe pneumonia was likely caused by a lack of protective antibodies, id. at 16; (4) “ignored [the] contradictions” in Dr. Romberg’s testimony regarding the role and importance of Th1 and Th17 cells, id. at 17; and (5) improperly relied on evidence–a sixty-five-year-old case study of one individual and testimony from Dr. Romberg–regarding the development of pneumococcal infections in individuals with dysfunctional immune systems when “Dr. Lokshin effectively countered” that evidence, id. at 18. Respondent, on the other hand, asserts that there was no legal error in either the special master’s credibility assessments or the special master’s conclusion, based on the evidence in the record, that a human’s response to a pneumococcal infection is not dependent on T cells. Taken as a whole, petitioners’ argument is that the special master’s determinations regarding the credibility of the parties’ experts tainted his consideration of the evidence in the record, causing him to improperly reject evidence supporting their theory of causation and accept evidence that did not support their theory of causation. The Federal Circuit remarked in Andreu that “[w]hile considerable deference must be accorded to the credibility determinations of special masters, this does not mean that a special master can cloak the application of an erroneous legal standard in the guise of a credibility determination, and thereby shield it from appellate review.” 569 F.3d at 1379 (citation omitted). The Federal Circuit expanded on these remarks in subsequent decisions: [T]his court has unambiguously explained that special masters are expected to consider the credibility of expert witnesses in evaluating petitions for compensation under the Vaccine Act. . . . In Moberly, we reiterated that a special master may not cloak the application of an erroneous legal standard in the guise of a credibility determination to shield it from appellate review. We went on to clarify that this does not mean that “a special master, as the finder of fact in a Vaccine Act case, is prohibited from making credibility determinations regarding -13- Case 1:13-vv-00675-MMS Document 105 Filed 08/25/17 Page 14 of 17 expert testimony.” We indicated that “[a]ssessments as to the reliability of expert testimony often turn on credibility determinations” and “[f]inders of fact are entitled–indeed, expected–to make determinations as to the reliability of the evidence presented to them and, if appropriate, as to the credibility of the persons presenting that evidence.” Our discussion of the issue in Broekelschen is equally clear.7 In that case, we recognized that “[e]xpert medical testimony is often very important in Vaccine Act cases based on off-Table injuries requiring proof of actual causation.” We again explained that “the special master’s decision often times is based on the credibility of the experts and the relative persuasiveness of their competing theories” and such credibility findings “‘are virtually unchallengeable on appeal.’” Finally, in Doe,8 we upheld a special master’s factual findings as not arbitrary and capricious “particularly in light of the credibility findings made as to the parties’ respective experts.” We found no basis for disturbing the special master’s credibility findings as to those experts, and again emphasized that “the special master’s unique position to see the witnesses and hear their testimony” makes “such credibility assessments . . . ‘virtually unreviewable on appeal.’” Porter v. Sec’y of HHS, 663 F.3d 1242, 1250-51 (Fed. Cir. 2011) (footnotes added) (citations omitted). As an initial matter, the special master was entitled to assess the credentials of the parties’ experts as a means of assisting his evaluation of the experts’ reports and testimony. Id. He was also entitled to gauge the credibility of the experts through a review of their reports and testimony. Id. Applying the deferential standard of review that is required in such circumstances, the court finds no error in the special master’s determination that Dr. Lokshin was a less credible expert witness than Dr. Romberg on immunological topics. The special master thoroughly reviewed the experts’ educational and professional backgrounds, and properly assessed the experts’ understanding of both the relevant immunological concepts and the relevant medical literature. In short, there is nothing arbitrary or capricious in the special master’s credibility determinations. Petitioners complain that by concluding that Dr. Lokshin was less suited than Dr. Romberg to render opinions on the immunological issues implicated in this case, the special master erroneously disregarded both the evidence that Dr. Lokshin relied upon in advancing petitioners’ theory of causation and the flaws in Dr. Romberg’s opinion and evidence. However, as repeatedly recognized by the Federal Circuit, special masters are entitled to use their credibility assessments to inform their conclusions regarding whether a petitioner has offered a reputable and reliable explanation supporting his or her theory of causation. Id. In this case, the 7 Broekelschen v. Sec’y of HHS, 618 F.3d 1339 (Fed. Cir. 2010). 8 Doe 11 v. Sec’y of HHS, 601 F.3d 1349 (Fed. Cir. 2010). -14- Case 1:13-vv-00675-MMS Document 105 Filed 08/25/17 Page 15 of 17 special master did not use his credibility determinations as an excuse not to evaluate the evidence in the record. Rather, he evaluated the evidence keeping in mind the experts’ credentials and understanding of the pertinent immunological topics, and thoroughly explained his reasons for crediting or discounting the evidence. The five purported errors highlighted by petitioners do not demonstrate otherwise. First, with respect to the mouse studies relied upon by petitioners, the special master discussed the studies, the experts’ testimony regarding the studies, Dr. Lokshin’s failure to explain how humans and mice are similar, and the evidence suggesting that the results of mouse studies cannot be applied to humans before concluding that “[w]ithout some reliable showing that an extrapolation from mice to people is appropriate, the studies based upon mice are not useful.” DePena, 2017 WL 1075101, at *14. Second, with respect to whether T cells can respond to pneumococcus, the special master discussed the relevant medical literature and the experts’ testimony, and explained that Dr. Lokshin conceded that “pneumococcus is a T cell independent antigen” and that “T cells do not respond directly to pneumococcal infection.” Id. at *12. Third, with respect to petitioners’ suggestion that Dr. Romberg erroneously posited that R.D.’s severe pneumonia was likely caused by a lack of protective antibodies, the special master–referring to two of Dr. Romberg’s reports and his hearing testimony–explained that petitioners had misconstrued Dr. Romberg’s opinion: “Dr. Romberg listed parts of the innate immune system, such as complement, as contributing to the protection against pneumococcal infection.” Id. at *18; accord id. at *5 (noting Dr. Lokshin’s agreement with Dr. Romberg’s opinion that “the innate immune system contributes to how the body responds when pneumococcus becomes infectious”), *10 (quoting Dr. Romberg’s first report for the proposition that parts of the innate immune system contribute to “‘human immunity’” to pneumococcus). Fourth, with respect to Dr. Romberg’s testimony regarding the role and importance of Th1 and Th17 cells, the special master reviewed the articles submitted by petitioners on this topic and petitioners’ interpretation of those articles in their posthearing brief, but found the articles unpersuasive in light of Dr. Lokshin’s concession that “T cells do not respond directly to pneumococcal infection.” Id. at *12. Finally, with respect to evidence presented by Dr. Romberg regarding the development of pneumococcal infections in individuals with dysfunctional immune systems, the special master discussed the relevant medical literature and the experts’ testimony, and concluded that such evidence “strongly support[ed] the argument that T cells are expendable in the body’s response to pneumococcal infection.” Id. at *10. Ultimately, by flagging these purported errors, petitioners are requesting that this court reevaluate the evidence and draw conclusions that are different from the conclusions reached by the special master. But so long as a special master “has considered the relevant evidence of record, drawn plausible inferences and articulated a rational basis for” his conclusions, Hines, 940 F.2d at 1528, the court must not reevaluate the evidence, id. at 1527; Lampe, 209 F.3d at 1363; Hodges, 9 F.3d at 961; Munn, 970 F.2d at 871. Here, as reflected in his decision, the special master considered the relevant evidence, drew plausible inferences, and articulated a rational basis for his conclusions. Therefore, petitioners have not established legal error under their second objection. -15- Case 1:13-vv-00675-MMS Document 105 Filed 08/25/17 Page 16 of 17 D. Petitioners Have Not Established That the Special Master Erroneously Concluded That They Failed to Satisfy the Second Prong of the Althen Test Petitioners’ third and final contention is that the special master erroneously determined, under the second prong of the Althen test, that they could not causally link R.D.’s September 15, 2010 MMR vaccination to his severe pneumonia. Specifically, they argue that the special master (1) improperly considered the lack of treating physician opinion supporting a causal link; (2) impermissibly implied that the failure of this case to fit within the challenge-rechallenge paradigm, a possibility raised and ultimately rejected by Dr. Lokshin, weighed against finding a causal link; (3) failed to recognize a flaw in Dr. Romberg’s proposition that R.D.’s severe pneumonia was likely caused by a lack of protective antibodies; and (4) improperly offered alternative explanations for R.D.’s development of severe pneumonia.9 In response, respondent observes that petitioners’ failure to establish that the MMR vaccine can cause severe pneumonia under the first prong of the Althen test means that petitioners cannot demonstrate that R.D.’s September 15, 2010 MMR vaccination did cause R.D.’s severe pneumonia under the Althen test’s second prong. Respondent further contends that even if petitioners had satisfied the first prong of the Althen test, the special master did not err in concluding that petitioners had not satisfied the Althen test’s second prong. Respondent is correct on both points. First, to prove causation-in-fact, a petitioner must satisfy all three prongs of the Althen test; a failure to satisfy one prong is fatal to the case. See Pafford, 451 F.3d at 1355; Althen, 418 F.3d at 1278. Because petitioners failed to establish that the special master erred in rejecting their theory of causation, the special master’s conclusion regarding the Althen test’s second prong is of no moment. Second, even if petitioners had demonstrated that the MMR vaccine can cause severe pneumonia, their objections to the special master’s analysis of the second prong of the Althen test lack merit. The Althen test’s second prong requires a petitioner to show “that the vaccine was the ‘but for’ cause of the harm,” Pafford, 451 F.3d at 1356, or, in other words, “‘that the vaccine actually caused the alleged symptoms in [the] particular case,’” id. (quoting the decision of the special master as recited by the trial court). To show that the vaccine did cause the injury, a petitioner may, but is not required to, offer evidence of “rechallenge, the presence of pathological markers or genetic disposition, or general acceptance in the scientific or medical communities,” or evidence in the form of epidemiological studies. Capizzano, 440 F.3d at 1325. Moreover, the “medical records and medical opinion testimony” of treating physicians can be 9 Petitioners also take issue with the special master’s “claim[ that] the innate system, including complement, contributes to protection against [invasive pneumococcal disease],” Mot. 19, inferring that the special master concluded that a flaw in R.D.’s innate immune system could have led to his development of severe pneumonia. Petitioners’ inference is unwarranted. The special master merely stated that R.D.’s “innate immune system could have protected [R.D.] from further pneumococcal infection” in the years following his severe pneumonia. DePena, 2017 WL 1075101, at *18 (emphasis added). -16- Case 1:13-vv-00675-MMS Document 105 Filed 08/25/17 Page 17 of 17 “probative” 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. at 1326 (quoting Althen, 418 F.3d at 1278); accord Lombardi v. Sec’y of HHS, 656 F.3d 1343, 1353 (Fed. Cir. 2011); Moberly, 592 F.3d at 1325; Andreu, 569 F.3d at 1375-76. Based on this precedent, the special master did not err in discussing whether a treating physician had opined on the cause of R.D.’s severe pneumonia or whether R.D.’s case fit within the challenge-rechallenge paradigm. Further, as noted above, with respect to petitioners’ contention that Dr. Romberg’s theory of causation was flawed, the special master observed that petitioners had misconstrued Dr. Romberg’s opinion, and the court finds no error in that observation. Finally, the special master did not err in discussing alternative explanations for R.D.’s development of severe pneumonia. Evidence of alternative causes can be used to demonstrate that a petitioner has not established a prima facie case of causation-in-fact, see Stone, 676 F.3d at 1379; de Bazan, 539 F.3d at 1352, and the special master supported his conclusions with evidence from the record. In sum, the special master did not err in concluding that petitioners did not satisfy the second prong of the Althen test. IV. CONCLUSION As reflected in his decision, the special master thoroughly reviewed the record before him, fairly considering and weighing the evidence presented by the parties. Thus, for the reasons stated above, the court DENIES petitioners’ motion for review and SUSTAINS the decision of the special master. The clerk is directed to enter judgment accordingly. IT IS SO ORDERED. s/ Margaret M. Sweeney MARGARET M. SWEENEY Judge -17-