Court Opinion

ID: 3168184
Source: CourtListenerOpinion
Date Created: 2016-01-08 17:01:39.867366+00
Date Added: 2024-06-11T12:01:37.113751
License: Public Domain

In the United States Court of Federal Claims
                                   OFFICE OF SPECIAL MASTERS
                                     Filed: December 18, 2015

* * * * * * * * * * * * * * * * * *
DONNA RAMSAY,                     *                                PUBLISHED
                                  *
               Petitioner,        *                                Case No. 11-549V
                                  *
v.                                *                                Special Master Hamilton-Fieldman
                                  *
SECRETARY OF HEALTH               *                                Causation; Gardasil Vaccine; Human
AND HUMAN SERVICES,               *                                Papillomavirus (“HPV”) Vaccine;
                                  *                                Juvenile Idiopathic Arthritis (“JIA”).
               Respondent.        *
* * * * * * * * * * * * * * * * * *

Patricia Leigh O’Dell, Beasley, Allen, et al., Montgomery, AL, for Petitioner.
Darryl Wishard, United States Department of Justice, Washington, DC, for Respondent

                                   RULING ON ENTITLEMENT 1

       On August 30, 2011, Tina Ramsay filed a vaccine claim under the National Vaccine
Injury Compensation Program (“the Program”) 2 on behalf of her minor daughter, Donna Ramsay
(hereinafter “Petitioner”). 3 Ms. Ramsay alleged that as a result of receiving human
papillomavirus (“HPV” or “Gardasil”) vaccines on March 19, 2008 and June 30, 2008, Petitioner
suffered from systemic Juvenile Idiopathic Arthritis (“sJIA”). 4

1
         Because this unpublished ruling contains a reasoned explanation for the undersigned’s action in
this case, the undersigned intends to post this order on the United States Court of Federal Claims website,
in accordance with the E-Government Act of 2002, Pub. L. No. 107-347, § 205, 116 Stat. 2899, 2913
(codified as amended at 44 U.S.C. § 3501 note (2006)). As provided by Vaccine Rule 18(b), each party
has 14 days within which to request redaction “of any information furnished by that party: (1) that is a
trade secret or commercial or financial in substance and is privileged or confidential; or (2) that includes
medical files or similar files, the disclosure of which would constitute a clearly unwarranted invasion of
privacy.” Vaccine Rule 18(b). Otherwise, “the entire” order will be available to the public. Id.
2
 The Program comprises Part 2 of the National Childhood Vaccine Injury Act of 1986, Pub. L. No. 99-
660, 100 Stat. 3755, codified as amended, 42 U.S.C. §§ 300aa-10 et seq. (hereinafter “Vaccine Act” or
“the Act”). Hereafter, individual section references will be to 42 U.S.C. § 300aa of the Act.
3
 Donna Ramsay, who has reached the age of majority since the petition was filed, has since been
substituted as Petitioner. See Order, December 16, at 1.
4
  Throughout the record, Petitioner’s sJIA has alternatively been referred to as juvenile rheumatoid
arthritis (“JRA”) and Still’s disease. These three terms refer to the same injury. See, e.g., Transcript
(“Tr.”) at 39-40.

                                                      1
        The undersigned now finds that Petitioner has proven, by a preponderance of the
evidence, that her sJIA was caused by her HPV vaccinations. The Clerk’s Office is ordered to
enter judgment in favor of Petitioner unless a motion for review is filed.

      I.          Facts

       Petitioner was born on June 16, 1993. Petitioner’s Exhibit (“Pet. Ex.”) 1 at 1. Prior to
administration of the first and second Gardasil vaccinations, Petitioner’s medical history was
unremarkable except for a tonsillectomy at age seven and migraine headaches and irritable bowel
syndrome diagnosed at age twelve. Pet Ex. 3 at 11; Pet. Ex. 4 at 47-48. Petitioner asserts, and the
records do not contradict, that she had no adverse reactions to any vaccination prior to
administration of the Gardasil vaccine. See Petitioner’s Post-Hearing Brief at 1.

       Petitioner was administered the first Gardasil vaccine on March 19, 2008, when she was
fourteen years old. Pet. Ex. 2 at 3-4. She was administered the second Gardasil vaccine on June
30, 2008, when she was fifteen years old. Pet. Ex. 3 at 11; Pet. Ex. 13 at 1.

        The medical records are inconclusive regarding the precise date of onset of Petitioner’s
sJIA. According to an affidavit authored by Tina Ramsay, Petitioner “began having flu-like
symptoms, such as sore throat, fever and aching all over her body” during the first week of
November 2008. Pet. Ex. 9 at 1; see also Pet. Ex. 6 at 46 (reporting that “aches and pains” began
“in the first part of November,” followed by headache, red eyes, and fever). Petitioner did not
seek medical attention, however, until November 13, 2008, when she presented to her primary
care physician, Dr. Carl Brutkiewicz, with complaints of muscle aches, fever, and wrist pain, as
well as “irritated eyes and headaches over the last week.” Pet. Ex. 3 at 12; Pet Ex. 5 at 42. Her
temperature was 99.1 degrees. Pet. Ex. 3 at 12. Dr. Brutkiewicz diagnosed Petitioner with
allergies and prescribed Petitioner with Xyxal #10 (anti-allergy eyedrops). Id. Dr. Brutkiewicz
would later describe her exam at this visit as “fairly unremarkable.” Pet. Ex. 5 at 38.

        On November 14, 2008, Petitioner’s mother, Tina Ramsay, called in to Dr. Brutkiewicz’s
office and reported that Petitioner was “achy all over today,” with a fever of 100.6 and
headaches. Pet. Ex. 3 at 12. She was prescribed amoxicillin. Id. No rash was reported, either
during this call or during the November 13, 2008 exam.

        On November 16, 2008, Petitioner reported to Mobile Infirmary West with generalized
rash and myalgia. 5 Pet. Ex. 4 at 29; see also Pet. Ex. 5 at 42 (noting retrospectively that
Petitioner’s rash developed in mid-November). She was referred to the University of South
Alabama Children’s and Women’s Hospital (hereinafter “South Alabama Hospital”), where she
reported that she had been experiencing “all over” aches and pain “off and on” for about a week.
Pet. Ex. 4 at 44. An exam revealed “pink, raised macular papular rashes on both arms” which
“blanch [] on pressure.” Id. at 49. Tests for various infectious etiologies and systemic
autoimmune diseases were all negative. See Pet. Ex. 4 at 29, 49 (documenting that monospot, C-

5
    Myalgia is muscle pain. Dorland’s Illustrated Medical Dictionary (“Dorland’s”), 1214 (32d ed. 2012).

                                                     2
reactive protein (“CRP”), 6 antistreptolysin O (“ASO”) titer, an ESR, and a rapid strep test were
all negative; see also Petitioner’s Post-Hearing Brief at 2. Petitioner was administered IV fluids
and IV penicillin before being discharged on November 17, 2008, with a diagnosis of “viral
illness.” Pet. Ex. 4 at 29.

        On November 20, 2008, Petitioner presented to the emergency department of South
Alabama Hospital “[with complaints of] fever, myalgia for 8 days.” Pet. Ex. 4 at 14. According
to Petitioner’s mother, Petitioner’s fevers, rash, and myalgias had persisted after she was
prescribed amoxicillin; her maximum temperature had been 104. Id. Upon exam, “patchy
erythematous rash” 7 was noted. Id. Petitioner was diagnosed with mononucleosis, 8 prescribed
Tylenol and naproxen, 9 and discharged. Id. at 4, 17.

        She followed up with Dr. Brutkiewicz on November 21, 2008. Pet. Ex. 3 at 12.
Petitioner reported that her “diffuse aches” had continued despite medication. Id. Dr.
Brutkiewicz noted that Petitioner had a temperature of 100.8, “moderate pharyngeal erythema,”
diffuse myalgias, and a fading macular rash on her upper extremities. Id. He diagnosed her with
“probable viral syndrome with post viral _____.” Id.

        On November 24, 2008, Petitioner was admitted to Springhill Memorial Hospital
(hereinafter “Springhill”) for treatment of a “fibrile [sic] illness.” Pet. Ex. 5 at 37. Upon
admission, her temperature was documented at 103.2. Pet. Ex. 5 at 38. Her condition had
“progressed to generalized aches and pains of all of her joints and extremities.” Id. at 42.
“[I]ntermittent macular rash on … her extremities and hands” was noted. Id. at 37, 42. Testing
revealed that Petitioner’s white blood cell count was elevated to 22,500; monospot, throat
culture, DNAase B titer, ASO titer, Hepatitis B surface antigen, Hepatitis C antibody, Parvovirus
B19 IgG/ IgM, ANA profile, rheumatoid factor, and Mycoplasma 10 IgM tests, as well as a PPD

6
 C-reactive protein is “a globulin that forms a precipitate with the somatic C-polysaccharide of the
pneumococcus in vitro; it is the most predominant of the acute phase proteins.” Dorland’s at 1532. CRP
“is found in the serum of various people with certain inflammatory, degenerative, and neoplastic
diseases.” Stedman’s Medical Dictionary (“Stedman’s”), 1580 (28th ed. 2006).
7
 Erythema is defined as a “redness of the skin produced by congestion of the capillaries.” Dorland’s at
643.
8
 A monospot test performed three days prior to this diagnosis, at the same hospital, had been negative.
Pet. Ex. 4 at 29.
9
  Naproxen is “a nonsteroidal antiinflammatory drug that is a propionic acid derivative, used in the
treatment of pain, inflammation, osteoarthritis [and] rheumatoid arthritis,” among other conditions.
Dorland’s at 1232.
10
  Mycoplasma is “a genus of bacteria of the family Mycoplasmataceae, made up of round, highly
pleomorphic, gram-negative cells that are bounded by a single triple-layered membrane and lack a true
cell wall.” Mycoplasma pneumo’niae is “a species that often causes inapparent infections or mild
respiratory tract disease but can also cause mycoplasmal pneumonia.” Dorland’s at 1216-1217.

                                                     3
test for tuberculosis, were all negative. Id. at 21-22, 45, 160-67. Petitioner’s CPK 11 was noted
to have been low (at 190), and her ferritin and adolase were elevated (at 4413 and at 12.5,
respectively). Id. at 21-22, 160-67. Her sedimentation rate 12 was 105. Id. While hospitalized,
Petitioner was administered steroids, which “significantly” improved her condition by decreasing
her joint pain, resolving her fever, and reducing her rash. Id. at 41. Petitioner was discharged on
November 28, 2008, with diagnoses of “probable autoimmune disease,” febrile illness,
arthralgias, 13 elevated sedimentation rate, elevated CRP, elevated ferritin level, and
polymorphous rash. Id. at 45.

        Several of Petitioner’s treatment providers at Springhill noted that her condition was
consistent with sJIA. Dr. Teresa Oglesby, a consulting rheumatologist, opined that, clinically
speaking, her illness was consistent with a “postviral” event or with Still’s disease. Id. at 29.
Among other things, Dr. Oglesby observed that an elevated ferritin level was commonly
associated with Still’s. Id. at 25. Dr. Adrien Bodet, an infectious disease specialist, suspected
either “1) [p]ost-infectious inflammatory [disease] or 2) [primary] immune [reaction] (Still’s?).”
Id. at 24. See also Pet. Ex. 5 at 41 (Dr. Sindel stated that “Still’s disease [is still] a
consideration”).

          After her discharge from Springhill, Petitioner followed up with Dr. Daren Scroggie, a
pediatric rheumatologist. Pet. Ex. 6 at 45-47. Following a visit on December 1, 2008, Dr.
Scroggie concluded that Petitioner “has a history consistent with systemic onset JIA, though she
is still early on.” Id. at 47; see also Pet. Ex. 3 at 10 (Dr. Brutkiewicz noting Dr. Scroggie’s
presumptive diagnosis of Still’s disease on December 4, 2008). On December 8, 2008, Dr.
Scroggie prescribed methotrexate. 14 Pet. Ex. 6 at 44. As of December 22, 2008, Dr. Scroggie
observed that Petitioner “[was] doing better and approaching baseline from [a] joint standpoint.”
Pet. Ex. 6 at 41.

        Throughout 2009, Petitioner’s physicians continued to treat her illness with methotrexate
and steroids. See, e.g., Pet. Ex. 6 at 3, 44. In 2010, Petitioner’s treaters also began referring to a
diagnosis of Crohn’s-related arthritis. See, e.g., Pet. Ex. 8 at 81. As Respondent concedes,
“[these physician] notes lack sufficient clarity to establish the basis for a change from JIA to
Crohn’s as the diagnosis.” Respondent’s Rule 4 Report at 5; see also tr. 43-44 (Respondent
declining to contest the accuracy of Petitioner’s sJIA diagnosis).

11
  CPK refers to creatine phosphokinase and creatine kinase, an “enzyme of the transferase class that
catalyzes the phosphorylation of creatine by ATP to form phosphocreatine.” Dorland’s at 427, 429.
12
  The erythrocyte sedimentation rate (ESR) [hereinafter “sedimentation rate”] is “the rate at which
erythrocytes precipitate out from a well-mixed specimen of venous blood … an increase in rate is usually
due to elevated levels of plasma proteins, especially fibrinogen and immunoglobulins.” Dorland’s at
1594. It is increased in “active inflammatory disease,” among other things. Id.
13
     Arthralgia is joint pain. Dorland’s at 150.
14
  Methotrexate is “a folic acid antagonist that acts by inhibiting synthesis of DNA, RNA, thymidylate,
and protein …. It is [] used as an antipsoriatic and antiarthritic in the treatment of severe, recalcitrant,
disabling psoriasis and severe rheumatoid and psoriatic athritis.” Dorland’s at 1151.

                                                       4
     II.      Procedural Overview

        Tina Ramsay filed this vaccine petition on Petitioner’s behalf on August 30, 2011. The
case was initially assigned to Special Master Gary Golkiewicz. Medical records, including
Exhibits 1 through 13, as well as a statement of completion, were filed between October 25,
2011 and December 28, 2011. On December 28, 2011, Petitioner filed an expert report authored
by Dr. Michael McCabe. See Pet. Ex. 14. The references cited in Dr. McCabe’s report were
filed on January 6, 2012. See Pet. Ex. 15-36.

        On March 20, 2012, Respondent filed a Rule 4 Report recommending against
compensation because, Respondent argued, Petitioner had not established by a preponderance of
the evidence that Petitioner had suffered a vaccine-related injury. Rule 4 Report (“Resp.
Report”) at 1, 6-14. Simultaneously, Respondent filed an expert report authored by Dr. Carlos
Rose. See Respondent’s Exhibit (“Resp. Ex.”) A.

        At a status conference held on March 29, 2012, Special Master Golkiewicz and “[t]he
parties discussed how to address respondent’s concerns regarding the proper medical diagnosis
and whether Dr. McCabe … is qualified to address such an issue.” See Order, filed March 30,
2012, at 1. Special Master Golkiewicz noted that “petitioner’s expert’s reasoning regarding a
medically appropriate time frame between vaccination and onset of injury is problematic.” Id.

        On April 30, 2012, Petitioner filed a status report in which she stated that her treating
rheumatologist, Dr. Peter Weiser, had agreed to write a letter clarifying Petitioner’s diagnosis.
Petitioner requested the opportunity to file Dr. Weiser’s letter, as well as a supplemental expert
report authored by Dr. McCabe. Both of these requests were granted. See Order, filed May 1,
2012, at 1.

           On May 9, 2012, this case was reassigned to then-Chief Special Master Campbell-Smith.

       Petitioner ultimately filed Dr. Weiser’s letter on May 22, 2012; she filed Dr. McCabe’s
supplemental expert report on June 15, 2012. 15 See respectively Pet. Exs. 37, 38.

        On July 11, 2012, Chief Special Master Campbell-Smith convened a status conference
during which she advised Petitioner to clarify the nature of Petitioner’s injury, to “address the
medical appropriateness of the four-month period between the onset of [Petitioner’s] symptoms
and her receipt of the vaccinations at issue,” and “to address the impact, if any, of a clarified
diagnosis of either sJIA or Crohn’s disease” on Dr. McCabe’s theory of causation. See Order,
July 12, 2012, at 2-3. Among other things, Chief Special Master Campbell-Smith observed that
the factual predicate underlying Petitioner’s theory remained unclear. Id. at 2. She directed
Petitioner to file clarifying opinions from Petitioner’s treating gastroenterologist, Dr. Jeanine
Maclin, “regarding the basis for the diagnostic impression that [Petitioner] has Crohn’s disease;”
from Dr. Weiser “clarify[ing] whether he attributes [Petitioner’s] inflammatory condition to a
15
 In the interim, Chief Special Master Campbell-Smith granted a motion for extension of time to file Dr.
Weiser’s letter. See Non-PDF Order, filed May 16, 2012.

                                                   5
diagnosis of sJIA or Crohn’s disease;” and from Dr. McCabe regarding the timeliness of onset.
Id. at 3. Petitioner ultimately filed clarifying opinions from Dr. Maclin and Dr. McCabe on
October 9, 2012. See Pet. Exs. 39 (Dr. Maclin) and 40 (Dr. McCabe). Petitioner declined to file
an additional report from Dr. Weiser. 16 See Status Report, filed October 15, 2012, at 1.

         During a status conference held on November 21, 2012, Chief Special Master Campbell-
Smith began the process of scheduling an entitlement hearing. See Order, filed November 21,
2012, at 1-2. A pre-hearing order was issued on December 6, 2012. Petitioner filed three
additional medical literature exhibits on November 30, 2012, see Pet. Exs. 41-43, and
Respondent filed a final expert report authored by Dr. Rose, as well as supportive medical
literature, on January 7, 2013. See Resp. Exs. G-J.

            On March 4, 2013, this case was reassigned to the undersigned.

        On June 7, 2013, Petitioner moved to continue the entitlement hearing that had been set
for August 5, 2013 and August 6, 2013, as well as its associated pre-trial deadlines. Motion to
Continue Entitlement Hearing and Pre-Trial Deadlines, filed June 7, 2013, at 1-2. Petitioner’s
counsel requested that the hearing be postponed pending appellate review of a decision denying
entitlement in a similar case. See Koehn v. Sec’y of Health & Human Servs., 773 F.3d 1239
(Fed. Cir. 2014) (affirming denial of entitlement in a Gardasil/ sJIA case that had been filed by
Ms. O’Dell on the basis of Dr. McCabe’s theory of causation). Id. Respondent objected to the
requested continuance. Id. at 2. The undersigned ultimately denied Petitioner’s motion to
continue, noting that there are “distinctive factual and medical differences between this case and
the Koehn case,” and that Koehn’s outcome was not binding on the undersigned. See Order,
June 11, 2013, at 2.

         On June 20, 2013, the undersigned granted Petitioner’s motion to file a supplemental
expert report, this time authored by Dr. Eric Gershwin. See Order, filed June 20, 2013; Motion,
filed June 18, 2013. Petitioner filed Dr. Gershwin’s expert report, as well as supportive medical
literature, on June 26, 2013. See Pet. Exs. 44-65. Petitioner filed additional medical literature, as
well as her experts’ CVs, on July 12, 2013. See Pet. Exs. 66-83.

        An entitlement hearing was held in Washington, D.C., on August 5th and 6th, 2013. Both
parties’ experts testified. At the close of the hearing, the undersigned granted Petitioner’s
counsel’s request to file post-hearing briefs. Tr. 428-31. The parties simultaneously filed post-
hearing briefs on September 3, 2013. This matter is now ripe for a ruling.

     III.          Analysis

               A. Standards of Adjudication

        To receive compensation under the Vaccine Act, Petitioner must demonstrate either that:
(1) she suffered a “Table injury” by receiving a covered vaccine and subsequently developing a
16
 Chief Special Master Campbell-Smith granted Petitioner two extensions to file these reports. See Non-
PDF Orders of August 10, 2012; September 7, 2012.

                                                   6
listed injury within the time frame prescribed by the Vaccine Injury Table set forth at 42 U.S.C.
§ 300aa-14, as amended by 42 C.F.R. § 100.3; or (2) that suffered an “off-Table Injury,” one not
listed on the Table as a result of her receipt of a covered vaccine. See 42 U.S.C. §§ 300aa-
11(c)(1)(C); Moberly v. Sec’y of Health & Human Servs., 592 F.3d 1315, 1321 (Fed. Cir. 2010);
Capizzano v. Sec’y of Health & Human Servs., 440 F.3d 1317, 1320 (Fed. Cir. 2006).

        Because Petitioner does not allege a Table injury in this case, she must prove that her
injury was caused-in-fact by an covered vaccine. To establish causation-in-fact, Petitioner must
demonstrate by a preponderance of the evidence that the vaccine was the cause of the injury.
42 U.S.C. § 300aa-13(a)(1)(A). Petitioners are required to prove that the vaccine was “not only
[the] but-for cause of the injury but also a substantial factor in bringing about the injury.”
Moberly v. Sec’y of Health & Human Servs., 592 F.3d 1315, 1321-22 (Fed. Cir. 2010) (quoting
Shyface v. Sec’y of Health & Human Servs., 165 F.3d 1344, 1352-53 (Fed. Cir. 1999)).

        In the seminal case of Althen v. Secretary of the Department of Health and Human
Services, the Federal Circuit set forth a three-pronged test used to determine whether a petitioner
has established a causal link between a vaccine and the claimed injury. See Althen v. Sec’y of
Health & Human Servs., 418 F.3d 1274, 1278-79 (Fed. Cir. 2005). The Althen test requires the
petitioners to set forth: “(1) a medical theory causally connecting the vaccination and the injury;
(2) a logical sequence of cause and effect showing that the vaccination was the reason for the
injury; and (3) a showing of a proximate temporal relationship between vaccination and injury.”
Id. To establish entitlement to compensation under the Program, a petitioner is required to
establish each of the three prongs of Althen by a preponderance of the evidence. See id.

         Specifically, under the first prong of Althen, Petitioners must offer a scientific or medical
theory that answers in the affirmative the question “can the vaccine(s) at issue cause the type of
injury alleged?” See Pafford v. Sec’y of Health & Human Servs., No. 01-0165V, 2004 WL
1717359, at *4 (Fed. Cl. Spec. Mstr. July 16, 2004). This may be accomplished in a number of
ways. Id. “Reliability and plausibility of pathogenesis can be bolstered by providing evidence
that at least a sufficient minority in the medical community has accepted the theory, so as to
render it credible.” Id. In addition, “epidemiological studies and an expert’s experience, while
not dispositive, lend significant credence to the claim of reliability; articles published in
respected medical journals, which have been subjected to peer review, are also persuasive.” Id.
However, publication “does not necessarily correlate with reliability,” because “in some
instances well-grounded but innovative theories will not have been published.” Daubert v.
Merrell Dow Pharmaceuticals, Inc., 509 U.S. 579, 593–94 (1993).

        In addition to showing that the vaccine at issue can cause a particular injury, a petitioner
must also prove that the vaccine actually did cause the alleged injury in a particular case. See
Pafford, 2004 WL 1717359, at *4 (emphasis added); Althen, 418 F.3d at 1279. A petitioner does
not meet this obligation by showing a temporal association between the vaccination and the
injury; the petitioner must explain “how and why the injury occurred.” Pafford, 2004 WL
1717359, at *4.

       While a temporal association alone is insufficient to establish causation under the third
prong of Althen, a petitioner must show that the timing of the injury fits with the causal theory.

                                                  7
See Althen, 418 F.3d at 1278. For example, if the petitioner’s theory involves a process that
takes several days to develop after vaccination, an injury that occurred within a day of
vaccination would not be temporally consistent with that theory. Conversely, if the theory is one
that anticipates a rapid development of the reaction post-vaccination, the development of the
alleged injury weeks or months post-vaccination would not be consistent with that theory. The
special master cannot infer causation from temporal proximity alone. In fact, it has been held,
that where a petitioner's expert views the temporal relationship as the “key” indicator of
causation, the claim must fail. See Thibaudeau v. Sec’y of Health & Human Servs., 24 Cl. Ct.
400, 403-04 (Fed. Cl. Oct. 23, 1991); see also Grant v. Sec’y of Health & Human Servs., 956
F.2d 1144, 1148 (Fed. Cir. 1992); Hasler v. United States, 718 F.2d 202, 205 (6th Cir. 1983)
(stating that inoculation is not the cause of every event that occurs within a ten-day period
following it).

        A petitioner who demonstrates by a preponderance of the evidence that he suffered an
injury caused by vaccination is entitled to compensation, unless the respondent can demonstrate
by a preponderance of the evidence that the injury was caused by factors unrelated to the
vaccination. See Althen, 418 F.3d at 1278; Knudsen v. Sec’y of Health & Human Servs., 35 F.3d
543, 547 (Fed. Cir. 1994).

             B. The Parties’ Arguments

                     i. Petitioners’ Arguments

                           1. Dr. Eric Gershwin

                                  a. Qualifications

        Dr. Eric Gershwin received his medical degree from Stanford University in 1971. Pet.
Ex. 67 at 1; tr. 5. He has been board-certified in internal medicine, rheumatology, and allergy
and clinical immunology since 1974, 1978, and 1980, respectively. Pet. Ex. 67 at 2; tr. 7. He is
currently a professor of medicine at the University of California School of Medicine in Davis,
California; since 1982, he served as the school’s chief of the Division of Rheumatology/ Allergy
and Clinical Immunology. Pet. Ex. 67 at 1; tr. 6-7.

         Between 1960 and the date of the entitlement hearing, Dr. Gershwin had published 859
peer-reviewed articles. Pet. Ex. 67 at 13-82; tr. 10. He has also written numerous books, book
chapters, and reviews. Tr. 7-10. Of particular note are Dr. Gershwin’s role in editing the first
published book on musculoskeletal diseases in children, and in publishing a peer-reviewed
article on issues related to the roles of familial factors, environmental factors, and activating
macrophages in juvenile arthritis. See generally Pet Ex. 67. Dr. Gershwin has published articles
specifically on the role of pro-inflammatory cytokines in sJIA. See, e.g., Pet. Ex. 46.

          At hearing, Dr. Gershwin was admitted as an expert in rheumatology and immunology.
Tr. 11.

                                                 8
                                       b. Theory

         Dr. Gershwin declined to opine in favor of causation in this case, citing a lack of
supportive epidemiological evidence. See generally Pet. Ex. 44; tr. 17, 30-31 (agreeing that “a
vaccine [can] be a trigger in a genetically susceptible host” and that vaccines are a “risk factor”
for Still’s, but that he “would not write a vaccination produced a disease, like Still’s disease, at
all …. [There is] no evidence that it [can] produce [] a disease like Still’s [in the absence of] a
clear-cut epidemiologic analysis, which, of course, with an incidence of … less than one per
hundred thousand, it’s just not possible in Still’s”).

         He agreed, however, that sJIA “is a disease caused by a genetic predisposition,” that it
needs “some environmental stimulus to set it off,” and that a vaccine can constitute this
environmental stimulus “in some people.” Tr. 17, 40-41. According to an article of which Dr.
Gershwin was a co-author, sJIA is “defined by arthritis with spiking fever persisting for more
than 2 weeks and at least one of the clinical features of systemic inflammation: skin rash,
lymphadenopathy, 17 hepatosplenomegaly, 18 or serositis 19 (pleuritis or pericarditis).” Pet. Ex.
46 20 at 2. sJIA is “very rare;” the incidence is less than one case per 100,000 per year. Tr. 12.
The rarity of its incidence is attributable to the fact that it is a polygenic 21 ailment; its occurrence
depends on a rare combination of variants, as well as a trigger. Tr. 296.

        sJIA is an autoinflammatory disease: 22 it is characterized by abnormality in the
functioning of the innate immune system. Tr. 15-17, 25-27 (“there are no obvious auto-
antibodies … but they seem to have an exaggerated innate response, and so they’re called
autoinflammatory.”), 40. The innate system consists of first responders, in contrast to the
adaptive immune system, which consists of secondary responders. Tr. 14, 16. Dr. Gershwin
explained that, notwithstanding sJIA’s identity as an autoinflammatory disease, the adaptive
immune system plays a role in its development. Tr. 15. The innate and adaptive immune
systems “interact with each other [like] … two wheels with cogs;” “the only way that both
wheels will function is if the cogs turn at the same time or in … some residence with each other.”

17
     Lymphadenopathy is “disease of the lymph nodes, usually with swelling.” Dorland’s at 1083.
18
     Hepatosplenomegaly is “enlargement of the liver and spleen.” Dorland’s at 847.
19
 Pleuritis is inflammation of the lung membrane; pericarditis is inflammation of the tissue of the heart.
Dorland’s at 1460-61, 1411-12.
20
  Lin, Y., et al., The pathogenesis of oligoarticular/ polyarticular vs. systemic juvenile idiopathic
arthritis, Autoimmun. Rev., 2011; 10: 482-489 [hereinafter “Lin”].
21
     Polygenic is “pertaining to or determined by the action of multiple different genes.” Dorland’s at 1489.
22
  Autoinflammatory is defined as “characterized by a disorder of the body’s innate immunity, with
inflammation that is not caused by an external irritant such as infection.” Dorland’s at 181. Autoimmune
disease, in contrast, is “characterized by a specific humoral or cell-mediated immune response against
constituents of the body’s own tissue constituents.” Id.

                                                       9
Id. at 14. Adaptive immunity only responds if it senses a threat, like infection; in cases of
autoimmune disease, the adaptive immune system attacks itself. Tr. 15.

        The uncontrolled activation – or “dysregulation” – of the innate immune response in sJIA
patients results in continuous production – or “upregulation” – of certain types of proteins
secreted by cells of the immune system. Tr. 15-16, 25-27, 35. These proteins are called
proinflammatory cytokines. Id. at 16. Specific cytokines - including interleukin-1 (“IL-1),
interleukin-6 (“IL-6”), and interleukin-18 (“IL-18”), among others – are associated with sJIA.
Tr. 15-16. 23 Cytokines are difficult to measure by any objective test; 24 though they can be
assessed indirectly with reference to clinical markers, these markers will not be apparent until a
cytokine “breakthrough” or “storm” occurs. Tr. 26-28, 35-36. Once the clinical threshold is
met, symptoms may include fever, achy joints, inflammation, and swelling in parts of the body,
including the pleura. 25 Tr. 12-13, 35-36. After upregulation of these cytokines has begun, they
continue to amplify and recruit other cells. Tr. 25-27.

       The Gardasil vaccine, by design, stimulates both the innate and adaptive immune
systems. Tr. 14. Like other vaccines, it is capable of precipitating autoimmune diseases. Tr. 30-
31. Moreover, Dr. Gershwin testified that sJIA is a genetic disease and that it can be prompted
by an environmental trigger. Tr. 16-17. According to Dr. Gershwin, studies have shown that the
concordance of sJIA among identical twins is “quite low,” “which means that although genetics
are important, environment has to start it off. Id. at 17. There has to be something that takes a
genetically predisposed person to produce inflammation.” Tr. 17.

        With respect to the instant case, Dr. Gershwin observed that Petitioner presented to her
treatment providers in November 2008 with symptoms that included fever, headache, and sore
throat; a high white blood cell count; and elevated C-reactive protein, all of which are consistent
with a Still’s presentation. Tr. 36-38. Dr. Gershwin agreed that the onset of her sJIA was in
November 2008, and that Petitioner exhibited no signs and symptoms of the disease between
March and November 2008. Tr. 44. Dr. Gershwin also observed that Petitioner’s treatment
regimen provides additional evidence that her injury was caused by upregulation of the cytokines
associated with sJIA: Petitioner was successfully treated with steroids and methotrexate, both of
which are drugs that inhibit the cytokines TNF-alpha, IL-6, and IL-1. Tr. 37-39; see also Pet.
Ex. 6 at 34-36, 41.

        Most importantly, Dr. Gershwin opined that four and a half months – the amount of time
it took Petitioner’s sJIA to manifest after the second Gardasil vaccine – is an appropriate interval

23
  Cytokines are “a generic term for nonantibody proteins released by one cell population … on contact
with specific antigen, which act as intercellular mediators, as in the generation of an immune response.”
Dorland’s at 466.
24
  Dr. Gershwin testified that “[i]n some diseases, like rheumatoid arthritis, you can actually find evidence
in the blood for years before they ever get sick. Not so in Still’s. It hasn’t even been looked at.” Tr. 30.
25
  IL-6 concentrations, in particular, have been shown to rise and fall in concert with temperature spikes
and drops (though IL-6 may be elevated even in the absence of a spiking fever). Tr. 48-50.

                                                    10
between a triggering event and sJIA manifestation. Tr. 16-30. Dr. Gershwin testified that “[t]he
protective response … to the HPV vaccination takes about seven months [from the first shot].”
Tr. 18-19, 30 (“the precipitation of [sJIA] ends up being an immunological imbalance, which
takes time to develop …. Because the latency time is a significant period of time, and something
is happening during that time.”). In support of this testimony, Dr. Gershwin pointed to the
results of the Frazer study, which showed that, among subjects who had received three HPV
vaccinations, peak immune response occurred at approximately seven months after the first
vaccination. Tr. 19-20; Pet. Ex. 29. 26 Conceding that Frazer did not study immune responses in
individuals who had only received the first and second vaccines, Dr. Gershwin argued that the
absence of a third vaccine was unlikely to have significantly altered the timing of her immune
response. Tr. 20-27. Whether or not a third “booster” vaccination is administered, the first two
Gardasil vaccinations are, by design, likely to prompt a significant immune response. Tr. 22.

        According to Dr. Gershwin, Still’s was likely to have eventually been triggered in
someone with Petitioner’s genetic predisposition. Tr. 41-42. There are multiple etiologies for
the disease. Tr. 41. It is unlikely, however, that Petitioner’s pre-existing IBS was the trigger,
because IBS does not produce inflammation or cytokines. Tr. 42-43.

        Dr. Gershwin acknowledged that, according to an article he co-authored in 2011 and that
discussed “triggering factors” of sJIA, there has only been one case of “an exacerbation of
systemic JIA” following vaccination. Lin at 5. In that case, onset occurred five days post-
vaccination, and the vaccine at issue was live-attenuated rubella. Id. The individual studied had
pre-existing Still’s. Id.; tr. 45-47. The authors of the article contemplated molecular mimicry,
rather than cytokines, as the initial mechanism of injury. Lin at 3 (“Vaccines, similar to
infectious agents, may trigger autoimmune diseases through various mechanisms such as
molecular mimicry of vaccine with self-antigens, antigen non-specific bystander activation and
polyclonal lymphocyte activation during immune response to vaccine.”). At hearing, Dr.
Gershwin clarified that, even though the authors argued that the process was initiated by
molecular mimicry, “the process of the inflammation, whether it’s mimicry or not, it’s still
cytokines, absolutely, carved in concrete, inescapable in Still’s.” Tr. 52-54.

                             2. Dr. McCabe

                                     a. Qualifications

        Dr. Michael McCabe earned a Ph.D. in Microbiology and Immunology from Albany
Medical College in 1991. Pet. Ex. 66 at 2. He subsequently served as a postdoctoral research
associate at the Karolinska Institute in Sweden, where he studied cell-signaling and regulation of
the cell death process. Id., tr. 58-59. Between 1992 and 2000, he was an assistant professor of
chemical toxicology and pharmaceutical sciences at Wayne State University. Pet. Ex. 66 at 2.
Between 2000 and 2009, Dr. McCabe served as an associate professor in the University of
Rochester School of Medicine’s Department of Environmental Medicine. Id. at 1. Between
2009 and the date of the hearing, Dr. McCabe served as an “associate” at Robson Forensic, Inc.,
“an expert witness consulting firm providing litigation support, expertise, [and] opinions [] to the
26
  Frazer, I., Correlating immunity with protection for HPV infection, Int. Society Infect. Dis., 2007;
11(S2): S10-S16 [hereinafter “Frazer”].

                                                    11
legal and insurance industries.” Id.; tr. at 68. He has authored approximately 40 peer-reviewed
articles and twelve book chapters, and is an editor of the Journal of Immunotoxicology. Pet. Ex.
66 at 4; 8-13.

        At hearing, Dr. McCabe was admitted as an expert in immunology. Tr. 74.

                                     b. Theory

                                                      1) The Gardasil vaccine is designed to elicit
                                                         proinflammatory cytokines

        Dr. McCabe’s theories regarding the immune system’s response to the Gardasil vaccine –
and its role in the etiology of sJIA – are essentially consistent with those of Dr. Gershwin.
Unlike Dr. Gershwin, however, Dr. McCabe believes that there is sufficient evidence upon
which to conclude that Petitioner’s Gardasil vaccinations caused her sJIA.

        According to Dr. McCabe, Gardasil, which is designed to stimulate both the innate and
adaptive immune systems, produces “a dramatic, robust, sustained response.” Tr. 79-80, 128,
181. One aspect of this response is an upregulation of cytokines, which “participate both in
adaptive immune signaling, as well as innate immune signaling, as well as interactions between
the adaptive and innate immune system.” Tr. 128. In particular, the vaccine causes a marked
upregulation of the proinflammatory cytokines IL 6, TNF-alpha, and IL 1. Tr. 128-30. In
practice, “Gardasil elicits proinflammatory cytokines in nearly everyone [to whom] the vaccine
is administered,” and “[i]n some genetically susceptible individuals, that trigger, cytokine
upregulation, is an environmental trigger contributing to the causation of the disease [sJIA].” Tr.
80; Pet Ex. 14 at 4 (“the cause of sJIA is thought to be multifactorial – with genetic susceptibility
factors and environmental triggers working together in complex ways to initiate and perpetuate
adaptive and/or innate immune activities resulting in tissue damage.”).

        In support of his theory, Dr. McCabe relied heavily on a study of the cytokine responses
elicited by the HPV-16 IL-1 viruslike particle (one of the components of the Gardasil vaccine) 27.
Pet. Ex. 30; 28 see also tr. 80-82. The Pinto study measured cytokine production in response to
the particle at zero- (before the first dose), two- (a month after the second dose), and seven- (one
month after the third dose) month intervals. Pet. Ex. 30 at 4; tr. 83-84, 94. The Pinto data show
that, “under both time frames, the two -month [after the first dose] and the seven-month [after the
third dose],… you get appreciable production of IL-6 at both time points.” Tr. 91. Within the
time frame of the experiment, IL-6 cytokine production increased 50-fold. Tr. 100-01. The
proinflammatory cytokines THF-alpha and IL-1 beta were similarly elicited over time, “the time
being tied to the immunization protocol schedule that these individuals received,” though to a

27
  Dr. McCabe testified that the absence of an adjuvant does not limit the application of the Pinto data to
“what we expect with the quadrivalent [Gardasil] vaccine.” Tr. 81-82.
28
 Pinto, L., et al., HPV-16 L1 VLP vaccine elicits a broad-spectrum of cytokine responses in whole blood,
Vaccine, 2005; 23: 3555-64 [hereinafter “the Pinto study” or “Pinto”].

                                                    12
lesser extent. Pet. Ex. 30 at 4; tr. 97, 101 (noting that there was a four-fold increase in TNF-
alpha and a nine- or ten-fold increase in IL-1).

        According to Dr. McCabe, the Pinto study data have largely been confirmed by other
medical literature. A 2007 study, the results of which were reported by lead author Garcia-
Pineras, revealed a seven-fold increase in IL-6 production following three doses of Gardasil.
Pet. Ex. 31 at 2; 29 tr. 102-03. The Garcia-Pineras study did not reveal dramatic changes in TNF
or IL-1. Pet. Ex. 31 at 2; tr. 102-03. Participants in the Garcia-Pineras study did not receive an
adjuvant, which would likely have increased the response; responses were measured pre-
vaccination and post-vaccination, but not between doses. Tr. 170-71.

       Dr. McCabe also cited the Evans study, which examined individuals at zero-, four-, and
16-week intervals and showed “a dramatic increase” in IF-gamma and IL-5 as a function of
vaccination, Pet. Ex. 33 30 at 2-4; tr. 110-11. A study by Emeny, in which the immunization
schedule was at zero, two, and six months, documented upregulation of IF-gamma, IL-5, and IL-
2 cytokines. Pet. Ex. 35 31 at 7; tr. at 111.

        Dr. McCabe conceded that none of the articles he cites studied arthritis or sJIA
specifically; they assessed only the cytokine responses in their subjects. Tr. 169-71. Dr.
McCabe also conceded that there are no published case reports, case control studies, or animal
models that show a relationship between HPV vaccines and sJIA. Tr. 154. Moreover, neither
the Meningococcus C nor the Measles-Mumps-Rubella (“MMR”) vaccinations, both of which
had been suggested as triggers and which were subject to prospective and retrospective studies,
have been confirmed to trigger sJIA. Pet. Ex. 16, 32 tr. 158-59. Dr. McCabe agreed that there is
no epidemiology to either confirm or deny a causal link between an HPV vaccine and sJIA. See
generally tr. 159-161.

         Dr. McCabe disputed that the studies cited by Dr. Rose – including the Chao study, the
Verstraeten study, and the Klein study – conclusively establish that Gardasil cannot play a causal
role in the development of sJIA. See Pet. Ex. 79 33 (duplicate at Resp. Ex. H); Pet. Ex. E; 34 Pet.
29
  Garcia-Pineras, A., et al., Cytokine and Chemokine Profiles following Vaccination with Human
Papillomavirus Type 16 L1 Virus-Like Particles, Clin. & Vaccine Immunol., 2007; 14(8): 984-89
[hereinafter “Garcia-Pineras”].
30
  Evans, T.G., et al., A Phase 1 Study of a Recombinant Viruslike Particle Vaccine Against Human
Papillomavirus Type 11 in Healthy Adult Volunteers, J. Infect. Dis., 2001; 183: 1485-93 [hereinafter
“Evans”].
31
  Emeny, R.T., et al., Priming of Human Papillomavirus Type 11 – Specific Humoral and Cellular
Immune Responses in College-Aged Women with a Virus-Like Particle Vaccine, J. Virol., 2002; 76(15):
7832-42 [hereinafter “Emeny”].
32
     Prakken, B., et al., Juvenile idiopathic arthritis, Lancet, 2011; 377: 2138-49 [hereinafter “Prakken”].
33
  Chao, C., et al., Surveillance of autoimmune conditions following routine use of quadrivalent human
papillomavirus vaccine, J. Intern. Med., 2011; 271: 193-203 [hereinafter “Chao”].

                                                       13
Ex. J. 35 Chao, which is the only epidemiological study involving Gardasil and autoimmune
diseases, and which did not document any link between the vaccine and autoimmune disease,
didn’t specifically study sJIA. Tr. 150-51. It revealed nothing about the number of subjects who
developed sJIA in the Gardasil group versus the unvaccinated control group. Id. Moreover, the
study only included 189,000 subjects, and the incidence of sJIA is less than 1 in 100,000; as
such, the study is “underpowered and is not able to be applied to an analysis of … the increased
risk attributable to … developing sJIA following vaccination.” Tr. 151-52.

         Klein, also cited by Dr. Rose, suffers from the same deficiencies. Id. at 160. To enable
researchers to draw any conclusions about the correlation between vaccination and sJIA, a study
would have to include a million to a million and a half subjects. Tr. 152-53; Pet. Ex. 80; 36 see
also tr. at 158 (“you are going to need to throw down on a million or 10 million subjects to …
investigate the genetic susceptibility factors and immunological responses in response to
whatever the putative environmental signal”).

        Verstraeten, which was a study of over 68,000 participants, found that the administration
of Cervarix – another HPV vaccine – did not increase the participants’ relative risk for
contracting lupus, sJIA, systemic lupus, Sjogren’s syndrome, or rheumatoid arthritis.
Verstraeten at 1. Dr. McCabe pointed out that Cervarix includes a different adjuvant than
Gardasil; that it includes immunization against only two – rather than four, as in Gardasil – HPV
strains; that it is inadequately powered; and that it did not examine sJIA specifically. Tr. 362-63.

                                                      2) sJIA is triggered by the same type of
                                                         cytokine upregulation that the Gardasil
                                                         vaccine is designed to produce

        sJIA is a multigenic disease that results from “an interaction between environmental and
genetic factors.” Tr. 118, 130. See also Pet. Ex. 83 37 at 1-2 (identifying, in Table 2,
considerations that are relevant to an assessment of whether rheumatic disorders are due to
environmental factors, and noting that there has been more progress in learning about the genetic
factors that produce autoimmune diseases than there has been in learning about the
environmental factors). sJIA is also autoinflammatory; it is characterized by abnormality in the
functioning of the innate immune system, and it occurs in people who have a predisposed innate
immune system. Tr. 118, 178-79; Pet. Ex. 46 at 1.

34
  Verstraeten, T., et al., Analysis of adverse events of potential autoimmune etiology in a large integrated
safety database of AS04 adjuvant vaccines, Vaccine, 2008; 26: 6630-38 [hereinafter “Verstraeten”].
35
  Klein, N.P., et al., Safety of Quadrivalent Human Papillomavirus Vaccine Administered Routinely to
Females, Arch. Ped. Adolesc. Med., 2012; 166(12): 1140-48 [hereinafter “Klein”].
36
 Schultz, K.F., and Grimes, D.A., Sample size calculations in randomised trials: mandatory and
mystical, Lancet, 2005; 365: 1348-53.
37
  Miller, F.W., et al., Approaches for identifying and defining environmentally associated rheumatic
disorders, Arthritis Rheum., 2000; 43(2): 243-49.

                                                    14
       Dr. McCabe testified that the term “idiopathic,” when used in the context of sJIA, means
“unique;” because it has an incidence of less than one in 100,000 people, all of whom have
unique genetic and immunologic profiles, epidemiological analysis is difficult. Tr. 209-10.
Therefore, the fact that there are no published case reports linking sJIA to the HPV vaccine, tr.
154, 248, is of limited relevance. Id. at 154.

        Dr. McCabe identified the proinflammatory cytokines IL-1, IL-6, IL-18, and TNF – the
upregulation of which Gardasil is designed to induce – as being involved in the development of
sJIA. 38 Tr. 117, 119, 129; Pet. Ex. 1739 at 4. Dr. McCabe agreed with Dr. Gershwin that these
proinflammatory cytokines “mediate the inflammation and then the inflammation being realized
by the clinical symptoms.” Tr. 120; see also Mellins at 4. He also agreed that clinical
manifestations include fever; an increase in acute phase proteins, such as C-reactive protein;
increases in common myeloid progenitors; increases in platelets; increases in synovial
inflammation; and increases in white blood cell recruitment and levels. Tr. 120- 21; Pet. Ex. 14
at 3 (“sJIA is characterized by prominent systemic features including high spiking fever and
elevation of systemic acute phase reactants and other markers of inflammation.”). “The classic
disease presentation (i.e., fever, rash, joint pain)[,] together with systemic elevation of
inflammatory markers[,] are indicative of an autoinflammatory disease process driven by
dysregulation of the innate immune system as evidenced by a role for pro-inflammatory
cytokines (e.g., IL-6, IL-1, and TNF-α) and activation of Toll-like receptor signaling pathways in
the development of the disease.” Pet. Ex. 14 at 3.

        Although “the complexity of interactions between genetic factors and unknown
environmental triggers has not been completely unraveled,” “a triggering role for infections and
vaccinations [in the development of sJIA] has been suggested and likely exists.” Pet. Ex. 14 at
4-5; see also tr. 111-17; Prakken at 4 (“[a] genetically susceptible individual might develop a
deleterious and uncontrolled response towards a self-antigen on exposure to an unknown
environmental trigger …. In juvenile idiopathic arthritis, infections and vaccinations have been
suggested as two candidates”). Supportive data for this conclusion comes both from human
population studies that implicate infection and from “mechanistic considerations.” Pet. Ex. 14 at
4. “Infections and vaccinations activate the innate and adaptive immune processes required for
functional immunity, which paradoxically can result in deleterious and improperly balanced
immune processes causing self tissue damage characteristic of autoimmune/ autoinflammatory
disease.” Id. The Gardasil vaccine contains a “spontaneous formation of non-infectious virus
like particles [(“VLPs”)] that lack the HPV genome but resemble native virions;” administration
of the vaccine “induce[s] high titers of neutralizing antibodies to” the L1 viral capsid proteins
from four of the most common disease-associated HPV strains.” Id. “In individuals immunized
with HPV-L1 VLPs, high levels of both adaptive and innate immune cytokines are produced.”

38
  Therapeutic intervention for sJIA patients targets these cytokines. Tr. 128-129. Some of the most
compelling evidence for the role of cytokines in the pathogenesis of sJIA is the successful treatment and
management of the disease with therapies that inhibit TNFa, IL-6, and IL-1. Tr. 38; Pet Ex. 14 at 5.
39
  Mellins, E.D., et al., Pathogenesis of systemic juvenile idiopathic arthritis: some answers, more
questions, Nat. Rev. Rheumatol., 2011; 7(7): 416-26 [hereinafter “Mellins”].

                                                    15
Id. Many of the cytokines elicited are the pro-inflammatory cytokines that have been implicated
in the etiology of sJIA. Id.

        According to Dr. McCabe, the fact that studies have not linked sJIA with naturally-
occurring HPV infections is “irrelevant.” Tr. 75-79; see generally Pet. Ex. 22 (discussing the
efficacy of HPV vaccines in prompting an immune response). 40 The antigen dose in the HPV
vaccine is much higher than it is in a natural infection; as a result, “the type of immune response,
the robustness, the potency, the sustained immune response that’s elicited by the vaccine, by
design, is very different than what occurs in the natural infection.” Tr. 77-78. There is a
consensus in the scientific community that the vaccine “elicits a robust, sustained immune
response that’s not seen in the natural infection.” Tr. 78-79. Because the natural infection does
not produce the same robust, sustained immune response, it does not result in inflammation or in
an upregulation of proinflammatory cytokines. Tr. 77-79.

                                                   3) The Gardasil vaccinations played a
                                                      causative role in triggering Petitioner’s
                                                      sJIA

        Dr. McCabe argued that Petitioner was genetically susceptible host for sJIA. Tr. 210.
Applying the mechanisms he had identified, Dr. McCabe testified that the Gardasil vaccine “was
an environmental trigger that, given her genetic and immunological susceptibility, caused her
disease to manifest when it did.” Tr. 154. More specifically, the vaccination “produced
upregulation in [Petitioner’s] adaptive and … innate immune response that included the
production of proinflammatory cytokines; . . . her genetic susceptibility and immune
susceptibility resulted in her presentation with symptoms that are well known and generally
accepted by the scientific and medical community to be tied to inflammatory cytokines.” Tr.
132; see also tr. 147-48 (“[Petitioner’s] macrophages, which may [have] initially contain[ed]
some [] control of secretion of cytokines, are being instructed, upon immunization with Gardasil,
by her adaptive immune system to make proinflammatory cytokines,” thereby “triggering the
process.”). The ongoing production of these pro-inflammatory cytokines triggered Petitioner’s
sJIA, which manifested clinically in November 2008. Tr. 131-32.

        Dr. McCabe conceded that there is no direct evidence in Petitioner’s medical record of an
upregulation of cytokines after either the first or second vaccine. Tr. 182. However, Dr.
McCabe observed that Petitioner’s medical records contain no alternative explanation for her
sJIA, either in the form of another vaccine or another infection. Tr. 195. He opined that while
her immune system was capable of handling a mild infection, any infection capable of producing
as robust an immune response as that elicited by the Gardasil vaccine would have had to be
debilitating, and likely would have been documented. Tr. 210-11.

        Dr. McCabe explained that none of Petitioner’s treating physicians attributed her injury
to the Gardasil vaccination because their primary goal was likely the treatment of her symptoms,
not an assessment of causation, and because they lacked a way to test for upregulation of
40
  Mariani, L. and Venuti, A., HPV vaccine: an overview of immune response, clinical protection, and
new approaches for the future, J. Transl. Med., 2010; 8; 1-8.

                                                  16
proinflammatory cytokines. Tr. 133, 196-97. Dr. McCabe also testified that, for the reasons set
forth in subsection (b)(4), the 3.5 month interval between her first and second doses does not
detract from the likelihood that the vaccine caused her sJIA, even though her vaccines were
administered at different intervals than the intervals described in Pinto and other studies. Tr.
213-14.

                                                      4) The onset of Petitioner’s sJIA was
                                                         temporally appropriate in light of the
                                                         timing of the vaccinations.

        Dr. McCabe opined that “the expected interval between a vaccination and this
autoinflammatory disease is predicted by the time period that measurable changes in the immune
response are known to be elicited by the vaccine.” Tr. 134-35. At least one study has shown
that, among individuals who are administered a quadrivalent HPV vaccine at zero, two, and six
months, over 99% of subjects experience a “robust” immune response within seven months. Pet.
Ex. 26 41 at 4; tr. 19-20, 135-36.

        According to Dr. McCabe, a vacinee’s immune response starts to rise after administration
of the first vaccine and continues to rise through the second, and possibly the third, dose of
vaccine. Tr. 136-37. Dr. McCabe cited the Frazer study, which conclusively documents, among
women who received three quadrivalent HPV doses, increased levels of antibody titers over a 5-
year period:

41
  Joura, E.A., et al., HPV antibody levels and clinical efficacy following administration of a prophylactic
quadrivalent HPV vaccine, Vaccine, 2008; 26: 6844-51 [hereinafter “Joura”].

                                                    17
Figure 2 Immunogenicity results from a double-blind, placebo-controlled, dose-ranging study of quadrivalent HPV (types 6, 11, 16, 18) L1 VLP
vaccine in 1106 young women indicated that vaccine-induced anti-HPV 6, 11, 16, and 18 geometric mean titers (GMTs) peak at month 7 and
gradually decrease to reach a plateau at Month 24. The per protocol immunogenicity (PPI) cohort comprised subjects who were naïve to HPV
6, 11, 16, and 18 infection at baseline, were free of infection with the same vaccine HPV type, and who received all three vaccine
doses. cLIA = competitive luminex immunoassay, GMT = geometric mean titer. •, per-protocol subjects; •, baseline HPV type seropositive
and polymerase chain reaction-negative subjects (placebo group); 6, per-protocol placebo. Adapted from Villa LL et al.

Frazer at 4 (internal citations omitted); tr. 136-37. The results summarized in Frazer suggest
that “vaccination induced a marked immune response, beginning approximately 1 month after
the initial dose, peaking at approximately month 7, and thereafter declining to a stable plateau for
2.5 years after the last vaccine dose.” Frazer at 4. Dr. McCabe’s opinion, therefore, was that the
timing of Petitioner’s clinical presentation for sJIA – in November 2008, approximately seven
months after she was administered the first dose of Gardasil – was temporally appropriate. Tr.
138-39.

       Dr. McCabe disagreed with Dr. Rose that upregulation of proinflammatory cytokines
occurs within 24 to 48 hours: “it takes days to mount a primary immune response, meaning an
immune response where we’re just looking at, focused on the proliferation of T cells.” Tr. 140.
Based on study data, Dr. McCabe testified that peak cytokine and antibody production occurs at
approximately one month after the second vaccine dose. Tr. 191-93.

        At hearing, Dr. McCabe gave two explanations for his theory that Petitioner experienced
an acute innate system reaction almost five months after the administration of the second
vaccine, and approximately four months after peak cytokine production. First, he explained that
the second dose of the vaccination caused a more “sustained” and “robust” reaction. Tr. 184,
186 (noting that most, if not all, vaccines include a second dose as a booster to stimulate

                                                                    18
secondary responses). Acknowledging that studies have documented a slight “downtick” in
antibody levels around a month after administration of the second HPV vaccine, Dr. McCabe
pointed out that the overall increase in antibody titer is so large after the first and second
vaccines that these slight decreases are relatively meaningless: “there is a large – a high level of
both immunoglobulin antibody and cytokine that I’d expect to be present even after the peak,
even after the second [immunization],” tr. 193-94; “to perseverate on the minor changes that
occur in antibody titer between month three and month seven … you’re missing that much of the
potency, the robustness of the response, is occurring within the time frame of those first two
immunizations.” Tr. 188. He cited at least one study for the proposition that “the highest
increments in … cytokine responses were seen after the second immunization (i.e., at month 2).”
Pet. Ex. 32 at 9; 42 tr. 93.

        Second, Dr. McCabe explained that the production of cytokines was merely the initiation
of Petitioner’s immune response:

       it’s not just the wave of cytokines … that come from immunization, but it’s the
       regulatory response and the continued development of the immune system, both
       in the context of a response to the vaccine and this response that produces the
       disease. So, [the vaccine] starts the production of those cytokines … and it’s
       changed her cells and it’s changed her immune system and she’s had … other
       genetic and immunological preconditions that contribute to the development of
       her disease at that time.

Tr. 194. As Petitioner clarified in her post-hearing brief, the analysis of temporal association
involves two distinct processes: the development of sJIA and the development of immunity
provided by Gardasil. Pet. Brief at 19-20; tr. 395-96.

        Dr. McCabe also explained in detail why, notwithstanding the lack of a third Gardasil
shot, the timing of onset of Petitioner’s sJIA was plausible. Dr. McCabe testified that the first
two shots provided an ongoing stimulus to Petitioner’s adaptive and innate immune systems. Tr.
136-38, 185, 419-21. Any contribution of the third vaccine to the robustness of Petitioner’s
immune response would have been minor compared to the contributions of the first two
vaccines. Tr. 189-90; see also tr. 139, Pinto (noting that, according to the Pinto article, the peak
cytogram response occurs within the time frame of the second HPV immunization). Thus, even
though there are no known studies documenting subjects’ immune response in the absence of a
third shot, the studies referenced by Dr. McCabe – which document almost-peak cytokine
production approximately a month following administration of the second vaccine – are a
sufficient basis, in his view, upon which to conclude that the timing of onset of Petitioner’s sJIA
was proximate to the administration of the first two Gardasil injections. Tr. 190-93.

        Dr. McCabe did agree that in light of the timing of onset, he would have been less
inclined to view the vaccine as causal if Petitioner had received only one dose of the vaccine. Tr.
42
  Pinto, L., et al., Cellular Immune Responses to Human Papillomavirus (HPV) – 16 L1 in Healthy
Volunteers Immunized with Recombinant HPV-16 L1 Virus-Like Particles, J. Infect. Dis., 2003; 188: 327-
38 [hereinafter “Pinto 2”].

                                                 19
182-83 (observing that, if Petitioner had received only one vaccination, the onset of her sJIA
should have occurred in approximately two months).

                      ii. Respondent’s Argument

                              1. Dr. Rose’s Qualifications

        Dr. Carlos Rose graduated summa cum laude from the University of Buenos Aires School
of Medicine in 1977. Resp. Ex. B at 1. He completed his pediatric residency and pediatric
rheumatology training at Thomas Jefferson University; he completed his fellowship training at
the University of Pennsylvania. Tr. 222-23. Since 1994, he has been the chief of the Division of
Rheumatology, in the Department of Pediatrics, at DuPont Hospital for Children in Delaware.
Resp. Ex. B at 7; tr. 222. He has been a member of the American Board of Pediatrics since 1997
and of the American Board of Pediatric Rheumatology since 1998. Tr. 223; Resp. Ex. B. at 3-4.

         At the time of the hearing, Dr. Rose testified that he spent approximately 30-40% of his
time in clinical practice, treating clients “with mostly inflammatory conditions, including general
arthritis … systemic among them, lupus, [and] typical pediatric rheumatology diseases.” Tr.
223-24. He has spent a portion of his remaining time researching the mechanisms of
autoinflammatory diseases and the measurement of cytokines. Tr. 225-27, 231-32. Although he
had published numerous articles, none had been on the subjects of sJIA or Gardasil. Tr. 235.

          At hearing, Dr. Rose was qualified as an expert in pediatric rheumatology. Tr. 236.

                              2. Dr. Rose’s Theory

         Dr. Rose agreed with Dr. McCabe that sJIA results from innate immune system
dysfunction, and that it is characterized by the dysregulation of specific cytokines. Resp. Ex. A
at 4 (“[B]ased on its clinical features and gene expression profile[, sJIA is] . . . one of the auto-
inflammatory diseases likely associated with dis-regulation of cytokine networks likely IL-1 and
IL-6 rather than the adaptive immune system”) (internal citation omitted); tr. 241. Dr. Rose also
agreed that sJIA is an auto-inflammatory, not an autoimmune, condition, and that it has many
triggers. Tr. 241-42, 297. Dr. Rose did not agree, however, that the Gardasil vaccine played a
role in the development of Petitioner’s sJIA. Tr. 237. In almost 30 years of clinical practice in
rheumatology, Dr. Rose has never seen a natural infection “associated with a pattern reminiscent
of systemic JIA.” Resp. Ex. A at 4.

       Prior to the hearing, Respondent and Dr. Rose had espoused the theory that Petitioner’s
post-vaccine injury was, in fact, Macrophage Activation Syndrome (“MAS”). 43 See generally
Resp. Ex. A, G. Respondent ultimately conceded that Petitioner’s injury was sJIA. Tr. 237. Dr.
Rose, however, continued to maintain through the hearing that Petitioner’s injury would be more
accurately classified as MAS. Tr. 330. One reason for this theory was that Dr. Rose did not
believe that Crohn’s disease – with which Petitioner had been definitively diagnosed – and sJIA
can co-exist. According to Dr. Rose’s first expert report and his testimony at hearing, the
43
     Dr. Rose alternatively referred to MAS as “HLH.” See tr. 347.

                                                     20
diagnoses of Crohn’s disease and sJIA are “mutually exclusive,” because sJIA is a diagnosis of
exclusion. Tr. 314, 321. Dr. Rose ultimately acknowledged that studies from Western Europe
document that sJIA patients “had Crohn’s disease at a rate of 300-fold versus the healthy control
group.” Tr. 324-25. Dr. Rose explained that he had not had an opportunity to review these
studies, and that he had never encountered such a case in clinical practice. Tr. 325.

        Assuming that sJIA was, in fact, an accurate diagnosis, Dr. Rose’s opinion was that a
November 2008 viral infection – evidenced by a sore throat, fever, achiness, and irritated eyes –
is the most likely cause of Petitioner’s sJIA. Tr. 303, (“the preceding and most immediate viral
infection could be a good alternative explanation for the triggering aspects”), 328-29. 44

        Dr. Rose also pointed out that there are no case-control prospective epidemiologic studies
addressing sJIA following HPV vaccination. Resp. Ex. A at 5. Indeed, Dr. Rose cited several
studies for the proposition that, statistically speaking, administration of the HPV vaccine did not
increase vaccinees’ risk for developing autoimmune diseases. See generally tr. 287-94;
Verstraeten (finding, based on a study of over 68,000 participants, that administration of
Cervarix – another HPV vaccine – did not increase the participants’ relative risk for contracting
lupus, sJIA, systemic lupus, Sjogren’s syndrome, or rheumatoid arthritis); Chao (finding, based
on a study of 189,000 recipients of the HPV vaccine, that the vaccine presented no increased risk
for sJIA); Klein (finding, based on a study of the same population, that there was no increase in
emergency room visits or hospitalizations, both of which one would expect to see in a patient
with sJIA); 45 Joura (concluding that “spontaneous secretion of cytokines in the absence of any
stimuli did not show any significant increases following vaccination”).

        Dr. Rose’s position was that none of the studies cited by Dr. McCabe supports his
argument that the HPV vaccine (or HPV virus-like particles) causes “the massive amount of
cytokine production that you need sustained … in a person with systemic JIA day after day.” Tr.
276. For the Gardasil vaccine to have caused her injury, Petitioner would have had to have
“suffered an extraordinary powerful [sic] cytokine response to the vaccine (not noticed clinically
… during the days immediately following the inoculation) and that the normal mechanisms of
control of the cytokine response are ineffective.” Resp. Ex. G at 3-4. The medical literature
cited by Petitioner’s experts, therefore, does not support a causative link, because it does not
document a sustained pattern of cytokine upregulation in response to vaccination. Id. Dr. Rose
argues that such a pattern is essential to show that the Gardasil can cause sJIA. Id.

        With regard to the timing of onset of Petitioner’s sJIA, Dr. Rose described as “baseless”
Dr. McCabe’s theory that a plausible time frame for onset should be assessed with reference to
the timing of measurable changes in the immune response. Resp. Ex. G at 3. According to Dr.
Rose, the body’s immune response to a vaccine, as documented by sero-conversion and T cell
response, has no pathological implication. Id. The production of pro-inflammatory cytokines

44
  Notwithstanding Dr. Rose’s testimony that a viral infection was the likely cause of Petitioner’s sJIA,
Respondent’s counsel clarified at hearing that “[w]e’re not alleging an alternate cause …. there may be
other explanations out there [] that may not rise to the level of . . . more probable than not.” Tr. 315-17.
45
     See also tr. 300-02 (parenthetical).

                                                     21
does not always result in disease; such production is a normal, protective response that vaccines
are designed to elicit, not evidence of disease onset. Id.

       Dr. Rose testified that, if the cytokine upregulation caused by Petitioner’s second
Gardasil dose had, in fact, triggered her sJIA, she would have manifested the disease almost
immediately. sJIA patients who take a daily dose of anakinra 46 – an IL-1 cytokine inhibitor –
generally experience clinical manifestations of their disease, in the form of fever, within 12 hours
of a missed dose. Tr. 307. Petitioner’s medical records contain no evidence of any signs or
symptoms of sJIA within the days following the first or second vaccination. Id.

     IV.   Analysis

           a. Althen Prong 1.

        The Supreme Court has recognized that a novel theory that is relatively unexamined by
the relevant scientific community may not be as persuasive as a theory that has been thoroughly
peer-reviewed. This is so because “submission to the scrutiny of the scientific community …
increases the likelihood that substantive flaws in methodology will be detected.” Daubert, 509
U.S. at 593-94 (clarifying that the lack of publication is a “relevant, though not dispositive,
consideration in assessing … scientific validity”). However, special masters have also
recognized that a theory’s novelty is not dispositive in determining its scientific validity. Cedillo
v. HHS, No 98-916V, 2009 WL 331968, at *111 (Fed. Cl. Spec. Mstr. Feb. 12, 2009) (“At times
novel theories can be persuasive”). See also Daubert, 509 U.S. at 593 (“in some instances well-
grounded but innovative theories will not have been published.”)(internal citations omitted).

        In the instant case, the undersigned finds that Drs. Gershwin and McCabe have set forth a
novel, but nevertheless reliable and plausible theory by which two Gardasil vaccinations can
cause sJIA. Several aspects of Petitioner’s experts’ theory – that Gardasil is designed to elicit
proinflammatory cytokines, and that sJIA is triggered by the same type of cytokine upregulation
that the Gardasil vaccine is designed to induce – are essentially uncontested by Respondent. Dr.
Rose also did not dispute, as discussed by Dr. Gershwin, that sJIA is an autoinflammatory
disease, and that it occurs in genetically predisposed individuals exposed to an environmental
trigger. Thus, most of the mechanism of causation put forth by Petitioner’s experts was not
disputed. Dr. Rose did, however, disagree that the Gardasil vaccine can trigger sJIA, because he
has never seen a natural HPV infection associated with sJIA, and because there is a dearth of
supportive epidemiological evidence. Resp. Ex. A at 4-5; see generally tr. 225-300.

        The undersigned finds that the lack of an association between sJIA and naturally
occurring HPV infections is not dispositive. As Dr. McCabe pointed out, natural infections do
not produce the same sustained immune response, or the same upregulation of proinflammatory
cytokines, as does the vaccine. Tr. 77-79. This conclusion is supported by the Pinto study,
which found that “[t]he cellular immune responses (lymphoproliferation and cytokine levels)
after healthy individuals are immunized with []vaccine are consistently higher than those

46
  Anakinra is “a … form of the human interleukin-1 receptor antagonist, used as an antiinflammatory in
the treatment of rheumatoid arthritis.” Dorland’s at 71.

                                                  22
previously reported in the context of natural infection. In fact, T cell responses to HPV antigens
in natural HPV infection have been difficult to measure.” Pinto 2 at 10 (citations omitted).

         The undersigned often relies on epidemiological evidence such as that cited by Dr. Rose
in this case. However, particularly in the Prong One context, its persuasiveness is tempered by
the fact that, while it may show that a vaccine has not caused a particular injury, at least to a
statistically relevant extent, it cannot show that the vaccine cannot cause that particular injury.
The Chao study, which followed subjects until 180 days after they had received a third
quadrivalent HPV vaccine (Gardasil), did not specifically study sJIA. See generally Chao; tr.
150-51. Moreover, the study only included 189,000 subjects, and the incidence of sJIA in the
general population is less than 1 in 100,000; as such, the study is “underpowered and is not able
to be applied to an analysis of … the increased risk attributable to … developing sJIA following
vaccination.” Tr. 151-52. During the hearing, Dr. Rose appeared equivocal, at best, about his
assertion that the studies he cited were “sufficiently powered” to be statistically useful. For
example, when asked whether the Verstraeten study was sufficiently powered, Dr. Rose testified,
“I did not do my power calculations. I’m sorry. That was the only thing I had at the time. I
thought it was a good number. I saw they didn’t see the signals. I wasn’t in the peer review, I’m
not an epidemiologist.” Tr. 363-64. In light of the rarity with which sJIA presents, the
undersigned finds that the lack of supportive epidemiological evidence is not dispositive in this
case

         Finally, the undersigned finds that the reliability of Dr. Rose’s methodology, particularly
as it relates to his definition and description of Petitioner’s injury, was somewhat compromised
by his insistence that Petitioner’s actual injury was MAS, not sJIA, and that sJIA and Crohn’s
disease are mutually exclusive diagnoses. 47 See, e.g., tr. 314-21. This diagnosis had no support
in the medical records; almost all of the treating physicians who initially assessed Petitioner’s
injuries ultimately concluded that they were attributable to sJIA. Indeed, Respondent ultimately
decided to concede the nature of Petitioner’s injury, notwithstanding Dr. Rose’s continued
opinion to the contrary. Tr. 314-17, 321-23, 327-28.

        Based on the foregoing analysis, the undersigned finds that Petitioner has demonstrated
by a preponderance of the evidence that the Gardasil vaccine can act as a trigger and cause sJIA.

           b. Althen Prong 2.

        Petitioner was administered the first Gardasil vaccine on March 19, 2008, and the second
Gardasil vaccine on June 30, 2008. Pet. Ex. 2 at 3-4; Pet. Ex. 3 at 11. Four months after the
administration of the second vaccine, she presented to medical treatment providers with clinical
markers of elevated proinflammatory cytokines; namely, persistent fever, myalgia, rash, and
joint pain. Pet. Ex. 4 at 14; Pet. Ex. 7 at 36-38; tr. 131-32. Tests for infectious and systematic
autoimmune diseases were all negative. Pet. Ex. 4 at 54; Pet. Ex. 5 at 160-68. Blood tests in

47
  The reliability of Dr. Rose’s methodology was also adversely impacted by his confusion of the
cytokines IL-8 and IL-18, tr. 357-358, his misreading of a chart in the Pinto article, tr. 359-360,
and his reliance on statistically underpowered studies in support of his epidemiological
arguments. Tr. 362-68.

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December 2008 were consistent with an ongoing systemic inflammatory process. Pet. Ex. 5 at
11-16. Her ferritin, CRP, sedimentation rate, and white blood cell counts were elevated, all of
which were consistent with sJIA. Tr. 13, 17, 338-44. Petitioner was successfully treated with
steroids and methotrexate, both of which are drugs that inhibit the cytokines TNF-alpha, IL-6,
and IL-1. Tr. 37-39; Pet. Ex. 6 at 34-36, 41.

         The undersigned finds these records to be sufficient evidence of an uncontrolled
activation of Petitioner’s genetically susceptible innate immune system, including elevated
serum levels of acute phase reactants, including C-reactive protein, as well as serum complement
components, ferritin, and elevated leukocytes and platelets accompanied by a rising erythrocyte
sedimentation rate, which occurred in November and December 2008. Pet. Ex. 6 at 4, 82, 86;
Pet. Ex. 5 at 16, 162-65; tr. 36-37 (Dr. Gershwin opining that Petitioner’s symptoms and test
results in November and December 2008 were reflective of the uncontrolled activation of her
innate immune system that ultimately resulted in sJIA). Although there is no direct evidence of
an upregulation of Petitioner’s inflammatory cytokines, the medical record contains ample
circumstantial evidence in the form of her clinical symptoms, her blood test results, and her
favorable response to cytokine-suppressing drugs.

        Dr. Rose’s argument that Petitioner’s sJIA may have been triggered by a viral infection is
compromised by Respondent’s decision not to pursue it under an alternative causation theory.
Standing alone, Dr. Rose’s unembellished theory does not undermine the reliability of
Petitioner’s prima facie case. The undersigned finds plausible Dr. McCabe’s theory that
Petitioner’s immune system was capable of handling a mild infection (as it had many times in the
past), notwithstanding her genetic predisposition to sJIA; Petitioner’s immune system was more
likely to, and did, produce a “dramatic” response to the Gardasil vaccination, which is designed
to produce such a response. Tr. 79-80, 210-11. Any viral infection capable of producing a
comparable response would have had to be debilitating, and would likely have been specifically
documented. Tr. 210-11.

        Finally, the undersigned finds that the absence of a third Gardasil vaccine does not
compromise Petitioner’s theory under Althen Prong 2. Whether or not a third “booster”
vaccination is administered, the first two Gardasil vaccinations are, by design, likely to prompt a
robust, sustained immune response. Tr. 22-23. This immune response is near its peak after the
second dose. Frazer at 4; tr. 188-90 (opining that any contribution of the third vaccine to the
robustness of the immune response would have been minor compared to the first two vaccines;
“to perseverate on the minor changes that occur in antibody titer between month three and month
seven … you’re missing that much of the potency, the robustness of the response, is occurring
within the time frame of those first two immunizations.”); see also Pinto 2 at 6-7, which found
that the further increases in cytokine levels from post-dose two to post-dose three of the vaccine
“were, for the most part, small and nonsignificant.”

       Accordingly, the undersigned finds, by a preponderance of the evidence, that Petitioner’s
Gardasil vaccinations played a causative role in the development of her sJIA.

                                                24
           c. Althen Prong 3.

         Both of Petitioner’s experts testified that four and a half months after the second Gardasil
vaccination – and seven to eight months after the first vaccination – are appropriate intervals
between vaccination and onset. Tr. 16-30, 134-45. Dr. Gershwin opined that the protective
response to the Gardasil vaccination takes about seven months after administration of the first
shot. Tr. 18-19. Dr. McCabe cited numerous articles for his opinion that a vaccinee’s peak
immune response is likely to occur around seven months after the first Gardasil vaccination. Tr.
138. In light of the undersigned’s finding that development of sJIA is triggered by the
upregulation of the same cytokines as those peaking in response to the Gardasil vaccine, it is
reasonable to conclude that the timing of onset of Petitioner’s sJIA would be consistent with the
peak cytokine responses documented in the studies cited by Petitioner. See, e.g., Pinto 2 at 1
(“The strongest cytokine responses at month 7 were observed in individuals with high antibody
titers at month 2, suggesting that neutralizing antibodies generated by initial vaccination may
augment T cell responses to subsequent booster vaccinations.”). See generally Prakken, Pinto,
Pinto 2, Garcia-Pineras, and Evans.

        Dr. Gershwin’s testimony that there may be a significant period of time between the
incidence of cytokine dysregulation and the “breakthrough” that leads to clinical manifestation of
sJIA, tr. 26-28, 30, and that this latency period may last months, tr. 19-20, 50, was also
persuasive on the temporal issue.

       The undersigned finds that Dr. Rose’s Althen Prong 3 theory – that onset should have
occurred much earlier – simply lacks substantiation in the record. The undersigned
acknowledges Dr. Rose’s argument that sJIA patients who miss doses of their cytokine inhibitors
generally experience symptoms within 12 hours. However, that timing is associated with the
recurrence of sJIA, where the manifestation threshold is already met, and is therefore inapposite.

        The undersigned finds that Petitioner has proven, by a preponderance of the evidence,
that there is a proximate temporal relationship between Petitioner’s Gardasil vaccinations and the
onset of her sJIA.

   V.      Conclusion

       For the reasons set forth above, the undersigned finds that Petitioner has shown by
medical records and competent medical opinion that her medical condition was “more likely than
not” vaccine-caused, and that she is entitled to compensation. This case is now ready to proceed
to damages.

        IT IS SO ORDERED.
                                                      s/Lisa Hamilton-Fieldman
                                                      Lisa Hamilton-Fieldman
                                                      Special Master

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