Terhune v. Secretary of Health and Human Services

In the United States Court of Federal Claims

OFFICE OF SPECIAL MASTERS

No. 16-393V

Originally Filed: December 17, 2021

Filed in Redacted Form: January 13, 2022

PUBLISHED

Special Master Horner

A.T.,

Petitioner, Ruling on the Written Record;

v. Narcolepsy Cataplexy

Syndrome; Human

SECRETARY OF HEALTH AND Papillomavirus (“HPV”) vaccine

HUMAN SERVICES,

Respondent.

Danielle Strait, Maglio Christopher & Toale, P.A., Seattle, WA, for petitioner.

Catherine Stolar, U.S. Department of Justice, Washington, DC, for respondent.

DECISION 1

On March 29, 2016, petitioner, A.T. 2, filed a petition under the National Childhood

Vaccine Injury Act, 42 U.S.C. § 300aa-10-34 (2012), 3 alleging that her receipt of a

second human papillomavirus (“HPV”) vaccine on May 1, 2013 caused-in-fact, or

alternatively, significantly aggravated her narcolepsy with cataplexy. 4 (ECF No. 1.) For

the reasons set forth below, I conclude that petitioner is not entitled to an award of

compensation.

1 When this decision was originally filed the undersigned advised his intent to post it on the United States

Court of Federal Claims' website, in accordance with the E-Government Act of 2002. 44 U.S.C. § 3501

note (2012) (Federal Management and Promotion of Electronic Government Services). In accordance

with Vaccine Rule 18(b), petitioner filed a timely motion to redact certain information. This decision is

being reissued with petitioner’s name reduced to initials. Except for those changes and this footnote, no

other substantive changes have been made. This decision will be posted on the court’s website with no

further opportunity to move for redaction.

2 Petitioner was a minor when the petition was filed, so her mother filed the petition as her legal

representative. Petitioner reached the age of majority on March 27, 2017 and was substituted as

petitioner on December 19, 2017. (ECF Nos. 30, 31.)

3 All references to “§ 300aa” below refer to the relevant section of the Vaccine Act at 42 U.S.C. § 300aa-

10-34.

4 The brand name of the HPV vaccine administered to petitioner is Gardasil. (See Ex. 21.)

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I. Applicable Statutory Scheme

Under the National Vaccine Injury Compensation Program, compensation

awards are made to individuals who have suffered injuries after receiving vaccines. In

general, to gain an award, a petitioner must make a number of factual demonstrations,

including showing that an individual received a vaccination covered by the statute;

received it in the United States; suffered a serious, long-standing injury; and has

received no previous award or settlement on account of the injury. Finally – and the key

question in most cases under the Program – the petitioner must also establish a causal

link between the vaccination and the injury. In some cases, the petitioner may simply

demonstrate the occurrence of what has been called a “Table Injury.” That is,

petitioners may show that they suffered an injury of the type enumerated in the “Vaccine

Injury Table,” corresponding to the vaccination in question, within an applicable time

period following the vaccination also specified in the Table. In such cases, the Table

Injury is presumed to have been caused by the vaccine. § 300aa-13(a)(1)(A); § 300 aa-

11(c)(1)(C)(i); § 300aa-14(a); § 300aa-13(a)(1)(B).

In many cases, however, the vaccine recipient may have suffered an injury not

covered by the Vaccine Injury Table. In these “off-Table” cases, an alternative means

exists to demonstrate entitlement to a Program award. The petitioner may demonstrate

entitlement by showing that the recipient’s injury was “caused-in-fact” by the vaccine

they received, a showing often referred to as “actual causation.” § 300aa-13(a)(1)(B); §

300aa-11(c)(1)(C)(ii). In off-table cases, the presumptions available under the Vaccine

Injury Table are inoperative, and the burden is on the petitioner to introduce evidence

demonstrating that the vaccination was responsible for the injury in question. Althen v.

Sec’y of Health & Human Servs., 418 F.3d 1274, 1278 (Fed. Cir. 2005); Hines v. Sec’y

of Health & Human Servs., 940 F.2d 1518, 1525 (Fed. Cir. 1991).

To show actual causation, petitioner must satisfy the “preponderance of the

evidence” standard, the same standard ordinarily used in tort litigation. § 300aa-

13(a)(1)(A); see also Althen, 418 F.3d at 1279; Hines, 940 F.2d at 1525. Under that

standard, the petitioner must show that it is “more probable than not” that the

vaccination caused the alleged injury. Althen, 418 F.3d at 1279. The petitioner need

not show that the vaccination was the sole cause of the injury or condition, but must

demonstrate that the vaccination was a “substantial factor” and a “but for” cause.

Shyface v. Sec’y of Health & Human Servs., 165 F.3d 1344, 1352 (Fed. Cir. 1999).

This standard has been interpreted to require “proof of a logical sequence of cause and

effect showing that the vaccination was the reason for the injury;” the logical sequence

must be supported by “reputable medical or scientific explanation, i.e., evidence in the

form of scientific studies or expert medical testimony.” Althen, 418 F.3d at 1278; Grant

v. Sec’y of Health & Human Servs., 956 F.2d 1144, 1148 (Fed. Cir. 1992). A petitioner

may not receive a Vaccine Program award based solely on his or her assertions; rather,

the petition must be supported by either medical records or by the opinion of a

competent physician. § 300aa-13(a)(1).

2

In what has become the predominant framing of this burden of proof, the Althen

court described the “causation-in-fact” standard, as follows:

Concisely stated, Althen’s burden is to show by preponderant evidence

that the vaccination brought about her injury by providing: (1) a medical

theory causally connecting the vaccination and the injury; (2) a logical

sequence of cause and effect showing that the vaccination was the reason

for the injury; and (3) a showing of proximate temporal relationship

between vaccination and injury. If Althen satisfies this burden, she is

“entitled to recover unless the [government] shows, also by a

preponderance of the evidence, that the injury was in fact caused by

factors unrelated to the vaccine.”

Althen, 418 F.3d at 1278 (citations omitted). The Althen court noted that a petitioner

need not necessarily supply evidence from medical literature supporting petitioner’s

causation contention, so long as the petitioner supplies the medical opinion of an

expert. Id. at 1279-80. That expert’s opinion must be “sound and reliable.” Boatmon v.

Sec’y of Health & Human Servs., 941 F.3d 1351, 1359-60 (Fed. Cir. 2019). The Althen

court also indicated, however, that a Program fact finder may rely upon “circumstantial

evidence,” which the court found to be consistent with the “system created by Congress,

in which close calls regarding causation are resolved in favor of injured claimants.”

Althen, 418 F.3d at 1280.

Where a petitioner in an off-Table case is seeking to prove that a vaccination

aggravated a pre-existing injury, petitioners must also establish three additional factors.

See Loving v. Sec’y of Health & Human Servs., 86 Fed. Cl. 135, 144 (Fed. Cl. 2009)

(combining the first three Whitecotton factors for claims regarding aggravation of a

Table injury with the three Althen factors for off table injury claims to create a six-part

test for off-Table aggravation claims); see also W.C. v. Sec’y of Health & Human Servs.,

704 F.3d 1352, 1357 (Fed. Cir. 2013) (applying the six-part Loving test.). The additional

Loving factors require petitioners to demonstrate aggravation by showing: (1) the

vaccinee’s condition prior to the administration of the vaccine, (2) the vaccinee’s current

condition, and (3) whether the vaccinee’s current condition constitutes a “significant

aggravation” of the condition prior to the vaccination. Id.

In this case, petitioner filed her petition alleging that her receipt of a second HPV

vaccine caused, or alternatively, significantly aggravated her narcolepsy. (ECF No. 1.)

However, petitioner now contends only that the HPV vaccine significantly aggravated

her narcolepsy. (See ECF Nos. 26-28, 73.) Because this injury is not listed as a Table

Injury relative to the HPV vaccine, petitioner must satisfy the six-part Loving test. See

42 C.F.R. § 100.3(a).

II. Procedural History

Petitioner’s mother filed a petition on her behalf on March 29, 2016. (ECF No.1.)

Petitioner was later substituted as petitioner once she reached the age of majority.

(ECF Nos. 30, 31.) The case was assigned to Special Master Laura Millman. (ECF No.

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4.) Petitioner filed supporting medical records marked as Exhibits 1-7 on April 7, 2016.

(ECF No. 6.) Following an initial status conference on May 19, 2016, petitioner

submitted additional medical records, petitioner’s mother’s affidavit, and a Statement of

Completion. (Exs. 8-12, ECF Nos. 9, 11, 12.)

On May 19, 2016 Special Master Millman issued an order, noting that statements

made by petitioner’s mother in her medical records regarding symptom onset “[we]re

not consistent.” (ECF No. 8.) Special Master Millman observed that petitioner’s mother

reported on May 11, 2013 “that [petitioner’s] narcolepsy worsened two weeks before

[petitioner] received the Gardasil vaccine,” but claimed “just three days later on May 14,

2013,” that petitioner’s “symptoms increased after she received the vaccination.” (ECF

No. 8 (citing Ex. 4, pp. 52, 63).)

On August 23, 2016 Special Master Millman issued a subsequent order, and

again noted that “[petitioner’s] medical records show that she was experiencing

symptoms of narcolepsy cataplexy syndrome before she received her second Gardasil

vaccine on May 1, 2013.” (ECF No.13, citing Ex. 4, p. 52; Ex. 11, pp. 2, 31.) Special

Master Millman ordered petitioner’s mother to file an affidavit explaining the discrepancy

in the records regarding the alleged onset of her daughter’s injury. (Id.) Petitioner’s

mother filed an affidavit on September 22, 2016 wherein she alleged that “[t]here was

nothing wrong with my daughter on May 1, 2013. She was given two vaccines that day,

hepatitis and the second Gardasil.” (ECF No. 14, Ex. 13, p. 1.)

Following a telephonic status conference, on September 26, 2016 Special Master

Millman noted that she felt this was a significant aggravation case and ordered

petitioner to file an expert report supporting her claim. (ECF. No. 15.) On November

27, 2017, Special Master Millman issued an order questioning whether it was

reasonable to proceed. (ECF No. 26.) Concurrently, Special Master Millman filed Court

Exhibit 1, an epidemiological study “showing that among almost one million adolescent

girls, [the] HPV vaccine was not [r]elated causally to narcolepsy.” (ECF No. 26.)5 On

December 11, 2017, Special Master Millman granted petitioner’s Motion for Clarification,

finding this case to be an allegation that petitioner’s second HPV vaccine significantly

aggravated her preexisting narcolepsy-cataplexy. (ECF Nos. 27, 28.)

On February 8, 2018, petitioner filed her first expert report from Dr. Lawrence

Steinman and additional medical literature. (ECF Nos. 39-41, Exs. 14-39.) On May 18,

2018, respondent filed his Rule 4(c) report, arguing that the evidence presented did not

meet petitioner’s burden and recommending against compensation. (ECF No. 46.)

Respondent also filed medical literature and expert reports from Dr. Maryann Deak

(neurology and sleep medicine) (Ex. A) and Dr. Lindsay Whitton (virology and

immunology) on the same day. (Ex. C) (ECF No. 43.) Each party subsequently filed

5 Special Master Millman also noted the increased incidence of narcolepsy following the Pandemrix (2009

H1N1 flu vaccine) and the H1N1 flu virus “suggests that that the flu virus in the 2009 H1N1 flu vaccine,

not the adjuvant, was responsible for the increase in narcolepsy cases. HPV does not contain H1N1 flu

virus.” (ECF No. 26, p. 2.)

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additional expert reports and the case was later reassigned to me on June 5, 2019.

(Exs. 40, 43, 49, 55; Exs. EE, GG, KK, RR; ECF No. 57 (Notice of Reassignment).)

On August 25, 2020 I held a status conference to discuss possible resolution of

petitioner’s claim, proposing a resolution based on the written record. (ECF No. 71.)

The parties agreed. 6 (Id.) Petitioner filed her Motion for a Ruling on the Record on

December 18, 2020. (ECF No. 73.) Respondent filed her response to petitioner’s

motion on March 22, 2021 and petitioner filed her reply to respondent’s response to

petitioner’s motion on April 13, 2021. (ECF Nos. 75, 76.)

I have determined that the parties have had a full and fair opportunity to present

their cases and that it is appropriate to resolve this issue without a hearing. See Vaccine

Rule 8(d); Vaccine Rule 3(b)(2); Kreizenbeck v. Sec’y of Health & Human Servs., 945

F.3d 1362, 1366 (Fed. Cir. 2020) (noting that “special masters must determine that the

record is comprehensive and fully developed before ruling on the record.”).

Accordingly, this matter is now ripe for resolution.

III. Medical History

Petitioner was born on March 27, 1999. (Ex. 2, p. 3.) Prior to vaccination,

petitioner suffered only minor health issues, including a history of congenital cataract at

age two and obstructive sleep apnea requiring a tonsillectomy at age five. (Ex. 3, p.

55.) On April 2, 2012, petitioner received her first HPV vaccination at 13 years of age.

(Ex. 4, p. 74.) Then on May 1, 2013, petitioner presented to her pediatrician, Sidney

Randel, M.D., for her routine well visit. (Ex. 4, p. 70.) Dr. Randel’s physical

examination of petitioner was normal. 7 (Id. at 71.) Dr. Randel noted “[f]ine and gross

motor sensory intact,” petitioner’s deep tendon reflexes were equal, no pathological

reflex; petitioner’s tone was normal, no focal deficits; and petitioner’s gait was normal

and appropriate for her age. (Id.) He recorded that petitioner was overweight but a

“well child.” 8 (Id. at 72.) Dr. Randel discussed with petitioner a healthy diet and

6 I also advised the parties that “[i]f upon preparing their written submissions either party comes to

believe that this case is not ripe for resolution on the existing record, they may address those concerns in

the form of a motion to amend the schedule. Otherwise, the parties should anticipate that I will resolve the

question of petitioner’s entitlement to compensation without further proceedings.” (ECF No. 71.) No such

motion was filed.

7 The record notes in the section “Patient/Parent Questions,” that “Mom says [petitioner] does not sleep.”

(Ex. 4, p. 70.)

8

Later accounts of petitioner’s symptoms reveal a history of sleep disruption and daytime sleepiness with

prolonged napping prior to her hospitalization on May 11, 2013 for four to six weeks, discussed further

below. (Ex. 3, p. 43, Ex. 4, p. 52 (Dr. Neidenberg); Ex. 3, p. 84-85 (Dr. Martinez); Ex. 3, pp. 5-6, Ex. 4,

pp. 9-10, Ex. 11, pp. 31-33 (Dr. Dubrovsky); Ex. 3, pp. 64-67 (Dr. Brown); Ex. 3, pp. 48-50 (Dr. Maragh),

Ex. 3, pp.54-55 (Dr. Chiang); Ex. 3, pp. 67-68 (Dr. Gutierrez).) In one note, petitioner described “waking

up 1-2 [times] a night 4 weeks ago.” (Ex. 3, p. 5.) This would place onset of petitioner’s symptoms in

approximately April 2013. Between 2-4 weeks prior to hospitalization, petitioner reported additional

symptoms including: legs buckling (Ex. 3, p. 65, Ex. 3, p. 85), falls (Ex. 3, p. 65, Ex. 3, p. 69), slurred

speech (Ex. 3, pp. 5-6), and gait difficulties (Ex. 3, p. 69, Ex. 3, p. 85). Petitioner does not allege that her

narcolepsy began after the May 1, 2013 vaccination. (ECF No. 73, p. 14.)

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exercise. (Id.) Petitioner also received a Hepatitis A vaccination and her second HPV

vaccination. (Id. at 71.)

On May 11, 2013, ten days after receiving her second HPV vaccination,

petitioner presented to the emergency department at Joe DiMaggio Children’s Hospital

complaining of sleeplessness, weakness, twitching and slurred speech. (Ex. 3, p. 43.)

Petitioner’s mother reported a history of petitioner’s symptoms to Ilhana Gilderman

Neidenberg, D.O. (Id.) The history of present illness included: a six-week history of

“sleeplessness,” a two-and-a-half-week history of “knees twitching while standing,” and

a three-day history of “slurred speech and hands twitching and shaking.” (Id.)

Petitioner’s mother also remarked that “sometimes [petitioner] can[not] stand up without

leaning against the wall because she is disoriented.” (Id.) According to petitioner’s

mother, she had “fallen down several times” because petitioner was unaware of her fall

or unable to catch herself. (Id.) Petitioner’s history of present illness also noted that

she was able to fall asleep at night, only to “wake up a few hours later unable to fall

asleep.” (Id.)

Petitioner’s mother further reported to Dr. Neidenberg that she attributed

petitioner’s sleeplessness to the end of the soccer season, approximately six weeks

prior, concluding that she “was not getting enough exercise to tire her out.” (Ex. 3, p.

43.) The history of present illness also documented a six-week history of prolonged

naps after school lasting three hours. (Id.) Petitioner’s mother reported that her

symptoms “have worsened so she brought [petitioner] to [primary care provider] 2

weeks ago where she received Gardasil vaccine and [the pediatrician] also

recommended melatonin for sleeplessness with no relief.” (Id.) Petitioner was admitted

to the hospital May 11, 2013 for further evaluation. (Id. at 46.)

Later that day, petitioner was seen by Diana Martinez, M.D., for a neurology

consult. (Ex. 3, p. 47) CT and EEG results were reviewed as normal. (Id. at 56.) The

MRI was reported as normal and the MRA of the brain was inconclusive due to

interference from petitioner’s braces. (Id. at 58.) Dr. Martinez recommended a thyroid

function test and that infectious disease be contacted to see whether “this could

possibly be a side effect of [G]ardasil, although [she had] never seen this.” (Id. at 90.)

In her neurological exam Dr. Martinez observed that “when [petitioner] got up to use the

bathroom she felt loss of balance and had some twitches….” (Id. at 92.)

On May 12, 2013 Dr. Martinez returned for a follow-up and noted in the

subjective portion of the medical record that petitioner’s “[m]other has concerns that the

[petitioner] had a [G]ardasil immunization a[nd] this may have contributed to the

[petitioner’s] symptoms.” (Id. at 99-100.) Dr. Martinez’s assessment noted that “the

etiology of [petitioner’s] symptoms [is] unknown[;] it’s possible that this is related to the

green coffee extract [petitioner] was taking.” (Id. at 102.)

On May 13, 2013, pediatric neurologist Tatyana Dubrovsky, M.D., met with

petitioner and noted that petitioner had received a “Gardasil vaccination 2 weeks ago.”

(Ex. 3, p. 5.) Dr. Dubrovsky questioned whether “the vaccination has anything to do

6

with the escalat[ion] of the symptoms” petitioner was experiencing. (Id. at 6.) In the

physical exam, Dr. Drubrovsky noted that petitioner “actually had an episode” where

she began slurring her speech and nodding her head. (Id.) The same day, pediatric

infectious disease specialist Robert Reid, M.D., examined petitioner for “suspected

toxicity from Gardasil vaccine.” (Id. at 51.) Dr. Reid concluded that petitioner’s

condition was “not likely a reaction to the vaccine since the symptoms of insomnia

started way before the vaccine was given.” (Id. at 53.)

On May 14, 2013, petitioner was seen by pediatric neurologist Stuart Brown,

M.D. (Ex. 3, pp. 65-66.) Dr. Brown noted that petitioner received a Gardasil vaccination

approximately two weeks prior and “[s]ince that time, her symptoms have seemingly

increased, but she has also been noticing, and the mother has been noticing, that in the

last week she has not only been falling, but she has been having difficulty in walking,

being very unsteady on her feet.” (Id. at 65.) Dr. Brown also questioned whether

petitioner’s Gardasil vaccination “triggered [] narcolepsy on an autoimmune basis,” and

observing that “[t]his has been reported occasionally with other immunizations.” (Id. at

66.) Dr. Brown further commented that “[a]lthough Gardasil was thought to perhaps be

associated with increased precipitation of Guillain-Barre Syndrome, the statistics for this

are questionable as to a cause and effect relationship.” (Id.)

On May 15, 2013, petitioner was seen by pediatric infectious disease specialist

Maria Gutierrez, M.D. (Ex. 3, p. 68.) In her consultation, Dr. Gutierrez noted that

“[s]ome sleep disturbance, narcolepsy, have been associated with previous infections.

There have also been cases of narcolepsy associated with Influenzae [sic] vaccine with

an adjuvant that is not available in this country.” (Id. at 70.) Dr. Gutierrez also observed

that petitioner “had received the Gardasil [vaccination] after the symptoms had started”

and “d[id] not believe there has been association.” (Id.) On May 16, 2013 petitioner

had a consultation with pediatric allergist and immunologist Gary Kleiner, M.D. (Ex. 3,

p. 62.) Dr. Kleiner noted that petitioner’s “mother believes that some of [petitioner’s]

symptoms may have occurred shortly after her Gardasil vaccination.” (Id. at 62-63.) Dr.

Kleiner requested a follow-up visit to review petitioner’s pending lab results. (Id. at 63-

64.) Petitioner’s lab results ultimately revealed that she had the HLA DQB1*0602 gene

and low hypocretin, consistent with narcolepsy. 9 (Ex. 2, p. 4; Ex. 11, p.103.)

Petitioner was discharged from the hospital on May 17, 2013 after receiving

intravenous immunoglobulin for treatment of possible autoimmune narcolepsy. (Ex. 3,

p. 72; Ex. 11, p. 2.) The discharge summary, dated May 16, 2013, indicates that

petitioner was seen by two infectious disease physicians, Drs. Reid and Gutierrez, and

three neurologists, Drs. Martinez, Dubrovsky and Brown and that her “presumptive

diagnosis [wa]s narcolepsy.” (Ex. 11, p. 3.) Her symptoms were listed as “ongoing but

not worsening.” (Id.) On May 23, 2013 petitioner returned to see Dr. Dubrovsky for a

follow-up appointment. (Ex. 11, p. 31.) The history of present illness noted that

9 It is not clear from the records when these lab results were reported, but petitioner appears to have

been discharged prior to the tests’ completion. (Ex. 11, pp. 3-7) (lab results available at discharge do not

include hypocretin or genetic testing results) (But see Ex. 2, p. 4; Ex. 11, p. 103) (reporting test results

from May 14, 2013).)

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petitioner “presented with excessive daytime sleepiness, cataplexy, and episodes of

sleep paralysis since mid-April, exacerbated after Gardasil shot at the end of April.”

(Id.) Per her assessment, Dr. Dubrovsky noted that she was “not certain[] if the

symptoms are associated with the vaccination, but would recommend to report it to the

registry.” (Id.)

On June 27, 2013 petitioner consulted with pediatric neurologist Marcel Deray,

M.D. (Ex. 7, p. 126.) The history of petitioner’s present illness noted that her

narcolepsy symptoms “[s]tarted with insomnia in April 2013.” (Id.) Dr. Deray noted that

petitioner saw her primary care provider on May 1, 2013 for a routine visit and was

started on 3 mg of melatonin. (Id.) Dr. Deray also noted that petitioner received a

“Gardasil [sic] shot and another Hep A vaccine” during that visit. (Id.) Dr. Deray

remarked that petitioner’s left leg buckled three days after her vaccinations, the

“[f]ollowing day speech was slurred,” and “[f]ive days after the shot, at dinner, [her] right

arm would shake.” (Id.) Dr. Deray’s impression was narcolepsy with cataplexy

syndrome and petitioner was prescribed Ambien. (Id. at 129.) Petitioner’s mean sleep

latency test (“MSLT”) conducted in June of 2013 recorded REM onset sleep periods at

5/5 and an msl of 1.6 min., although a follow-up study in August of 2013 was normal.

(Ex. 7, pp.110, 138.)

On October 17, 2013 petitioner returned to see Dr. Dubrovsky, who confirmed

petitioner’s diagnosis of narcolepsy cataplexy syndrome. (Ex. 11, p. 104.) In this visit,

Dr. Dubrovsky noted that petitioner’s “mother [] want[ed] to clarify the history, the

[petitioner] started having difficulty staying asleep and taking daytime naps since mid-

April. She had Gardasil shot on 5/1/13 and since then developed sleep attacks and

cataplexy that was debilitating.” (Id. at 103.) Dr. Dubrovsky suggested scheduled naps

and continued petitioner’s prescriptions for Ambien and Concerta. (Id. at 103-104.)

Petitioner was later prescribed Xyrem for her narcolepsy, and continued

treatment with Dr. Deray throughout the rest of 2013 and until March 2016. (See Ex. 9,

pp. 2-10.) As of December 2019, petitioner was seeing pulmonologist Samuel

Gurevich, M.D., regarding treatment for excessive daytime somnolence, narcolepsy,

and parasomnias. (Ex. 53, p. 24.) Petitioner’s most recent records, from July 23, 2020,

indicate that she is participating in weekly psychotherapy for reasons unrelated to the

condition at issue in this case. (Ex. 54, p. 1.)

a. Petitioner’s Mother’s Affidavits

In her first affidavit, petitioner’s mother avers that petitioner received the Gardasil

vaccine and “sustained Narcolepsy cataplexy syndrome, which was actually caused by

the vaccine received.” (Ex. 10, p. 1.) In response to Special Master Millman’s order,

petitioner’s mother provided a supplemental affidavit, explaining the inconsistences in

petitioner’s medical records. (Ex. 13.)

In her second affidavit, petitioner’s mother states that “[t]here was nothing wrong

with [petitioner] on May 1, 2013” during her well-child visit and petitioner had “no

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medical problems that day.” (Ex. 13, p. 1.) Petitioner’s mother also claims that she “did

note that [petitioner] was not sleeping,” and “[p]rior to that visit, [petitioner] had had a

work up for sleep apnea[.]” (Id.) According to petitioner’s mother, petitioner had recently

stopped playing soccer and “[she] felt at the time that the sleep issues were related to a

lack of exercise which would result in being less tired at bed time.” (Id.) She added that

this visit was “entirely a routine check-up and [] [petitioner] was cleared for participation

in athletics at its conclusion.” (Id.)

Petitioner’s mother avers that the history of present illness recorded in

petitioner’s hospital discharge record from May 16, 2013 appears to be “an accurate

narrative of what I remember to be the time line of events before and after May 1,

2013.” (Ex. 13, p. 1-2 (citing Ex. 11, p. 2).) Prior to May 1, 2013, petitioner’s mother

claims that “the only noteworthy issue involving [petitioner’s] health was her problems

falling asleep.” (Id. at 2.) However, she states that “that issue was NOT what brought

us to the pediatrician that day. In fact, as [she] reported on May 11, the character of []

[petitioner’s] sleep issues changed dramatically in the week before May 11.” (Id.)

Petitioner’s mother also avers that she has “no independent memory of saying

that [petitioner’s] narcolepsy/cataplexy symptoms began in April,” and that “at the time

of the May 11 admission [of petitioner to the hospital],” petitioner’s mother “felt that her

symptoms began after the May 1 Gardasil vaccine.” (Ex. 13, p. 2 (citing Ex. 11, p. 31).)

She is unsure “where the individual who wrote that history got the April dates

referenced,” and she does not believe that “[she] would have made the mistake of

saying that the symptoms had begun in April.” (Id.) Regardless, her mother states that

petitioner’s symptoms did not start until after May 1. (Id.)

Petitioner’s mother further avers that the history given to Dr. Gilderman

Neidenberg on May 11, 2013 which “suggests that [petitioner’s] narcolepsy/cataplexy

symptoms started in early April 2013” was in fact “wrong.” (Ex. 13, p. 2 (citing Ex. 4, p.

52.).) Additionally, petitioner’s mother asserts that the history written by Dr. Randel

during her daughter’s well-child visit on May 1, 2013, and the history given by Dr. Lazar

at discharge “reflect what [she] remember[s] about the onset of [petitioner’s]

narcolepsy/cataplexy.” (Ex. 13, p. 2 (citing Ex. 11, pp. 2, 52-56).) Though the record

suggests that she took petitioner to her primary care physician on May 1 “because of

worsened narcolepsy symptoms,” petitioner’s mother states that she did not. (Ex. 13, p.

3.) She maintains that petitioner’s May 1 visit “was a well-child visit only.” (Id.)

IV. Expert Opinions

a. Petitioner’s expert, Lawrence Steinman, M.D., initial report

Dr. Steinman received his medical degree from Harvard in 1973. He is currently

a professor of the department of neurology at Stanford University. (Ex. 14, p. 1.) Dr.

Steinman has treated patients, both adults and children, who suffered from various

forms of autoimmune disease of the nervous system, including optic neuritis, ADEM,

Bechet’s disease, inflammatory neuropathy, transverse myelitis, neuromyelitis optica

9

(NMO), and multiple sclerosis (MS). (Id.) Dr. Steinman’s research focuses on how the

immune system attacks the nervous system and he has published on the subject of

narcolepsy. (Id. at 1-3.) He holds over 50 American and European patents, including

several U.S. patents relating to vaccines. (Id. at 5.)

Dr. Steinman opines that petitioner’s HPV vaccination on May 1, 2013 “caused a

significant aggravation of a sleep disorder, leading to narcolepsy that was explicitly

diagnosed two weeks thereafter.” (Ex. 14, p. 1.) Dr. Steinman’s theory on how the HPV

vaccination “trigger[ed] narcolepsy” relies on the principles of molecular mimicry. (Id. at

9.) According to his theory, the Gardasil vaccine 10 contains molecular mimics of

hypocretin, also called orexin 11, and hypocretin-2 receptor, also known as the orexin-2

receptor. (Id.) Dr. Steinman notes three groups who have “reported immune responses

to hypocretin reception 2 in narcolepsy”: (i) a group led by Dr. Steinman who found that

“in vaccine-induced narcolepsy, there are antibodies to HCRT-R2” and who identified a

region of the HCRT-R2 molecule located at the site where hypocretin binds the

receptor12 (ii) a group in Japan which found antibodies to HCRT-R2 in narcolepsy13 and

(iii) as did a group from Oxford. 14 (Id. at 10.) Dr. Steinman also mentions a fourth

group, Mignot’s group, who showed “some evidence of antibodies to HCRT-R2 in

narcolepsy,” though he discounts these findings due to a “major flaw” in one of the

assays for HCRT-R2 that appears in their supplementary data. (Id. (citing (citing De la

Herrán-Arita et al., CD4+ T cell Autoimmunity to Hypocretin/Orexin and Cross-Reactivity

to a 2009 H1N1 Influenza A Epitope in Narcolepsy, 5(216) SCI. TRANSL. MED. 1-13

(2013) (Ex. 25); De la Herrán-Arita et al., CD4+ T cell Autoimmunity to

Hypocretin/Orexin and Cross-Reactivity to a 2009 H1N1 Influenza A Epitope in

Narcolepsy, 5(216) SCI. TRANSL. MED. 1-13 (2013) (Retraction published on July 30,

2014) (Ex. 26)).)

10Petitioner received the Gardasil Quadrivalent HPV vaccine on May 1, 2013, which contains the L1

proteins from four different strains of HPV: HPVs 6, 11, 16, and 18. (Ex. 14, p. 9 (citing Ex. 21)).

Presently, “Gardasil-9 (Merck), a nine-valent HPV vaccine (9vHPV) that protects against HPV types 6, 11,

16, 18, 31, 33, 45, 52, and 58, is the only HPV vaccine currently distributed in the U.S.” What Ty[es of

HPV Vaccines Are There?, CDC, https://www.cdc.gov/vaccines/vpd/hpv/public/index.html (last updated

Mar. 17, 2020).

11 “Either of two neuropeptides (orexin A and orexin B) produced in the hypothalamus and regulating

feeding behavior as well as the sleep-wake cycle.” Orexin, DORLAND’S MEDICAL DICTIONARY ONLINE,

https://www.dorlandsonline.com/dorland/definition?id=13359 (last visited Sept. 8, 2021).

12 Ahmed et al., Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2,7

(294) SCI. TRANSL. MED. (2015) (Ex. 27). Dr. Steinman notes that his group identified the region of the

HCRT-R2 molecule that was previously identified at the University of Texas Southwestern Medical

School, “precisely at the site where hypocretin binds the receptor.” (Ex. 14, p. 10) (citing Yin et al,

Structure and ligand-binding mechanism of the human OX1 and OX2 orexin receptions, 23(4) NAT.

STRUCT. MOL. BIOL. 293-9 (2016)).)

13 Tanaka et al., Detection of autoantibodies against hypocretin, hcrtr1, and hcrtr2 in narcolepsy: anti-hcrt

system antibody in narcolepsy, 29(5) SLEEP 633-638 (2006) (Ex. 29).

14 Giannocarro et al., Antibodies against HCRT-R2 are rare in narcolepsy, 40(2) SLEEP (2017) (Ex. 30.)

10

Dr. Steinman carried out BLAST15 searches to identify homologies between the

components of the Gardasil vaccine and various components of the hypocretin

pathway, including hypocretin itself and the HCRT-R2 receptor. (Ex. 14, p. 11.) Dr.

Steinman classifies his criteria for a “meaningful molecular mimic” as a run of 5 or more

of 12 amino acids that are identical. (Id.) Based on his own published research, Dr.

Steinman opines that the identity of 5 of 12 amino acids, or sometimes even 4 or 11

amino acids, were sufficient to “trigger experimental neuroinflammation with paralysis.”

(Id. (citing Gautam et al, A polyalanine peptide containing only five native myeline basic

protein residues induces autoimmune encephalomyelitis, 127 JOURNAL OF EXPERIMENTAL

MEDICINE 605-609 (1992) (Ex. 32); Gautam et al., Minimum structural requirements for

peptide presentation by major histocompability complex class II molecules: Implications

in induction of autoimmunity, 91 PROC. NATL. ACAD. SCI. USA 767-771 (1994) (Ex. 33);

Gautam et al., A viral peptide with limited homology to a self-peptide can induce clinical

sign of experimental autoimmune encephalomyelitis, 161 J. IMMUNOL., 60-64 (1998) (Ex.

34)).) He also adds that the 5/12 or 4/11 amino acids that are identical need not be

consecutive. (Id.)

Through his BLAST searches, Dr. Steinman identified several homologies

between the human protein (hypocretin and hypocretin-2 receptor) and the HPV

proteins that were 5/12 or better. (Ex. 14, pp. 14-25.) Dr. Steinman acknowledges that

his report only includes the “positive” or “relevant” searches, though “[m]any searches

were performed where the criterion” were not met. (Id. at 25.) In support of his theory,

Dr. Steinman cites a paper by Ufret-Vicenty et al., whose experiments passively

transferred T cells that cross-reacted with myelin basic protein and HPV (in mice) and

found that the experimental animals became paralyzed. (Id. at 25-26 (citing Ufret-

Vincenty et al., In Vivo Survival of Viral Antigen—specific T Cells that Induce

Experimental Autoimmune Encephalomyelitis, 188 JOURNAL OF EXPERIMENTAL MEDICINE

1725-1738 (1998) (Ex. 35)).) However, it is not possible to test petitioner for immunity

to these mimics. (Id. at 26.)

Dr. Steinman acknowledges that “[m]olecular mimicry may indeed be

widespread.” (Ex. 14, p. 26.) He explains “[o]ther genetic and environmental factors”

are necessary before these self-reactive immune responses to HCRT-R2 may trigger an

immune response. (Id. at 28-29.) He maintains that his theory of molecular mimicry,

nonetheless, is a “key mechanism” in understanding how the vaccination may cause

injury. (Id.)

In response to Court Exhibit 1, Dr. Steinman suggests that this epidemiological

study, in fact, shows an increased rate of narcolepsy among those who received the

Gardasil vaccine. (Ex. 14, p. 29.) According to Dr. Steinman, the 2.61 cases of

15 According to its own website, the Basic Local Alignment Search Tool (BLAST) “finds regions of local

similarity between sequences. The program compares nucleotide or protein sequences to sequence

databases and calculates the statistical significance of matches. BLAST can be used to infer functional

and evolutionary relationships between sequences as well as help identify members of gene families.”

See https://blast.ncbi.nlm.nih.gov/Blast.cgi (last visited Dec. 2, 2021).

11

narcolepsy per 105 in the vaccinated group versus the 1.81 cases per 105 in the

unvaccinated group indicates that the Gardasil vaccine is associated with a higher rate

of narcolepsy compared to the unvaccinated, “even though it may not reach so-called

‘statistical significance.’” (Id. at 31.)

Finally, Dr. Steinman opines that petitioner’s HPV vaccination on May 1, 2013,

“changed the trajectory of the case.” (Ex. 14, p. 31.) Dr. Steinman remarks that

“though there were symptoms prior to the May 1, 2013 immunization, there was clear

worsening about 10 days after the May 1, 2013, Gardasil shot.” (Id.) Dr. Steinman

quotes the “history of present illness” in Dr. Lazar’s discharge summary from May 16,

2013:

Over the past 3 days she reports to “twitching” of her left upper extremity

and left leg lasting for approximately 20 seconds followed by a tingling

sensation in her hands. She would have approximately 2 episodes per day.

During these “twitching” episodes she would be fully awake and states that

she would use her right hand to hold on to her left upper extremity while it

was jerking but this would not stop the jerking movements. She also reports

recent episodes of light headedness and fell twice 2 days ago and once

today.

(Id.)

Dr. Steinman stresses that “[t]his type of activity was NOT present prior to the

May 1, 2013, immunization, based on the contemporaneous record.” (Id.) (emphasis in

original). According to Dr. Steinman, the progression of petitioner’s symptoms is

consistent with the progression of narcolepsy in patients studied in Finland and England

who received the Pandemrix vaccination. (Id. at 32 (citing Partinen et al., Increased

Incidence and Clinical Picture of Childhood Narcolepsy following the 2009 H1N1

Pandemic Vaccination Campaign in Finland, 7 PLOS ONE e33723 (2012) (Ex. 38);

Winstone et al., Clinical features of narcolepsy in children vaccinated with AS03

adjuvanted pandemicA/H1N1 2009 influenza vaccine in England, 56 DEV. MED. CHILD.

NEUROL. 1117-1123 (2014) (Ex. 39).)

b. Respondent’s expert, Maryann Deak, M.D., initial report

Dr. Deak received her medical degree from Georgetown University School of

Medicine in 2004. (Ex. B.) Dr. Deak currently serves as the Associate Medical Director

in Sleep Medicine for eviCore Healthcare. (Ex. A.) Dr. Deak is board certified in both

neurology and sleep medicine, with significant clinical experience treating sleep

disorders, including narcolepsy and other hypersomnia. (Id.) She completed a clinical

and research fellowship in sleep medicine at Brigham and Women’s Hospital and

Harvard Medical School in 2010. (Id.)

Dr. Deak opines that the presence of narcolepsy symptoms prior to vaccination,

the evolution of petitioner’s symptoms consistent with pediatric narcolepsy, and the lack

12

of evidence supporting an increased risk of narcolepsy with Gardasil, taken together,

show no causal link between the Gardasil vaccination and petitioner’s narcolepsy. (Ex.

A.) Both Drs. Steinman and Deak agree that petitioner developed symptoms of

narcolepsy prior to petitioner’s May 1, 2013 vaccination. (Ex. 14, p. 31; Ex. A, p. 4.) Dr.

Deak notes that petitioner presented with symptoms of sleep disruption and daytime

sleepiness with prolonged napping 4-6 weeks prior to her hospitalization. (Ex. A, p. 4

(citing Exs. 3, 4).) While petitioner’s symptoms of sleep paralysis, cataplexy, slurred

speech and gait difficulties appeared 2-4 weeks prior to hospitalization. (Ex. A, p. 4.)

Dr. Deak explains that the full narcoleptic tetrad of symptoms–excessive daytime

sleepiness, cataplexy, hypnagogic/hypnopompic hallucinations and sleep paralysis–is

rarely present at initial presentation. (Ex. A, p. 5.) The order in which symptoms appear

can also vary. (Id. (citing Dauvilliers et al., Narcolepsy with Cataplexy, 369 THE LANCET

499-511 (2007) (Ex. H)).) Due to the “insidious onset” of narcolepsy, as well as

accompanying behavioral, metabolic, and mood symptoms, narcolepsy is often

misdiagnosed. (Ex. A, p. 5.) Dr. Deak notes that in more than 80% of cases cataplexy

develops within two to three months; disturbed night sleep is reported in more than 90%

of narcolepsy type 1 patients; and more than 70% of patients report a decrease in

academic performance. (Ex. A, pp. 5-6 (citing Dauvilliers et al., supra, at Ex. H. p. 499-

511).); Aran et al., Clinical and therapeutic Aspects of Childhood Narcolepsy-Cataplexy:

a Retrospective Study of 51 Children, 33 SLEEP 1457 (2010) (Ex. I).)

Dr. Deak likewise notes that narcolepsy is caused by hypocretin deficiency, likely

due to the selective loss of hypocretin-producing neurons in the hypothalamus. (Ex. A,

p. 6.) She adds that the autoimmune hypothesis is the leading theory for narcolepsy

type 1, due to a strong association between narcolepsy type 1 and the human leukocyte

antigen (HLA) DQB1*0602. (Id.) Dr. Deak also notes that (i) seasonal differences in

narcolepsy incidence, (ii) the rise in incidences post 2009-2010 administration of the

AS03-adjuvanted H1N1 vaccine and (iii) the association with anti-streptococcal

antibodies all support the theory that environmental factors contribute to the

development of narcolepsy in patients who are genetically susceptible. (Id. citing

Postiglione et al., the Clinical Spectrum of Childhood Narcolepsy, 5 SLEEP MED. REV.

70-85 (2018) (Ex. K)).) However, unlike Dr. Steinman, Dr. Deak stresses that

“autoantibodies specific to hypocretin peptides have not been found,” and to date, direct

evidence supporting the autoimmune hypothesis is lacking. (Id. (citing Mignot,

Narcolepsy: Genetics, Immunology, and Pathophysiology, in Principles and Practice of

Sleep Medicine (6th ed. 2017) (Ex. O)).)

Dr. Deak questions Dr. Steinman’s causation theory, suggesting that Dr.

Steinman relies upon data from autoimmune disorders such as multiple sclerosis and

other vaccines such as H1N1 – without presenting a causal link to Gardasil or

narcolepsy. (Ex. A, p. 7.) Dr. Deak acknowledges the increased incidence of

narcolepsy after the administration of the AS03-adjuvanted H1N1 vaccine in several

European countries. (Id.) Yet, Dr. Deak stresses that there is no increased risk of

narcolepsy with either H1N1 vaccines that contained other adjuvants, such as Focetria,

or among non-adjuvanted H1N1 vaccines given in the United States. (Id. (citing

13

Partinen, Narcolepsy as an Autoimmune Disease: the Role of H1N1 Infection and

Vaccination, 13 THE LANCET 600-13 (2014) (Ex. E); Duffy et al., Narcolepsy and

Influenza A (H1N1) Pandemic 2009 Vaccination in the United States, 83 NEUROL. 1823-

30 (2014) (Ex. Q); Nguyen et al., Vaccine-Associated Inflammatory Disease of the

Central nervous System: Form Signals to Causation, 29 CURR. OPIN. NEUROL. 1-10

(2016) (Ex. R).)

Lastly, Dr. Deak contends that Court Exhibit 1, the Arnheim-Dahlstrom et al.

study does not demonstrate any significant association between narcolepsy and HPV

vaccination. (Ex. A, p. 7.) Quoting the authors in that study, Dr. Deak notes that “this

large cohort study found no evidence supporting associations between exposure to

HPV vaccine and autoimmune, neurological, and venous thromboembolic adverse

events.” (Id. (citing Arnheim-Dahlstrom et al., Autoimmune Neurological, and Venous

Thromboembolic Adverse Events After Immunisation of Adolescent Girls with

Quadrivalent Human Papillomavirus Vaccine in Denmark and Sweden: Cohort Study,

347 Brit. Med. J. 1-11 (2013) (Ex. S.))

c. Respondent’s expert, J. Lindsay Whitton, M.D., Ph.D., initial report

Dr. Whitton received his medical degree from the University of Glasgow in 1979

and his doctorate degree in virology (focusing on herpesvirus transcription) also from

the University of Glasgow in 1984. (Ex. D.) Dr. Whitton has not sought licensure in the

United States, nor has he practiced medicine in the United States. 16 (Ex. C.) As of the

time of his submissions in this case, Dr. Whitton serves as a professor in the

Department of Immunology and Microbiology at the Scripps Research Institute. (Ex. D.)

He has published extensively on the adaptive and innate immune response and on

molecular mimicry. (Id.)

Dr. Whitton likewise agrees with Drs. Steinman and Deak that the onset of

petitioner’s disease preceded the vaccination. (Ex. C, p. 3-4.) Dr. Whitton disagrees

with Dr. Steinman’s opinion that the HPV vaccine “changed the trajectory of the case”

and would be a “significant aggravation.” (Id. at 4 (citing Ex. 14, p. 6.)) Rather, Dr.

Whitton opines that petitioner’s disease severity “was clearly increasing prior to, or

contemporaneous with, the vaccination.” (Ex. C, p. 4.) Like Dr. Deak, Dr. Whitton finds

that the onset and progression of petitioner’s symptoms are consistent with the typical

evolution of pediatric narcolepsy. (Id.)

Additionally, Dr. Whitton opines that there is no significant association reported

between narcolepsy and the HPV vaccine. Dr. Whitton believes that Dr. Steinman’s

reliance on various studies of the Pandemrix vaccine and narcolepsy is misplaced. (Ex.

C, pp. 4, 12-13.) According to Dr. Whitton, Dr Steinman attempts to “tar Gardasil using

the Pandemrix brush.” (Id. at 5.) Dr. Whitton stresses that Dr. Steinman’s theory is “not

16In his report Dr. Whitton notes that while he is “medically qualified,” he has never sought licensure in

the United States, and he shall defer to Dr. Deak’s expertise in the area of sleep disorders and

diagnoses. (Ex. C at 2.)

14

scientifically appropriate; one cannot reasonably infer that what may happen with one

vaccine must happen with all vaccines.” (Id.) (emphasis in original.)

With regard to causation, Dr. Whitton opines that Dr. Steinman’s molecular

mimicry theory is not a valid causal theory for the development, or exacerbation of,

narcolepsy. Dr. Whitton takes issue with Dr. Steinman’s classification of a “meaningful

molecular mimic.” (Ex. C, p. 5.) First, he explains that in order to identify an amino acid

sequence as a “mimic,” one cannot rely on a shared homology alone. (Id.) Mimicry is

defined by the “immune response that the sequence induces” and to be a “mimic” the

amino acid sequence must “(i) [] trigger an immune response and, (ii), that response

must recognize (i.e., cross-react with) the other peptide[.]” (Id.) (emphasis in original).

Unless both criteria are met, then it is not a mimic, but merely a homology. (Id.)

With respect to Dr. Steinman’s BLAST searches, Dr. Whitton notes that for the

L1 protein of HPV11 and hypocretin, he found seven additional homologies of 5/12 or

better; and for hypocretin receptor 2 and L1 protein HPV18, he found twenty-three

additional homologies of 5/12 or better. (Ex. C, p. 6.) According to Dr. Whitton these

additional “hits,” demonstrate that Dr. Steinman’s rare and “meaningful molecular

mimics” are in fact commonplace and not meaningful. (Id.) Even statistical probability

demonstrates how the presence of numerous homologies is entirely predictable among

a large number of proteins. 17 (Id. at 7-10.)

Dr. Whitton also stresses that most homologies do not trigger biologically-

meaningful cross-reactivity. (Ex. C, p. 11.) Dr. Whitton compared two of the L1 proteins

from HPV6 and HPV 11 and found 487 homologies of 5/12 or better. (Id.) Following Dr.

Steinman’s logic, Dr. Whitton suggests that every one of these 487 homologies should

trigger cross-reactive immunity. (Id.) And if each one of these 487 responses were

“meaningful,” Dr. Whitton explains, the immune response against the HPV6 L1 protein

“should confer protection against both the parental virus (HPV6) and the other virus

(HPV11).” (Id.) If this were the case, the HPV vaccine would require only one of the

viral proteins to induce immune responses that would protect against both viruses. (Id.)

“But, of course, this isn’t the biological reality.” (Id.) Dr. Whitton therefore concludes

that even when there are 487 homologies, it would be wrong to conclude that one of

them must have a meaningful biological impact. (Id.) Studies such as Trost et al.,

which compared bacterial proteins against the human proteome identified thousands of

short homologies. (Id. (citing Trost et al., Bacterial peptides are intensively present

throughout the human proteome, 1 SELF NONSELF 71-74 (2010) (Ex. U)).) Dr. Whitton

stresses that molecular mimicry is “real,” however, the mere existence of a homology is

insufficient to trigger an immune-mediated disease. (Id.)

Dr. Whitton notes that large studies have failed to identify any causal relationship

between the HPV vaccine and several autoimmune diseases. (Ex. C, p. 12.) Dr.

17 Dr. Whitton explains, in part, “[i]t’s like being given a lottery ticket, and being told that there is a

1/32,000 chance of its being a winning ticket. You wouldn’t be too excited. But if a truck delivered another

218,239 tickets to your doorstep, you’d be ecstatic.” (Ex. C, p. 8.)

15

Whitton cites only one published scientific study which in his estimation suggests that

the HPV vaccine may have autoimmune consequences. (Id. at 13 (citing Andrews et

al., No Increased Risk of Guillain-Barre Syndrome After Human Papilloma Virus

Vaccine: a Self-Controlled Case-Series Study in England, 35 VACCINE 1729-1732

(2017) (Ex. AA)).) Yet, he finds that the association was weak, the paper did not use

clinician-validated cases of the disease and did not find any association with GBS. 18

(Id.) Turning to the HPV vaccine, Dr. Whitton cites a 2018 review which states:

We identified 109 studies, including 15 population-based studies in over

2.5 million vaccinated individuals across six counties. All vaccines

demonstrated an acceptable safety profile; injection-site reactions were

slightly more common for 9vHPV vaccine than for 4vHPV vaccine. There

was no consistent evidence of an increased risk of AESI 19, including

demyelinating syndromes or neurological conditions such as

complex regional pain or postural orthostatic tachycardia syndromes.

The risk-benefit for HPV vaccines remains highly favourable.

(Id. (citing Phillips et al., Safety of Human Papillomavirus Vaccines: an Updated Review,

41 DRUG SAF. 329 (2018) (Ex. CC)) (emphasis in original).

Dr. Whitton likewise notes that the authors of the Arnheim-Dahlstrom et al.

study–which evaluated the frequency of several diseases (including narcolepsy)

appearing within a 180-day window following HPV vaccination–concluded “no significant

association was observed with narcolepsy.” (Ex. C, p. 14) (quoting Arnheim-Dahlstrom

et al., supra, at Ex. S, p. 5 (2013)).) Dr. Whitton notes that Dr. Steinman’s analysis of

this study “ignore[s]” the statistical significance of the results, in favor of the absolute

number of cases of narcolepsy in those vaccinated versus unvaccinated. (Ex. C, p. 14.)

d. Dr. Steinman’s first supplemental report, Exhibit 40

In his first supplemental report, Dr. Steinman highlights the development of

“twitching episodes” a few days prior to petitioner’s May 11 admission as a new

symptom that developed after petitioner’s HPV vaccination. (Ex. 40, pp. 2-3.)

Additionally, Dr. Steinman reiterates that the worsening of petitioner’s symptoms over a

12-month period is consistent with studies involving narcolepsy and the H1N1 vaccine

in England and Sweden. (Id. at 3 (citing Partinen et al., supra, at Ex. 38; Winstone et

al., supra, at Ex. 39).) Dr. Steinman proposes that the Arnheim-Dahlstrom et al. study,

Court Exhibit 1, “does reinforce the Petitioner’s theory to the level of a ‘preponderance

of evidence.’” (Ex. 40, p. 7.) In the context of what Dr. Steinman describes as a

“meaningful metric when the burden of proof is described as 50% and a feather,” he

18 Dr Whitton writes “[o]bviously, GBS is not claimed in the present matter. However, to my knowledge,

this is the only published scientific study to suggest that HPV vaccine may have any autoimmune

consequences whatsoever and, as such, it is worthy of a little dissection.” (Ex. C, p. 13.)

19 “AESI = adverse event of special interest” (Ex. C, p. 13)

16

suggests that the 2.4-fold increase in the upper limit for Gardasil vaccinated versus

unvaccinated is significant. (Id. at 6-7.)

In response to criticism of his molecular mimicry theory, Dr. Steinman quotes a

passage from one of Dr. Whitton’s papers, in part, “showing that almost 4% of antiviral

monoclonal antibodies also reacted with self proteins.” (Ex. 40, p. 9 (citing Fujinami et

al., Molecular Mimicry, Bystander Activation, or Viral Persistence: Infections and

Autoimmune Disease, 19(1) CLIN. MICROBIOL. REV. 80-94, 81 (2006) (Ex. 41).) Dr.

Steinman explains that “[i]f 4% of viral antibodies reacted with self-proteins, it is

expected that over the life of a human subjected to viral infections, that there would be a

large component of anti-viral antibodies that are also ‘anti-self.’” (Ex. 40, p. 9.)

Following this logic, Dr. Steinman stresses that autoimmunity is in fact widespread. (Id.)

Dr. Steinman explains that his references to the Pandemrix vaccine provided

background, and his theory in regard to petitioner’s case is based on “how the contents

of the Gardasil vaccine share structural similarities with molecules that are key in

narcolepsy, orexin (hypocretin) and its receptor.” (Ex. 40, p. 9.) Furthermore, Dr.

Steinman disputes Dr. Whitton’s “simple math,” and instead proposes that “these

homologies are NOT inevitable.” (Ex. 40, p. 10.) As evidence Dr. Steinman provides

examples of his positive searches (where he identifies a homology) and negative

searches (where he failed to identify a homology of an acceptable degree.) (Id. at 10-

12.) With these searches Dr. Steinman appears to suggest that when a homology is

identified (a positive search) it is therefore biologically-significant.

In response to Dr. Whitton’s results (identifying 487 homologies of 5/12 or better

between HPV6 and HPV11) Dr. Steinman explains that these two strains “are closely

related.” (Ex. 40, p. 12.) Finding a match between these two strains is “akin to

marveling at how similar are members of a biologic family,” according to Dr. Steinman.

(Id.) He explains that what is significant is that HPV6 and HPV11 have “mimics of

significance” with orexin, while there are no matches for HPV16 and HPV18 (though all

four L1 proteins, HPV6, HPV11, HPV16 and HPV18, are present in the Gardasil

vaccine). (Id.)

Dr. Steinman also suggests the presence of alum makes the HPV components

more immunogenic. (Ex. 40, p. 13.) As a result, “[t]he Gardasil vaccine leads to a 40-

fold increase in HPV antibodies compared with the physiological antibody level triggered

by a natural HPV infection.” (Id. (quoting Souayah et al., Guillain-Barre Syndrome after

Gardasil vaccination: Data from Vaccine Adverse Event Reporting System 2006-2009,

29 Vaccine 886-889 (2011) (Ex. 42).) Dr. Steinman appears to suggest that the alum

adjuvant increases the probability that a cross-reactive immune response may be

induced.

e. Dr. Deak’s first supplemental report, Exhibit GG

In her supplemental report, Dr. Deak opines that “[a] vaccine given in the midst of

typical symptom evolution does not constitute a causal relationship.” (Ex. GG, p. 1.)

17

While Dr. Steinman highlights the presence of hand twitching a few days prior to

petitioner’s admission as a new symptom that she developed post-vaccination, Dr. Deak

explains that cataplexy may present differently in children than in adults. (Id.) Cataplexy

in children may not be linked to emotional stimuli and may present as loss of muscle

tone or increased motor movements. (Id. (citing Nevsimalova, The Diagnosis and

Treatment of Pediatric Narcolepsy, 14 CURR. NEUROL. NEUROSCI. Rep. 469 (2014) (Ex.

G); Postiglione et al, supra, at Ex. K).) Furthermore, Dr. Deak reiterates that petitioner

was already experiencing symptoms suggestive of cataplexy prior to her vaccination.

(Id.) That certain symptoms manifested as petitioner’s narcolepsy progressed “is only

evidence of the expected progression and does not constitute significant aggravation of

her underlying disease course.” (Id. at 1-2.)

Dr. Deak also takes issue with Dr. Steinman’s theory of a greater-than-12-month

narcolepsy onset. (Ex. GG, p. 2.) In the first article Dr. Steinman cites from Finland, Dr.

Deak points out that the status and date of Pandemrix vaccination was obtained from

vaccination certificates filed by health care professionals in Finland and the presence of

narcolepsy symptoms and time of onset were retrospectively obtained from the medical

records. (Id. (citing Partinen et al., Increased incidence and clinical picture of childhood

narcolepsy following the 2009 H1N1 pandemic vaccination campaign in Finland, 7

PLOS ONE e33723 (2012) (Ex. HH)).) That study reported a mean interval of 53 days

from the date of vaccination to the onset of symptoms – for children aged 17 or

younger. (Id.) Furthermore, Dr. Deak notes that the study from England that Dr.

Steinman cites is also a retrospective review, where vaccination status and time of

onset was determined by questionnaires sent to general practitioners. (Id. (citing

Winstone et al., supra, at Ex. 39).) In that study, Dr. Deak highlights that only eleven

children received the Pandemrix vaccine prior to the onset of symptoms of narcolepsy,

while seven of the eleven children received the vaccine six months or less prior to the

reported onset of symptoms, and six children received the vaccine within three months.

(Ex. GG, p. 2.) Generally, Dr. Deak notes that the reported timing of symptom onset is

prone to recall bias. (Id.) Based on her own clinical experience, and the insidious

nature of narcolepsy onset, Dr. Deak stresses that the onset of symptoms in a

retrospective study is likely to have occurred prior to the reported time of presentation.

(Id.)

Dr. Deak cites a retrospective study conducted in Sweden where symptom onset

was determined based on medical record review and telephone interviews with parents

and patients. (Ex. GG, p. 2 (citing Attila Szakacs et al., Increased childhood incidence

of narcolepsy in western Sweden after H1N1 influenza vaccination, 80 NEUROLOGY,

1315-1321 (2013) (Ex. II)).) In that study, the median time from H1N1 vaccination to

symptom onset was nine and a half weeks, with nineteen of the twenty-eight patients

developing symptoms in twelve weeks or less. (Id.) Additionally, Dr. Deak cites a study

in Norway where onset was defined by reports from physicians based on interactions

with parents or patients; and in that study the median time from vaccination to onset

was eleven weeks, with forty-two of the fifty-eight patients experiencing clinical

symptoms within six months of vaccination. (Id. (citing Heier et al., Incidence of

narcolepsy in Norwegian children and adolescents after vaccination against H1N1

18

influenza A, 14 SLEEP MEDICINE 867-871 (2013) (Ex. JJ)).) Dr. Deak notes that this

study found “no significant difference in the incidence of narcolepsy during the second

year after vaccination compared to unvaccinated children in the same time period.” (Id.)

In light of these studies, Dr. Deak “[do[es] not agree that causation can be inferred with

a greater than one year time interval between vaccination and the development of

symptoms in H1N1.” (Id.)

Nor does Dr. Deak believe that the HPV vaccine is analogous to the H1N1

vaccine. (Ex. GG, p. 3.) She emphasizes that there is no literature demonstrating an

increased incidence of narcolepsy with the HPV vaccine administered in this case. (Id.)

Dr. Deak disagrees with Dr. Steinman’s claim that results that are not statistically

significant are still consistent with “a greater than 50% likelihood” that there is a

relationship between HPV vaccination and development of narcolepsy. (Id.) Dr. Deak

stresses that without a significant association, reviewing experts cannot determine

whether there is any difference in narcolepsy incidence between unvaccinated and

vaccinated individuals in this study. (Id.)

f. Dr. Whitton’s first supplemental report, Exhibit EE

In his first supplemental report, Dr. Whitton echoes Dr. Deak’s opinions on the

Arnheim-Dahlstrom et al. study. (Ex. EE, pp. 1-2.) Dr. Whitton observes that the

authors in the Arnheim-Dahlstrom study did not provide the actual p value of their

findings regarding narcolepsy, but only state that there was no significant association

between vaccinated and unvaccinated groups. (Id. at 2.) Thus, Dr. Whitton explains,

Dr. Steinman’s inference regarding “95% certainty” is unjustified. (Id.) Dr. Whitton also

notes a more recent study in which the authors again studied the frequency of

narcolepsy following HPV vaccination and “again, no significant association between

the two was identified.” (Id. (citing Hvid, et al., Human papillomavirus vaccination of

adult women and risk of autoimmune and neurological diseases, 283 J. Intern. Med.

154-165 (2018) (Ex. FF)).)

Dr. Whitton also seeks to further refute the significance of Dr. Steinman’s positive

and negative BLAST searches. (Ex. EE, pp. 2-3.) Dr. Whitton explains that Dr.

Steinman’s “negative searches” are BLAST searches which failed to identify a

homology within an acceptable degree (per Dr. Steinman’s criteria, 5/12 amino acids).

(Id. at 3.) However, Dr. Whitton notes that when he replicated the same “negative”

BLAST search, comparing the same two proteins, hypocretin and the L1 protein of

HPV18, he identified thirteen homologies of 5/12 or better. (Id.) Dr. Whitton also

replicated the “negative” BLAST search for HPV16 and identified nine homologies of

5/12 or better. (Id.) These results, Dr. Whitton explains, again demonstrate that

homologies are commonplace. (Id.)

Like Dr. Steinman, Dr. Whitton agrees that there are “many perfect matches”

between the two HPV L1 proteins and that “such similarities ‘are expected.’” (Ex. EE, p.

4.) Yet Dr. Whitton suggests that the question that remains unanswered is, why then,

despite the presence of so many similarities, do these proteins not induce cross-

19

protective immune responses? (Id.) Again Dr. Whitton explains that despite the 487

homologies, the L1 protein of HPV6 does not protect against HPV11, and vice-versa.

(Id.) Thus, no biologically-relevant cross-reactivity is induced by the HPV vaccine, even

in the presence of alum as Dr. Steinman suggests. (Id.) According to Dr. Whitton, Dr.

Steinman also provides no evidence that these suspected immune responses would be

harmful. (Id.)

g. Dr. Steinman’s second supplemental report, Exhibit 43

In his second supplemental report, Dr. Steinman emphasizes that his molecular

mimicry theory demonstrates how a vaccine could cause the claimed injury; the theory

is “not based on ‘certainty,’ and thus never intended to ‘surely be biologically-

significant.’” (Ex. 43, p. 1.) Dr. Steinman cites the Latorre et al. study which he

suggests confirms his “smoking gun.” (Ex. 43, p. 2; Latorre et al., T cells in patients with

narcolepsy target self-antigens of hypocretin neurons, 562 NATURE 63 (2018) (Ex. 45).)

Dr. Steinman highlights results which discovered a T cell that responded to the

sequence MGRRAGAEPAPRP in the spinal fluid of a patient with narcolepsy. (Id. at 3.)

This cytotoxic T cell, Dr. Steinman concludes, “would have the capacity to target and kill

hypocretin neurons.” (Id.)

Dr. Steinman further remarks that the BLAST searches with hypocretin did not

identify a large number of epitopes. (Ex. 43, p. 5.) For HPV11 Dr. Steinman reports

only one region of hypocretin (a 5/10 sequence) and for HPV6 Dr. Steinman reports

three regions were identified but only the 5/10 sequence was identified as causing

experimental neuroinflammation. (Id.) The other two sequences were considered “not

to be ‘of interest.’” (Id.) According to Dr. Steinman, the “confirmation with actual

experimental data” from LaTorre indicates that the BLAST search efforts “are fruitful and

that they can definitively identify a mimic in the HPV vaccine with orexin.” (Id.)

Dr. Steinman also suggests that Dr. Whitton may not have used the alignment

algorithms of BLAST, possibly explaining the differences in their BLAST results. (Ex.

43, p. 5-8.) Given that the HPV vaccine contains a molecular mimic identified as a

target of killer T cells found in the spinal cord of narcolepsy patients, Dr. Steinman

disagrees with Dr. Deak’s conclusion that no causal relationship can be found. (Id. at

9.) Dr. Steinman also opines that if an individual, such as petitioner, receives an HPV

vaccine that “‘boosts’ immunity to orexin, even during the early onset of narcolepsy” the

vaccine could aggravate the pathologic immune response, culminating in “full blown

narcolepsy.” (Id.) Dr. Steinman reiterates his conclusions regarding the studies from

Sweden, Norway, and England; but adds that the findings from the Latorre et al. study

also support his conclusion that the administration of the HPV vaccine “could

exacerbate incipient narcolepsy and renders the studies cited by Dr. Deak on

Pandremix far less significant.” (Id. at 9-10.)

h. Dr. Whitton’s second supplemental report, Exhibit KK

In his second supplemental report, Dr. Whitton stresses that “BLAST [searches]

trade[] accuracy for speed.” (Ex. KK, p. 5.) Dr. Whitton asserts that his own sliding

20

window searches “do not have any such tradeoff.” (Id.) Rather, Dr. Whitton claims his

searches “accurately identify all instances of the sought-after homologies (e.g., 5

identities out of 12 resides), and they are by far the best way by which to identify short

homologies.” (Id.)

Dr. Whitton questions Dr. Steinman’s methodology because Dr. Steinman’s

smoking gun (RAGAEPAPRP) falls short of the Silvanovich et al. standard, which

Steinman relies upon in his own report. (Ex. KK, p. 6; Ex. 43, pp. 4-5.) The Silvanovich

standard requires “(i) a window of at least 80 amino acids in length (ii) in which there is

at least 35% amino acid identity and (iii) whose E-value 20 must be lower than 3.9 x 10-7.”

(Id. at 7 (citing Silvanovich et al., The value of short amino acid sequence matches for

production of protein allergenicity, 90 TOXICOL. SCI. 252-258 (2006) (Ex. OO);

Silvanovich et al., The use of E-scores to determine the quality of protein alignments 54

REGUL. TOXICOL. PHARMACOL. S26 (2009) (Ex. PP)).) According to Dr. Whitton, none of

Dr. Steinman’s BLAST results meet these criteria. (Id. at 6.) Moreover, a BLAST result

that meets the three Silvanovich criteria, “may provide a hint about the overall shape of

a protein” and “may provide a hint about IgE responses, but it can tell us absolutely

nothing about whether or not that sequence may trigger a T cell response.” (Ex. KK, p.

8) (emphasis in original).

According to Dr. Whitton, Dr. Steinman’s “chance finding” (RAGAEPAPRP) did

not predict the observations later made by Latorre et al. (Ex. KK, p. 12.) Dr. Whitton

frames Dr. Steinman’s theory as follows: “if ‘vaccine X’ contains a homology to Latorre’s

20 amino acid peptide, then that vaccine more likely than not causes narcolepsy.” (Id.)

To test the validity of Dr. Steinman’s theory, Dr. Whitton compared the short orexin

sequence against the measles vaccine. (Ex. KK, pp. 14-15.) Dr. Whitton identified four

homologies, and then carried out the same comparison using BLAST, and one hit was

returned, containing a 5/11 homology with an E-value of 0.17. (Id. at 15.) Dr. Whitton

explains that these results indicate that the measles vaccine, more likely than not,

triggers narcolepsy. (Id.) Yet, “[t]he MMR vaccine was introduced in 1963” and “no

association has ever been reported between MMR and narcolepsy.” (Id.) The mere

existence of a homology to the orexin sequence, therefore, does not “inculpate[] a

vaccine.” (Id.)

Dr. Whitton also remarks that narcolepsy and orexin deficiency are commonly

associated with MHC class II, which tends to impact CD4+ T cells (not CD8+ T cells).

(Ex. KK, p. 15.) Dr. Steinman notes in his report that petitioner carries the class II MHC

allele. (Id. (citing Ex. 14, p. 6.) However, Dr. Steinman’s smoking gun responds to an

epitope that is presented by MHC class I (stimulating CD8+ T cells), not by MHC class

II. (Id.) Moreover, Dr. Whitton concludes that there is no evidence that that the orexin-

peptide-responsive CD8+ T cells are the cause of the disease. (Id.) Instead, they could

20 The Expect value € is “a parameter that describes the number of hits one can “‘expect’ to see by

chance when searching a database of ap articular size.” (Ex. KK, p. 6.) See

https://blast.ncbi.nlm.nih.gov/Blast.cgi?CMD=Web&PAGE_TYPE=BlastDocs&DOC_TYPE=FAQ#expect

(last visited Sept. 1, 2021).

21

“well be the result of the disease; perhaps orexin released from damaged neurons has

induced these cells.” (Id.) (emphasis in original.)

i. Dr. Steinman’s third supplemental report, Exhibit 49

In his third supplemental report, Dr. Steinman opines that Dr. Whitton’s analysis

“‘conveniently ignore[s]’ a key amino acid or series of key amino acids.” (Ex. 49, p. 4.)

According to Dr. Steinman, Table 1 in Exhibit KK does not show whether the smoking

gun (RAGAEPAPRP) by itself would stimulate the clone found in the spinal fluid of a

narcolepsy patient because Dr. Whitton’s table lacks the terminal amino P. (Id. (citing

Sakai et al, Involvement of distinct murine T-cell receptors in the autoimmune

encephalitogenic response to nested epitopes of myeline basic protein, 85 PROC. NATL.

ACAD. SCI. USA 8608-8612 (1988) (Ex. 51)).) Without one or more critical amino acids,

Dr. Steinman stresses that Dr. Whitton’s analysis is “deeply flawed.” (Ex. 49, p. 4.)

Dr. Steinman also summarizes his search process in detail, at the request of Dr.

Whitton. (Ex. 49 pp. 5-8 (see Ex. KK, p. 7 n. J.) Dr. Steinman adds two additional steps

beyond the BLAST searches and explains that this filtration “eliminates sequences

homologies that are below a threshold that has been shown to induce

neuroinflammation.” (Ex. 49, p. 5.) Finally, Dr. Steinman adds a third filter “using the

LaTorre paper” and the Immune Epitope Database (IEDB). 21 (Id.)

j. Dr. Whitton’s final supplemental report, Exhibit RR

In his final supplemental report, Dr. Whitton likewise agrees that removing a

single amino acid can alter how a peptide is “seen” by a CD8+ T cell. (Ex. RR, p. 4.)

However, Dr. Whitton suggests that Dr. Steinman’s “missing proline” argument is

flawed. (Id. at 5.) A peptide that does not trigger CD8+ T cells does not transform into a

peptide that can stimulate CD8+ T cells simply by the addition of an amino acid. (Id.)

According to Dr. Whitton, the opposite is true. (Id.) The proper method is to “identify a

peptide that can stimulate T cells, and then [] remove peptides from either side, until you

identify the minimal number of peptides that can still activate the T cells” – known as the

minimal epitope. (Id.) (emphasis in original).

Dr. Whitton remarks that Dr. Steinman’s smoking gun is in fact “an empty barrel.”

(Ex. RR, p. 6.) He explains that peptide 13 is recognized by the CD8+ T cells, while

peptide 12 is not. (Id.) From this, Dr. Whitton opines, it is possible to conclude that the

T cells respond to peptide 13 because there are an additional 8 amino acids at the right-

hand end. (Id.) It is unclear, however, how many of those 8 amino acids are needed to

trigger the T cells. (Id.) Yet, by looking at peptide 14, which the T cells also recognize,

Dr. Whitton opines that it is possible to discard half of the smoking gun peptide without

21 The IEDB “catalogs experimental data on antibody and T cell epitopes studied in humans, non-human

primates, and other animal species in the context of infectious disease, allergy, autoimmunity, and

transplantation. The IEDB also hosts tools to assist in the prediction and analysis of epitopes.” See

https://www.iedb.org/home_v3.php (last visited Sept. 1, 2021).

22

preventing T cell recognition. (Id.) Ultimately, of the remaining half, only 2 residues are

identical between HPV L1 and orexin. (Id. at 7.)

Dr. Whitton agrees that the IEDB database is a valuable resource. (Ex. RR, p.

8.) According to Dr. Whitton, however, Dr. Steinman should have entered the vaccine

part of the homology in the IEDB database, not the sequences from the human protein

orexin. (Id. (citing Ex. 49, p. 7).) After entering Dr. Steinman’s homology into the IEDB,

Dr. Whitton reports that no match was found. (Ex. RR, p. 8.) Therefore, Dr. Whitton

concludes, Dr. Steinman’s homology in the HPV L1 protein is not known to be an

immunological epitope. (Id.)

k. Dr. Steinman’s final supplemental report, Exhibit 55

In his final supplemental report, Dr. Steinman reiterates that the epitope

RAGAEPAPRP from the BLAST search is contained in the epitope targeted by a CD8+

T cell in the spinal fluid of a patient with narcolepsy. (Ex. 55, p. 2.) Dr. Steinman

maintains his conclusion that “[t]here is a component of the vaccine that is a molecular

mimic of the orexin molecule targeted in narcolepsy.” (Id.) (emphasis in original). Dr.

Steinman also opines that the molecular mimics, along with the adjuvant in the vaccine

“could become problematic in a susceptible individual, triggering narcolepsy cataplexy

syndrome in [petitioner].” (Id. at 3.)

V. Party Positions

a. Petitioner’s contentions

Petitioner contends that the record evidence is clear in demonstrating that

petitioner’s May 1, 2013 HPV vaccination significantly aggravated the disease process

of narcolepsy. (ECF No. 73, p.1.) Petitioner asserts that, consistent with narcolepsy,

she experienced sleeplessness beginning in early April 2013, but the increase and

evolution of her symptoms were ultimately caused by the HPV vaccine. (Id. at 13-16.)

Petitioner asserts that her diagnosis of narcolepsy is not in controversy. (Id. at

7.) Petitioner contends that the medical records clearly indicate that petitioner was an

otherwise healthy child, with no complaints of neurological problems. (Id. at 17.) Ten

days after her vaccination, petitioner asserts that she presented to the hospital with new

and worsening symptoms including slurred speech, weakness, difficulty walking, muscle

twitching and significantly worsened sleep. (Id.) Dr. Steinman’s molecular mimicry

theory links the vaccination to petitioner’s subsequent significant aggravation, resulting

in her diagnosis of narcolepsy. (Id. at 19.)

Petitioner acknowledges that the results discussed in Court Exhibit 1 were not

statistically significant, nor did the authors provide the actual p value. (ECF No. 73, p.

24.) Petitioner contends that the rise in cases of narcolepsy in the unvaccinated group,

however, is evidence supporting the plausibility that petitioner’s HPV vaccine could

significantly aggravate her narcolepsy. (Id.) Petitioner also acknowledges some

23

variability in the recorded patient histories, but maintains that prior to her HPV

vaccination, petitioner only suffered awakenings at night accompanied by daytime

sleepiness. (Id. at 26.) Petitioner asserts that “[t]here is no evidence of another factor

that may have exacerbated [petitioner’s] narcolepsy.” (Id. at 26-27.)

In response to respondent’s contentions, petitioner stresses that there is

evidence in the contemporaneous records that petitioner’s symptoms dramatically

increased ten days after her vaccination. (ECF No. 76, p. 2.) Petitioner also stresses

that respondent’s reliance on the Trost et al. study is inappropriate. (Id. at 6.) Petitioner

argues that this study focuses on bacterial sequences, as opposed to viral proteins.

(Id.) In addition, petitioner contends that Dr. Steinman’s theory presents a causal link

between the HPV vaccine and narcolepsy based on T cell pathology, not antibody-

mediated dysfunction. (Id. at 7-8.) Petitioner emphasizes that the Pandemrix studies

were cited by Dr. Steinman to show a correlation of timing, not to draw comparisons

between the HPV and H1N1 vaccines. (Id. at 9.)

b. Respondent’s contentions

Respondent argues that Dr. Steinman employs an unreliable methodology and

does not cogently explain how the HPV vaccine may cause or significantly aggravate

narcolepsy through molecular mimicry. (ECF No. 75, pp. 17-18.) Respondent also

stresses that petitioner’s treating physicians do not support vaccine-causation, noting

that her neurologist noted daytime sleepiness, cataplexy and sleep paralysis were

“exacerbated after Gardasil shot.” (Id. at 18, 31.) Respondent argues this observation

only amounts to a temporal association. (Id.) Respondent further alleges that

petitioner’s reliance on epidemiological studies involving the Pandemrix H1N1 influenza

vaccine is unpersuasive. (Id. at 36.)

Respondent also contends that petitioner’s symptoms followed a typical course

of pediatric narcolepsy, and her symptoms were already progressing prior to

vaccination. (ECF No. 75, pp. 36-37.) Respondent stresses that petitioner overlooks

the fact that she has two “diagnostic markers” of narcolepsy, low levels of hypocretin in

her spinal fluid and the HLA DQB1*0602 gene. (Id. at 38.) Respondent contends that

pediatric narcolepsy diagnoses are often delayed, and the timing of petitioner’s

diagnosis “says nothing about the actual course of her disease.” (Id.) Finally,

respondent argues that any “substantial factor” claim would suffer the same limitations

with respect to establishing vaccine causation. (Id. at 41-42.)

VI. Discussion

The most extensively debated aspect of this case is the validity of petitioner’s

theory of causation explaining how petitioner’s HPV vaccine could have significantly

aggravated her condition. This presents a threshold issue in this case. Accordingly, I

will address petitioner’s theory of causation first. Having found that petitioner did not

meet her burden of proof on this point, I will then more briefly address the remaining

elements of the six-part Loving test discussed above.

24

a. Petitioner’s Medical Theory (i.e. the Althen prong one / Loving prong

four)

Petitioner’s burden under the first Althen prong/fourth Loving prong is to provide,

by preponderant evidence, “a medical theory causally connecting the vaccination and

the injury.” Althen, 418 F.3d at 1278. Such a theory must only be “legally probable, not

medically or scientifically certain.” Knudsen v. Sec’y of Human & Health Servs., 35 F.3d

543, 548-49 (Fed. Cir. 1994). Moreover, scientific evidence offered to establish Althen

prong one is viewed “not through the lens of the laboratorian, but instead from the

vantage point of the Vaccine Act's preponderant evidence standard.” Andreu v. Sec’y of

Health & Human Servs., 569 F.3d 1367, 1380 (Fed. Cir. 2009). However, to satisfy this

prong, petitioner’s theory must be based on a “sound and reliable medical or scientific

explanation.” Knudsen, 35 F.3d at 548; Boatmon, 941 F.3d at 1359.

Petitioner’s medical theory regarding how her HPV vaccination significantly

aggravated her narcolepsy cataplexy syndrome posits an autoimmune response to the

vaccination, “targeting human proteins that are implicated in the disease process of

narcolepsy.” (ECF No. 73, p. 19.) Petitioner relies on Dr. Steinman’s theory of

molecular mimicry to link the vaccination to her subsequent significant aggravation of

narcolepsy. (Id.) Below I shall address (1) the debate as to whether narcolepsy is an

autoimmune condition and whether a relevant autoantibody has been identified; (2)

whether the epidemiologic evidence links narcolepsy to the HPV vaccine by

preponderant evidence; and (3) whether Dr. Steinman’s demonstrated homologies can

be shown to demonstrate a causal relationship between the HPV vaccine and injury.

i. Narcolepsy Type 1 and autoimmunity

Narcolepsy type 1 is a disorder characterized by excessive daytime sleepiness

and signs of REM-sleep dissociation, the most specific of which is cataplexy. (American

Academy of Sleep Medicine, Narcolepsy Type 1, International Classification of Sleep

Disorders (3d ed. 2014) (Ex. F).) Narcolepsy is caused by hypocretin deficiency, likely

due to the selective loss of hypocretin-producing neurons in the hypothalamus. (Mignot,

supra, at Ex. O.) According to Mignot, when cataplexy is present, “the cause is almost

always an immune-mediated destruction of the hypocretin-producing (also called orexin)

neurons in the hypothalamus.” (Id.) The autoimmune hypothesis is the leading theory

for narcolepsy type 1, due to a strong association between narcolepsy type 1 and the

human leukocyte antigen (HLA) DQB1*0602. (Postiglione, supra, at 70 (Ex. K).)

Respondent’s expert, Dr. Deak, acknowledges that the autoimmune hypothesis

is the leading theory for the pathophysiology of narcolepsy type 1, but stresses that

“autoantibodies specific to hypocretin peptides have not been found,” and that direct

evidence supporting the autoimmune hypothesis is lacking. (Ex. A, p. 6.) Instead, she

notes that (i) seasonal differences in narcolepsy incidence, (ii) the rise in incidences

post 2009-2010 administration of the AS03-adjuvanted H1N1 vaccine and (iii) the

association with anti-streptococcal antibodies, all circumstantially support the theory that

25

environmental factors contribute to the development of narcolepsy in patients who are

genetically susceptible. (Ex. A, p. 6 (citing Postiglione et al., supra, at Ex. K).)

In that regard, Dr. Steinman notes three groups 22 who have “reported immune

responses to hypocretin reception 2 in narcolepsy”: (i) a group led by Dr. Steinman who

found that “in vaccine-induced narcolepsy, there are antibodies to HCRT-R2” and who

identified a region of the HCRT-R2 molecule located at the site where hypocretin binds

the receptor 23 (ii) a group in Japan which found antibodies to HCRT-R2 in narcolepsy24

and (iii) as did a group from Oxford. 25 (Ex. 14, p. 10.) Upon examination, these three

studies do not preponderantly establish HCRTR2 antibodies as the cause of

narcolepsy.

Tanaka et al. developed a study testing serum from one-hundred eighty-one

patients with narcolepsy, ten patients with other hypersomnia and ninety-one control

subjects. (Tanaka et al., supra, at 634 (Ex. 29).) As a result, they observed

autoantibodies against hypocretin in nine narcolepsy patients, HCRTR in three patients,

HCRTR1 in one patient, and HCRTR2 in five patients. (Id. at 635.) Eight of these

22

As noted above, Dr. Steinman also mentions a fourth group, Mignot’s group, who showed “some

evidence of antibodies to HCRT-R2 in narcolepsy” post Pandemrix vaccination, though he discounts

these findings due to a “major flaw” in one of the assays for HCRT-R2 that appears in their

supplementary data. (Id. (citing De la Herrán-Arita et al., supra at Ex. 25; De la Herrán-Arita et al., supra

at Ex. 26 (Retraction published on July 30, 2014)).) In the De la Herrán-Arita et al. study (2013)

(“Mignot’s group”) researchers tested for the presence of T cell reactivity toward HCRT epitopes HCRT56-

68 and HCRT87-99. (De la Herrán-Arita, supra, at Ex. 25, p. 7-9.) The results indicated that CD4 T cells

+

reactive to the presentation of HCRT56-68 and/or HCRT87-99 by DQ0602 were present in most patients with

narcolepsy. (Id. at 7.) The autoantigens primarily elicited a TH1 response, which the authors explain is

“characteristic of many autoimmune diseases.” (Id.) Yet, these results were later retracted. (De la

Herrán-Arita, supra, at Ex. 26, p. 14.) In a later article, Mignot explained that the hypocretin cell loss in

narcolepsy and the presence of the HLA DQB1*0602 is what “rekindled the hypothesis of autoimmunity,”

with hypocretin as the logical target. (Mignot, supra, at Ex. O, p. 865.) Despite this association,

“[s]uprisingly, however, autoantibodies targeting hypocretin peptides have not been found, and immune

staining of hypothalamic tissue with human narcolepsy sera has not revealed autoantibodies target

colocalized antigens on these neurons.” (Id.) Passive transfer experiments of human sera in mice have

been published, which suggested the presence of functional autoantibodies, however, Mignot explains

that these studies could not be replicated. (Id.) After the results of De la Herrán-Arita et al. study (2013),

researchers felt “a blood test for narcolepsy might be close at hand, but on finding these data were

invalid, [the authors] withdrew the paper.” (Id. at 866.) Ultimately, Mignot suggests that there is strong

circumstantial evidence supporting an autoimmune hypothesis though direct evidence is lacking. (Id.)

23 Ahmed et al., Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2,7

(294) SCI. TRANSL. MED. (2015) (Ex. 27). Dr. Steinman notes that his group identified the region of the

HCRT-R2 molecule that was previously identified at the University of Texas Southwestern Medical

School, “precisely at the site where hypocretin binds the receptor.” (Ex. 14, p. 10) (citing Yin et al,

Structure and ligand-binding mechanism of the human OX1 and OX2 orexin receptions, 23(4) NAT.

STRUCT. MOL. BIOL. 293-9 (2016)).)

24 Tanaka et al., Detection of autoantibodies against hypocretin, hcrtr1, and hcrtr2 in narcolepsy: anti-hcrt

system antibody in narcolepsy, 29(5) SLEEP 633-638 (2006) (Ex. 29).

25 Giannocarro et al, Antibodies against HCRT-R2 are rare in narcolepsy, 40(2) SLEEP (2017) (Ex. 30.)

26

patients had anti-HCRT neurotransmission system antibodies, with one patient having

positive reactions against both HCRTR1 and 2. (Id.) However, positive reactions were

also noted against HCRTR1 in two control subjects and HCRTR2 in one control subject.

(Id. at 636.) Tanaka et al. indicated that “[anti-HCRT antibodies] might be naturally

occurring autoantibodies without pathologic function or might not cross the blood-brain

barrier to cause narcolepsy.” (Id. at 637.) The authors observed that no relationships

existed between these autoantibodies and HLA DRB1*1501/DRQB1*0602 haplotypes,

the presence of cataplexy, the presence of subjective nocturnal sleep disruption, or the

scores on the Epworth Sleepiness Scale. (Id.) Ultimately, their results do not support

the hypothesis that autoantibody-mediated dysfunction in the hypocretin system

underlies the pathophysiology of narcolepsy. (Id.)

The Ahmed et al. study suggested a possible link between the Pandemrix

vaccine (an adjuvanted, influenza pandemic vaccine) and the development of

antibodies between hypocretin receptors. (Ahmed et al., supra, at 1 (Ex. 27).) In that

study, Dr. Steinman and his colleagues hypothesized that differences in the

nucleoprotein make-up of vaccines could explain why an increased incidence of

narcolepsy was observed following one type of influenza vaccine, Pandemrix, but not a

differently manufactured influenza pandemic vaccine, Focetria. (Id.) Differences

between the protein sequences from A(H1N1) pdm09 virus and the Pandemrix and

Focetria vaccines identified an influenza nucleoprotein peptide similar to human HCRT

receptor 2. (Id. at 2.) Antibodies were detected in the blood sera of higher numbers of

Pandemrix-vaccinated participants with narcolepsy than with individuals who did not

suffer from narcolepsy. (Id.) Key to this study was the authors’ comparison of the

nucleoprotein antibody content found in individuals who received eight different

inactivated flu vaccines, in addition to three monovalent A(H1N1) pmd09 vaccines (a

group which included Pandemrix). (Id. at 4.) Of the three monovalent vaccines,

Focetria had 72.7 percent fewer nucleoproteins than Pandemrix. (Id.) This suggested

“the possibility that lower [nucleoprotein] concentrations in Focetria could have

attenuated both the immune response to nucleoprotein and the subsequent generation

of [nucleoprotein] antibodies capable of cross-reactivity with HCRT receptor 2.” (Id.)

Ahmed et al. do not propose an explanation for this difference, other than to say that the

vaccines were manufactured differently. (Id. at 1.)

In the third group cited by Dr. Steinman, Giannocarro et al. (2017), sera from fifty

narcolepsy type 1 patients and eleven narcolepsy type 2 patients, twenty-two patients

with other sleep disorders, fifteen health controls, and ninety-three disease controls

were tested for the HCRTR2 antibodies. (Giannocarro et al., supra, at 1 (Ex. 30).)

Using a live cell-based assay approach, the researchers found only three narcolepsy

patients had IgG antibodies to HCRTR2. (Id. at 4-5.) They further observed that the

titers were low in all three patients and no HCRTR2 antibodies were found in their CSF.

(Id. at 5.) The authors note the earlier study from Tanaka et al., which also found a low

proportion of patients with antibodies immunoprecipitating HCRTR2. (Id.) Taken

together, Giannocarro et al. conclude that antibodies to HCRTR2 in patients with

idiopathic narcolepsy “appear to be rare.” (Id.) The results of both studies, as well as

the low titers in the serum and the absence of CSF antibodies (which are usually

27

present in patients with typical antibody-mediated diseases) suggests that these

antibodies “may not be clinically relevant.” (Id.) However, the authors note that their

results, as well as Tanaka et al., contrast with the results from Ahmed et al. (Id.)

Giannocarro et al. suggest that their results could reflect different methodologies. (Id.)

Moreover, they acknowledge that their three positive results were atypical because one

patient presented with narcolepsy type 1 and psychosis, and two patients were

DQB1*602 negative. (Id.) Ultimately, however, they suggest that the significance of

any HCRTR2 antibodies, even in a subset of narcolepsy patients, should be interpreted

with caution.

The proposition that narcolepsy may be “an immune-mediated condition is fairly

well-established” in the Program. McCollum v. Sec'y of Health & Human Servs., No. 14-

790V, 2017 WL 5386613, at *16 (Fed. Cl. Spec. Mstr. Sept. 15, 2017), review denied,

135 Fed. Cl. 735 (2017), aff’d, 760 Fed. Appx. 1003 (2019). Other prior decisions have

observed the likelihood that narcolepsy is autoimmune. See D'Tiole v. Sec'y of Health &

Human Servs., No. 15-085V, 2016 WL 7664475 (Fed. Cl. Spec. Mstr. Nov. 28, 2016),

review denied, decision aff'd, 132 Fed. Cl. 421 (2017), aff'd, 726 F. App'x 809 (Fed. Cir.

2018); Dougherty v. Sec'y of Health & Human Servs., No. 15-1333V, 2018 WL

3989519, at *43 (Fed. Cl. Spec. Mstr. July 5, 2018), aff'd, 141 Fed. Cl. 223 (2018); E.S

v. Sec'y of Health & Human Servs., No. 17-480V, 2020 WL 9076620, at *44 (Fed. Cl.

Spec. Mstr. Nov. 13, 2020). Here, although petitioner has preponderantly established

that narcolepsy is likely an autoimmune condition, she has not preponderantly

established a causal role for HCRTR2 autoantibodies in the development of the

condition.

ii. Epidemiological Evidence

Even in the absence of an identified autoantibody, an epidemiological association

between narcolepsy and the HPV vaccination could still potentially support a causal

theory. Here again, however, epidemiological evidence showing a causal link between

the HPV vaccine and the onset of narcolepsy, or in petitioner’s case, significant

aggravation, is also absent from this case. As a general matter, it is true that petitioners

in the Vaccine Program are not required to present epidemiological evidence to

establish their causation burden under Althen. Moberly v. Sec'y of Health & Hum.

Servs., 592 F.3d 1315, 1325 (Fed. Cir. 2010). However, “[n]othing in Althen or

Capizzano requires the Special Master to ignore probative epidemiological evidence

that undermines petitioner’s theory.” D'Tiole, 726 F. App'x at 811 (citing Andreu, 569

F.3d at 1379 (“Although Althen and Capizzano make clear that a claimant need not

produce medical literature or epidemiological evidence to establish causation under the

Vaccine Act, 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.” (emphasis added)); Grant v. Sec’y of Health & Human Servs., 956

F.2d 1144, 1148-49 (Fed. Cir. 1992) (considering negative epidemiological studies).

Partinen et al. (2012) focused on an outbreak of narcolepsy among children in

Finland in 2010. (Partinen et al., supra at 1 (Ex. 38).) The authors speculated whether

28

the cause of narcolepsy was attributable to adjuvants in the Pandemrix vaccine, or

some other environmental factors or genetic predisposition. (Id. at 7-8.) Between 2002

and 2009, 335 cases of narcolepsy (all ages) were diagnosed in Finland. (Id. at 4.) In

2010, 54 children were diagnosed with narcolepsy, a 17-fold increase. (Id. at 5.) Based

on patient records, the authors placed onset of excessive daytime sleepiness at 0-242

days after receiving the H1N1 vaccine (Pandemrix, GSK). (Id.) Yet the authors

stressed the fact that the Pandemrix flu vaccine was the only form of the vaccine

associated with an increased incidence of narcolepsy. (Id. at 7) (“there is no evidence

of an increased risk of narcolepsy with any other vaccine than the AS03 adjuvanted

Pandemrix”).

Winstone et al. (2014) sought to investigate the onset of narcolepsy among

English children who received the AS03 adjuvanted pandemic A/H1N1 2009 vaccine

(Pandemrix). (Winstone, supra, at 1 (Ex. 39).) The authors identified seventy-five

patients with narcolepsy, though only eleven received the Pandemrix vaccine before

narcolepsy onset, a “relatively small number.” (Id. at 1.) As Dr. Steinman points out,

among the eleven patients who received the Pandemrix vaccine: six patients reported

onset of narcolepsy within three months, one patient reported onset between four and

six months, and four patients reported onset between seven and fourteen months. (Id.

at 4.) However, the authors acknowledged that the small number of patients who in fact

received the Pandemrix vaccine reduces the likelihood of finding statistically significant

differences between vaccinated and unvaccinated patients. (Id. at 8.)

Szakacs et al. (2013) designed a retrospective study conducted in Sweden

where symptom onset was determined based on medical record review and telephone

interviews with parents and patients. (Szakacs et al., supra, at Ex. II).) In that study,

the median time from H1N1 vaccination to symptom onset was nine-and-a-half weeks,

with nineteen of the twenty-eight patients developing symptoms in twelve weeks or less.

(Id. at 1315.) In addition, Heier et al. (2013) conducted a study in Norway where onset

was defined by reports from physicians, based on interactions with parents or patients;

and in that study the median time from vaccination to onset was eleven weeks, with

forty-two of the fifty-eight patients experiencing clinical symptoms within six months of

vaccination. (Heier et al., supra, at Ex. JJ.) The authors, however, found no significant

difference in the incidence of narcolepsy during the second year after vaccination

compared to unvaccinated children in the same time period. (Id. at 868)

The literature cited by Drs. Deak and Steinman, discussed above, demonstrates

an increased incidence of narcolepsy after the administration of the AS03-adjuvanted

H1N1 vaccine in several European countries. Yet, there is no increased risk of

narcolepsy with either H1N1 vaccines that contained other adjuvants, such as Focetria,

or among non-adjuvanted H1N1 vaccines given in the United States. (Partinen, supra,

at Ex. E; Duffy et al., supra, at Ex. Q; Nguyen et al., supra, at Ex. R.)

Gardasil, in this case the quadrivalent vaccine, is prepared from four Human

Papillomavirus type-specific virus-like particles (VLPs) from the L1 proteins of HPV 6,

11, 16, and 18, and is entirely unrelated to the above-discussed vaccines. In contrast to

29

the above, the epidemiological study by Arnheim-Dahlstrom (2013) introduced into the

record by Special Master Millman, “show[ed] that among almost one million adolescent

girls, [the] HPV vaccine was not [r]elated causally to narcolepsy.” (ECF No. 26.) This

population-based study included all adolescent girls aged between 10 and 17 years in

Denmark and Sweden who received the quadrivalent HPV vaccine between 2006 and

2010. (Arnheim-Dahlstrom et al., supra, at 2 (ECF No. 26-1) (Court Ex. 1).) The

incidence rate for immunized subjects in this study was 2.61 incidents of narcolepsy per

100,000 person years whereas the unvaccinated rate was 1.81 per 100,000 person

years. (Id. at 8.) The authors concluded that there was no significant association

between the HPV quadrivalent vaccine and narcolepsy. (Id. at 5, 8.)

In Dr. Steinman’s interpretation of this study, he concludes that the Gardasil

vaccine is associated with a higher rate of narcolepsy compared to the unvaccinated,

“even though it may not reach so-called ‘statistical significance.’” (Ex. 14, p. 31.) In

contrast, Dr. Whitton stresses that the authors do not provide the actual p value 26 of

their findings regarding narcolepsy. (Ex. EE, p. 2; ECF No. 26-1, p. 5.) In my review, I

note that Table 2 of the study expresses a confidence interval of 95 percent for the

incidence rate for both unvaccinated and vaccinated groups showing that the lower

confidence limit for the incidence rate of narcolepsy among the vaccinated group (1.17)

is lower than the lower confidence limit for the unvaccinated group (1.34). 27 Thus, this

data does not even express confidence that the actual incidence rate is higher among

the vaccinated group at all. (ECF No. 26-1, p. 8.) Although they noted the results

should be viewed with caution, the authors likewise indicated that no safety signal was

detected by the study. (Id. at 5.) Thus, I am not persuaded by Dr. Steinman’s

subjective impression of the difference as “impressive” despite lacking statistical

significance. (Ex. 14, p. 31 (“these are large samples and the difference is impressive

in my opinion…even though it may not reach so-called ‘statistical significance.’”) See

Thompson v. Sec’y of Health & Human Servs., No. 99-436V, 2003 WL 21439672, at *18

(Spec. Mstr. Fed. Cl. May 23, 2003) (observing that “professionals in the field of

epidemiology rely upon statistical significance in order to reach valid, credible

conclusions.”)

Dr. Whitton also provides a more recent study, Hvid et al. (2018), where the

authors again studied the frequency of narcolepsy following HPV vaccination and still no

significant association between the two was identified. (Ex. EE, p. 2 (citing Hvid, et al.,

supra, at Ex. FF).) Like the earlier population-based study, researchers included all

26 P value is “the probability of obtaining by chance a result at least as extreme as that observed, even

when the null hypothesis is true and no real difference exists; when P ≤ 0.05 the sample results are

usually deemed significant at a statistically important level and the null hypothesis rejected.” P-value,

DORLAND’S MEDICAL DICTIONARY ONLINE, https://www.dorlandsonline.com/dorland/definition?id=13359

(last visited Oct. 8, 2021).

27 Confidence interval is “a type of statistical interval estimate for an unknown parameter: a range of

values believed to contain the parameter, with a predetermined degree of confidence. Its endpoints are

the confidence limits, and it has a stated probability (the confidence coefficient) of containing the

parameter.” Confidence interval, DORLAND’S MEDICAL DICTIONARY ONLINE,

https://www.dorlandsonline.com/dorland/definition?id=13359 (last visited Oct. 12, 2021).

30

women from Denmark and Sweden who received the quadrivalent HPV vaccine

between 2006-2010, only this time among women 18-44 years old. (Hvid et. al., supra,

at 155 (Ex. FF).) Among 431 reported events of narcolepsy, the authors recorded 21

reports of narcolepsy any time after vaccination, with 10 reported within 179 days post-

vaccination and 11 reported within 180 days or more. (Id. at 9.) These results were not

highlighted as “significant associations.” (Id.) Taken together, the Arnheim Dahlstrom

et al. study and the Hvid et al. study suggest no significant association between the

frequency of narcolepsy and HPV vaccination.

Dr. Deak raises a further concern that the reported timing of symptom onset is

generally prone to recall bias. (Ex. GG, p. 2.) Based on her own clinical experience,

and the insidious nature of narcolepsy onset, Dr. Deak stresses that the onset of

symptoms in a retrospective study is likely to have occurred prior to the reported time of

presentation. (Id.) Researchers in Hvid et al. acknowledge that “[f]or many of the

included outcomes, there will be a delay between onset and diagnosis.” (Hvid et al.,

supra, at 163 (Ex. FF).) For this reason, the authors included two risk periods: a 180-

day period for outcomes “with little delay between onset and diagnosis” and a period

following 180 days for outcomes “with a more insidious onset.” (Id.) Even still, despite

the large size of the cohort, the authors stress that “many of the included outcomes are

rare and null findings should be interpreted in the context of statistical power.” (Id.)

The fact that a relationship between the HPV vaccine and narcolepsy has not

been uncovered epidemiologically is not in itself fatal to petitioner’s claim. Nonetheless,

review of the above demonstrates that the epidemiological evidence that does exist

does not support petitioner’s allegations.

iii. Dr. Steinman’s Theory Regarding Molecular Mimicry

Petitioner presents the theory of molecular mimicry to “[link] the vaccination to

her subsequent, significant aggravation that led to her diagnosis of narcolepsy.” (ECF

No. 73-1.) Petitioner contends that Dr. Steinman has demonstrated that components of

the HPV vaccine present molecular mimics of hypocretin and hypocretin-2 receptor.

(Id.) Specifically, Dr. Steinman carried out BLAST searches to identify homologies

between the components of the Gardasil vaccine and various components of the

hypocretin pathway, including hypocretin itself and the HCRT-R2 receptor. (Ex. 14, p.

11.)

Dr. Steinman classifies his criteria for a “meaningful molecular mimic” as a run of

5 or more of 12 amino acids that are identical. (Id.) Dr. Whitton, however, explains that

in order to identify an amino acid sequence as a “mimic,” one cannot rely on a shared

homology alone. (Ex. C, p. 5.) Rather, mimicry is defined by the “immune response

that the sequence induces” and to be a “mimic” the amino acid sequence must “(i) []

trigger an immune response and, (ii), that response must recognize (i.e., cross-react

with) the other peptide[.]” (Id.) (emphasis in original). Unless both criteria are met, then

it is not a mimic, but merely a homology. (Id.)

31

Indeed, “molecular mimicry is a generally accepted scientific principle, [though]

mere invocation of the scientific term does not carry a petitioner’s burden in a Program

case.” Deshler v. Sec'y of Health & Human Servs., No. 16-1070V, 2020 WL 4593162,

at *20 (Fed. Cl. Spec. Mstr. July 1, 2020) (citing Forrest v. Sec’y of Health & Human

Servs., No. 14-1046V, 2019 WL 925495, at *3 (Fed. Cl. Spec. Mstr. Jan. 18, 2019)).

This is because, as Dr. Whitton opines in this case, “the finding of sequence homology

does not necessarily mean the similarity has significance to the immune system.” Tullio

v. Sec'y of Health & Human Servs., No. 15-51V, 2019 WL 7580149, at *15 (Fed. Cl.

Spec. Mstr. Dec. 19, 2019), review granted, decision aff'd, 149 Fed. Cl. 448 (2020); see

also Caredio v. Sec'y of Health & Human Servs., No. 17-0079V, 2021 WL 4100294, at

*31 (Fed. Cl. Spec. Mstr. July 30, 2021), review granted, decision aff’d, Fed. Cl.

(2021) (“demonstration of homology alone is not enough to establish a preponderant

causation theory”) (emphasis in original) (citing Schultz v. Sec'y of Health & Human

Servs., No. 16-539V, 2020 WL 1039161, at *22 n. 24 (Fed. Cl. Spec. Mstr. Jan. 24,

2020) (“[m]ere demonstration of theoretical homology alone, based on computer-driven

searches involving databases of amino acid sequences, does not carry the day”)).

Both Drs. Steinman and Whitton rely on the study from Silvanovich et al. (2006)

in their discussions on the reliability and value of BLAST searches. It is true, as Dr.

Steinman asserts, the authors concluded that “for large proteins and an expanding

allergen database, a FASTA or BLAST bioinformatics search appears to be the

optimum method for identifying potential similarities between newly expressed proteins

and known allergens.” (Silvanovich et al., supra, at Ex. OO.) The study performed a

series of analyses to determine whether there was a scientifically justified search

window size that could identify allergen sequence characteristics, in the context of

genetically engineered crops. (Id. at 252.) Based on the results, Silvanovich et al.

concluded that searches for short amino acid sequence matches of eight amino acids or

fewer, used to identify proteins as potential cross-reactive allergens, “is a product of

chance and adds little value to allergy assessments for newly expressed proteins.” (Id.

at 258.) These results, Dr. Whitton explains, show that Dr. Steinman’s 5/12 homologies

are entirely predictable. (Ex. C, p. 9.)

The “Silvanovich standard,” as Dr. Whitton describes it, requires a window of at

least 80 amino acids in length, in which there is at least 35% amino acid identity, and

whose E-value must be lower than 3.9 x 10-7. (Silvanovich et al., supra, at Ex. OO;

Silvanovich et al., supra, at Ex. PP.) According to Dr. Whitton, none of Dr. Steinman’s

BLAST results meet these criteria. (Ex. KK, p. 6.) Even assuming arguendo that Dr.

Steinman’s BLAST results did meet these criteria, nothing in this article reveals whether

Dr. Steinman’s sequence may trigger a T cell response.

The Latorre study identified a 20 amino acid sequence in orexin that can

stimulate CD8+ T cells from a single narcolepsy patient’s spinal fluid— which Dr.

Steinman suggests confirms the BLAST searches linking the HPV vaccine and a key

portion of the orexin molecule. (Latorre, supra, at Ex. 45, p. 5; Ex. 43, p. 2-5.)

However, to challenge the validity of Dr. Steinman’s theory, Dr. Whitton compared the

short orexin sequence against the measles vaccine. (Ex. KK, pp. 14-15.) Dr. Whitton

32

identified four homologies, and then carried out the same comparison using BLAST,

and one hit was returned, containing a 5/11 homology with an E-value of 0.17. (Id. at

15.) Dr. Whitton explains that, following Dr. Steinman’s logic, these results indicate that

the measles vaccine, more likely than not, triggers narcolepsy. (Id.) Yet, “[t]he MMR

vaccine was introduced in 1963” and “no association has ever been reported between

MMR and narcolepsy.” (Id.) The mere existence of a homology to the orexin sequence,

therefore, does not “inculpate[] a vaccine.” (Id.) Accordingly, in the context of this

vaccine and this injury, Dr. Steinman’s finding of homology is not sufficient to establish

causation.

While the demonstrated homology offered by Dr. Steinman is potentially useful,

the scientific literature suggests that homologies are predictable and do not inevitably

lead to cross-reaction. There have been instances where Dr. Steinman’s use of BLAST

searches has been found to help support a finding of vaccine causation. See E.M. v.

Sec’y of Health & Human Servs., No. 14-753V, 2021 WL 3477837, at *36-39 (Fed. Cl.

Spec. Mstr. July 9, 2021) (finding persuasive Dr. Steinman’s evidence of “numerous

examples of sequences in the 2011 Fluarix vaccine and between earlier seasonal flu

vaccines, that share similar homologies with the [protein] alpha3 nicotinic AChR, which

is associated with small fiber neuropathy”); White v. Sec’y of Health & Human Servs.,

No. 15-1521, 2019 WL 7563239, at *24 (Fed. Cl. Spec. Mstr. Dec. 19, 2019) (crediting

Dr. Steinman's molecular mimicry theory and BLAST searches where there were

“sufficient homologies between the basic myelin protein and two of the strains of the

HPV L1 strains…and between MOG and all four HPV antigens in the vaccine[,]” which

could cause TM). However, Dr. Steinman’s use of BLAST search result homologies

has also separately been criticized in the absence of some evidence of cross reaction

as being mere uninvestigated hypothesis. Forrest v. Sec'y of Health & Human Servs.,

No. 14-1046V, 2019 WL 925495, at *4-5 (Fed. Cl. Jan. 28, 2019) (finding that Dr.

Steinman's theory that a flu vaccine caused TM via molecular mimicry was not

sufficiently developed to meet Petitioner's burden under Althen prong one because Dr.

Steinman had “not investigated his hypothesis[,]” other than through computerized

homologies revealing “some overlap in sequences of amino acids[.]”) Even where Dr.

Steinman has shown in a separate context that a 5 out of 12 homology can be

experimentally shown to cause disease, homology alone does not in any given instance

show that a causal relationship exists between vaccine and injury. 28

28 Dr. Steinman relies upon animal studies in which researchers studying multiple sclerosis sought to

induce paralysis in mice using mimics of myelin basic protein. Dr. Steinman derives his criteria for a

“meaningful molecular mimic” from studies where scientists induced experimental allergic

encephalomyelitis (“EAE”) in mice using a viral peptide with homology with myelin basic protein. (See Ex.

14 at 11.) Similarly, Dr. Steinman cites Ufret-Vicenty et al., wherein researchers “passively transferred T

cells that cross-reacted with myelin basic protein and HPV, and saw that the experimental animals

became paralyzed[.].” (Ex. 14 at 26 (discussing Ex. 35)). Dr. Steinman fails to explain why these animal

studies involving a different protein and a different disease are relevant to petitioner’s case. See D.G. v.

Sec'y of Health & Human Servs., No. 11-577V, 2019 WL 2511769, at *77 (Fed. Cl. Spec. Mstr. May 24,

2019) (“[I]t [is] irrelevant that Dr. Steinman can make mice ill with inflammation of their brains and spinal

cords with a mere homology of five amino acids,” as “[p]etitioner is not a mouse” and “never had

inflammation of her brain or spinal cord.”)

33

In fact, as Dr. Steinman points out, the significance of the homology is informed

by other areas of inquiry. (See Ex. 14, p. 28-29 (“[o]ther genetic and environmental

factors are necessary before these self-reactive immune responses to myelin for

example, or to HCRT-R2, may trigger inflammation in the brain.”).) In this case,

however, the other available areas of inquiry do not support a causal relationship for all

the reasons discussed in the two preceding sections.

Overall, I am more persuaded by Dr. Whitton’s opinion (discussed in much

greater detail above) that Dr. Steinman is not in this case generating reliable evidence

of molecular mimicry via his BLAST searches. Thus, I find that petitioner has not

provided a medical theory causally connecting the HPV vaccine to her worsening

narcolepsy, and petitioner is therefore unable to carry her burden under prong 4 of the

Loving test. In the Vaccine Program, it is well understood that petitioners are not

obligated to prove the precise mechanism as a component of their causation theory.

Kottenstette v. Sec'y of Health & Human Servs., No. 2020-2282, 2021 WL 2434329, at

*7 (Fed. Cir. June 15, 2021); Knudsen, 35 F.3d at 548-59. Yet, when a mechanism is

presented as the basis for petitioner’s theory, it must be based on sound and reliable

scientific explanation. Boatmon, 941 F.3d at 1359-60.

b. Significant Aggravation (Loving prongs one through three)

Assuming arguendo that petitioner did prove a medical theory demonstrating that

her HPV vaccination could have caused or aggravated her narcolepsy, the remainder of

the Loving test queries whether petitioner would be able to show that it did do so in this

particular case. The threshold question in that remaining analysis is whether

petitioner’s condition was, in fact, significantly aggravated. To demonstrate significant

aggravation, the Vaccine Act requires a “change for the worse in a preexisting

condition,” and “markedly greater disability, pain, or illness accompanied by substantial

deterioration of health.” 42 U.S.C. § 300aa-33(4). Under the Loving test, petitioner

demonstrates this by showing (1) her condition before the vaccination, (2) her current

condition, and (3) that her current condition constitutes a significant aggravation of her

prior condition.

In this case, there is no dispute that petitioner had at least some initial symptoms

of narcolepsy prior to vaccination and that she developed additional symptoms after the

vaccination. (ECF No. 73 (citing Ex. 3, pp. 43, 48); ECF No. 75 (citing Ex. 3, p. 43.))

What is contested, however, is Dr. Steinman’s assertion that the Gardasil vaccine

“changed the trajectory” of her condition. (Ex. 14, pp. 6, 31; ECF No. 75, p. 40.) There

are two cases, Locane and Sharpe, that illustrate the Circuit’s significant aggravation

analysis with regard to the evolution of petitioner’s clinical course. Locane v. Sec’y of

Health & Human Servs., 685 F.3d 1375 (Fed. Cir. 2012); Sharpe v. Sec’y of Health &

Human Servs., 964 F.3d 1072 (Fed. Cir. 2020).

In Locane, petitioner alleged her Crohn’s disease, an inflammatory bowel

disease, was significantly aggravated by the hep B vaccine. Locane, 685 F.3d at 1377-

78. The special master determined that petitioner failed to show “by a preponderance

34

of the evidence that she was entitled to compensation under the significant aggravation

theory because the course of her disease was not affected by the vaccination.” Id. at

1378. The Federal Circuit found that the special master’s finding—that petitioner’s

clinical course was not inconsistent with the disease generally and not affected by the

vaccinations—was considered from “the relevant evidence of record, [drawn from]

plausible inferences and articulated a rational basis for the decision,” therefore, the

decision was not arbitrary or capricious. Id. at 1381-82. The Court continued, stating

that petitioner was “given ample opportunity to develop her significant aggravation claim

but ‘failed to present persuasive evidence that separates [her] problems from an

expected course of Crohn's disease.’” Id. at 1382.

In Sharpe, petitioner alleged L.M. had a pre-existing “seizure disorder” and the

administration of the several childhood vaccines at her six-month wellness check-up

significantly aggravated L.M.’s pre-existing condition. Sharpe, 964 F.3d at 1076-77.

The special master denied petitioner’s significant aggravation claim because L.M.’s

genetic mutation, and not the vaccination, was the sole, substantial cause of L.M.’s

seizure disorder. Id. at 1080. The Circuit found the special master’s analysis “required

[p]etitioner to prove the expected outcome for a child with a DYNC1H1 gene mutation

and to show that L.M.’s current, post-vaccination condition was worse than that

expected outcome.” Id. at 1081. The Circuit stated, “a court should consider all

evidence in the record, including evidence of other possible sources of injury. There is,

however, a fine line between a court properly considering evidence in the record . . .

and improperly placing the burden on the petitioner to prove that her significantly

aggravated condition was not caused by her gene mutation.” Id. at 1082. The Court

distinguished the special master’s decision from Locane stating, in Locane “the special

master did not require the petitioner to prove that her significantly aggravated condition

was not caused by her preexisting condition. Instead, the special master found that the

petitioner’s condition ‘was not affected by the vaccination.’” Id.

In this case, petitioner presented to the emergency department on May 11, 2013,

with symptoms of sleep disruption and daytime sleepiness with prolonged napping 4-6

weeks prior to her hospitalization. (Ex. 3, p. 42; Ex. 4, p. 52.) Several other physicians

also noted sleep disruption and daytime sleepiness with prolonged napping prior to her

hospitalization. (Ex. 3, p.43, Ex. 4, p. 52 (Dr. Neiderman); Ex. 3, p.85 (Dr. Martinez);

Ex. 3, pp. 5-6, Ex. 4, p. 9, Ex. 11, p. 31 (Dr. Dubrovsky); Ex. 3, p. 66 (Dr. Brown); Ex. 3,

p. 48 (Dr. Maragh), Ex. 3, p. 54 (Dr. Chiang); Ex. 3, 69 (Dr. Gutierrez).) In one note,

petitioner described “waking up 1-2 [times] a night 4 weeks ago.” (Ex. 3, p. 5.) This

would place onset of petitioner’s symptoms in approximately April 2013, prior to the

vaccination at issue. Petitioner reported additional symptoms between 2-4 weeks prior

to hospitalization, including: legs buckling (Ex. 3, p. 65, Ex. 3, p. 85), falls (Ex. 3, p. 65,

Ex. 3, p. 69), slurred speech (Ex. 3, pp. 5-6), and gait difficulties (Ex. 3, p. 68, Ex. 3, p.

85).

Dr. Deak explains that the full narcoleptic tetrad of symptoms–excessive daytime

sleepiness, cataplexy, hypnagogic/hypnopompic hallucinations and sleep paralysis–is

rarely present at initial presentation. (Ex. A, p. 5.) The order in which symptoms appear

35

can also vary. (Id. (citing Dauvilliers et al., supra, at Ex. H).) Due to the “insidious

onset” of narcolepsy, as well as accompanying behavioral, metabolic, and mood

symptoms, narcolepsy is often misdiagnosed. (Ex. A, p. 5.) In fact, petitioner’s case

“followed a typical time course for pediatric narcolepsy,” with excessive daytime

sleepiness and nocturnal sleep disruption as her initial symptoms. (Id. at 6.) Dr. Deak

explains that “[i]t is not surprising that [petitioner] developed cataplectic active

phenomenon, in addition to negative phenomenon already present, as her symptoms

progressed.” (Ex. GG, p. 1.) I am persuaded by Dr. Deak’s assessment of petitioner’s

progression of narcolepsy: petitioner exhibited “symptoms represent[ing] a clear change

from [petitioner’s] baseline” and a “significant alteration in functioning” well before her

vaccination. (Ex. A, p. 4)

Dr. Steinman suggests that, although petitioner reported symptoms prior to the

May 1, 2013 immunization, “there was clear worsening” approximately 10 days after the

May 1, 2013, Gardasil shot. (Ex. 14, p. 31.) He quotes the “history of present illness” in

Dr. Lazar’s discharge summaries from May 16, 2013 which details “twitching” episodes

in petitioner’s left upper extremity and left leg, as well as episodes of light headedness

and falling. 29 (Id. (See Ex. 11, p. 2.) Dr. Steinman stresses that “[t]his type of activity

was NOT present prior to the May 1, 2013, immunization, based on the

contemporaneous record.” (Id.) (emphasis in original). Petitioner also asserts that her

case of narcolepsy is an “outlier,” one which presented with a “fast evolution and

diagnosis.” (ECF No. 73, p. 30.) Though petitioner notes that she suffered many of the

hallmark symptoms of narcolepsy, she contends that she “did so in a seemingly

abbreviated time frame compared to many children.” (Id.) Citing to the Aran et al.

study, petitioner suggests that petitioner’s case falls within a time frame of three months

between onset of sleepiness in children and development of cataplexy. (Id. at 29.)

Yet the authors of that study report that “[c]ataplexy occurred within 3 months of

onset in 85% of cases,” and within 2 months of onset in 82% of cases. (Aran et al.,

supra, at Ex. I.) These time frames fit squarely with the progression of petitioner’s

alleged symptoms. Additionally, the medical records suggest that petitioner was

already experiencing symptoms suggestive of cataplexy prior to her vaccination. In fact,

several providers documented symptoms of cataplexy, including legs buckling (Ex 3. pp.

65, 85, 90), falls (Ex. 3, pp. 65, 85), slurred speech (Ex. 3, pp. 5-6, 51), 30 and gait

difficulties (Ex. 3, p. 68) during the 2-4 weeks prior to hospitalization. The providers

29 (See Ex. 3, p. 43 (On May 11, 2013 “[m]other reports slurred speech and hands twitching and shaking

started 3 days ago, knees twitching (while standing) started 2.5 weeks ago and the sleeplessness started

6 weeks ago.); (Ex. 3, p. 48 (On May 11, 2013 “[o]ver the past three days [petitioner] report[ed]

“twitching” of her left upper extremity and left leg”); (Ex. 3, p. 71 (same)).

30 Dr. Neidenberg’s narrative from May 11, 2013 states that “slurred speech and hands twitching and

shaking started 3 days ago.” (Ex. 3, p. 43.) While Dr. Deray’s report from June 27, 2013 suggests that

petitioner’s slurred speech began approximately four days after the Gardasil shot. (Ex. 9, p. 6.)

Petitioner’s discharge summary, which petitioner’s mother claims is the most accurate summary of

petitioner’s onset of symptoms, simply notes that “Mother reports that at time patient’s speech was noted

to be ‘slurred,’” without any indication of onset. (Ex. 11, p. 2.)

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documented the presence of the above symptoms preceding vaccination based on real-

time interviews with petitioner and her mother.

In light of the above, I do not find preponderant evidence on this record that

petitioner’s vaccination significantly aggravated her condition. I have not required

petitioner to prove that her post-vaccination condition was worse than the expected

outcome. Instead, I find that the evidence taken as a whole shows that her course was

not inconsistent with pediatric narcolepsy generally and that her condition was not

affected by the vaccination. This finding is consistent with Locane. It is also further

reinforced by the discussion of the treating physician opinions below.

c. Logical sequence of cause and effect showing the vaccination was

the reason for the injury (Althen prong two/Loving prong five)

The second Althen prong/fifth Loving prong requires proof of a logical sequence

of cause and effect showing that the vaccine was the reason for the injury, usually

supported by facts derived from a petitioner's medical records. Althen, 418 F.3d at

1278; Andreu, 569 F.3d at 1375–77; Capizzano v. Sec’y of Health & Human Servs., 440

F.3d 1317, 1326 (Fed. Cir. 2006); Grant, 956 F.2d at 1148. However, medical records

and/or statements of a treating physician do not per se bind the special master to adopt

the conclusions of such an individual, even if they must be considered and carefully

evaluated. See 42 U.S.C. §300aa-13(b)(1) (providing that “[a]ny such diagnosis,

conclusion, judgment, test result, report, or summary shall not be binding on the special

master or court”); Snyder v. Sec'y of Health & Human Servs., 88 Fed. Cl. 706, 746 n.67

(2009) (“there is nothing ... that mandates that the testimony of a treating physician is

sacrosanct—that it must be accepted in its entirety and cannot be rebutted”). Dr.

Steinman’s assessment of a vaccine-caused “change in trajectory” is addressed above.

Here, I additionally note that there is not preponderant evidence that petitioner’s treating

physicians concluded that her HPV vaccination caused a significant aggravation of her

preexisting narcolepsy.

The medical record closest to supporting petitioner’s contention is Dr.

Dubrovsky’s note that petitioner “presented with excessive daytime sleepiness,

cataplexy, and episodes of sleep paralysis since mid April, exacerbated after Gardasil

shot at the end of April.” (Ex. 11, p. 31.) At this visit, Dr. Dubrovsky also

recommended reporting petitioner’s condition “to the registry” (presumably referring to

the Vaccine Adverse Event Reporting System (VAERS). (Id.) Importantly, however,

she made a point of specifically noting in the same assessment that “I am not certain[] if

the symptoms are associated with the vaccination.” (Id.) Dr. Dubrovsky previously

wrote that she “wonder[ed] if the vaccination ha[d] anything to do with the escalating of

the symptoms.” (Ex. 3, p. 6.) Considering Dr. Dubrovsky’s records as a whole, her

statements of mere suspicion fall short of an opinion supporting a vaccine-related

significant aggravation of petitioner’s condition. See Stapleford v. Sec’y of Health &

Human Servs., No. 03-234V, 2009 WL 1456441, at *17 n.24 (Fed. Cl. Spec. Mstr. May

1, 2009) (referencing medical record “is quite different from an indication that such

physician has reached a conclusion concerning a causal relationship”) (emphasis in

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original), aff’d, 89 Fed. Cl. 456 (Fed. Cl. 2009). Moreover, “[a] treating physician’s

recognition of a temporal relationship does not advance the analysis of causation.”

Isaac v. Sec’y of Health & Human Servs., No. 08-601V, 2012 WL 3609993, at *26 (Fed.

Cl. Spec. Mstr. July 30, 2012); see also Devonshire v. Sec’y of Health & Human Servs.,

No. 99-031V, 2006 WL 2970418, at *19 (Fed. Cl. Spec. Mstr. Sept. 28, 2006) (medical

expert’s “post hoc ergo prompter hoc reasoning…has been consistently rejected by the

Court and is ‘regarded as neither good logic nor good law’”) (quoting Fricano v. U.S., 22

Cl. Ct. 796, 800 (1991) (emphasis in original)).

The records from petitioner’s other treating physicians regarding causation were

no less equivocal. Pediatric neurologist Dr. Martinez questioned whether petitioner’s

symptoms “could possibly be a side effect of Gardasil,” but ultimately concluded that the

“etiology of [petitioner’s] symptoms [is] unknown” and speculated that her symptoms

could be due to green coffee extract that petitioner was taking. (Ex. 3, pp, 90, 102.) Dr.

Stuart Brown also questioned whether petitioner’s Gardasil vaccination “triggered []

narcolepsy on an autoimmune basis,” noting that “[t]his has been reported occasionally

with other immunizations,” but with respect to Gardasil, “the statistics for this are

questionable as to a cause and effect relationship.” (Id. at 66.) Pediatric infectious

disease specialist Dr. Robert Reid also examined petitioner and concluded that her

condition was “not likely a reaction to the vaccine since the symptoms of insomnia

started way before the vaccine was given.” (Id. at 53.) Dr. Gutierrez, a second pediatric

infectious disease specialist, observed that petitioner “had received the Gardasil

[vaccine] after the symptoms had started” and did “not believe there has been any

association.” (Id. at 70.)

On the whole, I find that petitioner’s treating physicians considered, though did

not conclude, that petitioner’s HPV vaccine significantly aggravated her preexisting

narcolepsy. See Cedillo v. Sec’y of Health & Human Servs., 617 F.3d 1328, 1348 (Fed.

Cir. 2010) (special master did not err in affording little weight to the opinions of

petitioner’s treating physicians where “none of the treating physicians concluded that

the MMR vaccine caused [petitioner’s] autism”); Moberly, 592 F.3d at 1324-25 (finding

no treating physician evidence to support the claim of causation where the “medical

records regarding the temporal proximity of the [vaccination] to the seizures were all

speculative.”)

Other records suggest that petitioner’s treating physicians considered Gardasil

as a possible cause of petitioner’s narcolepsy in large part due to her mother’s

prompting. (See Ex. 3, p. 100 (“[m]other has concerns that the [petitioner] had a

Gardasil [sic] immunization at [sic] this may have contributed to the [petitioner’s]

symptoms”); Ex. 48, p. 29 (petitioner’s “mom related [daughter’s illness] to the gardasyl

[sic] shot”); Ex. 3, pp. 62-63 (petitioner’s “mother believes that some of [petitioner’s]

symptoms have occurred shortly after her Gardasil vaccination.”)) That petitioner’s

treating physicians noted her mother’s concerns in their records, however, provides little

support for the proposition that they themselves believed Gardasil to be a cause for

petitioner’s condition. E.g., Moriarty by Moriarty v. Sec'y of Health & Human Servs., No.

03-2876V, 2014 WL 4387582, at *15 (Fed. Cl. Spec. Mstr. Aug. 15, 2014) (petitioner’s

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parent’s “views about causation are not persuasive because she is not a medical

doctor’”), review denied, decision aff'd, 120 Fed. Cl. 102 (2015), vacated and remanded

on other grounds, 844 F.3d 1322 (Fed. Cir. 2016); accord 42 U.S.C. § 300aa–13 (a

special master may not find in favor of the petitioner “based on the claims of a petitioner

alone, unsubstantiated by medical records or medical opinion”); James-Cornelius v.

Sec’y of Health & Human Servs., 984 F.3d 1374, 1380 (Fed. Cir. 2021) (“lay opinions as

to causation or medical diagnosis may be properly characterized as mere ‘subjective

belief’ when the witness is not competent to testify on those subjects[.]”)

Lastly, petitioner also contends that “[t]here is no evidence of another factor that

may have exacerbated her narcolepsy.” (ECF No. 73, p. 27.) In this Program,

however, absence of another cause is not persuasive evidence in support of petitioner’s

burden to show causation. See D.G., 2019 WL 2511769, at *183 (“[T]he Federal Circuit

in Grant state[]d [that] petitioner’s burden is to prove vaccine causation with affirmative

evidence. Saying since there is no other cause, it has to the vaccine is not affirmative

proof.”) (citing Grant, 956 F.2d at 1149).

d. Proximate temporal relationship between vaccination and injury

(Althen prong three/Loving prong six)

The third Althen prong/sixth Loving prong requires establishing a “proximate

temporal relationship” between the vaccination and the injury alleged. Althen, 418 F.3d

at 1281. That term has been equated to the phrase “medically-acceptable temporal

relationship.” Id. A petitioner must offer “preponderant proof that the onset of

symptoms occurred within a timeframe which, given the medical understanding of the

disorder's etiology, it is medically acceptable to infer causation.” de Bazan v. Sec'y of

Health & Human Servs., 539 F.3d 1347, 1352 (Fed. Cir. 2008). The explanation for

what is a medically acceptable timeframe must also coincide with the theory of how the

relevant vaccine can cause an injury. Id.; Shapiro v. Sec'y of Health & Human Servs.,

101 Fed. Cl. 532, 542 (2011), recons. den'd after remand, 105 Fed. Cl. 353 (2012), aff'd

mem., 503 Fed. Appx. 952 (Fed. Cir. 2013); Koehn v. Sec'y of Health & Human Servs.,

No. 11–355V, 2013 WL 3214877, at *26 (Fed. Cl. Spec. Mstr. May 30, 2013), mot. for

review den'd (Fed. Cl. Dec. 3, 2013), aff'd, 773 F.3d 1239 (Fed. Cir. 2014).

Petitioner received her second HPV vaccination on May 1, 2013. (Ex. 4, pp. 70-

71.) Petitioner was subsequently hospitalized ten days later, on May 11, 2013. (Ex. 3,

p. 43.) Thus, petitioner contends that her medical records show “an increase of

narcolepsy symptoms in the span of four to ten days after receipt of the May 1, 2013

vaccination.” (ECF No. 73, p. 31.) However, petitioner’s Althen prong three / Loving

prong six argument lacks a reliable medical or scientific explanation for how her HPV

vaccine significantly aggravated her narcolepsy. Dr. Steinman relies solely on literature

evaluating the onset of narcolepsy following the administration of another vaccine, the

Pandemrix H1N1 influenza vaccine, to establish a temporal relationship between the

HPV vaccination and worsening of petitioner’s narcolepsy. (Ex. 14, pp. 32-33

(discussing Partinen et al., supra, at Ex. 38; Winstone et al., supra, at Ex. 39).)

39

Although the timing in this case is consistent with what is generally thought to be

an appropriate timeframe for the adaptive immune response underlying the molecular

mimicry theory in other contexts, the specific data from these Pandemrix studies cannot

be extrapolated to the HPV vaccine where an increased risk of narcolepsy has not been

shown. (See Arnheim-Dahlstrom et al., supra, at ECF No. 26; Hvid et. al., supra, at Ex.

FF.) This is especially true “in a case like the present, where a vaccine’s formulation

bears heavily on [p]etitioner’s claim[.]” D’Tiole, 2016 WL 7664475, at *22 (citations

omitted). Where “[p]etitioner wants to leverage findings about a different vaccine

formulation [and] epidemiologic evidence relevant to the version of the vaccine in

dispute,” here the HPV vaccine, such findings “ought to be weighed against [p]eitioner’s

proof in evaluating whether [s]he has carried h[er] overall burden.” Id.

VII. Conclusion

Petitioner has my sympathy for the pain and suffering she endured during her

hospitalization and the symptoms she suffers from presently. However, for all the

reasons discussed above, after weighing the evidence of record within the context of his

program, I cannot find by preponderant evidence that the HPV vaccine significantly

aggravated petitioner’s narcolepsy. Accordingly, this claim is DISMISSED. 31

IT IS SO ORDERED.

s/Daniel T. Horner

Daniel T. Horner

Special Master

31In the absence of a timely-filed motion for review of this Decision, the Clerk of the Court shall enter

judgment accordingly.

40