Tarsell v. Secretary of Health and Human Services

In the United States Court of Federal Claims

OFFICE OF SPECIAL MASTERS

*********************

EMILY TARSELL, as the Executrix *

of the Estate of CHRISTINA * No. 10-251V

TARSELL, * Special Master Christian J. Moran

Petitioner, *

* Filed: February 16, 2016

v. *

* Entitlement; human papillomavirus

SECRETARY OF HEALTH * (“HPV”) vaccine; sudden

AND HUMAN SERVICES, * death

*

Respondent. *

*********************

Mark T. Sadaka, Mark T. Sadaka, LLC, Englewood, NJ, for petitioner;

Ann D. Martin, United States Dep’t of Justice, Washington, D.C., for respondent.

PUBLISHED DECISION DENYING COMPENSATION1

Emily Tarsell alleges that the human papillomavirus (“HPV”) vaccine

caused her daughter, Christina, to die unexpectedly. Ms. Tarsell, acting as the

executrix of Christina’s estate, is seeking compensation pursuant to the National

Childhood Vaccine Injury Compensation Program, codified at 42 U.S.C.

§ 300aa−10 through 34 (2012).

After Christina received the first dose of the HPV vaccine, she was

diagnosed with a heart problem, known as arrhythmia. The arrhythmia is likely to

have caused Christina’s death.

1

The E-Government, 44 U.S.C. § 3501 note (2012) (Federal Management and Promotion

of Electronic Government Services). Pursuant to Vaccine Rule 18(b), the parties have 14 days to

file a motion proposing redaction of medical information or other information described in 42

U.S.C. § 300aa-12(d)(4). Any redactions ordered by the special master will appear in the

document posted on the website.

To connect the HPV vaccination and Christina’s arrhythmia, Ms. Tarsell

relies upon the opinion of an immunologist, Yehuda Shoenfeld, and a cardiologist,

Michael Eldar. 2 Dr. Shoenfeld asserted that the arrhythmia developed after the

first HPV vaccination. Dr. Shoenfeld and Dr. Eldar opined that the HPV vaccine

caused the arrhythmia, which led to Christina’s death.

The Secretary disagreed with Ms. Tarsell’s claim. The Secretary presented

the opinions of cardiologist Scott Yeager and immunologist S. Michael Phillips. 3

Dr. Yeager opined that the onset of Christina’s arrhythmia is unknown. Dr.

Yeager and Dr. Phillips opined that evidence did not support the causal mechanism

proposed by Ms. Tarsell’s two experts.

Ms. Tarsell has not met her burden of establishing her case with

preponderant evidence. Ms. Tarsell has not persuasively established a basic

proposition of her claim, that Christina did not experience an arrhythmia until after

the first dose of the HPV vaccine. Without this foundation, the rest of Ms.

Tarsell’s claim cannot stand. In addition, even if Christina’s arrhythmia did arise

after the vaccination, the proposed theory contains too many leaps and unsupported

assumptions to be persuasive. Furthermore, a study of Christina’s heart tissue that

pathologists at the Centers for Disease Control and Prevention (“the CDC”)

conducted showed that Christina did not experience damage in the way her

experts’ theories predicted. Consequently, despite the sympathetic position of Ms.

Tarsell as the mother of a woman who died far too early, Ms. Tarsell is not entitled

to compensation.

I. Background

The relevant facts include information from Christina’s life as well as the

way that she died – suddenly and unexpectedly.

2

Dr. Shoenfeld, whose curriculum vitae spans over 120 pages, has nearly 40 years of

researching autoimmune response, writing numerous articles on the subject. Exhibit 37. Dr.

Shoenfeld has testified previously before the Vaccine Program. Dr. Eldar also has nearly 40

years of experience authoring over 170 articles. Exhibit 137.

3

Dr. Yeager has written more than 90 peer-reviewed reports, abstracts, book chapters,

and presentations in cardiology over his 40-year career. Exhibit GG. Dr. Phillips’s 50 years of

research experience has produced more than 130 original papers, editorials, reviews, chapters,

and books. Exhibit B.

2

A. Christina’s Medical History

In May 2008, Christina had just completed her third year of college, where

she was studying art and playing tennis. Athletics had been part of Christina’s life

for many years. She played tennis even though during one sports physical, a

doctor detected an irregular pulse.

After Christina’s end-of-the-semester college exams in 2008, and before

starting a job at a museum, Christina visited her parents in Maryland. While

visiting her parents, Christina received the third dose of the HPV vaccine on June

3, 2008. Exhibit 3 at 99. On June 5, 2008, 2 to 12 dots appeared on Christine’s

neck near her right ear. Exhibit 15 ¶ 4. On June 7, 2008, Christina felt dizzy and

faint. Findings of Fact, issued Mar. 30, 2012, at 7.

Christina returned to her college apartment on June 12, 2008. In the

following week, Christina worked at an art museum four days, including Thursday,

June 19, 2008. Exhibit 22 at 277. Later that day, Christina ate dinner with her

apartment mates. They talked until the early morning on Friday, June 20, 2008.

Exhibit 6 at 152.

On Monday, June 23, 2008, Christina did not report for work. One of her

apartment mates investigated and found Christina in her bed, unresponsive.

Exhibit 6 at 152. The undersigned found that Christina had died on Saturday, June

21, 2008 at approximately noon. Findings of Fact at 9.

A medical examiner, Keri Reiber, performed an autopsy on June 24, 2008.

Dr. Reiber found that the cause of Christina’s death was cardiac arrest of an

undetermined cause. Exhibit 8 at 158. Knowing that Christina had received the

HPV vaccine in the days prior to her death, Dr. Reiber reported the death to

VAERS and sent tissue to the CDC for further examination. Id.; exhibit 10.

The CDC’s Infectious Disease Pathology Branch performed a microscopic

examination of Christina’s heart tissue. The results showed that the heart tissue

exhibited no “conspicuous inflammatory cell infiltrates.” Exhibit 10 at 170.

Christina’s mother holds the opinion that the cause of her beloved daughter’s

death was the HPV vaccine. Ms. Tarsell talked about Christina’s life and her death

with local media. Exhibit 23, 26. The emotion apparent in those videotapes is

consistent with the demeanor Ms. Tarsell presented during her testimony. Tr. 19-

24. There is no doubt that Christina was a wonderful young adult, whom Bard

College honored with an honorary degree the year after her premature death. Tr.

3

20. Ms. Tarsell is certainly entitled to sympathy for having endured the loss of her

only child at a premature age. But, sympathy is not a basis for awarding

compensation in the Vaccine Program. 42 U.S.C. § 300aa–13; Hodges v. Secʼy of

Health & Human Servs., 9 F.3d 958, 961 (Fed. Cir. 1993) (noting that special

masters are responsible for “the unenviable job of sorting through these painful

cases”).

Setting aside emotion, what is the basis for concluding that the HPV vaccine

caused Christina’s death? Some reasons lie in Christina’s early medical history.

Christina was born in 1986. Her early medical history contains typical

illnesses. Exhibit 1 at 15-40. As mentioned earlier, Christina played sports. Tr.

21. Her participation in sports required her to have physical examinations at which

her pulse was measured periodically. The list of measurements is presented in the

following chart:

Date Context Pulse Citation

8/14/01 Routine assessment. Age 14, 9 72 Exhibit 1 at 19

months.

7/18/02 Routine assessment. Age 15, 8 60 Exhibit 1 at 18

months.

11/29/02 Pulled muscle 70 Exhibit 1 at 17

2/28/05 Motor vehicle accident 76 Exhibit 1 at 8

6/16/05 Physical for college 104 Exhibit 2 at 78

6/23/06 Routine preventative medicine 84 Exhibit 1 at 5

visit

8/22/07 Annual gynecologist visit. First Not noted but Exhibit 3 at 109

dose of HPV vaccine given. cardiovascular

is marked

negative

9/12/07 Pre-participation Physical 72; heart, Exhibit 2 at 87-88

evaluation murmurs, and

pulses marked

normal

11/20/07 Dr. Lafferman. Second dose of Irregular Exhibit 4 at 136

HPV vaccine given.

4

Dr. Lafferman’s detection of an irregular pulse on November 20, 2007, was

the first time a doctor discovered an irregularity in Christina’s cardiac rhythm. 4

This discovery occurred approximately three months after Christina received the

first dose of the HPV vaccine. Exhibit 3 at 109-10.

This discussion about Christina’s irregular heartbeat requires a brief (and

simplified) digression about regular heartbeats. The heart pumps blood by

contracting. Tr. 42-43; Dorland’s Illus. Med. Dictionary, at 825-26 (32d ed. 2012).

A normal rate of contraction is typically around 60 beats per minute, but the rate

can range from 40 to 200. Tr. 44.

The rate of contraction is controlled by the autonomic nervous system. Tr.

45; Dorland’s at 1859. The autonomic nervous system sends electrical current

throughout the heart. Tr. 45-49.

These electrical signals initiate a process known as polarization,

depolarization, and repolarization. Tr. 52-58; Dorland’s at 495 (depolarization),

1484 (polarization), 1625 (repolarization). The polarization-depolarization-

repolarization cycle involves the passage of different ions through channels, such

as sodium channels. Another type of channel involved in the cycle is a calcium

channel. Dorland’s at 337; Tr. 54. The polarization-depolarization-repolarization

process is depicted in electrocardiograms. Dorland’s at 599; Tr. 62.5

When the heart functions normally, the heart follows an expected rhythm.

When not normal, the person suffers from “arrhythmia.” Tr. 61; Dorland’s at 133.

One type of arrhythmia is known as “bigeminy,” which means the second beat is

abnormal. Tr. 495-96; Dorland’s at 214.

Dr. Lafferman detected an irregular heartbeat on November 20, 2007. She

described it as “bigeminy.” Exhibit 4 at 136. Dr. Lafferman ordered an

electrocardiogram, which was also conducted on November 20, 2007. The EKG

was abnormal. The report stated “[p]remature ventricular complexes.” Id. at 142.

Dr. Lafferman also administered the second dose of the HPV vaccine on

November 20, 2007. Exhibit 3 at 124.

4

Ms. Tarsell argues that this detection in November 2007 implies that the irregularity

developed shortly before November 2007. However, as discussed in section IV below, the

Secretary disagrees with this reasoning.

5

“Electrocardiogram” is abbreviated both ECG and EKG. Tr. 59; Dorland’s at 599.

5

Approximately one month later, on December 27, 2007, Christina had a

follow-up appointment. Her heartbeat was again irregular. Exhibit 4 at 135. An

EKG showed the same pattern as the November 20, 2007 EKG. Exhibit 4 at 141;

Tr. 83 (Dr. Eldar), 504 (Dr. Yeager). 6 Dr. Lafferman recommended an

echocardiogram.

Christina had an echocardiogram on February 12, 2008. The heart structure

was found to be normal. Exhibit 4 at 139; see also Tr. 146 (Dr. Eldar), 510-11 (Dr.

Yeager). In Dr. Yeager’s opinion, Christina did not have an irregular heart rhythm

when the echocardiogram was performed. Tr. 511-12. Christina’s doctors did not

recommend a Holter monitor or periodic follow-up. Consequently, Christina’s

next medical appointment was on June 3, 2008, when, as noted above, she received

the third dose of the HPV vaccine.

Christina’s death on June 21, 2008, was both sudden and unexpected. After

an autopsy, the medical examiner, Dr. Reiber, determined that both the cause of

Christina’s death and the manner of her death were “undetermined.” Exhibit 8 at

158.

In this litigation, Ms. Tarsell’s experts offer a cause for Christina’s death:

the HPV vaccinations. However, before discussing the theory by which the

vaccination could have led to Christina’s death, it is worthwhile to place

Christina’s death in the context of other sudden unexplained deaths.

B. Sudden Unexplained Deaths

The unrebutted evidence is that in 2008, Christina was not the only

American woman who received the HPV vaccine and then died suddenly and

unexpectedly. Statistical information suggests that approximately 159 other young

women also unexpectedly died after receiving the HPV vaccine. The source of this

estimate was Dr. Phillips. Tr. 342-48; see also Tr. 518 (Dr. Yeager). Dr. Phillips

was qualified to explain epidemiological studies. Tr. 335-38.

Ultimately, Dr. Phillips’s opinion was that the HPV vaccination did not

cause Christina’s death. Tr. 338-39. In the absence of a causal relationship, a

6

The report from the December 27, 2007 EKG stated Christina had “atrial fibrillation.”

The finding that Christina’s premature contractions came from her atria was mistaken. The

testifying cardiologists agreed that the contractions actually originated from Christina’s

ventricles. Tr. 67-68 (Dr. Eldar), 502 (Dr. Yeager).

6

connection between the vaccination and Christina’s death is coincidental. See

Capizzano v. Secʼy of Health & Human Servs., 440 F.3d 1317 (Fed. Cir. 2006);

Grant v. Secʼy of Health & Human Servs., 956 F.2d 1144 (Fed. Cir. 1992).

Several epidemiological studies did not find an increased rate of sudden and

unexplained deaths after HPV vaccination. Two epidemiological studies that

looked for numerous adverse effects of an HPV vaccine were exhibit 109 (Chun

Chao et al., Surveillance of autoimmune conditions following routine use of

quadrivalent human papillomavirus vaccine, 271 J. Intern. Med. 193 (2012)) and

exhibit 95 (Barbara A. Slade et al., Postlicensure Safety Surveillance for

Quadrivalent Human Papillomavirus Recombinant Vaccine, 302 JAMA 750

(2009)). The Chao study evaluated medical records of over 189,000 women after

receipt of each dose of the HPV vaccine for new onset of autoimmune conditions.

The researchers compared their health to that of the control group of unvaccinated

women. The study found no evidence linking the HPV vaccine to autoimmune

conditions. Exhibit 109 at 1. The Slade group of researchers investigated HPV

VAERS reports from June 1, 2006 to December 31, 2008. There were 32 reported

deaths following vaccination with six being cardiac-related. The researchers

performed a clinical review of medical records and autopsy reports determining

that the deaths reported were attributable to causes other than the vaccine. Exhibit

95 at 6. Other studies focused on any evidence of an increased rate of death

following HPV vaccine.

In Dr. Phillips’s estimation, the strongest study was reported by the

Australian government. Tr. 471. In Australia, nearly seven million doses of the

HPV vaccine were distributed between 2007 and 2013. There were no reports of

“deaths directly linked to the vaccine.” Exhibit PP (Austl. Gov’t Dep’t of Health

Therapeutic Goods Admin., Gardasil (quadrivalent human papillomavirus

vaccine), update 1 (Apr. 25, 2014), http://www.tga.gov.au/safety/alerts-medicine-

gardasil-130516.htm.) at 2.

Ms. Tarsell’s experts did not challenge the Australian report, leaving Dr.

Phillips’s testimony unrebutted. One of Ms. Tarsell’s experts, Dr. Shoenfeld,

dismissed the findings from Chao because of a potential conflict of interest. Tr.

213. Dr. Shoenfeld appeared to approve the work by Slade as Dr. Shoenfeld cited

that study in connection with his opinion on the appropriate temporal relationship.

Tr. 255-58.

In addition to criticizing some (but not all) of the epidemiological studies

upon which the Secretary relied, Dr. Shoenfeld also attempted to draw support

7

from a study authored by Eva Vanamee and colleagues. When the authors

submitted the manuscript for publication, two peer reviewers rejected it. Tr. 250.

In their work, Vanamee and colleagues re-analyzed data that the

manufacturer of the HPV vaccine, Merck & Co., Inc., presented to the Food and

Drug Administration. They found that in the first month after vaccination, four

vaccinees died. See exhibit 38 (Eva Vanamee et al., An independent review of the

Gardasil clinical trial data: Do the benefits outweigh the risks (unpublished

manuscript) (on file with the clerk’s office)) at 4-6. From this piece of datum,

Vanamee concluded that the HPV vaccine may be contributing to an increased risk

of deaths.

Dr. Phillips opined that the Vanamee study was not reliable. Tr. 352.

Vanamee appeared to ignore additional details about the context of the deaths. For

example, one death was attributed to a trauma that followed a car accident. See

exhibit 81 (Memorandum from Nancy B. Miller, Medical Officer, Food and Drug

Administration (June 8, 2006) (on file with the clerk’s office)) at 190. Dr.

Shoenfeld’s opinion was that the vaccination was still the reason for the death

either because the reporter of information manipulated the data or because the

vaccination impaired the person’s ability to operate a car. Tr. 262-65. Dr.

Shoenfeld’s opinion on this point is not credible as he had no foundation for his

charges. 7 Instead, Dr. Phillips’s opinion that the Vanamee study was not reliable is

more persuasive. 8

Without the Vanamee study, all the epidemiological evidence points in one

direction. As Dr. Phillips explained, some epidemiological studies are designed

well and others are not designed well. The particular strengths and weaknesses of

any particular epidemiologic study are relatively unimportant because the findings

7

Dr. Shoenfeld appears to be developing a propensity for selective ad hominem attacks.

When researchers such as Dr. Chao find no evidence that a vaccine is causing an increased

incidence of disease, Dr. Shoenfeld attacks the integrity of the researcher. However, Dr.

Shoenfeld readily accepts the reports of a vaccination preceding the onset of various diseases

without considering the bias or prejudice of those reporters.

8

After the hearing, Ms. Tarsell did not cite the Vanamee study in her brief. The

Secretary argued that Ms. Tarsell “has abandoned any reliance on it.” Resp’t’s Posth’g Br. at 17.

In her reply brief, Ms. Tarsell did not respond to this contention and also did not cite the

Vanamee paper.

8

that HPV vaccination has not caused an increase in the rate of death in the relevant

population are consistent across many studies. Tr. 349-51.

The Secretary “is permitted to offer evidence to demonstrate the inadequacy

of the petitioner’s evidence on a requisite element of the petitioner’s case-in-

chief.” Bazan v. Sec’y of Health & Human Servs., 539 F.3d 1347, 1353 (Fed. Cir.

2008). In a case from the beginning of the Vaccine Program, the Federal Circuit

stated “epidemiological studies are probative medical evidence relevant to

causation.” Grant, 956 F.2d at 1149 (Fed. Cir. 1992). On the other hand, a special

master may not deny compensation simply because a petitioner has failed to

introduce epidemiologic studies. Capizzano, 440 F.3d at 1325 (Fed. Cir. 2006).

The Secretary’s epidemiologic evidence in this case is comparable to the

approach the Secretary took in the Omnibus Autism Proceeding. There, the special

masters considered a multitude of epidemiologic studies that investigated whether

various vaccinations caused autism and found no causal relationship. The special

masters found that the epidemiologic evidence was one reason --- but not the only

reason --- for finding that the petitioners failed to carry their burden in those cases.

See, e.g., Cedillo v. Secʼy of Health & Human Servs., No. 98-916V, 2009 WL

331968, at *84-93 (Fed. Cl. Spec. Mstr. Feb. 12, 2009), mot. for rev. denied, 89

Fed. Cl. 158 (2009), aff’d, 617 F.3d 1328 (Fed. Cir. 2010); Hazlehurst v. Secʼy of

Health & Human Servs., No. 03-654V, 2009 WL 332306, at *34-39 (Fed. Cl.

Spec. Mstr. Feb. 12, 2009), mot. for rev. denied, 88 Fed. Cl. 473 (2009), aff’d, 604

F.3d 1343 (2010).

However, after resolution of the test cases in the Omnibus Autism

Proceeding, the Federal Circuit issued Koehn v. Sec'y of Health & Human Servs.,

773 F.3d 1239 (Fed. Cir. 2014). In the underlying case, a special master denied

compensation, in part, because the epidemiologic evidence was against the

petitioner’s claim. Koehn v. Sec'y of Health & Human Servs., No. 11-355V, 2013

WL 3214877, at *25-26 (Fed. Cl. Spec. Mstr. May 30, 2013), mot. for rev. denied,

113 Fed. Cl. 757 (2013), aff’d, 773 F.3d 1239 (Fed. Cir. 2013). At the Federal

Circuit, two members of the panel stated that the special master erred in evaluating

the evidence relating to the first prong of Althen. Although the Federal Circuit did

not specify the actual errors the special master made, the broad language in Koehn

at least raises a question about relying upon epidemiologic evidence. 773 F.3d at

1244 n.1. But, this interpretation of Koehn might itself be problematic because

several other Federal Circuit cases have endorsed a special master’s reliance on

epidemiologic studies. See Hunt v. Sec'y of Health & Human Servs., No.

12-232V, 2015 WL 1263356, at *17 n.18 (Fed. Cl. Spec. Mstr. Feb. 23, 2015),

mot. for rev. denied, 123 Fed. Cl. 509 (2015); Holt v. Secʼy of Health & Human

9

Servs., No. 05-136V, 2015 WL 4381588 at *30 n.84 (Fed. Cl. Spec. Mstr. June 24,

2015), mot. for review filed (July 23, 2015).

Regardless of any questions about how special masters may rely upon

epidemiological studies, it is clear that some young women die suddenly,

unexpectedly, and without any known cause. These deaths shock the affected

family and broader community. The deaths of apparently healthy and thriving

young people for no reason are “not the way life is supposed to be.” Tr. 518 (Dr.

Yeager). Yet, they happen regardless of whether the women received any

vaccination. Tr. 137 (Dr. Eldar). When researchers have looked to see whether

these senseless deaths occur more frequently after the decedent received the HPV

vaccination, they have not detected any increase. Thus, the epidemiological

studies teach either that the HPV vaccine has not increased the rate of death or if

the HPV vaccine is increasing the rate of death, then the increase happens so rarely

that multiple studies have not found it.

II. Overview of Ms. Tarsell’s Arguments and the Secretary’s Responses

Ms. Tarsell claims that Christina’s case is not one of these tragic events that

statistics would unemotionally predict. She claims Christina’s case is an example

of the very rare case that statistics cannot detect.

Ms. Tarsell presents opinions from two experts. Dr. Shoenfeld, but not Dr.

Eldar, asserts that Christina’s arrhythmia began after the first dose of the HPV

vaccine. From this assumption, Dr. Shoenfeld then opines that the HPV vaccine

caused Christina to develop arrhythmia.

Dr. Shoenfeld begins the explanation for how HPV vaccine can cause a

sudden death. His primary theory is that the HPV vaccine causes the body to

produce antibodies that are misdirected against a part of the heart, known as an L1

calcium channel. Dr. Eldar finishes Ms. Tarsell’s theory. The cumulative damage

to the L1 calcium channel impairs the heart’s functioning leading to arrhythmia,

and arrhythmia caused Christina’s death.

The Secretary also presented the opinions of two experts. Dr. Phillips, as

just discussed, presented information about epidemiology. He also responded to

the immunologic aspects of Dr. Shoenfeld’s theory. Dr. Yeager is a cardiologist.

Like Dr. Eldar, he did not know when Christina’s arrhythmia began.

These experts presented their opinions in a series of reports. Exhibits 36, 94,

101, 108, 138 (all Dr. Shoenfeld); 100, 107, 140 (all Dr. Eldar); A, UU, XX (all

10

Dr. Phillips); FF, VV, ZZ, OOO (all Dr. Yeager). 9 They and Ms. Tarsell testified

at a hearing. Following the hearing, the parties submitted briefs, making the case

ripe for adjudication.

III. Standard for Adjudication

A petitioner is required to establish her case by a preponderance of the

evidence. 42 U.S.C. § 300aa–13(1)(a). The preponderance of the evidence

standard requires a “trier of fact to believe that the existence of a fact is more

probable than its nonexistence before [he] may find in favor of the party who has

the burden to persuade the judge of the fact’s existence.” Moberly v. Sec’y of

Health & Human Servs., 592 F.3d 1315, 1322 n.2 (Fed. Cir. 2010) (citations

omitted). Proof of medical certainty is not required. Bunting v. Sec’y of Health &

Human Servs., 931 F.2d 867, 873 (Fed. Cir. 1991).

Distinguishing between “preponderant evidence” and “medical certainty” is

important because a special master should not impose an evidentiary burden that is

too high. Andreu v. Sec’y of Health & Human Servs., 569 F.3d 1367, 1379-80

(Fed. Cir. 2009) (reversing special master’s decision that petitioners were not

entitled to compensation); see also Lampe v. Sec’y of Health & Human Servs., 219

F.3d 1357 (Fed. Cir. 2000); Hodges v. Sec’y of Health & Human Servs., 9 F.3d

958, 961 (Fed. Cir. 1993) (disagreeing with dissenting judge’s contention that the

special master confused preponderance of the evidence with medical certainty).

The elements of Ms. Tarsell’s case are set forth in the often cited passage

from the Federal Circuit’s decision in Althen: “(1) a medical theory causally

connecting the vaccination and the injury; (2) a logical sequence of cause and

effect showing that the vaccination was the reason for the injury; and (3) a showing

of a proximate temporal relationship between vaccination and injury.” Althen v.

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

IV. Analysis

The three prongs of the Althen test are evaluated in separate sections below.

The order of presentation begins with timing because a gap in Ms. Tarsell’s

evidence is most readily apparent in the context of attempting to identify when

9

Relatively early in the case, Ms. Tarsell filed a report from Dr. Werner Spitz. Exhibit

32. However, his opinions do not advance Ms. Tarsell’s case.

11

Christina started to suffer arrhythmia. The next issue is the theory or theories that

Ms. Tarsell and her experts presented. The last factor is the “logical sequence of

cause and effect.” Each section analyzes the evidence (medical records, testimony

and medical literature) in relation to the relevant precedent.

A. Timing

Ms. Tarsell’s first challenge is establishing when Christina’s arrhythmia

began. When a petitioner cannot establish the onset of the injury the vaccine

allegedly caused, the petitioner cannot fulfill the third Althen prong. See Hopkins

v. Secʼy of Health & Human Servs., 84 Fed. Cl. 517, 524-27 (2008) (denying

motion for review).

Here, the most persuasive evidence indicates that the onset of Christina’s

arrhythmia is unknown. The arrhythmia could have begun either before or after

the vaccination. When Dr. Eldar, Ms. Tarsell’s cardiologist, was asked when

Christina’s arrhythmia began, he stated “I cannot say exactly when it started.” Tr.

120. Similarly, when Dr. Yeager, the respondent’s cardiologist, was asked when

Christina’s arrhythmia began, he stated “I don’t think I can date when she began

having cardiac arrhythmia.” Tr. 493. Given their expertise in treating heart

problems, Dr. Eldar and Dr. Yeager are credible when their answer essentially is “I

don’t know when the arrhythmia began.”

Ms. Tarsell has no effective response. A close reading of her post-hearing

brief reveals that Ms. Tarsell has not proposed any specific date of onset. See

Pet’r’s Posth’g Br., filed Feb. 17, 2015, at 15-18. Here, Ms. Tarsell states

“Christina was a healthy young woman prior to her first [HPV] vaccine. She

developed new-onset arrhythmia which did not resolve.” The order of these two

sentences implies that the vaccination preceded the onset of her arrhythmia.

In making this argument, Ms. Tarsell appears to be following the reasoning

of her immunologist, Dr. Shoenfeld. When Dr. Shoenfeld was asked when

Christina’s cardiac symptoms started, he answered “November 20, 2007,” which

was the day her irregular pulse was first detected. Tr. 286. When asked to explain

the basis for his opinion, Dr. Shoenfeld noted that before the vaccination, none of

Christina’s treating doctors had found an irregular pulse. Dr. Shoenfeld reasoned

“if you don’t have an evidence [of an irregular pulse], and then if you have an

evidence that the first time was after the second vaccine, it was after the second

vaccine.” Tr. 287.

12

Dr. Shoenfeld’s conclusion is based on superficial logic and is, ultimately,

not persuasive. Dr. Shoenfeld is correct that Dr. Lafferman detected an irregular

pulse in Christina for the first time on November 20, 2007. In other appointments,

Christina’s pulse was measured but no irregularity was detected. For a detailed list

of when those appointments occurred, see the table in section I, above. Dr.

Shoenfeld assumes that if Christina were suffering from an irregular pulse on the

days she was examined, the doctors would have detected it.

Contrary to Dr. Shoenfeld’s assumption, people who suffer from arrhythmia

do not suffer the arrhythmia continuously. Dr. Yeager explained that a person can

have 20 minutes of bigeminy and then a few hours of normal rhythm. Tr. 540. In

one study, patients with severe symptomatic arrhythmia wore Holter monitors and,

in these patients, abnormal beats were found approximately 17 percent of the time.

Exhibit 106 (Takashi Noda et al., Malignant Entity of Idiopathic Ventricular

Fibrillation and Polymorphic Ventricular Tachycardia Initiated by Premature

Extrasystoles Originating from the Right Ventricular Outflow Tract, 46(7) J. Amer.

Coll. Cardiology 1288 (2005)); Tr. 496-97. When the Noda article was brought to

Dr. Eldar’s attention, he did not dispute Dr. Yeager’s opinion. See Tr. 564-65.

Because people with arrhythmia have periods in which their heart beats in

normal rhythm, it is not possible to conclude that a doctor’s failure to detect an

irregular pulse necessarily means that the patient was not suffering from

arrhythmia at other times during the day of examination. Tr. 495-96; exhibit OOO

(Dr. Yeager Supp’l Rep.) at 3 (“I have no confidence that an unremarkable

physical exam tells us anything other than the patient was probably not having a

significant arrhythmia during those few seconds of auscultation”). This means that

there is no good evidence about when Christina first started to experience the

arrhythmia.

The lack of evidence is damaging to Ms. Tarsell’s claim for compensation.

She bears the burden of establishing when Christina’s disease began. See Bazan,

539 F.3d at 1353-54 (Fed. Cir. 2008); Hopkins, 84 Fed. Cl. at 524-27. When there

is no persuasive evidence on a particular point, the special master should rule

against the party with the burden of proof. See Knudsen v. Secʼy of Health &

Human Servs., 35 F.3d 543, 550 (Fed. Cir. 1994) (when the evidence is in

equipoise, the party with the burden of proof has failed to carry the burden of

persuasion); In re Claims for Vaccine Injuries Resulting in Autism Spectrum

Disorder or a Similar Neurodevelopmental Disorder, Master Autism File, 2004

WL 1660351, at *8 (Fed. Cl. Spec. Mstr. July 16, 2004) (“in legal factfinding if

there is no evidence, the factual issue simply is resolved against the party having

13

the ‘burden of proof’”). Here, the evidence is not in equipoise. Ms. Tarsell has no

persuasive evidence of onset.

While the failure to establish on a more-likely-than-not basis the onset of

Christina’s arrhythmia is a sufficient basis to resolve Ms. Tarsell’s claim that the

HPV vaccination caused the arrhythmia that led to Christina’s death, this is not the

only problem with Ms. Tarsell’s case.10 Accordingly, the other Althen prongs will

be analyzed.

B. Theory

If Ms. Tarsell had established that Christina’s arrhythmia began after her

first HPV vaccination, then, as a matter of logic, the HPV vaccination could have

possibly caused the arrhythmia. Cf. Locane v. Sec’y of Health & Human Servs.,

685 F.3d 1375, 1381 (Fed. Cir. 2012) (stating that when a disease arises before the

vaccination, the “Althen inquiry is inapplicable”). Part of Ms. Tarsell’s burden

would be to establish, with preponderant evidence, a “causal theory connecting the

vaccination to the injury.” Althen, 418 F.3d at 1278.

To satisfy her burden under the first prong of Althen, to present a theory

causally connecting the HPV vaccine to Christina’s death, Ms. Tarsell has

advanced the theory of molecular mimicry involving the L1 calcium channels. In

addition, she may also be advancing a theory involving beta adrenergic receptors.

Because the beta adrenergic theory is more easily addressed, it is considered first.

1. Beta Adrenergic Receptors

Procedurally, whether Ms. Tarsell is proceeding on the beta adrenergic

theory is not entirely clear. Dr. Shoenfeld’s fourth report disclosed an opinion that

a possible defect in Christina’s beta adrenergic receptors could have caused her

arrhythmia. Exhibit 108 at 9; see also exhibit 36 at 6 (mentioning adrenergic

10

Conceptually, if the evidence persuasively showed that Christina was suffering from an

irregular heartbeat before vaccination, Ms. Tarsell could argue that the vaccination significantly

aggravated the pre-existing arrhythmia. Although Ms. Tarsell referenced this theory of recovery

in her pre-hearing brief, Pet’r’s Preh’g Br. at 17 n.1, 19, Ms. Tarsell did not assert this theory in

her posthearing brief or her posthearing reply. If Ms. Tarsell intended to pursue a significant

aggravation theory, it was incumbent on her to present evidence that Christina's arrhythmia

would not have progressed as it did. See Locane v. Sec’y of Health & Human Servs., 99 Fed. Cl.

715, 732-33 (2011), aff’d, 685 F.3d 1375 (Fed. Cir. 2012).

14

stimulation but not in the context of Christina’s history). However, Ms. Tarsell’s

pre-trial brief did not reference this theory at all. See Pet’r’s Br., filed Sept. 26,

2014, at 13 (“Christina Tarsell died from molecular mimicry and subsequent cross-

reactivity between HPV 16 L1 and L-type calcium channel”). Nevertheless, Dr.

Eldar and Dr. Shoenfeld discussed beta adrenergic receptors in their testimony and

Dr. Yeager responded. Ms. Tarsell included the beta adrenergic theory in her

initial brief after the hearing. Pet’r’s Posth’g Br. at 12. After the Secretary raised

challenges, see Resp’t’s Posth’g Br., filed Apr. 17, 2015, at 13-14, Ms. Tarsell’s

reply did not defend the theory at all. Under these circumstances, Ms. Tarsell may

have relinquished this theory. But, any potential waiver is academic because Ms.

Tarsell has failed to establish the persuasiveness of the beta adrenergic theory.

The beta adrenergic theory focuses on the wiring leading to and existing in

the heart. As mentioned earlier, the autonomic nervous system controls the rate at

which the heart beats. The autonomic nervous system includes a set of receptors

known as beta adrenergic receptors. Dorland’s at 33, 1603-04.

One group of researchers investigated whether people suffering from

different types of arrhythmias had autoantibodies directed against their beta

adrenergic receptors. These researchers found that slightly more than one-half the

people with ventricular arrhythmias had anti-beta adrenergic receptor antibodies.

The prevalence in the control group was approximately 15 percent. Exhibit 128

(Pablo A. Chiale et al., High Prevalence of Antibodies Against Beta1- and Beta2-

Adrenoceptors in Patients With Primary Electrical Cardiac Abnormalities, 26 J.

Am. Coll. Cardiol. 864 (1995)) at 864. Dr. Eldar’s opinion was that the difference

between the two groups “make[s] you think that there is . . . maybe a cause and

effect between the one and the other.” Tr. 171. From this foundation, Dr.

Shoenfeld extended the association to causation, opining that the autoantibodies

can cause arrhythmias. Tr. 235; see also Tr. 189 (“pathogenic autoantibodies”).

In addition, Dr. Shoenfeld also asserted that the HPV vaccine can induce the

creation of antibodies to the beta adrenergic receptors. Tr. 270. For this

proposition, Ms. Tarsell’s case rests nearly entirely on the simple assertion of Dr.

Shoenfeld.

When pressed to explain the basis for his belief that the HPV vaccine can

lead to the production of antibodies directed against beta adrenergic receptors, Dr.

Shoenfeld relied on a series of articles suggesting that the HPV vaccine caused a

different disease, postural orthostatic tachycardia syndrome (POTS). Tr. 279. Dr.

Yeager persuasively explained why relying upon a putative connection between

15

HPV vaccination and POTS cannot serve as a reliable foundation for HPV

vaccination and arrhythmia. Tr. 523-27.

Unlike the situation with respect to the L1 calcium channel discussed below,

there is no reliable evidence that the HPV vaccine causes the body to produce

antibodies to the beta adrenergic receptors in the heart. The only evidence was Dr.

Shoenfeld’s opinion. Ms. Tarsell has failed to demonstrate that this aspect of his

opinion is reliable. See Caves v. Sec’y of Health & Human Servs., 100 Fed. Cl.

119, 134 (2011) (“it should be obvious to petitioner that a scientific theory that

lacks any empirical support will have limited persuasive force”), aff’d without

opinion, 463 F. App’x 932 (Fed. Cir. 2012). Dr. Shoenfeld’s assertion, by itself, is

not persuasive. Doyle v. Sec’y of Health & Human Servs., 92 Fed. Cl. 1, 8 (2010)

(“Mere conclusory opinions - or ones that are nearly so as unaccompanied by

elaboration of critical premises - will not suffice as proof of causation, no matter

how vaunted or sincere the offeror”); see also Cedillo v. Sec’y of Health & Human

Servs., 617 F.3d 1328, 1339 (Fed. Cir. 2010) (a special master may find an analytic

gap in the opinion of a petitioner’s expert that precludes compensation).

Because the beta adrenergic theory does not satisfy Ms. Tarsell’s burden on

the first Althen prong, her other theory involving the L1 calcium channel will be

discussed. The L1 calcium channel is a theory separate from the beta adrenergic

theory. See Tr. 150-55 (Dr. Eldar discussing differences between the two

theories), 292-93 (Dr. Shoenfeld).

2. Molecular Mimicry with the L1 Calcium Channel

a) Introduction to Molecular Mimicry and Homology

Ms. Tarsell’s primary theory is based upon molecular mimicry. Tr. 238.

Molecular mimicry posits that the molecular structure of an antigen (like a

vaccine) resembles the molecular structure of human tissue. When the body’s

immune system responds to the antigen, the immune system mistakenly attacks the

host. Tr. 193; see also Tr. 375, 418. The term for a similarity in molecular

structure is “homology.” See Dorland’s at 868. Dr. Shoenfeld states that only

genetically prone individuals will develop molecular mimicry. Tr. 305.

Dr. Shoenfeld has identified a specific basis for the molecular mimicry

between the HPV vaccine and the heart. He relies upon research of computer

16

databases that identified a particular sequence of amino acids present in both the

HPV vaccination and calcium channels found in the heart.11 Tr. 278-79.

The evidence showing a relevant homology derives from four articles in

which Darja Kanduc is either the author or co-author. In the earliest article, Dr.

Kanduc stated that her colleagues and she wanted to investigate the belief that “an

autoimmune reaction is mostly caused by a host receiving an antigen that has

amino acid homology/similarity with amino acid sequences in self-antigens of the

host.” Exhibit LLL (Darja Kanduc et al., Massive peptide sharing between viral

and human proteomes, 29 Peptides 1755 (2008)) at 1755.

Dr. Kanduc used a consistent methodology in the four articles. The

foundation for her experiments was that “[p]rotein sequences of the human

proteome [12] as well as a number of viral proteomes have become available in

databanks.” Id. The proteins may contain thousands of amino acids and the

relevant calcium channel contains more than 2500 amino acids. Tr. 387, 392

(discussing exhibit FFF (Charles Antzelevitch et al., Loss-of-Function Mutations in

the Cardiac Calcium Channel Underlie a New Clinical Entity Characterized by ST-

Segment Elevation, Short QT Intervals, and Sudden Cardiac Death, 115

Circulation 442 (2007))). With computers, Dr. Kanduc searched for sequences of

amino acids that appear both in the human proteome and in invasive organisms,

such as bacteria and viruses. See Tr. 301 (Dr. Shoenfeld), 375 (Dr. Phillips), see

also exhibit LLL at 1756-57 (detailed description of methodology). The length of

the sequence varied from five amino acids to nine amino acids.13

Dr. Kanduc and colleagues tried to identify homologies because “the

mathematical quantification of peptide overlap extent between viruses and humans

is essential to understand the role of structural viral similarity in the pathogenesis

of autoimmunity.” Exhibit LLL at 1756. In the earliest experiment reported, the

computerized screening found “a massive, indiscriminate, unexpected pentapeptide

overlapping between viral and human proteomes.” Id. at 1755. Part of the reason

11

There are 20 amino acids and each amino acid has been assigned a letter. For example,

“L” stands for leucine. Dorland’s at 60-61, Tr. 377, 389.

12

A proteome is “the complete set of proteins produced from the information encoded in

a genome.” Dorland’s at 1535.

13

A sequence of five amino acids is known as a pentamer. See Dorland’s at 1407; Tr.

375.

17

for the overlap is that sequence of amino acids repeat. Mathematically, a sequence

of five amino acids contains more than three million combinations. (520 =

3,200,000.) However, less than 10 percent of the pentamers actually appear in

either the viral or human proteome. Id. at 1756. The researchers concluded “the

mathematical redundancy present in the protein world is not stochastic (i.e. is not

pure random chance), but rather reflects strong peptide usage bias since certain

peptides are repeatedly used (and shared) in (and among) viral and human

proteins.” Id. at 1762.

A premise of molecular mimicry is that when invading organisms have a

structure similar to the molecular structure of human beings, the body’s response to

the bacteria or virus can produce an autoimmune reaction. Because Kanduc’s 2008

research found “massive” overlap between viruses and humans, “autoimmune

diseases should theoretically approach a 100% real incidence.” Id. at 1765.

However, autoimmune diseases are not that common. Thus, Dr. Kanduc and

colleagues stated that their datum “call into question the possibility of a direct

causal association between virus-host sharing of amino acid motifs and incitement

of autoimmune reactions.” Id. at 1755.

In 2009, Dr. Kanduc, writing alone, reported on an experiment using the

HPV 16 proteome. She discovered a perfect sequence of seven amino acids 82

times in the human proteome. Exhibit 75 (Darja Kanduc, Quantifying the possible

cross-reactivity of an HPV16 vaccine, 8 J. Experimental Therapeutics and

Oncology 65 (2009)) at 66. The abstract to the article concluded that “[a]ny

antigen-based vaccine needs to be carefully and thoroughly designed and critically

screened for potential side effects by comparing sequence similarity at the

molecular level.” Id. at 65.

Dr. Kanduc, again writing alone, reported about a more specific experiment

in 2010. She looked for similarities between a particular portion of the HPV 16

virus known as the L1 capsid and “human proteins that, when altered, are

associated with cardiovascular diseases and arrthythmogenic disorders.” Exhibit

74 (Darja Kanduc, Potential cross-reactivity between HPV16 L1 protein and

sudden death-associated antigens, 9(2) J. Experimental Therapeutics and

Oncology, 159 (2010)) at 1. One of these sequences of five amino acids, LQAGL,

occurs in the L-type calcium channel. Defects in the L-type calcium channel cause

Timothy syndrome and Brugada syndrome. Id. at 5. Dr. Kanduc stated that her

finding “suggests that possible immune cross-reactions deriving from utilization of

HPV L1 in vaccination might be a source of cardiac implications.” Id. at 6.

18

The final article to which Dr. Kanduc contributed was also published in

2010. A group of researchers, including Dr. Kanduc, compared 40 bacteria with

the human genome, looking for matches of nine amino acids. They found more

than 47,000 perfect matches, comprising about one-third of the human proteome.

Exhibit KKK (Brett Trost et al., Bacterial peptides are intensively present

throughout the human proteome, 1 Self/Nonself 71 (2010)) at 71; see also Tr. 376-

79 (Dr. Phillips’s description of Trost experiment). The authors stated that their

findings called into question the molecular mimicry theory. They wrote:

According to the molecular mimicry hypothesis, the

widespread overlap between viral and bacterial

proteomes and the human proteome (see Table 1 and ref

5) would predict that autoimmune diseases should have a

much higher incidence than actually observed, both in the

total number of individuals affected and the number of

autoimmune pathologies per individual. Thus, it is

difficult to reconcile the enormous number of viral and

bacterial peptides disseminated throughout the human

proteins with a fundamental role for molecular mimicry

in the etiology of certain autoimmune conditions.

Id. at 73.

To some, Dr. Shoenfeld’s invocation of molecular mimicry plus an

identified homology would constitute a persuasive medical theory. 14 However, the

evidence persuasively showed that the LQAGL homology Kanduc discovered in

2009 is not an adequate basis for finding that a cross-reaction actually occurs.

Dr. Phillips explained that it is not entirely unexpected for a particular

sequence of amino acids to reappear. Tr. 378-79. Dr. Shoenfeld concurred, stating

that there is “a lot of molecular mimicry.” Tr. 227. To Dr. Phillips, “showing a

homology at a pentameric level — that is, five amino acids — is many steps from

showing that that [homology] is causally related to an autoimmune disease.” Tr.

375.

14

Dr. Shoenfeld refrained from describing his theory as “more likely than not.” In his

view, the theory was “plausible,” meaning that it is a “mechanism which is understood [that] can

occur.” Tr. 268.

19

b) From Homology to Autoimmune Reaction

Ms. Tarsell did not rest her case simply upon Dr. Kanduc’s identification of

the LQAGL pentamer in both the HPV16 L1 capsid and the calcium channel. Ms.

Tarsell developed a specific application of molecular mimicry by presenting

testimony from Dr. Shoenfeld and Dr. Eldar that explains how a homology can

lead to a fatal arrhythmia. It appears that the theory contains several discrete

assertions. These include the following:

1. The HPV vaccine contains a sequence of amino acids, known as

LQAGL. The Secretary agrees with this assertion.

2. The body responds to the HPV vaccine by producing antibodies against

the LQAGL sequence.

3. The anti-LQAGL antibodies are produced in large quantities that remain

present at meaningful concentrations in the serum.

4. The heart, specifically the L1 calcium channel, contains the LQAGL

sequence. The Secretary agrees with this assertion with a caveat,

discussed at length below.

5. The antibodies produced in response to the LQAGL sequence in the HPV

vaccine cross-react with the LQAGL sequence in the L1 calcium channel

of the heart.

6. The damage to the L1 calcium channel in the heart causes arrhythmia.

As noted, the Secretary agrees with two of the six propositions: that the

LQAGL sequence appears in the HPV vaccine and this pentamer appears in the L1

calcium channel. This basic homology, as explained above, does not mean that

there is a cross-reaction.

For the remaining four assertions, the Secretary has challenged the reliability

of the theory. See id. at 11-16. Dr. Phillips stated that Dr. Shoenfeld is not

“incorrect,” but that he has presented a theory with no evidence. Tr. 380.

c) Response to LQAGL

After an administration of the HPV vaccine, which contains the HPV 16 L1

capsid, the petitioner’s theory indicates that the body will respond to the particular

sequence of amino acids LQAGL. Dr. Phillips explained why the presence of

amino acids L-Q-A-G-L in the HPV vaccine does not necessarily mean that the

body actually reacts to that pentamer. He began by explaining that a “protein is a

very complex structure. . . [with] primary, secondary, and tertiary structure.” Tr.

386. The primary structure refers to a linear sequence, the secondary structure

20

refers to shapes that the protein can form, and the tertiary structure refers to a

three-dimensional configuration. Id. at 386-87. The immune system responds to

the antigen in a three-dimensional form. Id. at 387.

Thus, the body must break down the HPV vaccine in exactly the correct way

to release the LQAGL peptide. See Tr. 386. Quoting Dr. Phillips’s testimony, the

Secretary argued that “‘there’s no guarantee that this short pentamer is going to

contribute to that structure.’” Resp’t’s Posth’g Br. at 10, quoting Tr. 387-88. In

reply, Ms. Tarsell did not cite any evidence to refute Dr. Phillips’s opinion about

how the immune system responds to proteins. See Pet’r’s Reply Br., filed May 15,

2015, at 5-6 (stating that Dr. Shoenfeld stated that the LQAGL peptide is contained

in the HPV vaccine, but not addressing whether the body would respond to that

sequence).

d) Concentration

Assuming that the body produces an immune response to the LQAGL

pentamer, the body must produce a sufficient quantity of antibodies that the

antibodies can cause damage. Although some Vaccine Program cases have

considered issues about dose response curves, see, e.g., Kolakowski v. Secʼy of

Health & Human Servs., No. 99-625V, 2010 WL 5672753 at *17-21 (Fed. Cl.

Spec. Mstr. Nov. 23, 2010), Snyder v. Secʼy of Health & Human Servs., No. 01-

162V, 2009 WL 332044 at *65 (Fed. Cl. Spec. Mstr. Feb. 12, 2004), mot. for rev.

denied, 88 Fed. Cl. 706 (2009), the parties did not elicit any testimony about this

aspect of petitioner’s theory. Because the Secretary did not raise any direct

challenge to the amount of antibodies, Ms. Tarsell’s lack of evidence is not held

against her.

e) Location of the Calcium Channel in Heart

In Dr. Kanduc’s 2009 article, she identified the LQAGL pentamer as part of

the “[v]oltage-dependent L-type calcium channel subunit alpha-1C.” Exhibit 74 at

5. Dr. Kanduc did not provide any additional information about where the protein

appears in the heart cells.

The LQAGL pentamer is located on an intra-cellular portion of the calcium

channel. See exhibit FFF at 446 (figure D); exhibit 120 (Victor A. McKusick,

Calcium Channel, Voltage-Dependent, L-Type, Alpha-1C Subunit; CACNA1C,

Online Mendelian Inheritance in Man, OMIM. Johns Hopkins Univ., Baltimore,

MD. 114205 (March 19, 2014) http://www.omim.org/); see also Tr. 392-96. Ms.

21

Tarsell did not dispute this evidence.15 See exhibit 138 (Dr. Shoenfeld’s post-

hearing report) at 1.

The Secretary argues that the location of the LQAGL pentamer makes Ms.

Tarsell’s theory less likely. Usually, antibodies react with material located outside

of the cell membrane. See Tr. 397. The extra-cellular location allows antibodies,

which circulate through the blood stream, to bind to the cognate antigen. In

contrast, the relevant pentamer is located on an intra-cellular portion of the channel

– behind the cell membrane. The cell membrane generally prevents antibodies

from reaching the calcium channel to cross-react with the LQAGL pentamer. Tr.

7; Resp’t’s Posth’g Br. at 11-12.

To ameliorate the prejudice associated with the late disclosure of exhibit

NNN and the late raising of an argument based on the intracellular location of

LQAGL, Ms. Tarsell was allowed to file supplemental reports from Dr. Shoenfeld

and Dr. Eldar that addressed whether antibodies can penetrate the cell membrane.

Tr. 9, 400-01, 571; order, issued Nov. 21, 2014. Ms. Tarsell filed those reports as

exhibits 138 and 140.

f) Penetrating Cell Membrane

After the Secretary asserted that any antibodies produced in response to the

HPV vaccine could not react with the LQAGL pentamer in the calcium channels of

the heart, the parties elicited testimony from the experts about this issue. In

addition, Ms. Tarsell was permitted to submit supplemental reports.

Usually, antibodies bind to the outside of a cell, where the antibodies start

their attack against an invading organism. See Tr. 397 (Dr. Phillips: “the vast

majority of antibodies bind to conformational determinants on the surface of

cells”). But, as discussed above, this typical process is not relevant to petitioner’s

15

At the hearing, the Secretary presented one more article locating the pentamer as

behind the cell wall. See Tr. 5, exhibit NNN (The Universal Protein Resource (“UniProt”),

UniProtKB - Q13936 (CAC1C_HUMAN) Voltage-dependent L-type calcium channel subunit

alpha-1C, http://www.uniprot.org/uniprot/Q13936 (last visited Nov. 13, 2014)). Ms. Tarsell,

appropriately, objected to the late disclosure of this evidence. Tr. 7-9, 400-01. Substantively, it

is not clear that the UniProt article added anything more to the information contained in exhibit

120 and exhibit FFF, which were in the record before the hearing. Nonetheless, the Secretary is

expected to be more diligent about disclosing evidence before the hearing.

22

experts’ opinions here because the calcium channel is inside the cell, protected by

the cell’s membrane. Tr. 398.

When Dr. Shoenfeld was asked whether antibodies can penetrate a cell’s

membrane, he asserted that they could. He spontaneously referenced a conference

devoted to this topic and offered to produce papers on the topic. Tr. 273-75. Then,

after the hearing, he identified specific articles discussing the process of

endocytosis. Exhibit 138 (Dr. Shoenfeld’s Nov. 25, 2014 report).

In the hearing, Dr. Phillips stated that certain antibodies can penetrate the

cell membrane and when there is penetration, the antibodies may damage the cell.

Tr. 398; see also Tr. 461. Although Dr. Phillips did not raise this point in this

context, Christina’s autopsy did not show any damage to the cells in her heart.

Exhibit 10 at 170; Tr. 481-82.

When the Secretary responded to the post-hearing supplemental reports from

Dr. Shoenfeld and Dr. Eldar, the Secretary presented a report from Dr. Yeager. Dr.

Yeager recognized that Dr. Shoenfeld relied upon endocytosis, but argued that Dr.

Shoenfeld did “not offer any animal or human model of cardiac disease mediated

through this mechanism.” Exhibit OOO at 2. It seems telling that the Secretary’s

response about endocytosis came from a cardiologist, not an immunologist (Dr.

Phillips).

The evidence, therefore, demonstrates that antibodies can penetrate a cell’s

membrane. The Secretary’s complaint that Ms. Tarsell’s evidence on this point is

not robust is misdirected because she raised arguments about the intracellular

location of the pentamer at the hearing. Compare Resp’t’s Preh’g Br., filed Oct.

20, 2014, with Tr. 400 (statement from respondent’s counsel that Dr. Phillips’s

report did not disclose an opinion about intracellular antibodies). A more timely

presentation by the Secretary would have allowed both parties to develop evidence

on this point more thoroughly.

Dr. Phillips stated: “I’m not making a statement that [molecular mimicry]

. . . is totally disproven by the fact that [the calcium channel is] intracellular, but I

did want to make the point that since it is intracellular, it makes it more difficult for

these antibodies . . . to penetrate.” Tr. 401-02. The undersigned finds his analysis

on this point persuasive.

g) Type of Disease

Assuming that antibodies produced in response to the LQAGL pentamer of

the HPV vaccine reach the calcium channel, the final step is to consider how the

23

antibodies would affect the functionality of that channel. Because the calcium

channel is a tube (Tr. 236), the two obvious possibilities are that damage to the

tube either lets too much or too little calcium pass or lets too little calcium pass.

Tr. 99 (Dr. Eldar), 532 (Dr. Yeager).

The 2009 Kanduc paper on which Ms. Tarsell relies to establish homology

provides some guidance as to what happens when the relevant calcium channel is

damaged. Dr. Kanduc associated defects in the gene for the LQAGL pentamer

with causing two diseases: Timothy’s syndrome and Brugada syndrome. Exhibit

74 (Kanduc) at 5; see also Tr. 389. Brugada’s syndrome is very distinctive and

Christina’s electrocardiogram was not consistent with Brugada’s syndrome. Tr.

97-98, 529-30; see also Dorland’s at 1823. There was also no testimony that

Christina suffered from Timothy’s syndrome. See Tr. 299-300; see also Tr. 558-

59.

After Dr. Shoenfeld disclosed his reliance on the 2009 Kanduc article, Dr.

Yeager discussed the implication of relying upon a genetic defect associated with

Brugada’s syndrome.

If we are speculating that a hypothetical antibody is

stimulating the phenotypic expression of Brugada-

associated sudden death, how are we to explain the lack

of the electrocardiographic manifestations of the

underlying calcium channel disorder? The only

electrocardiographic abnormality identified in Christina

was her ventricular ectopy, and Brugada Syndrome is not

typically associated with increased baseline ventricular

ectopy.

Exhibit AAA at 2.

Thus, before the experts testified orally, there was a problem in Ms. Tarsell’s

evidence. Her experts were proposing a theory that appeared to lead to either

Brugada’s syndrome or Timothy’s syndrome. Yet, Christina did not suffer from

either of those problems. See Hibbard v. Sec’y of Health & Human Servs., 698

F.3d 1355, 1364 (Fed. Cir. 2012) (finding that special master was not arbitrary in

denying compensation when petitioner’s theory involved the vaccine causing

dysfunction in the autonomic nervous system and the petitioner did not display any

problems in her autonomic nervous system); Ricci v. Sec’y of Health & Human

Servs., 101 Fed. Cl. 385 (2011) (finding that special master was not arbitrary in

denying compensation when petitioner’s theory proposed that a vaccine caused

24

inflammation in the central nervous system and the vaccinee did not show signs of

such an injury).

However, Dr. Eldar testified about how problems in the calcium channel

would present. He stated that the flow of calcium has been linked to ventricular

tachycardia through catecholamines. Tr. 103-04, 568-69; see also Pet’r’s Posth’g

Br. at 11. He developed this opinion in his report filed after the hearing. Exhibit

140.

Like the Secretary’s introduction of exhibit NNN during the hearing, the

initial presentation of an opinion involving catecholamines during the hearing

caught the opposing party off guard. See Tr. 570. Although the parties did not

flesh out this issue fully, there appears to be a reliable basis for finding that if the

calcium channel were damaged, the consequence could be a form of ventricular

tachycardia. Thus, on this limited point, Ms. Tarsell's case was persuasive.

h) Summary: Theory

The Federal Circuit has stated that petitioner’s burden of proof is “more

likely than not,” not mere plausibility. Moberly, 592 F.3d 1315, 1322 (Fed. Cir.

2010). Decisions from the Court of Federal Claims have followed Moberly.

M.S.B. by Bast v. Sec’y of Health & Human Servs., 117 Fed. Cl. 104, 123 (2014),

appeal dismissed, 579 F. App’x 1001 (Fed. Cir. 2014); Taylor v. Sec’y of Health &

Human Servs., 108 Fed. Cl. 807, 819 (2013).16

Here, Dr. Shoenfeld described his theory as “plausible,” meaning that it can

occur. Tr. 268. It is true that the Secretary has not presented evidence to show that

the molecular mimicry theory is impossible. Yet, the Secretary has raised

sufficient challenges to the theory that Ms. Tarsell has not met her burden of proof.

These challenges include:

16

Ms. Tarsell argues that her burden is only to present a “‘viable’ medical theory.”

Pet’r’s Reply Br., at 5, quoting Contreras v. Sec’y of Health & Human Servs., 121 Fed. Cl. 230,

246 (2015), appeal docketed, No. 2015-5097 (Fed. Cir. June 22, 2015). At the Federal Circuit,

the Secretary has argued that the formulation of a petitioner’s burden on prong 1 set forth in

Contreras is not consistent with Moberly. Brief for Respondent-Appellee at 36, Contreras v.

Sec’y of Health & Human Servs., No. 2015-5097 (Fed. Cir. Oct. 2, 2015), 2015 WL 5971936, at

*36.

25

• The likelihood that LQAGL homology could be an inconsequential

coincidence in light of the relative commonness of pentamer level

homology between invasive organisms and the human proteome,

• The likelihood that a human’s immune system would recognize and

respond to the five particular amino acids LQAGL when the HPV 16

contains thousands of amino acids,

• The likelihood that any antibodies produced in response to the LQAGL

pentamer would cross the cell membrane,

• The likelihood that antibodies to LQAGL would inflict autoimmune

damage to the calcium channel that would appear as bigeminy, not

Brugada syndrome or Timothy’s syndrome as genetic studies would

predict.

In finding that Ms. Tarsell has not presented reliable evidence to make her

theory persuasive, the undersigned does not intend to suggest that either Dr.

Shoenfeld or Dr. Eldar were insincere. To the contrary, all the experts generally

appeared to express their honestly held opinions about the theoretical basis for the

HPV vaccine to cause a fatal arrhythmia and generally expressed those opinions

respectfully. Ms. Tarsell’s case falls short of the preponderance of evidence

standard due to a lack of support. See Caves, 100 Fed. Cl. at 134.

The experts, themselves, recognized that much of the theory remains

untested and unexamined. For example, Dr. Shoenfeld stated that the Kanduc

article “didn’t finish the whole work.” Tr. 269. Dr. Shoenfeld asserted that he

could continue Kanduc’s work by isolating the calcium channels to see if they

react with antibodies. See Tr. 271; see also Tr. 300-02. With respect to his

opinion that a defect in the calcium channel would manifest differently from

Brugada’s syndrome or Timothy’s syndrome, Dr. Shoenfeld said “We will not

know it. We will have to test it.” Tr. 300.

Dr. Phillips testified that “showing a homology at a pentameric level . . . is

many steps away from showing that that [similarity] is causally related to an

autoimmune disease.” Tr. 375. He also stated: “I'm not saying that -- that the

theory is incorrect, but I'm saying it's an inadequate explanation, and there's no

evidence that it was an explanation in this case.” Tr. 380. This assessment is

accurate.

In stating that (a) the theory is unpersuasive and (b) additional testing could

make the theory more persuasive, the undersigned could be viewed as requiring

scientific certainty. The undersigned is aware that Ms. Tarsell does not have to

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prove her case to that degree. Andreu v. Sec’y of Health & Human Servs., 569

F.3d 1367, 1380 (Fed. Cir. 2009), Bunting, 931 F.2d at 873. The undersigned

recognizes the difference in proof between the preponderance of evidence standard

and a beyond a reasonable doubt standard. See Hodges, 9 F.3d at 962 (the “fact

that the opinion of petitioner’s doctors was rejected does not mean that the Special

Master was demanding scientific certainty; he might simply have been demanding

some degree of acceptable scientific support”). Here, Ms. Tarsell’s evidence does

not meet even the simpler more-likely-than-not standard.

V. Logical Sequence

If Ms. Tarsell had established that the HPV vaccine can, as a theoretical

matter, cause arrhythmia and if she had established that Christina’s arrhythmia

arose in a time interval for which an inference of causation is appropriate, then Ms.

Tarsell would also be required to present preponderant evidence that “a logical

sequence of cause and effect” linked the HPV vaccine to Christina’s death. In the

absence of this predicate showing, an Althen prong 2 analysis is not needed. See

Caves, 100 Fed. Cl. at 134. Nevertheless, a brief overview of the evidence

particularly relevant to prong 2 is conducted to demonstrate that all the evidence

has been reviewed.

A. Prong 2 standards

The Federal Circuit has identified several factors that may be probative with

respect to the petitioner’s burden on the second prong of Althen. These include,

among other things, the opinions of treating physicians, expert testimony,

challenge-rechallenge, and pathological markers. See Capizzano, 440 F.3d at

1322.

B. Factors

1. Treating Doctors

The doctor who performed Christina’s autopsy, Kari Reiber, was aware that

Christina received a third dose of the HPV vaccine a few days before she died. 17

17

Dr. Reiber’s date of vaccination (June 8, 2008) is not the correct date, which was June

3, 2008. Exhibit 3 at 99.

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Dr. Reiber submitted information about Christina’s death to the Vaccine Adverse

Event Reporting Service (VAERS).

The submission of a VAERS report is not necessarily evidence that the

doctor considers the vaccination to have caused the injury being reported.

La Londe v. Sec’y of Health & Human Servs., 110 Fed. Cl. 184, 206 n. 37 (2013),

aff’d, 746 F.3d 1334 (Fed. Cir. 2014), Vig v. Secʼy of Health & Human Servs., No.

01-198V, 2013 WL 6596683, at *17 (Fed. Cl. Spec. Mstr. Nov. 14, 2013). In

addition, Ms. Tarsell did not present any argument based upon either the VAERS

report or Dr. Reiber’s notation that the HPV preceded Christina’s death. See

Pet’r’s Posth’g Br.; Pet’r’s Posth’g Reply Br. Under these circumstances, the

opinions of treating doctors do not favor a finding of causation.

2. Challenge-Rechallenge

“A rechallenge event occurs when a patient who had an adverse reaction to a

vaccine suffers worsened symptoms after an additional injection of the vaccine.”

Capizzano, 440 F.3d at 1322. The basic chronology may appear to support a

challenge-rechallenge argument. According to Ms. Tarsell’s perspective, the

following events happened: (1) Christina did not suffer from arrhythmia until she

received the first HPV vaccination, (2) the first HPV vaccination caused Christina

to suffer arrhythmia, which was detected on the date of the second HPV

vaccination, (3) the second HPV vaccination worsened Christina’s arrhythmia, and

(4) the third HPV vaccination, on June 3, 2008, made Christina’s arrhythmia so

much worse that she died from it on June 25, 2008.

However, Ms. Tarsell has not presented any argument based upon challenge-

rechallenge. The concept does not appear in Ms. Tarsell’s pre-trial brief, initial

post-hearing brief, or post-hearing reply brief. In addition, Dr. Shoenfeld

mentioned challenge-rechallenge only fleetingly. See Tr. 245-46, 257-58, 328-30.

Even if Ms. Tarsell had directly argued challenge-rechallenge, it is not clear

that Christina’s case fulfills the challenge-rechallenge paradigm. See Nussman v.

Sec’y of Health & Human Servs., 83 Fed. Cl. 111, 119-20 (finding special master

did not err in rejecting petitioner’s argument regarding rechallenge). To start, as

discussed extensively in section IV, the onset of Christina’s arrhythmia is

unknown. She may have had an undetected arrhythmia for many years. If so, the

first dose of the HPV vaccination did not cause the arrhythmia. In addition,

patients who have an arrhythmia do not follow one clinical course. As Dr. Eldar

explained, “somebody has a problem, he lives with it or she lives with it for a

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month or years, and then one day, that’s it.” Tr. 138. In other words, a seemingly

benign arrhythmia can become fatal for completely unknown reasons.

3. Response as Predicted by the Causal Theory

The essence of the theories Ms. Tarsell presented is that the HPV

vaccination prompted an autoimmune attack on some part of the heart, either the

beta adrenergic receptors or the L1 calcium channel. Dr. Phillips explained the

implications of these theories:

If, in fact, it was a significant autoimmune reaction going

on, one would expect to see cellular infiltrates in various

organs, and if the autoimmune reaction was going on of

significance in the heart, you would expect that the

myocardium would be infiltrated with lymphocytes.

If there was a cytotoxic antibody there which had

been attacking these channels, that cytotoxic antibody

would also cause pathologic changes, with secondary

infiltration of other cell populations which were

inflammatory in nature, including polymorphonuclear

cells or mononuclear cells.

Tr. 407-08.

However, what the theories predicted was not found. Doctors from the CDC

examined tissue taken during Christina’s autopsy. Upon microscopic examination,

they reported: “Sections of myocardium show no conspicuous inflammatory cell

infiltrates.” Exhibit 10 at 170. Ms. Tarsell had no persuasive evidence for this

discrepancy.

Consequently, even if Ms. Tarsell had demonstrated the reliability of any

theory causally connecting the HPV vaccinations to fatal arrhythmia as an abstract

proposition, there is little persuasive evidence that this theory played out in

Christina’s case.

At the end, we have very little solid information about Christina’s

unfortunate death. We know that she was Ms. Tarsell’s beloved daughter, whose

future was bright. We know that her death was entirely shocking and caused Ms.

Tarsell a terrible kind of grief.

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But, sudden unexpected deaths happen with a greater frequency than may be

commonly appreciated. See section I. We do not know the reason why apparently

healthy young people die and, in the context of Ms. Tarsell’s claim in the Vaccine

Program, the Secretary does not bear the burden of supplying a reason for

Christina’s senseless death. See LaLonde, 746 F.3d at 1340.

VI. Conclusion

Ms. Tarsell claimed that the HPV vaccinations caused Christina’s

arrhythmia, which led to her death. The evidence was not sufficient to establish

the causal relationship between the vaccination and the arrhythmia. Consequently,

Ms. Tarsell is not entitled to compensation.

The Clerk’s Office is instructed to enter judgment in accord with this

decision.

IT IS SO ORDERED.

s/ Christian J. Moran

Christian J. Moran

Special Master

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