Forrest v. Secretary of Health and Human Services

In the United States Court of Federal Claims

OFFICE OF SPECIAL MASTERS

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

HELEN FORREST, *

* No. 14-1046V

Petitioner, * Special Master Christian J. Moran

*

v. * Filed: January 28, 2019

*

SECRETARY OF HEALTH * Entitlement, flu vaccine,

AND HUMAN SERVICES, * transverse myelitis, timing,

* shingles, varicella, Shyface,

Respondent. * concurrent causes

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

Curtis R. Webb, Twin Falls, ID, for petitioner;

Colleen C. Hartley, United States Dep’t of Justice, Washington, DC, for

respondent.

PUBLISHED DECISION DENYING COMPENSATION1

Ms. Forrest claims that an influenza vaccination, given to her on January 6,

2014, caused her to suffer transverse myelitis. After Ms. Forrest filed her medical

records, the undersigned directed that the expert reports could constitute the

experts’ direct testimony at any hearing. The parties filed a series of reports from

Dr. Lawrence Steinman (petitioner’s expert) and Dr. Kathleen Collins

(respondent’s expert).

1

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

Promotion of Electronic Government Services), requires that the Court post this decision on its

website (https://www.uscfc.uscourts.gov/aggregator/sources/7). This posting will make the

decision available to anyone with access to the internet. 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.

A hearing was started on February 2, 2018, and continued December 6,

2018. The undersigned has considered all the evidence, including the medical

records, expert reports, medical articles, and oral testimony.

The undersigned finds that Ms. Forrest has not met her burden of proof. The

primary reason is that her transverse myelitis arose too soon after the vaccination

for the vaccination to have caused the transverse myelitis. A second reason is that

the Secretary has identified an alternative factor, a reactivation of the varicella

zoster virus (VZV), that is a much more likely cause of the transverse myelitis than

the flu vaccination. Finally, although this reason is less important than the other

reasons, the theory Ms. Forrest proposes to explain a causal connection between

the flu vaccination and her transverse myelitis, molecular mimicry, is insufficiently

developed to be persuasive.

Facts

Relatively few events in Ms. Forrest’s medical record hold significance for

determining whether she is entitled to compensation. In her childhood, she

suffered a bout of chickenpox. Tr. 49. Chickenpox is caused by a virus known as

varicella zoster virus. Exhibit A (Dr. Collins’s report) at 4. In adults, reactivation

of the varicella zoster virus causes shingles, more formally known as herpes zoster.

Id.

Much later in her life, Ms. Forrest became an employee of Walmart and

worked there for more than 20 years. Tr. 15, 48. She was basically healthy,

having survived breast cancer.

Ms. Forrest presented information about her history of receiving

vaccinations. On January 26, 2007, she received a dose of the flu vaccine. Exhibit

62. Based upon information available through FDA lot releases, Dr. Steinman

determined that the 2006-07 flu vaccine protected against three strains. Exhibit 63

at 1 (citing exhibit 64). On December 8, 2008, Ms. Forrest received another dose

of the flu vaccine. Exhibit 62. Again, Dr. Steinman found that the 2008-09 flu

vaccine immunized a person against three strains. Exhibit 63 at 1-2 (citing exhibit

65). These two vaccinations are the foundation for Dr. Steinman’s opinion that

Ms. Forrest had previously encountered the antigens in the allegedly causal flu

vaccine.

The allegedly causal dose of the flu vaccine was given to Ms. Forrest on

January 6, 2014. Exhibit 2. The 2013-14 season flu vaccine protected against

three strains. Exhibit 63 at 2; exhibit 32 at 6 (FDA lot release).

2

Late in the evening on January 7, probably around midnight of January 8,

2014, Ms. Forrest felt pain in her left flank as well as weakness and numbness in

her left leg. Exhibit 5 at 3. In the morning of January 8, 2014, she went to the

hospital, but the hospital discharged her. Exhibit 6 at 14. Although the exact

number of hours between the vaccination and onset of neurologic problems is not

known for certain, the parties agreed that a reasonable approximation is 36 hours.

See exhibit 12 at 1 (Dr. Snyder), exhibit 12 at 9 (Dr. Potter).

Because she did not have motor function in her left leg, Ms. Forrest returned

to the hospital. Exhibit 18 at 221. She was admitted to the hospital, where she

stayed until discharge on January 15, 2014. Exhibit 18 at 227.

In the emergency room, a doctor recorded that Ms. Forrest had a “macular

erythematous rash in the approximate L1-2 distribution. No vesicles.” Exhibit 18

at 241. The doctor included “herpes zoster” in his differential diagnosis. Id. A

neurologist reported more details about the rash and recommended treatment with

acyclovir. Exhibit 18 at 220. Acyclovir is a medication for treating shingles.2 A

doctor requested testing of Ms. Forrest’s spinal cord fluid to look for the presence

of the varicella virus, but this testing could not be performed due to an insufficient

amount of spinal cord fluid. Exhibit 7 at 28.

The possibility that Ms. Forrest suffered shingles complicates her claim that

the flu vaccine caused her to suffer transverse myelitis. The Secretary’s expert, Dr.

Collins, opined that the reactivation of the varicella zoster virus was a potential

cause for Ms. Forrest’s neurologic problems. Exhibit A at 9, exhibit B at 3.

Initially, before Dr. Collins wrote her first report, Dr. Steinman had stated that

there was not an alternative cause for Ms. Forrest’s transverse myelitis. Exhibit 20

at 28. However, once Dr. Collins identified the varicella zoster virus as a potential

cause, Dr. Steinman changed tack. Dr. Steinman then asserted that “[i]f Ms.

Forrest suffered VZV reactivation, the combination of the zoster activation and a

recall response to the influenza vaccine was a ‘perfect storm’ for eliciting an

autoimmune response to the myelin components resulting in transverse myelitis.”

Exhibit 63 at 8.

The experts discussed whether Ms. Forrest suffered a reactivation of the

varicella zoster virus during their oral testimony. Although Dr. Steinman

2

Other medications for treating shingles include valacyclovir, which is also known as

Valtrex. Exhibit A (Dr. Collins’s report) at 2.

3

expressed some doubt about whether Ms. Forrest actually suffered from shingles

during her January 2014 hospitalization, Tr. 83-85, Dr. Steinman ultimately

conceded that he believed, on a more-likely-than-not basis, that Ms. Forrest did

have a reactivation of the varicella zoster virus. Tr. 142-43. For Dr. Steinman, the

critical fact was that the treating doctors had ordered acyclovir to treat the shingles.

Id. Thus, a preponderance of evidence supports a finding that Ms. Forrest was

suffering a reactivation of the varicella zoster virus when she was also having

neurologic problems in January 2014.

In addition to treating Ms. Forrest with acyclovir, her treating doctors

attempted to learn more about the potential causes of her neurologic problems. For

example, they ordered MRIs for her brain, cervical spine, lumbar spine, and

thoracic spine. Exhibit 18 at 470-85. These MRIs did not detect any

demyelination. Id. A doctor, who reviewed the results of the MRIs, later stated

“[t]here was no spinal cord abnormality.” Exhibit 7 at 28.

At discharge, the relevant diagnoses were “left lower extremity weakness”

and “suspected transverse myelitis post influenza vaccination.” The doctor

recorded that Ms. Forrest had responded well to intravenous steroid therapy and

was still taking Valtrex. The discharge record also indicates that “the patient did

have [a] flu vaccination about one day prior to onset of symptoms.” The

discharging doctor recommended follow up with a neurologist, continuing

medications, and physical therapy. Exhibit 18 at 227-28.

After discharge, Ms. Forrest improved slowly but incompletely. The details

of her recovery from transverse myelitis say relatively little about the cause of

transverse myelitis.3 Thus, although the undersigned has reviewed these medical

records, they are not set forth in this decision.

One event possibly informing the analysis of causation was in July 2014.

Then, Ms. Forrest had a rash on her lower back. Her doctor assessed her as having

shingles, and prescribed valacyclovir, which Ms. Forrest had stopped taking.

Exhibit 15 at 6.

At hearing, Ms. Forrest recounted that she still has not recovered from

transverse myelitis. She uses a cane and a walker to ambulate. She had to stop

working at Walmart, a job that she had loved. Tr. 15.

3

In various records, Ms. Forrest’s doctors offered ideas about the possible causes for her

neurologic problems. These are discussed in more detail below.

4

Standards for Adjudication

Ms. Forrest bears a burden to establish her case on a more-likely-than-not

basis. 42 U.S.C. § 300aa-13(a); Bunting v. Secʼy of Health & Human Servs., 931

F.2d 867, 873 (Fed. Cir. 1991). The elements of an off-Table causation-in-fact

case are set out in Althen v. Sec’y of Health & Human Servs., 418 F.3d 1274, 1278

(Fed. Cir. 2005).

Analysis

Ms. Forrest is not entitled to compensation for several overlapping reasons.

These include: Ms. Forrest’s failure to present a persuasive theory to explain how

transverse myelitis can develop within approximately 36 hours (section I), and a

failure to establish a logical sequence of cause and effect connecting the flu

vaccine to Ms. Forrest’s transverse myelitis (section II). In addition, the Secretary

has established an alternative cause of Ms. Forrest’s transverse myelitis — a

reactivation of the varicella zoster virus (section III). Finally, the evidence does

not support a finding that the flu vaccine combined with the varicella zoster virus

to cause Ms. Forrest’s transverse myelitis (section IV).

I. Theory and Timing

To be entitled to compensation, Ms. Forrest is required to present a theory

that explains how the flu vaccination can cause transverse myelitis generally and,

for this theory to explain what happened to her, the theory must allow for an onset

of neurologic problems within 36 hours. See Langland v. Sec'y of Health &

Human Servs., 109 Fed. Cl. 421, 443 (2013) (linking Althen’s first prong (theory)

to Althen’s third prong (timing)). Here, there are gaps and flaws that make

crediting Dr. Steinman’s opinion not possible.

As a starting step, Dr. Steinman proposes that flu vaccination can cause

transverse myelitis via a process known as molecular mimicry. Molecular mimicry

is a generally accepted mechanism to explain how some antigens, including those

in certain vaccines, cause autoimmune diseases. Exhibit 35;4 National Vaccine

Injury Compensation Program: Revisions to the Vaccine Injury Table, 82 Fed.

Reg. 6,294, 6,304 (Jan. 19, 2017) (to be codified at 42 C.F.R. pt. 100) (added

Guillain-Barré syndrome as an injury for the influenza vaccine, which was

supported by an Institute of Medicine report that acknowledged molecular mimicry

4

Exhibit 35: Ang et al., Structure of Campylobacter jejuni lipopolysaccharides

determines antiganglioside specificity and clinical features of Guillain-Barré and Miller Fisher

patients, 70(3) Infect. Immun. 1202 (2002).

5

as a potential mechanism). Nevertheless, a simple invocation of the term

“molecular mimicry” does not carry a petitioner’s burden of proof. As explained

by the Court of Federal Claims, “Without any empirical evidence that the theory

actually applies to the influenza vaccine and [the disease in question], the first

prong of Althen would be rendered meaningless.” Caves v. Sec’y of Health &

Human Servs., 100 Fed. Cl. 119, 135 (2011), aff’d without opinion, 463 F. App’x

932 (Fed. Cir. 2012).

Then, to explain the 36-hour onset, Dr. Steinman proposes that Ms. Forrest’s

response to the January 6, 2014 flu vaccination was a recall response. For Dr.

Steinman, the January 26, 2007 vaccination and/or the December 3, 2008

vaccination led Ms. Forrest to develop either T cells or antibodies that were then

stimulated by the January 6, 2014 flu vaccination. These restimulated portions of

Ms. Forrest’s adaptive immune system damaged her neurologic system.

A preponderance of evidence does not show that Dr. Steinman has presented

a persuasive theory. The deficiencies are discussed below.

Experiments on Molecular Mimicry Generally. Molecular mimicry is a

complex process in which several steps must occur for a disease to arise. See

exhibit 385 (Markovic-Plese) at 38 (stating that the production of auto-antibodies is

not enough to produce disease); Tr. 126-27.

To ground his theory of molecular mimicry as a mechanism to link the 2013-

14 seasonal flu vaccine and transverse myelitis, Dr. Steinman looked for homology

between the portions of the vaccine and components of the nervous system that

might be involved in transverse myelitis. See exhibit 20 at 10-24. While Dr.

Steinman found some overlap in sequences of amino acids, Dr. Collins and he

disputed whether the overlap was sufficient. A close analysis suggests that Dr.

Steinman appears to have made errors in proclaiming the degree of similarity that

he found (Tr. 94-97), and these errors tend to reduce his credibility on this point.

Regardless, Dr. Steinman, at best, has identified homologies that may or

may not be immunologically significant. While Dr. Steinman professes the

homologies are meaningful, he has not investigated his hypothesis. Dr. Steinman’s

opinion in this case contrasts with the work of researchers whose work appears in

peer-reviewed journals. After using computers to discover overlaps in amino acid

5

Exhibit 38: Markovic-Plese et al., High level of cross-reactivity in influenza virus

hemagglutinin-specific CD4+ T-cell response: Implications for the initiation of autoimmune

response in multiple sclerosis, 169 J. Neuroimmunol. 31 (2005).

6

sequences, researchers then took a next step. They attempted to determine whether

theoretical homology led to actual cross-reactivity. See, e.g., exhibit 466

(Birnbaum) (figure 7); Tr. 120 (discussing Birnbaum). This type of experiment

would enhance the reliability of an opinion based upon computerized Blast

searches because as the Institute of Medicine (IOM) has stated:

Linear amino acid sequence homology or even similar conformational

structure between an exogenous agent and a self-antigen alone are not

sufficient to prove that molecular mimicry is the pathogenic

mechanism for a disease. Many such homologies exist, and the vast

majority of these are not associated with biologically relevant

autoimmune phenomena or actual human disease.7

This statement from the IOM is consistent with a view that Dr. Steinman

expressed in a peer-reviewed article. Exhibit 40.8 With other researchers, Dr.

Steinman wrote that injection with peptides is not sufficient to stimulate disease in

healthy animals. The article stated: “A monoclonal antibody (8–18C5) against

myelin oligodendrocyte glycoprotein (MOG) induces severe demyelination in mice

and rats with mild experimental autoimmune encephalomyelitis (EAE) but does

not induce disease in healthy animals because the antibody cannot gain access to

the CNS parenchyma.” Id. at 211. When asked about this paper, Dr. Steinman

stood by his research. Tr. 120. Other experts for petitioners have agreed with the

IOM’s statement that “similar conformational structure” is not sufficient to

establish molecular mimicry as the mechanism for a disease. See Purvis v. Sec'y

of Health & Human Servs., No. 14-1025V, 2017 WL 4001683, at *3 (Fed. Cl.

Spec. Mstr. Aug. 18, 2017).

Dr. Steinman, Dr. Collins, and the parties promoting their opinions spent a

great deal of time discussing whether Dr. Steinman’s computer searches yield

6

Exhibit 46: Birnbaum et al., Deconstructing the Peptide-MHC Specificity of T Cell

Recognition, 157(5) Cell 1073 (2014).

7

Exhibit 67: Institute of Medicine of the National Academies, Committee to Review

Adverse Effects of Vaccines, “Chapter 3: Evaluating Biological Mechanisms of Adverse

Events,” in Adverse Effects of Vaccines: Evidence and Causality, 57, 70 (Stratton et al., eds.,

2012).

8

Exhibit 40: O’Connor et al., Self-assembling Antigen Tetramers Identify an

Autoantibody-associated Form of Acute Demyelinating Encephalomyelitis, 13 Nature Medicine

211 (2007).

7

results that are consistent with the minimal level of homology that is required for

cross-reactivity. Dr. Collins seemed credible in identifying the faults in Dr.

Steinman’s proposal. However, an exhaustive analysis as to whether Dr. Steinman

has, for example, demonstrated a sequence homology for T cells (eight of nine

amino acids)9 is not necessary for this decision. Tr. 96; exhibit 20 at 13-15. For

even if Dr. Steinman’s identification of computerized homology were accepted

entirely, homology is only the first step in the molecular mimicry theory. To

explain the etiology of a disease, molecular mimicry also requires that the

homology leads to the production of cross-reacting autoantibodies. And even the

production of autoantibodies is not sufficient to cause disease because

autoantibodies are detected in people who apparently do not suffer from disease.

Ms. Forrest has not persuasively grounded the reliability of Dr. Steinman’s

extended opinion.10

Epidemiology. The Secretary introduced epidemiological studies to

undermine Ms. Forrest’s attempt to establish that the flu vaccine can cause

transverse myelitis. See Bazan v. Sec’y of Health & Human Servs., 539 F.3d

1347, 1352 (Fed. Cir. 2008) (“The government, like any defendant, is permitted to

offer evidence to demonstrate the inadequacy of the petitioner’s evidence on a

requisite element of the petitioner's case-in-chief”). Although Althen states that

petitioners are not required to present epidemiological studies to prevail, special

masters may consider epidemiological studies. Grant v. Secʼy of Health & Human

Servs., 956 F.2d 1144, 1149 (Fed. Cir. 1992); D’Tiole v. Secʼy of Health & Human

Servs., 726 F. App’x 809 (Fed. Cir. 2018); Caves, 100 Fed. Cl. at 135.

Here, a strong reason for Dr. Collins’s disagreement with Dr. Steinman was

the Baxter study. Exhibit D-1.11 In Baxter, researchers studied a patient-

9

Dr. Steinman had originally stated the T cell homology as nine of nine amino acids, see

exhibit 20 at 13, but Dr. Collins corrected his math. See exhibit A at 7.

10

The Federal Circuit has indicated that special masters may consider whether an

expert’s opinion is and has been “testable.” Terran v. Secʼy of Health & Human Servs., 195 F.3d

1302, 1316 (Fed. Cir. 1999). But, the Federal Circuit has also observed that petitioners do not

have to prove their cases with scientific certainty. Andreu v. Secʼy of Health & Human Servs.,

569 F.3d 1367, 1380 (Fed. Cir. 2009); Knudsen v. Secʼy of Health & Human Servs., 35 F.3d

543, 548-49 (Fed. Cir. 1994). The parties have not grappled with this potential tension. See

Pet’r’s Prehear’g Br. at 12; Resp’t’s Prehear’g Br. at 30-31. The undersigned is not requiring

scientific certainty.

11

Exhibit D-1: Baxter et al., Acute Demyelinating Events following Vaccines: A Case-

Centered Analysis, 63 Clin. Infect. Dis. 1456 (2016).

8

population who had received 64 million doses of vaccines, including

approximately 19 million doses of flu vaccine. The researchers did not detect an

increased incidence of transverse myelitis after vaccination. When submitted into

evidence in a Vaccine Program case, the Baxter article has served as one reason,

although not the primary reason, for not crediting the theory that the hepatitis A

and meningococcal vaccines can cause transverse myelitis. Bender v. Sec'y of

Health & Human Servs., No. 11-693V, 2017 WL 5381628, at *21 (Fed. Cl. Spec.

Mstr. Oct. 6, 2017), mot. for rev. granted, decision vacated, and remanded, 138

Fed. Cl. 197 (2018), decision after remand, 2018 WL 3679637, at *37 (Fed. Cl.

Spec. Mstr. July 2, 2018) (special master clarifying that epidemiology was not the

primary reason for denying compensation), second mot. for rev. denied and

decision sustained, ___ Fed. Cl. ___, 2019 WL 288280 (Jan. 23, 2019).

Other epidemiologic studies carry less weight because the researchers

studied a different disease (Guillain-Barré syndrome) and because the population

was smaller. Exhibits D-3 (Greene12), D-5 (Kwong13), and D-7 (Stowe14). To the

extent that these studies are useful, they too have failed to detect any increased

incidence of neurologic disease after flu vaccination.

Evidence regarding the Time for Molecular Mimicry. Even if molecular

mimicry could be accepted to explain how the flu vaccine can cause transverse

myelitis abstractly, Dr. Steinman faced the additional challenge of demonstrating

that molecular mimicry can happen in approximately 36 hours. Here, a

preponderance of the evidence shows that molecular mimicry is not likely to

happen within 36 hours, even for a recall response. (Whether Ms. Forrest

genuinely had a recall response is discussed below).

12

Exhibit D-3: Greene et al., Guillain-Barré Syndrome, Influenza Vaccination and

Antecedent Respiratory and Gastrointestinal Infections: A Case-Centered Analysis in the

Vaccine Safety Datalink, 2009-2011, 8(6) PloS ONE e67185 (2013).

13

Exhibit D-5: Kwong et al., Risk of Guillain-Barré Syndrome after Seasonal Influenza

Vaccination and Influenza Health-Care Encounters: A Self- Controlled Study, 13 Lancet Infect.

Dis. 769 (2013).

14

Exhibit D-7: Stowe et al., Investigation of the Temporal Association of Guillain-Barré

Syndrome with Influenza Vaccine and Influenzalike Illness using the United Kingdom General

Practice Research Database, 169 Am. J. Epidemiol. 382 (2009).

9

The term “molecular mimicry” is a shorthand expression for a process that

encompasses several steps of the adaptive immune system. Without precisely

delineating each of the steps, the IOM has categorized the immune response to

contain a “lag phase” and a logarithmic (or “log”) phase. Exhibit 67. During the

lag phase, the adaptive immune system encounters the antigen, transports the

antigen to the regional lymph node, processes the antigen, and initiates the

production of antibodies and/or T cells that attack the antigen. During the

logarithmic phase, the number of antibodies and/or T cells increase to defeat the

antigen. Tr. 265-69 (Dr. Collins’s description of the adaptive immune system).

The difference between the lag phase and the log phase is important because

several experiments on molecular mimicry start relatively far into the secondary

log phase. Tr. 216; see also Tr. 163 (Dr. Steinman’s testimony that the Ben-Nun

experiment starts with already manufactured T cells). Examples include Ben-Nun

(exhibit A-615), Bartholomäus (exhibit 2716), and Odoardi (exhibit 2817). Even

though Dr. Steinman cited the IOM for the basis that the lag phase generally can be

as short as one day, exhibit 63 at 6 (citing exhibit 67 at 58), he has not persuasively

addressed Dr. Collins’s argument that the next step, the log phase, takes a

minimum of three days and that actual presentation of symptoms is another step

taking additional time. Exhibit B at 2; Tr. 298. When considering the lag and log

phase together, Dr. Collins placed the minimum amount of time to develop

symptoms following a recall response at six days. Tr. 298.18

15

Exhibit A-6: Ben-Nun et al., The rapid isolation of clonable antigen specific T

lymphocyte lines capable of mediating autoimmune encephalomyelitis, 11(3) Eur. J. Immunol.,

195 (1981).

16

Exhibit 27: Bartholomäus et al., Effector T cell interactions with meningeal vascular

structures in nascent autoimmune CNS lesions, 462 Nature 94 (2009).

17

Exhibit 28: Odoardi et al., Blood-borne soluble protein antigen intensifies T cell

activation in autoimmune CNS lesions and exacerbates clinical disease, 104 Proc. Nat’l Acad.

Sci. 18625 (2007).

18

To rebut Dr. Collins’s proposed timing, Dr. Steinman presented the polio virus as a

counter example in his testimony. Dr. Steinman argued that if an immune response derived from

the polio vaccine took six days, as proposed by Dr. Collins, then the polio vaccine would be

ineffective at preventing polio. Tr. 144-45. In response, Dr. Collins distinguished the body’s

immune response to the polio virus from the case at hand. Dr. Collins explained that the

antibodies created by the polio vaccine persist in the blood for decades and are thereby able to

10

Dr. Collins’s opinion is consistent with other evidence. In animal

experiments that support the molecular mimicry theory, the animal did not begin to

show clinical symptoms until more than two days passed. Examples include

Herges (exhibit 3919) (after researchers injected 50 million T cells reactive against

myelin, the animal showed signs of neurologic problems six days later), Gautam

(exhibit 45 at 770, fig. 320) (incidence of neurologic symptoms did not start until

almost day 10) and Ho (exhibit 5121) (the change in clinical score starts on day 10).

Collectively, these animal experiments tend to contradict Dr. Steinman’s

opinion that a recall response can happen as quickly as 36 hours. However, Dr.

Steinman has pointed to some evidence supporting his opinion. The two strongest

pieces of evidence are Schonberger and Salmon.

Both Schonberger and Salmon are epidemiologic studies examining whether

a flu vaccine can cause Guillain-Barré syndrome (“GBS”), a disease only relevant

because it is autoimmune and demyelinating. In the course of presenting their

data, both Schonberger and Salmon showed that some cases of GBS occurred on

either the day of vaccination (day zero) or the day after vaccination (day one).

Exhibit 2322 at 112 (figure 5); exhibit 7123 at 1464-67. However, how the

researchers evaluated the presence of people who had illnesses before receiving the

vaccination (and before developing GBS) is not clear. Moreover, the researchers

respond much faster to the polio virus. Tr. 271-72. Ms. Forrest did not present any rebuttal

testimony from Dr. Steinman on this point regarding the polio virus.

19

Exhibit 39: Herges et al., Protective effect of an elastase inhibitor in a neuromyelitis

optica-like disease driven by a peptide of myelin oligodendroglial glycoprotein, 18(4) Mult.

Scler. J. 398 (2012).

20

Exhibit 45: Gautum et al., Minimum structural requirements for peptide presentation

by major histocompatibility complex class II molecules: Implications in induction of

autoimmunity, 91 Proc. Nat’l Acad. Sci. 767 (1994).

21

Exhibit 51: Ho et al., Identification of Naturally Occurring Fatty Acids of the Myelin

Sheath That Resolve Neuroinflammation, 4 (137) Sci. Transl. Med. 137ra73 (2012).

22

Exhibit 23: Schonberger et al., Guillain Barré Syndrome following vaccination in the

National Influenza Immunization Program, United States, 1976-1977, 100 Am. J. Epidem. 105

(1979).

23

Exhibit 71: Salmon et al., Association between Guillain-Barré syndrome and influenza

A (H1N1) 2009 monovalent inactivated vaccines in the USA: A meta-analysis, 381 Lancet, 1461

(2013).

11

did not specifically examine whether the incidence of GBS within two days of

vaccination occurred more frequently than expected. Thus, the two events

(vaccination and onset of GBS) may be a coincidence. The likelihood that the two

events (vaccination and onset of GBS) simply coincided draws some support from

the only study in this record that compared the incidence of GBS following flu

vaccination within a relatively short amount of time. In Kwong, the researchers

found that the relative incidence was 0.95 within one week. Exhibit D-5 at table 2.

This finding means that flu vaccine did not affect the incidence of GBS within one

week. While one week is not the same as two days, the immune system would be

more likely to cause an autoimmune reaction approximately five to seven days

after the presentation of the exciting antigen, a time that is in the log phase of the

immune response. Thus, Kwong’s inclusion of events occurring seven days after

vaccination would tend to overstate the relative risk of an adverse event in the first

two days. Thus, overall, the epidemiologic evidence concerning an onset within

two days is mixed.

The undersigned finds that in determining the amount of time for molecular

mimicry to happen, the animal models are more useful than the epidemiologic

studies Dr. Steinman cites. The animal experiments show the step-by-step process

by which the injection of the antigen can lead to autoimmune disease. For

example, in Bartholomäus, researchers grew cells in a petri dish in the lab for

months with constant exposure to the relevant antigen. Then, when the researchers

injected these specially manufactured T cells into the mice, the T cells still took

more than two days to invade the central nervous system. Exhibit 27 at 95; Tr.

299. In short, the level of detail reported from the animal experiments makes them

a more reliable source of information about the mechanics of the immune system.

Dr. Collins admitted if a person developed an immune response to a flu

antigen contained in one year’s flu vaccine, the person could potentially develop a

recall response to a subsequent year’s flu vaccine. Tr. 303. However, Dr. Collins

qualified the possibility of a recall response with the necessity that during the

interval between the flu vaccinations a person would need to be exposed to flu

antigen so that her immune memory cells remain active and do not transition into a

quiescent state. Id. She stated that immune memory cells become quiescent within

7 to 10 days after the pathogen has been destroyed. Tr. 267. After re-encountering

an antigen, Dr. Collins testified that quiescent memory cells take three days to

increase in number to reach the log phase and then later produce sufficient

antibodies to counter the antigen (or, in an autoimmune context, to cause

neurological symptoms). Tr. 230-31, 298; see also exhibit A-6 at 196 (where rats

were observed for the development of overt paralysis of the hind quarters). Dr.

12

Collins’s opinion is consistent with the Bartholomäus experiment in which

researchers kept the immune memory cells in a highly active state to create a faster

immune response, but even that response of more than two days is greater than Dr.

Steinman’s proposed time frame of only 36 hours.24

For all these reasons, Ms. Forrest has failed to present a persuasive or

reliable theory to explain how the flu vaccine can cause the onset of transverse

myelitis within approximately 36 hours. The epidemiologic evidence does not

favor a finding of causation. The theoretical (or experimental) basis is confusing

and incompletely developed. And, most of all, the timing is wrong.

II. Logical Sequence of Cause and Effect

Although the finding with regard to timing is a sufficient basis to deny

compensation, the evidence regarding Ms. Forrest’s case is briefly set forth to

demonstrate that the entire record has been reviewed under Althen prong two. For

this prong, the Federal Circuit has instructed special masters to consider the

statements of treating doctors. Capizzano v. Secʼy of Health & Human Servs., 440

24

The undersigned’s finding that a molecular mimicry reaction, even one predicated on a

recall response, probably takes longer than two days is consistent with the undersigned’s

previous finding that the somewhat shorter time of 24 hours is not sufficient for a molecular

mimicry reaction. See Contreras [5] v. Secʼy of Health & Human Servs., No. 05-626V, 2014

WL 8098606, at *37 (Fed. Cl. Spec. Mstr. Oct. 24, 2014) (“Dr. Steinman could present only

weak and unpersuasive support for his opinion that all the steps associated with molecular

mimicry can happen within one day”). After a motion for review was filed, an opinion

determined that this finding was not arbitrary or capricious. Contreras [6] v. Secʼy of Health &

Human Servs., 121 Fed. Cl. 230, 247 (2015). While the Federal Circuit vacated the judgment

denying compensation, the Federal Circuit did not reach the question of timing. Contreras [7] v.

Secʼy of Health & Human Servs., 844 F.3d 1363 (Fed. Cir. 2017).

Contreras [1] also contains an extended discussion of why a comparison to the tuberculin

skin test is inapt and why Dr. Steinman’s opinion regarding a recall response (referred to as

“priming”) was not persuasive. Contreras [1] v. Sec'y of Health & Human Servs., No. 05-626V,

2012 WL 1441315, at *18-20 (Fed. Cl. Spec. Mstr. Apr. 5, 2012), motion for review granted,

decision vacated and remanded on other grounds, Contreras [2], 107 Fed. Cl. 280, 305-06 n.40

(2012) (accepting the special master’s function of “weighing evidence for persuasiveness” in

regard to the tuberculin skin test, but ordered re-examination of the importance of this finding),

compensation denied on remand, Contreras [3], 2013 WL 6698382, at *48 n.41 (Fed. Cl. Spec.

Mstr. Nov. 19, 2013) (special master reaffirmed his finding on the tuberculin skin test), vacated

on non-relevant grounds and remanded, Contreras [4], 116 Fed. Cl. 472, 484-85 (2014),

compensation denied on remand, Contreras [5], 2014 WL 8098606, at *37 (Fed. Cl. Spec. Mstr.

Oct. 24, 2014), motion for review denied, Contreras [6], 121 Fed. Cl. 230, 247 (2015), vacated

on other grounds, Contreras [7], 844 F.3d 1363 (Fed. Cir. 2017).

13

F.3d 1317, 1326 (Fed. Cir. 2006). In addition, there is a question about whether

Ms. Forrest experienced a recall response to the 2013-14 flu vaccination.

Treating Doctors

Within the medical records, no treating doctor directly expressed an opinion

that the flu vaccine caused Ms. Forrest to suffer transverse myelitis.25 Some

treating doctors noted the temporal sequence in which Ms. Forrest was vaccinated

approximately 36 hours before she began to suffer neurologic problems. See, e.g.,

exhibit 18 at 143 (Dr. Snyder), exhibit 6 at 11 (Dr. Villena referencing a neurology

evaluation). However, notations of a sequence of events are distinct from

statements of causation. Cedillo v. Sec’y of Health & Human Servs., 617 F.3d

1328, 1348 (Fed. Cir. 2010). Furthermore, some statements from the treating

doctors are couched in terms of “possible,” exhibit 6 at 11 (Dr. Villena); “may be,”

exhibit 18 at 142; and “possibly,” exhibit 15 at 6 (Dr. Villena). This language is

not an expression of an opinion on a more-likely-than-not basis.

While those statements can be categorized as neutral, other statements from

treating doctors point, slightly, away from a finding of causation. Early in Ms.

Forrest’s hospitalization, a neurologist (Dr. Carrigan) proposed that she was

suffering a “viral” transverse myelitis. Exhibit 18 at 221. Months later, on August

28, 2014, Dr. Snyder observed that Ms. Forrest’s transverse myelitis “occurred 36

hours after flu vaccination,” and then commented: “This is a short time for post

vaccinal autoimmune transverse myelitis but temporally hard to dismiss.” Exhibit

12 at 1.

Finally, on October 9, 2014, Ms. Forrest saw Dr. Potter, who had learned

that Ms. Forrest was pursuing a claim in the Vaccine Program. Other than noting

that fact, Dr. Potter did not comment favorably or unfavorably on this claim.

Because Ms. Forrest bears the burden of proving her case by presenting some

affirmative evidence supporting a finding of causation, Dr. Potter’s silence does

not help her.

In short, the treating doctor’s statements are not persuasive evidence that the

flu vaccine caused Ms. Forrest’s transverse myelitis.

25

In her oral testimony, Ms. Forrest stated that one doctor, Dr. Fern, told her that the flu

vaccine caused her transverse myelitis. Tr. 45. However, this statement does not appear in any

medical record.

14

Recall response

Neither party disputes the onset of Ms. Forrest’s symptoms at approximately

36 hours following vaccination. According to Dr. Steinman’s first report, whether

the flu vaccination triggered the onset of Ms. Forrest’s transverse myelitis within

36 hours depends on “recall response, recall response, recall response.” Exhibit 20

at 24. As explained in the Theory and Timing section above, Ms. Forrest has not

presented persuasive evidence that a recall response can occur in approximately 36

hours. But, even if she had been persuasive on this theoretical point, she has not

demonstrated on a more-likely-than-not basis that her January 2014 vaccination in

fact provoked a recall response.

In opining that Ms. Forrest had a recall response, Dr. Steinman assumed that

Ms. Forrest “most likely had other exposures to influenza vaccine and probably to

natural influenza virus.” Id. But, evidence does not validate this assumption.

Between the flu vaccination Ms. Forrest received on December 3, 2008, and the flu

vaccination on January 6, 2014, the medical records do not support, nor has Ms.

Forrest claimed, that she received an interim flu vaccination. Dr. Collins argued

that it is unknown whether Ms. Forrest was exposed to the flu antigen again during

this interim time. Tr. 304. According to Dr. Collins, to satisfy petitioner’s recall

response theory, Ms. Forrest’s immune memory cells would have to be somewhat

active, having had some exposure to flu antigen, for the immune memory cells to

have a rapid recall response. Tr. 230-31. Dr. Steinman did not oppose Dr. Collins

statement that Ms. Forrest’s immune memory cells were quiescent. Tr. 381 (“Dr.

Collins may or may not be right about Mrs. Forrest having quiescent cells”). As

noted above, since immune memory cells become quiescent 7 to 10 days after the

foreign substance, here the flu antigen, is destroyed, Ms. Forrest would have

required exposure to the flu virus in a relatively short time frame preceding the

January 6, 2014 flu vaccination. Ms. Forrest has not presented sufficient factual

evidence to establish on a more-likely-than-not basis that she experienced a recall

response.

In sum, the entire record, including statements made by Ms. Forrest’s

treating doctors, does not support a logical sequence of cause and effect between

Ms. Forrest’s January 6, 2014 flu vaccination and her subsequent development of

transverse myelitis. Thus, Ms. Forrest has not established her vaccine claim on a

more-likely-than-not basis for any of the Althen prongs.

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III. Alternative Cause

Because Ms. Forrest has not met her burden under Althen, the Secretary

does not bear any burden to establish a factor other than the flu vaccine caused her

transverse myelitis. LaLonde v. Sec’y of Health & Human Servs., 746 F.3d 1334

(Fed. Cir. 2014). Nevertheless, because Dr. Collins has put forward the varicella

zoster virus as an alternative cause, the undersigned is permitted to consider the

evidence regarding the varicella zoster virus. Doe/11 v. Sec'y of Health & Human

Servs., 601 F.3d 1349, 1358-59 (Fed. Cir. 2010).

As explained previously, although the evidence that Ms. Forrest suffered a

reactivation of the varicella zoster virus is not perfect, a preponderance of the

evidence supports a finding that she did have a reactivation in January 2014. Tr.

142-43. This predicate is the basis for analyzing whether the varicella zoster virus

caused her transverse myelitis.

Varicella zoster virus can cause transverse myelitis. Dr. Steinman did not

dispute that varicella zoster virus can cause transverse myelitis. Tr. 142, 148.

The next question is whether the timing fits. Here, again, the evidence is not

perfect. Although at least two doctors noted a rash on Ms. Forrest’s back during

her hospitalization, see exhibit 18 at 220 and 241, Ms. Forrest did not, in her

testimony, recall when the rash began. Tr. 22-23. Thus, the interval between when

the varicella zoster virus first reactivated (marked by the beginning of the rash) and

when Ms. Forrest had neurologic problems cannot be known with certainty.

Nevertheless, the lack of precision in timing is not an obstacle in finding causation

when Ms. Forrest was suffering a reactivation of the virus before she started

having neurologic problems.26 See Tarsell v. Sec’y of Health & Human Servs.,

133 Fed. Cl. 782, 792 (2017).

The remaining question is whether a logical sequence of cause and effect

links the reactivation of the varicella zoster virus in Ms. Forrest caused her

transverse myelitis. On this point, the evidence is not particularly strong but

preponderates in favor of this. To begin, the treating doctors seemed uncertain as

to any cause of the transverse myelitis. As reviewed above, they did not say that

the flu vaccine caused the transverse myelitis and they did not say that the varicella

zoster virus caused the transverse myelitis. While Dr. Steinman seemed to criticize

26

In addition, neither Ms. Forrest nor Dr. Steinman has raised any challenge about the

appropriateness of the timing between the rash and the neurologic problems.

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the treating doctors for not obtaining definitive proof of a reactivation of the

varicella zoster virus, he recognized that they prescribed antiviral medication for

her. Tr. 391. After she received this medication and steroids in the hospital, she

improved. Thus, Dr. Steinman’s view that the treaters seemed not to consider the

varicella zoster virus as the cause, because they did not do more to treat Ms.

Forrest for a varicella zoster virus reactivation, is inaccurate.

While neither the statements nor the actions of the treating doctors

persuasively implicate the varicella zoster virus by themselves, the Secretary may

rely upon the report of an expert retained for the litigation. See 42 U.S.C. § 300aa-

13(a)(1). Here, Dr. Collins has filled this role and presented a persuasive opinion

that the varicella zoster virus was a more likely cause of the transverse myelitis.

See Tr. 173-81, 316-19.

IV. Contributing Causes

The final question is whether the flu vaccine combined with the varicella

zoster virus to create, in Dr. Steinman’s words, “a perfect storm” that led to Ms.

Forrest’s transverse myelitis. The evidence does not support this conclusion.

Vaccine Program precedent recognizes that a vaccine might join with an

ongoing infection to harm a vaccinee significantly. The most prominent example

is Shyface. Previously, the undersigned extensively examined Shyface, and

concluded that the substantial factor test applies when two forces act in concert.

Heinzelman v. Sec’y of Health & Human Servs., No. 07-01V, 2008 WL 5479123,

at *2–4 (Fed. Cl. Spec. Mstr. Dec. 11, 2008) (noting that in Shyface, the Federal

Circuit stated that the “Restatement recognizes that concurrent forces may bring

about a single harm”), mot. for rev. regarding entitlement den’d, 98 Fed. Cl. 808,

812-15 (2011), aff’d on unrelated point of damages, 681 F.3d 1374 (2012).

Here, Dr. Steinman has not presented any evidence that the effects of the flu

vaccine acted in concert with varicella zoster virus to cause Ms. Forrest to suffer

transverse myelitis. This omission might stem from the fact that Dr. Steinman’s

first report asserted that the flu vaccine caused the transverse myelitis without

mentioning the varicella zoster virus as an alternative or contributing cause. In

other words, originally Dr. Steinman saw the flu vaccine as a separate and

independent force causing the transverse myelitis. Then, after Dr. Collins

identified the varicella zoster virus as an alternative explanation for the cause of

Ms. Forrest’s transverse myelitis, Dr. Steinman tacked on the idea of a perfect

storm. Tr. 155. But, this proposal is clearly an afterthought with Dr. Steinman’s

17

discussion of it consisting of only three sentences. Exhibit 63 at 8. During the

hearing, his testimony was similarly cursory. Tr. 79, 156-61.

As Dr. Collins pointed out, the varicella zoster virus can cause transverse

myelitis by itself. The flu vaccine is unnecessary. Tr. 204. She stated that she

found no reports in the literature of a “perfect storm,” and Dr. Steinman testified

that he did not look for any literature on this point. Tr. 156, 204. For these

reasons, Ms. Forrest’s theory that the flu vaccine combined with ongoing varicella

zoster virus to produce transverse myelitis is not persuasive.

Conclusion

Ms. Forrest’s transverse myelitis has drastically changed her life and made it

more difficult. While Ms. Forrest’s situation is sad and warrants sympathy, she

has not presented persuasive evidence that the flu vaccine caused her to develop

transverse myelitis. Moreover, the Secretary established on a more-likely-than-not

basis that that the varicella zoster virus caused Ms. Forrest’s transverse myelitis.

Thus, Ms. Forrest’s petition for compensation is denied.

IT IS SO ORDERED.

s/Christian J. Moran

Christian J. Moran

Special Master

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