holding that the special master did not err in resolving case based upon the second prong of the Althen test
How later courts described this case
- holding that the special master did not err in resolving case based upon the second prong of the Althen test
- special master's finding that respondent's experts were more persuasive due in part to their current practice in neurology compared to petitioner’s expert who had no recent practice was not arbitrary or capricious
- reversing special master’s decision that petitioners were not entitled to compensation
- “Finders of fact are entitled-indeed, expected-to make determinations as to the reliability of the evidence presented to them and, if appropriate, as to the credibility of the persons presenting that evidence.”
Written by the judges who cited it.
The opinion
In the United States Court of Federal Claims
OFFICE OF SPECIAL MASTERS
*********************
BO DEPENA and NATALIE *
DEPENA, legal representatives of a * No. 13-675V
minor child, RHONE DEPENA , * Special Master Christian J. Moran
*
Petitioners, * Filed: February 22, 2017
*
v. * Entitlement, MMR vaccine,
* pneumococcal pneumonia,
SECRETARY OF HEALTH * animal models
AND HUMAN SERVICES, *
*
Respondent. *
*********************
Michael Baseluos, Baseluos Law Firm, San Antonio, TX, for petitioners;
Heather L. Pearlman, United States Dep’t of Justice, Washington, DC, for
respondent.
PUBLISHED DECISION DENYING COMPENSATION1
Rhone DePena, the son of the petitioners Bo and Natalie DePena, received a
dose of the measles-mumps-rubella (MMR) vaccine when he was seven years old.
Within a few weeks, he developed a severe pneumonia for which he was
hospitalized for many weeks. During this time, the treating doctors determined
that a bacteria, known as pneumococcus, infected his lungs and caused the
pneumonia.
The DePenas claim that the MMR vaccine caused Rhone’s pneumonia.
Through an expert with a background in pediatric pulmonology, Boris Lokshin,
they allege that the MMR vaccine weakened a portion of Rhone’s immune system
1
The E-Government Act, 44 § 3501 note (2012) (Federal Management and Promotion of
Electronic Government Services), requires that the Court post this decision on its website.
Pursuant to Vaccine Rule 18(b), the parties have 14 days to file a motion proposing redaction of
medical information or other information described in 42 U.S.C. § 300aa-12(d)(4). Any
redactions ordered by the special master will appear in the document posted on the website.
and, in his debilitated state, Rhone could not resist the pneumococcus infection.
The Secretary has disagreed with this argument and presented the views of an
expert with a background in pediatric immunology, Neil D. Romberg. In Dr.
Romberg’s view, the MMR vaccine does not affect the part of a human being’s
immune system that responds to pneumococcus infections.
Between the two experts, the Secretary’s expert was more persuasive. First,
Dr. Romberg has a stronger background in the relevant field, immunology.
Second, the Secretary established that his expert’s opinions are grounded in
immunologic principles that have been established and accepted for decades.
Indeed, even Dr. Lokshin did not seriously contest much of Dr. Romberg’s
opinion. Third, to the extent that Dr. Lokshin presented an innovative theory based
on relatively recent mouse models, the Secretary effectively rebutted that evidence
by showing that mice do not model what happens to human beings facing a
pneumococcal infection. For these reasons, the DePenas have failed to meet their
burden of proof.
Procedural History
The course of litigation has been relatively routine. The DePenas filed the
petition on September 12, 2013. Within approximately two months, they
submitted Rhone’s medical records.
On May 28, 2014, the Secretary submitted his report, filed pursuant to
Vaccine Rule 4. After a review of the medical records, the Secretary
recommended that compensation be denied because the DePenas had not presented
any evidence in the form of a medical record from a treating doctor or a medical
opinion to demonstrate that a vaccine caused Rhone’s pneumonia. Resp’t’s Rep. at
11.
The DePenas retained Dr. Lokshin. As mentioned previously, Dr. Lokshin’s
specialty is pediatric pulmonology. Exhibit 19 (curriculum vitae). Before the
hearing, they submitted four reports from him. Exhibits 21 (Feb. 28, 2015), 22
(May 31, 2015), 2 23 (Aug. 5, 2015), and 25 (Dec. 15, 2015). The literature on
which Dr. Lokshin relied was appended to his reports as numbered tabs. The
undersigned has reviewed all these articles.
In response to Dr. Lokshin, the Secretary retained Dr. Romberg, a pediatric
immunologist. See exhibit B (curriculum vitae). Dr. Romberg authored three
2
Dr. Lokshin’s May 31, 2015 report largely, but not entirely, repeats the material in the
February 28, 2015 report.
2
reports: exhibits A (May 5, 2015), P (June 30, 2015), and FF (Jan. 27, 2016). The
Secretary filed the literature on which Dr. Romberg relied as separate exhibits
marked with consecutively assigned letters. The undersigned has reviewed all
these articles as well.
After unsuccessful efforts to resolve the case informally, it was set for a
hearing. Before the hearing, the parties submitted briefs, which narrowed the
issues. For example, the Secretary conceded that the Rhone developed pneumonia
within a time after vaccination for which it is appropriate to infer causation.
Resp’t’s Preh’g Br., filed Jan. 27, 2016, at 23.
A hearing was held in San Antonio, Texas on February 11, 2016. Both Mr.
and Ms. DePena testified about Rhone’s health before and after the September 15,
2010 MMR vaccination. The DePenas also called Dr. Lokshin. The Secretary’s
witness was Dr. Romberg. For various reasons, the hearing did not proceed as
expeditiously as anticipated, and the hearing did not conclude despite continuing
until the early evening.
After the first session of the hearing ended, the DePenas submitted
additional information responding to issues that arose during the February 11, 2016
hearing. Another hearing was held on April 12, 2016, during which the attorneys
and the witnesses appeared by videoconferencing.
Following the hearing, the parties made additional submissions. The
DePenas filed another report from Dr. Lokshin. Exhibit 30. 3 The Secretary filed
one brief. With the submission of the DePenas’s reply brief and another report
from Dr. Lokshin, the case is ready for adjudication.
Facts
The parties’ disagreement in this case concerns whether Rhone’s MMR
vaccination weakened a relevant portion of his immune system, making him more
susceptible to pneumococcus. The facts outlined below which underlie that
disagreement, however, are largely undisputed. This section outlines Rhone’s
early health, the operation of pneumococcus, the general operation of the MMR
vaccine, Rhone’s health following the MMR vaccination, and the overall operation
3
Filing an unrequested expert report was a mistake. Rather than filing more evidence,
the DePenas should have filed a brief in which they marshalled the already admitted evidence in
support of their claim. Nevertheless, the DePenas’s recent submissions, including the attached
medical articles, have been considered.
3
of the immune system. These facts are the foundation for the subsequent
evidentiary analysis.
1. Rhone’s Early Health
Rhone was born in 2003. Exhibit 9 ¶ 1. Until he was seven years old,
Rhone’s health was normal. See exhibit 5 (records from Northeast Pediatric
Associates) passim. He participated in typical activities such as swimming, biking,
playing tennis, and playing basketball. Exhibit 9 ¶ 2; Tr. 16, 54.
In his periodic visits to his pediatrician, Rhone received vaccinations,
although not on the typically recommended schedule. See exhibit 1. In August
2004, Rhone received the first dose of the MMR vaccine. Exhibit 1 at 1.4 On
November 11, 2003, March 30, 2004, and June 22, 2005, Rhone received doses of
the pneumococcal conjugate vaccine. Exhibit 1 at 1.5
2. Pneumococcus6
Pneumococcus is a type of bacterium. Dorland’s Illustrated Medical
Dictionary 1470, 1782-83 (32d ed. 2012). There are more than 90 strains of
pneumococcus and the numerous strains contribute to the difficulty in developing
an effective vaccine. Exhibit 21.10 (Test ID: PN23 Streptococcus pneumoniae IgG
Antibodies, 23 Serotypes, Serum, Mayo Clinic (undated),
http://www.mayomedicallaboratories.com/test-
catalog/Clinical+and+Interpretive/83640); see also Tr. 274, 331. The outside
capsule of pneumococcus is comprised of polysaccharides. Tr. 231.
Polysaccharides are carbohydrates, like sugars. Tr. 268; Dorland’s at 1493
4
Early in the litigation, the DePenas contended that Rhone broke out in an extensive rash
shortly after receiving MMR at age two. Exhibit 8 (statement from Ms. DePena) at 1; see also
exhibit 6 at 9-11 (record from Dr. Infante, dated April 13, 2011); Suppl. Pet. No. 1, filed Nov.
11, 2013 ¶ 6. However, the evidence showed that Ms. DePena’s recollection was incorrect.
While Rhone did have a widespread rash in September 2005, see Tr. 40-41, exhibit 11, this rash
occurred more than one year after the first MMR vaccination. Tr. 38.
5
The pneumococcal conjugate vaccine is often referred to by its brand name: Prevnar.
The pneumococcal conjugate vaccine given to Rhone between 2003 and 2005 protected against
seven strains of the pneumococcal bacteria. Exhibit 21.11 (Pneumococcal Vaccination: Who
Needs It?, Centers for Disease Control and Prevention (Jan. 25, 2015),
http://www.cdc.gov/vaccines/vpd-vac/pneumo/vacc-in-short.htm.
6
A more formal name for pneumococcus is streptococcus pneumoniae. Tr. 268. For
consistency, this decision uses the term “pneumococcus.”
4
(defining polysaccharide). When faced with a polysaccharide invader, the body’s
adaptive immune system responds by producing antibodies, which come from B
cells, and the body does not produce T cells in response. Tr. 216-17.
Consequently, pneumococcus has been categorized as a type II T cell-independent
antigen. Tr. 217.
The body’s encounter with pneumococcus is unusual in the sense that the
first step is colonization. Tr. 110. Colonization means that a strain of
pneumococcus is living in a person’s nose and throat. Tr. 186; cf. Dorland’s at
387. This nasopharyngeal colonization is extremely common with estimates
exceeding 25 percent. Exhibit S (Jeremy S. Brown et al., The classical pathway is
the dominant complement pathway required for innate immunity to Streptococcus
pneumoniae infection in mice, 99(26) Proc. of Nat’l Acad. of Sci. of the U.S.
16969 (2002)) at 16969; exhibit 23, tab 4 (Jeffrey Pido-Lopez et al., Acquisition of
Pneumococci Specific Effector and Regulatory Cd4+ T Cells Localising within
Human Upper Respiratory-Tract Mucosal Lymphoid Tissue, 7(12) PLoS
Pathogens e1002396 (2011)) at e1002396; exhibit 25, tab 2 (R Wilson et al.,
Protection against Streptococcus pneumoniae lung infection after nasopharyngeal
colonization requires both humoral and cellular immune responses, 8(3) Mucosal
Immunology 627 (2015)) at 628 (“almost universal”); Tr. 144 (Dr. Lokshin:
pneumococcus is so common, “we cannot really avoid it”); see also Tr. 122 (Dr.
Lokshin reading from Wilson article). Colonization, which is also known as
carriage, is especially frequent in the very young and the very old. Tr. 272, 329-
30.
During colonization of the mucosal surfaces of the nose and throat, the
body’s adaptive immune system produces an antibody known as immunoglobulin
A. Tr. 344; exhibit 25, tab 12 (Jason W. Rosch et al., A live-attenuated
pneumococcal vaccine elicits CD4 T-cell dependent class switching and provides
serotype independent protection against acute otitis media, 6(1) EMBO Molecular
Med. 141 (2013)) at 142; see also Dorland’s at 919-20 (immunoglobulin secretory
i. A). On some occasions, and in some people, a colonization resolves without a
worsening of symptoms. Tr. 219-20; Resp’t’s Posth’g Br., filed July 27, 2016, at 2
(citing exhibit OO (Barry M. Gray et al., Epidemiologic Studies of Streptococcus
pneumoniae in Infants: Acquisition, Carriage, and Infection during the First 24
Months of Life, 142(6) J. Infect. Dis. 923 (1980)) at 928, fig. 5).
However, pneumococcus can also migrate from the nasopharynx to other
portions of the body. Although the petitioners describe the T cells’ role in the
change from colonization to infection as a “critical” issue in this case (Pet’rs’
Preh’g Br., filed Dec. 15, 2015, at 8), relatively little is known about how this
5
change occurs. See Tr. 111, 343. When pneumococcus moves to the ears and
sinuses, it causes otitis media and sinusitis. Tr. 237-38, 270; exhibit OO. These
types of infections are both relatively common and mild. Tr. 202-03. It is much
more alarming when pneumococcus infects the lungs, causing a condition called
pneumococcal pneumoniae. Dorland’s at 1474.
In the United States in 2015, more than one million people suffered from
pneumococcal pneumoniae. Tr. 270 (Dr. Romberg); see exhibit 21.10 (Mayo
Clinic); see also exhibit 25, tab11 (Marianne W. Mureithi et al., T Cell Memory
Response to Pneumococcal Protein Antigens in an Area of High Pneumococcal
Carriage and Disease, 200 J. Infect. Dis. 783 (2009)).
As previously mentioned, the body’s response to a pneumococcal infection
is to produce antibodies. For more than 100 years, scientists have believed that
antibodies (not T cells) are the way the adaptive immune system responds to
pneumococcus. Exhibit 23, tab 4 (Pido-Lopez); Tr. 439, 506. 7
According to Dr. Lokshin, it is likely that Rhone had pneumococcus in his
nasopharynx before receiving the MMR vaccination. Tr. 203.
3. MMR Vaccination
At an appointment with his pediatrician, Frederick Rhame, on September 15,
2010, Rhone received a series of vaccinations. Exhibit 1; exhibit 5 at 6, 15. For
this case, the relevant vaccine is the measles-mumps-rubella vaccine.
The MMR vaccine is an attenuated vaccine, that is, the vaccine contains a
weakened form of the live measles virus. In its wild (or natural) state, the measles
virus is extremely virulent. Measles causes the death of thousands of unvaccinated
people each year.
The people who survive measles infection are more vulnerable to infection
from other pathogens for 1-4 weeks. Scientists have recently theorized that the
measles virus destroys the memory aspect of the survivor’s immune system.
Without this memory in their immune system, survivors of the measles virus may
be unable to fight off infection and may contract diseases. Exhibit Y (Michael J.
Mina et al., Long-term measles-induced immunomodulation increases overall
childhood infectious disease mortality, 348(6235) Science 694 (2015)) at 694.
7
As discussed more extensively below, the petitioners, by contrast, are advancing a
theory in which the body’s response to pneumococcus requires T cells.
6
Dr. Romberg, the Secretary’s expert, conceded that the MMR vaccine can
have the same consequence as the wild measles virus: a suppression of some parts
of the adaptive immune system. Dr. Romberg’s concession on this point
simplified the litigation.8
4. Rhone’s Medical History Immediately Following MMR Vaccination
(September 2010 through October 2010)
As just stated, when he was vaccinated, Rhone encountered a weakened
form of the measles virus on September 15, 2010. Two days later, Rhone’s mother
called to report that he had a “bad reaction to shots” and requested a “steroid
cream.” Exhibit 5 at 31; see also Tr. 17. Although the nurse’s note does not
verbally describe the nature of the reaction, the pediatrician’s record includes a
photograph showing raised dots on his thigh. Exhibit 5 at 38; see also exhibit 11;
Tr. 17, 41, 56, 264, 372.
On Saturday, September 25, 2010, Rhone’s parents brought him to the
emergency room at Methodist Children’s Hospital because he was having lower
back pain. Rhone also had been coughing for two days and his temperature,
according to his mother, was “high for him.” Exhibit 7 at 32; exhibit 8 at 1. The
doctors diagnosed him as having an acute viral syndrome. Exhibit 7 at 35; see also
Tr. 21.
Rhone’s health did not improve over the next few days. On Tuesday,
September 28, 2010, Rhone’s mother took him to Dr. Rhame’s office because of a
high fever, greyish color, and grunting sounds when he was breathing. Tr. 22. Dr.
Rhame sent him for testing, including a chest X-ray. Exhibit 5 at 46; exhibit 8 at 1.
The chest X-ray showed bilateral pneumonia. Exhibit 5 at 46.
Rhone’s pneumonia was severe. He remained at Methodist Children’s
Hospital for 21 days. Exhibit 7 at 62. His mother described the frightening details
in her statement, although the course of how the doctors treated Rhone is not
8
In addition to the Mina article (exhibit Y), other articles relevant to how the measles
virus and the measles vaccine may suppress the immune system include exhibit 21, tab 1 (Philip
Fireman et al., Effect of Measles Vaccine on Immunologic Responsiveness, 43(2) Pediatrics 264
(1968)), and exhibit 21, tab 3 (Christopher L. Karp et al., Mechanism of Suppression of Cell-
Mediated Immunity by Measles Virus, 273 Science 228 (1996)).
7
relevant to determining whether the MMR vaccine contributed to the pneumonia.
See exhibit 8 at 2-3; Tr. 23-27.
The doctors determined that Rhone was infected with pneumococcus.
Exhibit 7 at 63, 91, 112, 171. There is no doubt that the pneumococcus caused
Rhone’s pneumonia. Tr. 203. The only question raised in this litigation is whether
the MMR vaccine contributed to it.
Near the end of Rhone’s hospitalization, the doctors tested Rhone’s blood
for the presence of titers against 14 serotypes of pneumococcus. For three strands,
Rhone had levels of antibodies that exceeded 1.3 μg/mL, which is considered the
threshold for protective levels. See exhibit 7 at 501 (results dated October 11,
2010); Tr. 97, 327, 334-36 (explaining protective level). One strand was 1.15
μg/mL. Rhone’s titers for the remaining antibodies were less than 1.0 μg/mL.
Exhibit 7 at 501.
After recovering in the hospital, Rhone was discharged on October 18, 2010.
Exhibit 7 at 62-64; see also Tr. 27-28, 58.
5. Medical History after October 2010
Rhone’s pulmonologist, Amanda M. Dove, followed his case for several
months. Exhibit 3 at 8-17. In June 2013, Dr. Dove assessed Rhone as having mild
reactive airway disease. Exhibit 3 at 2. She prescribes medication for an inhaler.
Tr. 46.
In August 2015, a CT scan of Rhone’s chest was normal, except for some
slight scarring. Exhibit 24 at 1. A spirometry test was also normal. Id. at 6; see
also Tr. 193.
Prompted by questions that arose in this litigation, the DePenas obtained
additional information about Rhone’s antibody levels in 2016. This testing
indicated that Rhone’s antibody levels were low to 13 serotypes of pneumococcus.
Exhibit 27; Tr. 455, 489.
At the time of the first hearing, Rhone had improved. He sometimes had
problems breathing and ran slower than his peers. Tr. 35-35, 60. The DePenas
emphasize that after Rhone’s 2010 pneumonia, which followed the MMR
vaccination, Rhone has not had another episode of pneumonia. Tr. 34, 59, 168.
8
6. Operation of the Immune System
A body’s responses to foreign invaders, often called antigens or pathogens,
are controlled by the immune system. See Dorland’s at 1861. Immunologists
generally divide the immune system into two branches: the innate immune system
and the adaptive immune system. Tr. 266.
Innate Immune System. The innate immune system is relatively primitive.
The innate immune system generally recognizes foreign invaders. Tr. 266.
Components of the innate immune system include cytokines, natural killer cells,
and complement. Tr. 214, 225-26.
According to Dr. Romberg, the innate immune system contributes to how
the body responds when pneumococcus becomes infectious. Exhibit P (Dr.
Romberg report) at 3 (citing exhibit S (Brown), exhibit T (Carolyn Mold et al.,
Protection from Streptococcus pneumoniae Infection by C-Reactive Protein and
Natural Antibody Requires Complement But Not Fcγ Receptors, 168 J. of
Immunology 6375 (2002))); Tr. 326-27. Dr. Lokshin stated that Dr. Romberg’s
report nicely described the innate immune system. Tr. 117. Dr. Lokshin also
acknowledged that the “Innate immune system clearly has a very big role in killing
pneumococcus. That’s not in question.” Tr. 467.
Adaptive Immune System. In comparison to the innate immune system, the
adaptive immune system is more advanced. The adaptive immune system
recognizes specific antigens. Tr. 266.
The adaptive immune system contains two types of cells: B cells and T
cells. See Dorland’s at 1084 (defining lymphocyte). Dr. Lokshin and Dr.
Romberg appear to agree about the primacy of B cells in responding to
pneumococcus. 9
B cells. B cells make antibodies. Tr. 267. Antibodies, in turn, can be
classified into different types of immunoglobulin. See Dorland’s at 100.
Antibodies recognize polysaccharides (or sugars). Tr. 269, 461. Antibodies’
ability to respond to polysaccharides is one trait that distinguishes them from T
cells.
9
The dispute is over the role of T cells in the body’s response to a pneumococcus
infection.
9
T cells. The other part of the adaptive immune system is T cells. T cells
derive their name from the thymus, where they mature. Tr. 302; Dorland’s at 1925
(thymus).
T cells are further classified. The basic division is into two groups, known
as cytotoxic T cells and helper T cells. Cytotoxic T cells, which are also known as
CD8+ cells, kill cells that are infected by viruses. Tr. 267, 358. For example,
when the body is infected by cytomegalovirus (“CMV”), cytotoxic T cells respond.
Tr. 435. 10
There are multiple types of helper T cells, also known as CD4+ cells. Th1
cells help cytotoxic T cells kill cells infected with infectious agents, especially
viruses.11 Tr. 267, 296. Th2 cells help B cells. Tr. 268, 297. Th17 cells help cells
at the mucosal level respond to infections by generating interleukin (“IL”) 17. 12
354. Another type of helper T cell makes sure that the immune system does not
overrespond. These helper T cells are known as T regulatory cells. Tr. 137, 268.
Adopting a simile that Dr. Lokshin proposed, Dr. Romberg described helper T
cells as the conductor of an orchestra in that they help other cells do their job. Tr.
267; see also Tr. 102-04.
The crux of the disagreement between Dr. Lokshin and Dr. Romberg
concerns whether T cells contribute to the body’s response to a pneumococcal
infection. Dr. Lokshin opines that T cells have a role in the immune system’s
response. In contrast, Dr. Romberg opines that T cells are expendable. The
following sections are reasons why Dr. Romberg’s opinion is more persuasive.
Standards for Adjudication
In the analysis section below, evidence in this case will be analyzed
according to the following standards of adjudication.
10
In this context, Dr. Romberg was asked hypothetically, if a person developed a CMV
infection within three weeks of an MMR vaccination, could the suppression of the immune
system by MMR contribute to the CMV infection? Dr. Romberg responded that this
“mechanism makes biologic sense.” Tr. 436. Dr. Romberg’s willingness to recognize the
potential adverse consequences to vaccination enhanced his credibility.
11
Without contradiction, Dr. Romberg stated that the measles vaccine can suppress Th1
cells, not Th2 cells. Tr. 421.
12
Interleukins are types of cytokines. Dorland’s at 949. Cytokines, in turn, are proteins
by which cells of the immune system communicate. Id. at 466.
10
Petitioners are required to establish their case by a preponderance of the
evidence. 42 U.S.C. § 300aa–13(1)(a). The preponderance of the evidence
standard requires a “trier of fact to believe that the existence of a fact is more
probable than its nonexistence before [he] may find in favor of the party who has
the burden to persuade the judge of the fact’s existence.” Moberly v. Sec’y of
Health & Human Servs., 592 F.3d 1315, 1322 n.2 (Fed. Cir. 2010) (citations
omitted). Proof of medical certainty is not required. Bunting v. Sec’y of Health &
Human Servs., 931 F.2d 867, 873 (Fed. Cir. 1991).
Distinguishing between “preponderant evidence” and “medical certainty” is
important because a special master should not impose an evidentiary burden that is
too high. Andreu v. Sec’y of Health & Human Servs., 569 F.3d 1367, 1379-80
(Fed. Cir. 2009) (reversing special master’s decision that petitioners were not
entitled to compensation); see also Lampe v. Sec’y of Health & Human Servs., 219
F.3d 1357 (Fed. Cir. 2000); Hodges v. Sec’y of Health & Human Servs., 9 F.3d
958, 961 (Fed. Cir. 1993) (disagreeing with dissenting judge’s contention that the
special master confused preponderance of the evidence with medical certainty).
Special masters are fact finders that use their accumulated expertise to judge
the individual merits of claims. See Hodges, 9 F.3d at 961; Munn v. Sec’y of
Health & Human Servs., 970 F.2d 863, 871(Fed. Cir. 1992). Thus, the probative
value of the evidence, the credibility of the witnesses, and the relative
persuasiveness of the competing medical theories of the case, are within their
purview. Moberly, 592 F.3d at 1326 (“Finders of fact are entitled-indeed,
expected-to make determinations as to the reliability of the evidence presented to
them and, if appropriate, as to the credibility of the persons presenting that
evidence.”); Lampe, 219 F.3d at 1361-62. Special masters may use the Daubert
framework for analyzing the admissibility of scientific, technical, or other
specialized knowledge, and the rules of evidence require the testimony to have a
reliable basis in the relevant discipline. Terran v. Sec’y of Health & Human
Servs., 195 F.3d 1302, 1316 (Fed. Cir. 1999).
The elements of the DePenas’ case are set forth in the often cited passage
from the Federal Circuit’s decision in Althen: “(1) a medical theory causally
connecting the vaccination and the injury; (2) a logical sequence of cause and
effect showing that the vaccination was the reason for the injury; and (3) a showing
of a proximate temporal relationship between vaccination and injury.” Althen v.
Sec’y of Health & Human Servs., 418 F.3d 1274, 1278 (Fed. Cir. 2005).
11
Analysis
To analyze the petitioners’ T cell-centered immunology theory requires both
an understanding of both the parties’ experts’ qualifications and basic principles of
immunology. The analysis below first focuses on the experts’ qualifications, and
second reviews widely accepted principles of immunology related to
pneumococcal infection. With the experts’ qualifications and the basic principles
of immunology as foundations, the analysis goes on to assess the reliability of the
petitioners’ new immunologic theory.
1. Expert Qualifications
In considering the value of opinion testimony, special masters may consider
the offeror’s expertise. See Snyder v. Sec’y of Health & Human Servs., 553 F.
App'x 994, 1000–02 (Fed. Cir. 2014) (special master's finding that respondent's
experts were more persuasive due in part to their current practice in neurology
compared to petitioner’s expert who had no recent practice was not arbitrary or
capricious); see also Copenhaver v. Sec'y of Health & Human Servs., 129 Fed. Cl.
176, 183 (2016) (rejecting argument that special master erred in evaluating the
qualifications of the experts); Tompkins v. Sec’y of Health & Human Servs., 117
Fed. Cl. 713, 719 (2014) (noting special master reasonably articulated one expert’s
relative lack of training and experience as a basis for not crediting the witness);
Holmes v. Sec’y of Health & Human Servs., 115 Fed. Cl. 469, 490 (2014) (stating
the special master was reasonable in considering a testifying expert’s “research
credentials in the field”); Locane v. Sec’y of Health & Human Servs., 99 Fed. Cl.
715, 727 (2011) (finding special master rationally credited an expert with
specialization in the disease in determining when the petitioner’s disease began),
aff’d, 685 F.3d 1375, 1380 (Fed. Cir. 2012).
Here, the primary question is how the body responds to pneumococcal
colonization or infection. This question is about human immunology. Therefore,
the qualifications of the experts are reviewed with an emphasis on immunology.
A. Dr. Lokshin
Dr. Lokshin graduated from medical school and completed a pediatric
internship in Russia. He completed a second pediatric internship in California,
where he also had a pathology residency and a pediatric residency. Exhibit 19
(curriculum vitae).
12
From 1988-90, Dr. Lokshin had a joint fellowship in allergy / immunology
and pediatric pulmonology at the University of Iowa. In describing his expertise in
immunology, Dr. Lokshin emphasized this stage of his medical career. Tr. 64.
After his Iowa fellowship ended, Dr. Lokshin completed another residency
in pediatrics and then completed another fellowship, this time in pediatric
pulmonology. Both of these fellowships were through the University of Missouri-
Columbia School of Medicine, where he also served as an assistant professor in
pediatric pulmonology from 1991 through 1993. Exhibit 19. In 1993, the most
recent of five articles written by Dr. Lokshin was published. Id.; see also Tr. 72.
Dr. Lokshin’s next teaching position was in Connecticut at the Yale-New
Haven School of Medicine. During this time (1993-95), he also served in the
pediatric pulmonology / allergy division within the department of pediatrics at
Danbury Hospital. He first became board certified in pediatric pulmonology in
1996, when he was living in Nevada. Exhibit 19; see also Tr. 62.
For some time after May 1996, Dr. Lokshin taught allergy to medical
students in large lecture classes at the University of Nevada, Reno. Exhibit 19; Tr.
73. Dr. Lokshin’s current teaching involves working with a single student for a
few weeks in his office. Tr. 74. His current employment, which started in 1995, is
working in a practice consisting of two doctors, called Allergy and Asthma
Associates. Exhibit 19; Tr. 63. He usually sees one patient or two patients with
pneumococcal pneumonia each year. Tr. 70.
After the petitioners offered Dr. Lokshin as an expert in the relationship
between “T cells and invasive pneumococcal disease,” the Secretary objected. Tr.
68. The ensuing voir dire brought out that Dr. Lokshin is not board certified in
immunology. He has not received any special training on T cells. Tr. 73. He was
not performing any research. Tr. 72. His work in treating patients with allergies
draws upon his knowledge of immunology because allergy is a subtype of
immunology. Tr. 75-79.
Ultimately, he was recognized as an expert in pediatric pulmonology. He
possesses the minimum qualifications to testify about immunologic concepts
because of his training and experience. However, his testimony on immunologic
topics was presented with the risk of being given less weight because of his
relative lack of experience in immunology. Tr. 80-81.
Dr. Lokshin’s lack of specialized training in immunology affected the
quality of his testimony. When Dr. Lokshin presented the articles on which he
13
relied, he frequently stated that he was not presenting his opinion, he was simply
presenting a view someone else expressed. Tr. 77, 84, 85, 100, 130, 213. While it
is hornbook law that a testifying expert may rely upon the work of another expert if
the testifying expert would normally rely upon the second expert’s work, see
Summit 6, LLC v. Samsung Electronics Co., Ltd., 802 F.3d 1283, 1299 (Fed. Cir.
2015), Dr. Lokshin often left the impression that he did not have the depth of
experience in immunology necessary to evaluate and render an opinion on
immunologic topics.
For example, when asked to explain the components of the innate immune
system, Dr. Lokshin provided a brief answer, but added that if more information
were needed, he would need to research the topic separately. Tr. 214. As another
example, Dr. Lokshin used terminology about the immune system that was at least
unusual, and possibly incorrect.13 He talked about the “three pillars of the immune
system,” referring to the innate immune system, B cells, and T cells. Tr. 115.
Traditionally, however, immunologists divide the immune system into the innate
immune system and the adaptive immune system. See Tr. 266. The adaptive
immune system is further divided into B cells and T cells. 14 Id.
Similarly, Dr. Lokshin’s presentation of articles was extremely cursory.
Despite the undersigned’s recommendation that the petitioners and Dr. Lokshin
discuss a smaller number of articles with a deep level of analysis, petitioners and
Dr. Lokshin more often skimmed the surface of many articles. The petitioners and
Dr. Lokshin would have been better served to focus on fewer articles but discuss
their complicated immunology more thoroughly. Although the undersigned has
reviewed all the articles, more in depth testimony from Dr. Lokshin about the
significance of the articles could have promoted the petitioners’ case.
The intent of these examples is not to catch Dr. Lokshin in small errors, but
explain why he did not appear fluent in the language of immunology. This lack of
fluency, again, gave the impression that Dr. Lokshin had limited experience on
13
Similarly, the petitioners’ briefs sometimes contain phrasing that lacks precision. For
example, petitioners asserted “The immune systems contains two (2) lines of defenses: T cell
lymphocytes (cell mediated immunity) and B cell dependent specific antibodies (humoral
immunity).” Pet’rs’ Preh’g Br. at 5. This statement overlooks the innate immune system. The
petitioners also asserted that “CD4 is a synonym for T cells.” Id. at 9 n.9. Actually, CD4 cells
are a type of T cells. Tr. 358. As explained above, some T cells are not CD4 cells.
14
The way Dr. Lokshin described the immune system is akin to saying that the federal
government of the United States is divided into four components: the Executive Branch, the
Judicial Branch, the Senate, and the House of Representatives.
14
which to base his opinions. This impression, in turn, diminished the overall value
of Dr. Lokshin’s testimony. See Snyder, 553 F. App'x at 1000–02 (noting the
special master did not find persuasive the testimony of expert who read literature to
support his opinion but did not actually treat patients with the relevant disease);
Daubert v. Merrell Dow Pharm., Inc., 43 F.3d 1311, 1317 (9th Cir. 1995) (“[o]ne
very significant fact to consider is whether the experts are proposing to testify
about matters growing naturally and directly out of research they have conducted
independent of the litigation, or whether they have developed their opinions
expressly for purposes of testifying”).
B. Dr. Romberg
Dr. Romberg graduated from Pennsylvania State College of Medicine in
2004. He was a resident in pediatrics at New York University School of Medicine
from 2004 to 2008, with the last year as pediatric chief resident. He completed a
fellowship in allergy and clinical immunology at Yale University from 2008-11.
Tr. 257-59; exhibit GG. 15
In 2011, Dr. Romberg began his teaching career at Yale. He remained at
Yale with various titles and responsibilities until 2015. During this time, he
obtained his board certification in allergy and immunology. He also wrote at least
six papers about immunology, which were published in peer reviewed journals.
Some of the papers focus on B cells. Exhibit GG at 3-5. Through grants, the
National Institute of Health funded his research on human immunology. Tr. 259.
In 2015, he was appointed to the Jeffrey Modell Chair of Pediatric
Immunology Research at Children’s Hospital of Philadelphia. Dr. Romberg
explained that this position gives him indefinite funding for his research on
deficiencies in the immune system. Tr. 260.
Although Dr. Romberg’s primary vocation is research, Tr. 259, he also treats
children whose immune systems are missing parts. Tr. 275. He estimated that he
has treated 40-60 patients with pneumonia, although he did not specify whether the
patients with pneumonia also had defective immune systems and did not specify
whether pneumococcus caused the pneumonia. Tr. 401.
Overall, Dr. Romberg’s knowledge about immunology was impressive. His
demeanor and the content of this testimony demonstrated that he understood how
the human immune system functions to a level of great detail. He took care to be
15
Exhibit GG is an updated version of Dr. Romberg’s curriculum vitae. The previous
curriculum vitae was filed as exhibit B.
15
precise in his wording. See Tr. 358. On immunologic topics, Dr. Romberg was,
simply, a much stronger witness than Dr. Lokshin. See Moberly, 592 F.3d at 1326
(recognizing that special masters are obligated to evaluate the evidence, including
the experts, before them). 16
2. Principles of Immunology Related to Pneumococcal Infection
Because the petitioners maintain that the MMR vaccine impaired Rhone’s
ability to create T cells and the ensuing lack of T cells created a vulnerability to a
pneumococcal infection, their case depends on T cells preventing a pneumococcal
infection in a human being. As expert testimony unfolded, there was little dispute
about the principles underlying the immune system’s response to pneumococcal
infection. Dr. Lokshin agreed with Dr. Romberg about multiple things that
undermine a primary role for T cells in fighting pneumococcal infection.
As outlined below, both Dr. Lokshin and Dr. Romberg agreed that an
effective response to pneumococcal infection requires both the innate immune
system and antibodies from the adaptive immune system. Additionally, Dr.
Lokshin did not dispute that T cells do not respond directly to pneumococcal
infection (most likely because the external surface of pneumococcus is primarily
composed of polysaccharides). Further, Dr. Lokshin did not dispute Dr.
Romberg’s observations regarding humans suffering from X-linked
agammaglobulinemia and severe combined immune deficiency (SCID), which
strongly support the argument that T cells are expendable in the body’s response to
pneumococcal infection. In short, the following concessions by Dr. Lokshin
undermine his ability to maintain that T cells have a significant role in fighting
pneumococcal infection in human beings.
16
As mentioned earlier, the theory that the DePenas and Dr. Lokshin advanced involved
immunology. Therefore, the qualifications of the respective experts in immunology are
paramount. In saying that Dr. Lokshin was not as persuasive on immunology, the undersigned
does not intend to denigrate Dr. Lokshin’s qualifications as a pediatric pulmonologist.
16
A. An Effective Response to Pneumococcal Infection requires both the
Innate Immune System and Antibodies from the Adaptive Immune
System
Throughout this litigation, Dr. Romberg has maintained that in response to
pneumococcal infections, T cells are expendable. In his first report, Dr. Romberg
wrote:
It has been known for more than 6 decades that serum
soluble factors like complement components, C-reactive
protein and immunoglobulins form the basis of human
immunity to Streptococcus Pneumonia. These serum
proteins target the capsular polysaccharide residues that
cover pneumococcus and it is the presence of
pneumo[co]ccal-specific IgG antibodies especially which
confer meaningful protection to blood borne and lung
infections.
Exhibit A at 3. He continued this position in a subsequent report and in his
testimony. Exhibit P at 3; Tr. 273, 418, 439-40.
On the other hand, Dr. Lokshin’s reports and testimony focused on the role
of T cells. E.g., Tr. 215, 485. He attempted to explain that T cells are a part of the
body’s response to a pneumococcal infection. Near the end of the second hearing
day, Dr. Lokshin presented his views on the value of antibodies. He stated:
antibodies “are highly effective. I don’t think anybody disagree[s] with that, and
that’s a pretty old finding that is well established, and there is absolutely no
disagreement about that.” Tr. 460.
Later still in his testimony, Dr. Lokshin also agreed that the innate immune
system also “has [a] very big role in killing pneumococcus. That’s not in
question.” Tr. 467.
With these two passages, Dr. Lokshin has essentially agreed with Dr.
Romberg that an effective response to a pneumococcal infection can come from
the innate immune system and antibodies. The only remaining question is whether
T cells contribute to this response.
B. T Cells Do Not Respond Directly to a Pneumococcal Infection
On a very simple level, antibodies respond to polysaccharides, and T cells
respond to proteins. The capsule of pneumococcus is (mostly) comprised of
17
polysaccharides. See Tr. 216-17 (Dr. Lokshin). Therefore, antibodies (and not T
cells) respond to pneumococcus.
Although the connection between antibodies and polysaccharides and the
lack of connection between T cells and polysaccharides was generally not
disputed, Dr. Romberg explained some of the highly technical experiments
underlying these postulates. For example, he discussed an article reporting on
competitive affinity experiments that demonstrated that T cells cannot see
polysaccharides. 17 Tr. 299-302, 421-24 (both discussing exhibit W (Clifford V.
Harding et al., Effects of pH and polysaccharides on peptide binding to class II
major histocompatibility complex molecules, 88 Proc. of Nat’l Acad. of Sci. of the
United States of America 2740 (1991))). According to the abstract, the Harding
article shows “T-cell independence of polysaccharide antigens.” Exhibit W at
2740.
T cell independence was another way in which the disagreement between
Dr. Lokshin and Dr. Romberg was manifest, particularly in regard to exhibit X
(James J. Mond et al., T Cell-Independent Antigens Type 2, 13 Annual Review
Immunology 655 (1995)). Dr. Lokshin quoted a portion of this article that states:
“All of these studies demonstrated that responses to TI [T cell independent]
antigens could be T cell regulated and/or T cell dependent, despite their inability to
stimulate MHC class II-dependent T cell help; thus their classification as T cell-
independent is not entirely accurate.” Tr. 147 (quoting exhibit X at 663). From
this basis, Dr. Lokshin asserted that T cell independence is a relative term. Tr.
149-50. When asked about this passage, Dr. Romberg stated that T cells can help
B cells make antibodies but producing antibodies that depend on T cells takes four
to six weeks. Tr. 306; Cf. Tr. 419 (Dr. Romberg stating that he had not reviewed
the underlying studies and, therefore, he could not comment on this portion of the
Mond article).
On the other hand, the same Mond article also discussed pneumococcus
specifically. Mond stated: “Early studies with Pneumococcus and other
encapsulated and nonencapsulated organisms established the T cell-independence
of the antibody response to the polysaccharide component.” Exhibit X at 679.
After citing Mond and Harding in his second expert report, Dr. Romberg asserted:
“Carbohydrate antigens like those on pneumococcus belong to the category named
type II T-cell independent antigens.” Exhibit P at 3. When asked in the first
hearing about Dr. Romberg’s classifying pneumococcus as a T cell independent
17
More technically, for a T cell to respond to a foreign invader, an antigen presenting cell
must interact with the invader. Tr. 525; see also Tr. 422-23.
18
antigen, Dr. Lokshin agreed. Tr. 217-18. Dr. Lokshin’s admission that
pneumococcus is a T cell independent antigen undermines much of his opinion.18
Prior to the second hearing, however, petitioners submitted additional
exhibits to further support the possibility that T cells can respond directly to
pneumococcus. See Tr. 466; exhibits 25, tab 7 (Qibo Zhang et al., Low CD4 T
Cell Immunity to Pneumolysin Is Associated with Nasopharyngeal Carriage of
Pneumococci in Children, 195 J. Infect. Dis. 1194 (2007)); exhibit 25, tab 10
(Adam K. A. Wright, Experimental Human Pneumococcal Carriage Augments IL-
17A-dependent T-cell Defence of the Lung, 9(3) PLOS Pathogens 1 (2013));
exhibit 25, tab 11 (Mureithi); Pet’rs’ Posth’g Br. Reply, filed Aug. 26, 2016, at 1-4
(discussing the exhibits submitted between the first and second hearing). In
support of a direct T cell response, petitioners argued T cells can respond to
proteins, and that many capsular proteins have been isolated on the pneumococcal
capsule, thus allowing T cells to see the pneumococcal capsule and respond. Tr.
441-42, 461. This argument, however, led to a nuanced discussion of how T cells
function, a discussion which further highlighted Dr. Romberg’s more thorough
understanding of the human immune system when compared to Dr. Lokshin. Dr.
Romberg did not dispute the presence of proteins outside the pneumococcal
capsule, but did draw on important distinctions that undermined petitioners’
response theory. See Tr. 443. He noted that the proteins outside of the
pneumococcal capsule are not part of the capsule, that although proteins may be
present they are not necessarily targetable by the immune system, and that T cells
cannot see proteins directly, but only interact with them through an antigen-
presenting cell. See Tr. 443, 524-525.
Despite the additional articles providing some evidence to the contrary, Dr.
Lokshin conceded that T cells do not respond directly to pneumococcal infection.
He emphasized that the T cells’ alternate role in attacking pneumococcus,
testifying: “It’s important I think for us because it is not necessarily the T-cells
themselves have [sic] to kill something. They may influence other parts of
immune [sic] system that will do the job; specifically, innate [sic] immune
system.” Tr. 466.
18
On redirect, the petitioners’ attorney attempted to “clarify” this testimony. However,
the exchange between counsel and Dr. Lokshin was confusing and did not provide a persuasive
reason for rescinding Dr. Lokshin’s earlier statement that pneumococcus is a T cell independent
antigen. See Tr. 244-50.
19
C. Human Beings’ Experience with Diseases is Consistent with the
Distinction between T Cells and B Cells
In addition to the persuasive immunological studies cited by Dr. Romberg,
his experience treating people with dysfunctional immune systems allowed him to
add insights about the significance of the difference between T cells and B cells in
preventing diseases. Some people do not produce B cells and they suffer from a
disease known as X-linked agammaglobulinemia. Tr. 275-76. These people
without B cells are vulnerable to pneumococcal infections, which they get
repeatedly unless they receive antibodies. Exhibit J (Ogden C. Bruton,
Agammaglobulinemia, 9 Pediatrics 722 (1952)).
Dr. Romberg interpreted the Bruton article as showing that T cells alone do
not prevent pneumococcal infections. If T cells alone were effective, then the child
reported in the Bruton article would not have suffered multiple pneumococcal
infections. The boy’s improvement after receiving antibodies is further evidence
that the reason for the repeated pneumococcal infections was due to a problem in
the B cells. Tr. 275-76. When asked about this article, Dr. Lokshin agreed that “If
somebody gets antibodies, they will stop getting sick [with pneumococcal
infections].” Tr. 505.
A different situation occurs with people suffering from severe combined
immune deficiency (SCID). People with SCID lack T cells and have either no B
cells or defective B cells. When untreated, they get many infections, including
fungal, viral, parasitic, and pneumococcal infections. After they receive
antibodies, people with SCID do not develop pneumococcal infections, although
they continue to develop other types of infections. Tr. 276-77. Again, Dr. Lokshin
did not disagree with Dr. Romberg on this point, although Dr. Lokshin noted that
the effectiveness of antibodies in responding to pneumococcus does not provide
any information about the effectiveness of T cells. Tr. 460.
3. Petitioners’ New Immunology Theory Related to Pneumococcal Infection
Against this background of well-established and generally accepted precepts
of immunology, Dr. Lokshin proposes a new idea. In Dr. Lokshin’s opinion, a
human being’s response to a pneumococcal infection includes a role for T cells.
Tr. 105, 114-16, 181-82.19 To support this opinion, Dr. Lokshin initially relied
upon murine (mouse) studies and later added articles based on human beings.
19
This step links the MMR vaccine, which can rarely depress the production of T cells, to
a pneumococcal infection.
20
Before examining the support provided by Dr. Lokshin, it bears repeating
that he seems ill-equipped to topple established immunologic ideas, such as T cells
do not respond to polysaccharides. Dr. Lokshin does not routinely treat patients
with immunologic disorders, he does not teach classes of medical school students
in immunology, he does not have any advanced certifications in immunology, and
he does not currently author articles on immunology. In short, when the topic is
cutting-edge immunology, Dr. Lokshin has less qualifications to present new ideas
persuasively.
A. Mouse Studies
In Dr. Lokshin’s initial reports, he cited several articles that reported on
experiments using mice. In these tests, the researchers discovered that mice do
produce T cells in response to a pneumococcal infection. At hearing, Dr. Romberg
agreed that mice respond to pneumococcus infection by having a particular type of
T helper cell, which is known as Th17, produce IL17. Tr. 284, 354, 516.20 Dr.
Lokshin attempted to argue that what happens in mice is what happens in human
beings. Tr. 135.
The Federal Judicial Center (“FJC”) has published a series of guides
designed to “assist judges ... in reaching an informed and reasoned assessment
concerning the basis of expert evidence.” Jerome P. Kassirer & Gladys Kessler,
Preface to Reference Manual on Scientific Evidence, at xv (Federal Judicial
Center, 3d ed. 2011). With respect to animal studies, the FJC offered the following
guidance: “The expert should review similarities and differences in the animal
species in which the compound has been tested and in humans. This analysis
should form the basis of the expert’s opinion as to whether extrapolation from
animals to humans is warranted.” Bernard D. Goldstein and Mary Sue Henifin,
“Reference Guide on Toxicology,” in Reference Manual on Scientific Evidence
(3d ed. 2011) at 661. In considering the usefulness of animal studies, a starting
point is that “there is an overwhelming similarity in the biology of all living things
and a particularly strong similarity among mammals.” Id. at 662. However, this is
not an iron-clad rule as “laboratory animals differ from humans in many ways.”
Id.
20
IL 17 is an interleukin type of cytokine. See Dorland’s at 949. Cytokines, in turn, are
proteins by which cells of the immune system communicate. Id. at 466.
21
In this case, although Dr. Lokshin wanted to extrapolate from mice to
humans, he did not review the similarities and differences between mice and
humans. This leads to a gap in his opinion. 21
Moreover, Dr. Romberg disagreed with Dr. Lokshin’s comparison, stating
that with respect to the response to pneumococcal infections, mice differ from
people. Tr. 285-86; see also Tr. 120 (Dr. Lokshin: “mice are not identical to
humans”), 281 (Dr. Lokshin: “Mouse immunology is not human immunology.”).
Literature supports this differentiation. One article stated that “mice lacking the
Ill7a and Ill7ra genes or, to a lesser extent, the Ill7f gene, are susceptible to a broad
range of infections with bacterial and fungal pathogens at the mucosal surface. In
contrast, human patients lacking a component of IL-17 immunity due to a genetic
defect, have a narrower spectrum of pathogen susceptibility.” Exhibit KK (Sophie
Cypowyj et al., Immunity to infection in IL-17-deficient mice and humans, 42(9)
Eur. J. Immunol. 2246 (2012)) at 2247; see also Tr. 286-87 (Dr. Romberg’s
discussion of Cypowyj).
An editorial presented a similar point, using less complex language. The
authors wrote: “Translation of many other important findings from murine models
to humans has been rather disappointing. This is best exemplified by models of
autoimmunity and cancer immunotherapy where numerous studies showing
promising outcomes in murine models have achieved limited success in a human
setting.” Exhibit NN (Rajiv Khanna and Scott R. Burrows, Human immunology: a
case for the ascent of non-furry immunology, 89 Immunol. and Cell Biology 330
(2011)) at 330. These authors continued: “Confidence in these model systems has
eroded, as we now know that there are significant differences in human physiology
and the immune regulatory pathways from these animal models.” Id.
This evidence has undermined the assumption that Dr. Lokshin appears to
have made about the transferability of mouse studies on pneumococcus to human
beings. Without some reliable showing that an extrapolation from mice to people
is appropriate, the studies based upon mice are not useful.
B. Human Studies
In addition to studies on mice, Dr. Lokshin relied upon human studies to
show that a person’s response to a pneumococcal infection involves T cells. One
21
Dr. Lokshin sometimes suggested that an extrapolation from mice to humans must be
appropriate because otherwise scientists would not conduct experiments on mice. Tr. 135-36;
138. This suggestion is illogical and not persuasive. See Tr. 281.
22
person exploring this possible connection is Richard Malley, a researcher at
Harvard Medical School and Boston Children’s Hospital. Dr. Malley is attempting
to develop a vaccine against pneumococcus that stimulates the production of T
cells. One advantage to this type of vaccine is that one dose of the vaccine could
lead to immunity from many (possibly all) strains of pneumococcus.
There is no doubt that some research is being done in the field. For
example, petitioners submitted an excerpt showing that the National Institutes of
Health has funded research into a T cell based vaccine against pneumococcus.
Exhibit 25, tab 8 (Kristin Leigh Moffitt, Innate and acquired immune responses to
novel pneumococcal T cell antigens, Grantome (January 27, 2017),
http://grantome.com/grant/NIH/K08-AI095352-04); see also Tr. 447-48. Dr.
Lokshin is “optimistic” about this research. Tr. 502.
Petitioners also submitted a press release in which a manufacturing
company, Genocea, touted its progression to “phase 2” for “a novel T cell vaccine”
against pneumococcal colonization. Exhibit 25, tab 9 (GEN-004 for
Pneumococcus, Genocea Biosciences (Feb. 28, 2016),
http://www.genocea.com/pipeline/gen004-for-pneumococcus/). Under some
circumstances, this undergirding could reinforce Dr. Lokshin’s opinion.
However, the company’s phase 2 trials did not show any statistically
significant improvement. Thus, the company suspended further development of
the vaccine. Exhibit 25, tab 9 (Genocea Biosciences); see also Tr. 437-40. This
failure suggests, although one failure does not absolutely prove, that the theory
needs reexamination. See Daubert, 509 U.S. at 593 (recognizing whether a theory
has been tested as one factor that may be considered in evaluating an expert’s
opinion); Terran, 195 F.3d at 1316 (endorsing a special master’s use of Daubert in
the Vaccine Program). Dr. Lokshin acknowledged that research into a T cell based
vaccine is “just too early” and “not moving as fast as we want.” Tr. 501-02;
accord Tr. 472-73 (Dr. Lokshin’s testimony that the Genocea article does not
constitute definitive proof of the effectiveness of a pneumococcus vaccine based
on T cells).
Despite the lack of success in developing a T cell based vaccine against
pneumococcus, Dr. Lokshin relied upon several other articles either written with
Dr. Malley or based upon his work. The goal of developing a T cell based vaccine
is certainly laudatory – a successful T cell based vaccine could protect against
many (maybe all) strains of pneumococcus. The potential benefits, especially in
the regions of the world with less access to medical care, could be immense.
23
However, the worthiness of the pursuit does not automatically make any of Dr.
Malley’s studies a reliable basis for an expert’s opinion.
As previously mentioned, Dr. Lokshin relied upon several articles from Dr.
Malley or Dr. Malley’s associates. The undersigned reviewed this material
multiple times and has considered the testimony from both Dr. Lokshin and Dr.
Romberg about those articles. 22 The articles did not present a persuasive basis for
toppling the generally accepted principle in immunology that a human being’s
response to a pneumococcal infection does not involve T cells.
Althen Analysis
The previous section explains why Dr. Romberg’s opinion was more
persuasive than Dr. Lokshin’s opinion. These reasons include Dr. Romberg’s
superior qualifications in immunology, the well accepted and well demonstrated
idea that T cells cannot recognize polysaccharides, and the undeveloped effort to
overturn immunologic dogma. The remaining task is to place these findings in the
context of the Althen criteria.
To review, the Federal Circuit set forth the petitioner’s burden regarding
causation in off-Table cases as “(1) a medical theory causally connecting the
vaccination and the injury; (2) a logical sequence of cause and effect showing that
the vaccination was the reason for the injury; and (3) a showing of a proximate
temporal relationship between vaccination and injury.” Althen, 418 F.3d at 1278.
1. Prong 3: Timing
The third prong of Althen requires “a showing of a proximate temporal
relationship between vaccination and injury.” Id. As part of their case-in-chief,
the petitioners bear the burden of establishing that the onset of their child’s disease
22
Petitioners noted multiple articles showing relationships between the quantity of T cells
and pneumococcal infection to support the concept that T cells influence other parts of the
immune system to respond to pneumococcus. See exhibits 25 tab 7 (Zhang), 25 tab 10 (Wright),
25 tab 11 (Mureithi); see, e.g., Tr. 475 (discussing exhibit 25 tab 10). For example, Wright states
that “increased rates of pneumococcal carriage in children and clinical cases of pneumonia in
adults were associated with a reduction in circulating . . . T-cells.” Dr. Romberg agreed that
there is likely a relationship, but explained the relationship by stating that T cells probably affect
pneumococcal infection by helping B cells to secrete antibodies – an idea inconsistent with
petitioners’ theory because it highlights the significance of B cells, vice T cells, in responding to
pneumococcal, and creates a timing issue. See Tr. 306 (Dr. Romberg stating that T cells can
help B cells make antibodies, however producing antibodies that depend on T cells takes four to
six weeks); 446, 515.
24
occurred within an acceptable time. Bazan v. Sec’y of Health & Human Servs.,
539 F.3d 1347, 1352 (Fed. Cir. 2008). This formulation implies that the third
prong from Althen actually contains two parts. First, there must be a showing that
a range of time is “acceptable” to infer causation. Second, there must be a showing
that the vaccinee’s disease arose in this acceptable time. Shapiro v. Sec’y of
Health & Human Servs., 101 Fed. Cl. 532, 542–43 (2011), recons. denied after
remand on other grounds, 105 Fed. Cl. 353 (2012), aff’d per curiam, 503 F. App’x
952 (Fed. Cir. 2013).
Before the hearing, the Secretary conceded that Rhone’s pneumococcal
infection developed within a “medically acceptable timeframe.” Resp’t’s Preh’g
Br., filed Jan. 27, 2016, at 23. Thus, the DePenas have met their burden of proof
on this prong.
However, a finding in a petitioner’s favor on prong 3, by itself, does not
mean that the petitioner is entitled to compensation. Hibbard v. Sec’y of Health &
Human Servs., 698 F.3d 1355, 1364 (Fed. Cir. 2012) (holding that the special
master did not err in resolving case based upon the second prong of the Althen
test); Grant v. Sec’y of Health & Human Servs., 956 F.2d 1144, 1148 (Fed. Cir.
1992) (“Temporal association is not sufficient, however, to establish causation in
fact.”). The petitioners are required to establish the first and second Althen prongs,
which is where their case falters.
2. Prong 1: Theory
The first prong from Althen requires the petitioners to establish “a medical
theory causally connecting the vaccination and the injury.” Althen, 418 F.3d at
1278. The Court of Federal Claims has interpreted this portion of Althen as
requiring not simply the presentation of a theory, but the presentation of a
persuasive theory. M.S.B. by Bast v. Sec’y of Health & Human Servs., 117 Fed.
Cl. 104, 123 (2014), appeal dismissed, 579 F. App’x 1001 (Fed. Cir. 2014); Taylor
v. Sec’y of Health & Human Servs., 108 Fed. Cl. 807, 819 (2013).
For the reasons previously set forth, Dr. Lokshin has failed to establish the
reliability of his theory that T cells have a substantive role in a human being’s
response to a pneumococcal infection. The theory Dr. Lokshin advanced seems
contrary to what science knows about the immune system of human beings. It is
not persuasive. Therefore, the petitioners have not met their burden regarding
prong 1.
25
3. Prong 2: Logical Sequence of Cause and Effect
Given that the DePenas have failed to establish prong 1, it follows that they
have also failed to establish prong 2. See Caves v. Sec’y of Health & Human
Servs., 100 Fed. Cl. 119, 134 (2011) (discussing the logical connections between
prongs 1 and 2). Nevertheless, to demonstrate that the entire record has been
reviewed, the following factors have also been considered.
Treating Doctors. In connection with prong 2, the Federal Circuit has
instructed special masters to consider carefully the views of treating doctors.
Capizzano v. Sec’y of Health & Human Servs., 440 F.3d 1317, 1326 (Fed. Cir.
2006). The DePenas conceded that they are “unaware of any statements expressed
by treating doctors that indicate the MMR vaccine caused [Rhone] DePena’s
vulnerability to pneumococcal infection.” Pet’rs’ Preh’g Br., filed Dec. 15, 2016,
at 19. An independent review of the record has also not located any suggestions
that treating doctors linked Rhone’s receipt of the MMR vaccine to his
pneumococcal pneumonia. Thus, this factor does not weigh in the petitioners’
favor.
Challenge-Rechallenge. The Federal Circuit defined a rechallenge event as
one in which “a patient who had an adverse reaction to a vaccine suffers worsened
symptoms after an additional injection of the vaccine.” Capizzano, 440 F.3d at
1322.
Here, Dr. Lokshin initially indicated that Rhone’s case fell into the
challenge-rechallenge paradigm. A foundation for this opinion was an assumption
that Rhone developed a rash shortly after receiving his first dose of the MMR
vaccine. See exhibit 21 (Dr. Lokshin report) at 3; exhibit 8 (Ms. DePena’s
Detailed Statement) at 1. However, further development of the evidence
eliminated this foundation because Rhone’s rash developed approximately one
year after the MMR vaccine.
On cross-examination, Dr. Lokshin graciously recognized that Rhone did not
manifest challenge-rechallenge. Tr. 196. Removing one of the beams of support
for Dr. Lokshin’s opinion results in a slight weakening of his opinion.
Titer levels after the vaccine and more recently. Before the first hearing, the
DePenas submitted the results of testing conducted on October 11, 2010. This
testing, which was conducted after Rhone developed pneumonia, showed that his
IgG antibody titers were below the level to confer immunity for several strains.
Exhibit 7 at 501; see also Tr. 168, 327, 334. Rhone’s parents testified that he has
26
not developed pneumonia after he was hospitalized for pneumonia in 2010. Tr. 34,
59.
From these two facts, Dr. Lokshin drew the inference that the only
difference between Rhone in 2010 and Rhone in the ensuing five years was that
Rhone received the MMR vaccine in 2010. This exposure to the MMR vaccine,
according to Dr. Lokshin’s theory, created a vulnerability in Rhone that was not
present in other times of his life. Tr. 144-45.
Dr. Romberg’s response included an observation that Rhone’s current levels
were not known. Tr. 333-34. Therefore, between the first hearing and the second
hearing, the DePenas had Rhone tested. His antibody levels from 2016 remained
below protective levels for several strains. Exhibit 27; see also Tr. 455, 489. To
Dr. Lokshin, this finding reinforced his conclusion that antibodies cannot be the
only way to prevent infection because if antibodies were the only way to prevent
infection, Rhone would have become infected again. Tr. 489-90, 502-03; see also
exhibit 30 (Dr. Lokshin’s post-hearing expert report) at 7-9; Pet’rs’ Posth’g Reply,
filed Aug. 26, 2016, at 9.
This reasoning is not persuasive. First, the process from colonization to
infection is not understood. Some people develop pneumococcal pneumonia
entirely apart from an MMR vaccination. The factor (or factors) that permitted
pneumococcal infections in those cases could have been present in Rhone. To
isolate the MMR vaccination and consequent decrease in T cells as the reason for
Rhone’s pneumococcal pneumonia seems to overlook many other potentially
contributory factors. For example, the particular bacteria that infected Rhone in
2010 could have been especially virulent and Rhone could have encountered more
mild bacteria since then. See Tr. 251; exhibit I (E. Alonso DeVelasco et al.,
Streptococcus pneumoniae: Virulence Factors, Pathogenesis, and Vaccines, 59(4)
Microbiological Reviews 591 (1995)); exhibit 23 (Dr. Lokshin’s report) at 2. The
variability in type of pneumococcal infection, ranging from relatively mild cases of
ear infections, to full blown pneumonia, further suggests that process from
colonization to infection is complicated.
Second, Dr. Lokshin appears to misunderstand Dr. Romberg’s opinion. Dr.
Lokshin asserted that “The ‘titers’ are the antibody levels that, according to Dr.
Romberg's theory, is the one and only protection from the pneumococcal
infection.” Exhibit 31 at 1. Actually, Dr. Romberg listed parts of the innate
immune system, such as complement, as contributing to the protection against
pneumococcal infection. Exhibit A at 3; exhibit P at 3; Tr. 326-27. These parts of
27
Rhone’s innate immune system could have protected him from further
pneumococcal infection in the past six years. 23
Conclusion
Rhone’s pneumococcal pneumonia inflicted a toll on him and his parents.
His parents demonstrated their concern for Rhone’s well-being during their
testimony and have reached the belief that the MMR vaccine caused the
pneumonia.
However, the evidence does not rise to a “more likely than not” level. The
more persuasive evidence is consistent with a finding that the MMR vaccine did
not alter the effectiveness of Rhone’s innate immune system or his ability to
produce antibodies in response to pneumococcus. Thus, the DePenas have not
established that the MMR vaccine contributed to Rhone’s pneumococcus infection.
The DePenas are not entitled to compensation. The Clerk’s Office is
instructed to issue judgment in accord with this decision.
IT IS SO ORDERED.
S/ Christian J. Moran
Christian J. Moran
Special Master
23
More generally, Dr. Lokshin contended that human beings’ response to pneumococcus
cannot depend on antibodies because the lag in producing antibodies would permit
pneumococcus to flourish and to kill the host. See Tr. 110-11. The innate immune system is a
partial response to Dr. Lokshin. The other part of the response is that pneumococcus
unfortunately has killed many people over the millennia. See Tr. 156-57, 329. The advent of
antibiotics prevents many deaths from pneumococcus. See exhibit 31 (Dr. Lokshin’s second
post-hearing report) at 2; Tr. 218.
28