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“Protecting the health and informed consent rights of
children since 1982.”
KWilliams Note: This is a long article but well worth the time
to read it.
The Bitter Feud over LYMErix
from BiomedNet :The Bitter Feud over LYMErix: Big Pharma Takes
on the Wrong
Little Osp
by Pamela Weintraub
While Glaxo insists that LYMErix is safe and effective,
the questions continue to mount. Is the vaccine provoking a raging, destructive
immune response? Is it turning asymptomatic Lyme into symptomatic forms of infection?
Is the disease definition itself arbitrary or wrong? And, finally, why are
these questions being asked now, after LYMErix has already been released?
---- Heading to Bethesda this past January for the Food
and Drug Administration’s (FDA) meeting on the Lyme disease vaccine LYMErix, I expected
a somber and orderly affair. Instead, for the price of gas and tolls from New
York, I bought a ringside seat at a raucous, riotous, and bitter free-for-all
worthy of Jerry Springer. Before the meeting was through, enraged FDA panel
members questioning the manufacturer, GlaxoSmithKline, would alternately yell
and laugh at the company’s experts, sometimes making such pointed fun of them I
thought I was at a roast. When the FDA advisors were done, a lineup of furious,
litigious patients - the “LYMErix vaccine victims” - delivered testimony both
shocking and heartbreakingly sad. Yet in the end, LYMErix was left standing.
Without asking for so much as a label change, the FDA charged GlaxoSmithKline
with the task of submitting more data and validating the vaccine’s worth. Was there
a method to this madness? The answers, I would learn, lay in the politics of
drug approvals, a protracted debate about Lyme disease, and the bizarre saga of
a molecule called OspA.
The most common vector-borne illness in the United States,
Lyme disease, is caused by the spirochete bacterium Borrelia burgdorferi (Bb),
and is spread by the Ixodes tick. About 16,000 new cases a year are reported to
the Centers for Disease Control and Prevention (CDC), a figure the CDC itself estimates
may represent 10 to 20 percent of those meeting its surveillance criteria,
although no recent study pinpoints the number exactly. With about 100,000 new
cases a year meeting the CDC’s strict standard, and an uncertain number of
infected individuals the agency says fall outside those parameters, this group
presents an important health concern. The reason is that while Lyme disease is
usually easily cured if treated early on, late or partial treatment can leave
patients extremely ill or even disabled, their arthritic, neuropsychiatric, or
gastrointestinal symptoms lasting for months to years.
The problem is compounded by debates over who qualifies
for diagnosis at all. The question is so difficult because Bb bacteria are
elusive, quickly leaving the bloodstream for tissue of the joints or brain.
Tests must, therefore, detect the organism indirectly through measurement of an
immune response that varies according to bacterial strain, the infected
individual, and stage of the disease. Because there were so many different
tests and diagnostic standards in the early 1990s, chaos reigned. All agreed
the uncertainty called for new, more accurate testing. And no one wanted to settle
the confusion through standardization more than SmithKline Beecham, at the time
the parent company for LYMErix. Without an official definition, after all, the
company could not tell the difference between adverse event and vaccine
failure. Without a definition, it would be impossible to conduct clinical
trials or move a product toward approval at the FDA.
The case definition includes a two-step diagnostic test.
To resolve the matter, the company, the CDC, and the FDA
got together in the spring of 1994 and agreed upon a case definition, including
a two-tier diagnostic test based on measurement of antibody response in the
blood. In the first step, an ELISA (enzyme-linked immunoabsorbent assay),
scientists looked for antibodies responsive to a mixture of whole-cell Bb
spirochetes. Because the mixture
included not just proteins specific to the microbe, but others found more
widely, the scientists adopted a second, confirmatory test, a Western blot that
detected a smaller, more specific set of antigens; these antigens (and the
Western blot bands that represented them) were derived from a statistical
analysis of patients in a study conducted by the vaccine’s chief investigator,
Allen Steere, the Yale University rheumatologist who first recognized Lyme disease
in Connecticut and now heads the Rheumatology and Immunology Department at the
New England Medical Center, Tufts University School of Medicine.
Five months later, in October, the same two-step
serological standard was adopted for surveillance and research purposes in
Dearborn, Michigan, at the Second National Conference on Lyme Disease Testing,
sponsored by the Association of State and Territorial Public Health Laboratory
Directors and the CDC. The most divisive part of the two-step diagnostic
standard - now called the Dearborn criteria - was elimination from the Western
blot of two Bb proteins, outer surface protein A (OspA), from which LYMErix was
made, and outer surface protein B (OspB), the intended component of next-generation
vaccines. For the vaccine trials, this made sense. In a universe of the
vaccinated, testing for OspA antibodies would only serve to blur the line
between inoculation and disease. But removal of OspA and OspB for other
purposes was viewed with alarm by many practitioners, who knew these proteins
were specific to Lyme disease and sometimes the only markers present in those
with late-stage disease.
Many of the sickest patients no longer meet the standard.
“The CDC said the standard was not to be used for
diagnosis,” said Nick Harris, president of IgeneX, a California reference
laboratory that tests for vector-borne diseases, “but they did not seem to
realize how difficult they were making that choice for local physicians, who
look to CDC definitions for guidance and take test results at face value -
positive or negative - without reading between the lines. Without OspA or OspB
to serve as markers, many of the sickest patients no longer met any diagnostic standard,”
Harris says. “By excluding these patients from diagnosis, we excluded them from
treatment as well.”
One of the most political molecules in the history of
science, OspA has, since those early days, become a cause celebre in the
embattled world of Lyme disease. Was OspA removed from the Dearborn definition
by power players who callously disregarded the sickest of the sick to enable a
vaccine to be developed, as many angered physicians believe to this day? Or, as
asserted by the CDC and the Dearborn voting panel, was the definition used in
both venues because it was, in fact, the most precise?
War Room at Versailles: Concerns over approval were
legion.
Whatever the answer, it was under the umbrella of the
Dearborn criteria that LYMErix journeyed through the product pipeline and
finally received a pass from FDA scientists in the Versailles Room of the
Bethesda Holiday Inn in May of 1998. But the stamp of approval was about as
ambivalent as members of the committee had ever seen. In fact, despite the go-ahead,
concerns were legion. Some panel members wondered whether the OspA vaccine
would prevent accurate diagnosis of Lyme disease caught after protection wore
off. Others worried that LYMErix might cause relapses in those with previously
diagnosed Lyme disease, or worsen symptoms in those with current Lyme disease.
The biggest concern was voiced by the chief investigator, Allen Steere.
Findings from his lab at Tufts University suggested the possibility that
LYMErix could cause a particularly onerous form of treatment-resistant Lyme arthritis
in people with a gene called HLA-DR4, present in about 30 percent of the U.S.
population and linked to severe rheumatoid arthritis. Published a few months
later in the journal Science, Steere’s evidence, while circumstantial, showed a
striking resemblance between a portion of the OspA molecule and the human
protein, LFA-1. In genetically susceptible individuals, Steere’s theory went, T
cells primed to attack OspA might also recognize and attack human cells lined
with the “molecular mimic,” LFA-1. The
result, Steere suggested, might be autoimmune disease, in which T-cells continued
their attack on the mimic even when OspA was gone. [1].
In the end, the committee signed off, reluctantly,
declaring a leap into the unknown. The group’s sentiment was best expressed by
panel member David Karzon, professor at Vanderbilt University Medical Center: “Those
who did the trial,” he said, “have unearthed some very interesting sinister possibilities
that may or may not be real.”
Given this turbulent history and the hailstorm of lawsuits
that have followed the vaccine’s commercial distribution, it’s no surprise that
this past January, when FDA panelists reconvened in the Versailles Room on the issue
of LYMErix, they were prepared to joust.
There is no sign of autoimmune disease - in mice.
Plentiful ammo was provided by the sponsor (now, following
a merger, called GSK, or GlaxoSmithKline.) To cast doubt on the genetic risk
factor, for instance, GSK scientists had inoculated arthritis-prone mice with
OspA and found no sign of autoimmune disease. Isn’t this study “irrelevant,”
several panel members asked, since the mice had no analog to the human mimic in
question, the protein LFA-1. Glaxo also reviewed a safety study conducted at an
HMO. Unfortunately, the vaccine had had such bad press, the study coordinator
said, that the uptake had been slow - while 25,000 participants were required
for completion, the company had only 2,800 participants to date. How would the
sponsor get so many additional participants in the year remaining, asked a
panel member, “when it is possible that a hearing like this will make people
less comfortable and doctors less comfortable, and there will be a gigantic
falloff. Do you have any idea what is going on?” Finally, the company touted a
pregnancy registry with “no unexpected findings” and only 4 miscarriages out of
13. “You make it sound as though you find no consequences. I don’t consider
that . . . no pattern of anything,” the Mayo Clinic’s Michael O’Fallon fumed.
The comments “really disturb me,” he said. That was when a tall, well-dressed
man swept up to the podium from somewhere in the back and motioned the
presenting scientists away. It was time for damage control, and David Wheadon,
vice president of regulatory affairs at GSK, took charge. “Certainly
spontaneous abortion, within the context of pregnancy, in an overall
population, is not something that is unexpected,” Wheadon told the panel, “and
I think that was, indeed, what was intended to be said.”
Twenty “vaccine victims” told their stories.
The LYMErix vaccine victims could not have engineered it
better if they had written the Glaxo script themselves - the panel was primed
to hear their stories, 20 in all. There was Emily Biegel, who addressed the
panel for her husband, John, vaccinated in April and May of 1999. “Some of you
may have seen him come in with a walker,” she said. An active outdoorsman
before vaccination, John has since been through four hospitalizations, atrophy,
insulin dependence, compression fractures, tremors, and 25 plasmaphoresis treatments.
He is positive for HLA-DR4.
Jenny Marra, a New Jersey hospice nurse positive for
HLA-DR4, said she had been living with “severe joint and muscle pain since
vaccination in 1999. SmithKline did not
include a warning about the potential risk for this information in the product
labeling or inform the health care providers of this concern. Had I known this
I personally would not have taken the vaccine.” Physicians aware of the
political controversy, she added, are turning the LYMErix vaccine victims away “with
statements like, ‘I don’t want to get involved.’”
A “twilight zone” exists between patient testimony and the
sponsor’s denial. Karen Burke, the
mother of two toddlers from the Pocono Mountains of Pennsylvania, said that her
husband, the vigorous owner of a construction business, got his second dose of
LYMErix in July of 1999. By October, he couldn’t roll over in bed. “My standing
joke with him is, honey, at least when our kids are big enough to go to Disney
World you’ll be well enough to sit in a wheel chair, and we’ll get to the front
of the line. It’s not funny, but you have to have some fun in your life,” Burke
said.
Benjamin Luft, a panel member from the Department of
Medicine University Hospital and Medical Center Health Sciences Center at the
State University of New York at Stony Brook, described the “twilight zone” of
the “disconnect” between the patient testimony and the sponsor’s denial of significant
adverse events.
Would he be tempted to try this new vaccine. “The answer,”
said O’Fallon, was emphatically “No!”
“My concern is greater than it was before,” said Patricia
Ferrieri, University of Minnesota Medical School, Minneapolis, a longtime panel
member and the person who chaired the FDA meeting on LYMErix in 1998. “Are we
going to be able to resolve these issues expeditiously, or should you put a moratorium
on the vaccine until you are able to very critically examine what we have. . .
. I’ve never had to say this before,” she told the FDA scientists in the room.
But “in all of the years I’ve been on the committee, I’ve never heard this type
of concern iterated without agency response that has satisfied the
dissatisfying. . . . I consider what we’re dealing with today to be very, very
serious, and I would like to throw back to you the need to reexamine how this
fits into your mission and in the public health realm. There are too many ifs
here for us to feel secure that the answers will be forthcoming . . . you have
to examine where you are and what we owe to the public.”
A metaphor for science-gone-wrong among the tick disease
crowd at the annual Lyme Disease Foundation Conference this past April in
Farmington, Connecticut, LYMErix was, as expected, omnipresent - mentioned in
talk after talk, it functioned as data, as anecdote, as the proverbial wrench
in the works. In fact, the news coming out at the conference and elsewhere
around the country was bizarre. In physician offices, in diagnostic labs, and
now in clinical and controlled studies, LYMErix recipients without any known exposure
to Bb and no symptoms of Lyme disease were testing Dearborn positive. What’s
more, those who once had Lyme seemed to be relapsing into the symptoms of the
disease.
Researchers report the first controlled cases of
arthritis.
Paul Fawcett, director of the immunology laboratories at
the duPont Hospital for Children in Wilmington, Delaware, and a noted expert on
Lyme disease serology, says he’d observed the ability of the OspA vaccine to
provoke a wide range of Borrelia-specific bands on Western blots well before
the product reached market, as patients involved in clinical trials appeared
for routine Lyme disease tests. Fascinated by the phenomenon, he coordinated a study
of 20 adult volunteers, all employees of the hospital, who received three
vaccine doses each and submitted blood for analysis.
As it turned out, the elaborate banding patterns showed up
in all but one subject in Fawcett’s experimental group. In fact, the banding
was so robust that 30 days after the second dose of vaccine, the only two
commercial Western blots then approved by the FDA were “rendered virtually
useless for diagnostic purposes.” On one of the FDA-approved tests, for
instance, he found that OspA vaccinees tested with “antigens covering the whole
length of the strip, so that they were positive for Lyme disease by CDC criteria. These people were so reactive,” adds
Fawcett, “that they often showed 15 to 20 bands,” far more than the minimum
requirement of five. The other FDA-approved Western blot, he notes, “showed
several bands below the OspA region and one dark gray smear of reactivity at
OspA and above.”
What’s more, Fawcett found that the odd patterns were
sometimes accompanied by adverse events. Two of the 20 in his study - one
physician and one therapist - developed severe arthritic pain, and the strange
symptom, not generally seen in Lyme disease itself, of swelling hands. “There’s
absolutely no question these are the result of the vaccine,” Fawcett states. His feeling was only strengthened in yet
another study, this one of children participating in LYMErix clinical trials.
Here, he found the vaccine could literally retrigger or worsen symptoms of the
disease. In one instance, a 16-year old presenting with severe, recurrent
arthritis had been infected at around the time of his third LYMErix dose. “This
was a vaccine failure,” says Fawcett, treatable with antibiotics, “but LYMErix
apparently worsened the course of the disease.” In another instance, a
six-year-old vaccinee with previous, neurological Lyme disease but no evidence
of current infection experienced a full-blown return of symptoms as his banding
pattern bloomed.
What could be going on? Describing himself as a “fan of
data,” Fawcett reviewed his findings and concluded the only explanation was a “hyperactivation”
of the immune system after exposure to the vaccine. “This test group was clean,”
he says of his adult trial, “with absolutely no serological evidence of prior
exposure to B. burgdorferi at baseline. Part of what we see could be cross-reactivity,
with OspA stimulating antibodies that match, even if imperfectly, the Borrelia
burgdorferi bands on the Western blot. But that can’t be all of it.” The rest,
Fawcett theorizes, “may be a generalized, nonspecific, broad-spectrum
activation of the immune system.” It is this phenomenon, he notes, that would
account for adverse events.
LYMErix may retrigger “cured” cases.
A study from Sam Donta, professor of infectious disease at
Boston University School of Medicine, suggests that LYMErix can retrigger old,
presumably “cured” cases of Lyme. Donta says he was alerted to the possibility
after the vaccine hit the market and he began to see, within his own practice, LYMErix
recipients who appeared to have the symptoms of chronic Lyme disease, most
often reported after the third shot. Donta found that these patients tended to
test positive for Lyme bacteria proteins other than Osp-A on Western blots.
Moreover, treating them with antibiotics, he found most got well, just as he
would expect in bona fide cases of the disease. In a formal study of 50 such
patients, 25 within his own practice, Donta has found the observations hold.
Why does he believe these adverse events represent
reactivation of previous Lyme disease instead of the autoimmune reaction
suggested by Steere? “Because in cases
where patients have had Lyme before, the flare-ups induced by the vaccine
caused the same types of symptoms in the same location of the body, revealing a
disease fingerprint specific to each patient, and generally observed in those
who relapse. Either they coincidentally got Lyme disease during the series of
vaccinations, or they had the disease already,” Donta adds. The latter seems
more likely, he says, “because patients have responded to antibiotics after
suffering from their vaccine reaction for months or years.”
Providing a third perspective is rheumatologist Philip J.
Molloy, medical director of Imugen, the Massachusetts diagnostic laboratory
identified by many in the mainstream as the sine qua non for diagnosing
vector-borne disease. Molloy’s investigation, published last year in Clinical
Infectious Diseases, concludes that the problem is not the vaccine, but the
Western blot itself [2]. Like everyone else, Molloy found that vaccination led
a complex pattern of multiple bands, including CDC diagnostic bands, on Western
blots, making it difficult to determine which bands came from the vaccine and
which ones from infection. “It was possible to tell whether or not they had
been vaccinated,” says David Persing, vice president of research for Corixa,
who did the study with Molloy, “but not whether they had Lyme.”
“Dearborn is irrelevant, an artifact.”
To resolve the problem, the researchers have patented an
OspA-less strain of Bb, which they now use to make vaccine-specific ELISAs and
Western blots. “We know the bands that
show up are due to infection,” says Molloy, “when they show up on Western blot
strips made without OspA.” While Molloy says the phenomenon “has yet to be
fully explained,” the theory he favors is degradation of OspA into smaller
fragments and buildup of OspA into larger particles, resulting in Western blot
tests with a diversity of bands that seem to confirm the disease. One
interesting implication of the finding, he adds, is that the banding pattern
chosen at Dearborn may “represent an immune response to OspA, which is being ‘counted’
several times, while other bands presumed to be present are not really there at
all.” In fact, says Molloy, “Dearborn is irrelevant, an artifact of the Western
blot strip” misinterpreted by experts for years. Many of the bands the CDC
considers diagnostic for Lyme disease, he adds, may often appear in reaction to
antibodies for OspA - the very molecule removed as statistically insignificant
in 1994. “We’re working on finding more appropriate banding patterns for our
own tests,” he adds.
Defending the accuracy of the serological criteria adopted
at Dearborn, Ned Hayes, chief of epidemiology at the Bacterial Zoonoses Branch
of the Division of Vector-borne Infectious Diseases at the CDC, says that “the two-stage
testing has close to 100 percent sensitivity in patients with Lyme arthritis
and appears to be somewhat less sensitive in patients with late neurologic
disease.” Moreover, adds Hayes, “we believe that experienced laboratories are
able to discriminate between vaccination and infection in most cases through
careful interpretation of the blot pattern.”
There may be a lot more Lyme out there.
“If the CDC is correct and Dearborn is relevant, then the
vaccine may be triggering an immune response to Borrelia burgdorferi in people
we never recognized as infected with the spirochete, although they were. It
could mean there is a lot more Lyme out there than we ever realized,” says
Harris of IgeneX. “But, if Imugen is right, we need to go back to the drawing
board and determine a new definition for the disease.”
Fawcett takes a middle ground, disputing the notion that
latent infection emerges, but contending the hyperactive banding patterns
represent an immune reaction of serious concern. “This indicates not only that
the vaccine is immunologically reactive,” he says, “but also that the disease
pathology is far more complex than we have understood. Forgive me for being a
scientist,” Fawcett adds, “but these OspA bands are the most interesting thing
to come along in Lyme disease in years.”
As for GlaxoSmithKline, communications director Carmel
Hogan says the company cannot add to the debate about the banding patterns
right now. “We would need more time,” she states, “for our scientists to study
the papers and reports in depth.”
In June 2001, five months after the meeting in Bethesda,
LYMErix is now in data-gathering mode - one aimed at determining whether it
causes irreversible autoimmune disease or other adverse events. Yet the
concerns expressed by the panel members have not been provided to patients, who
must be inoculated with LYMErix to enable the review. According to Robert Ball,
director of the FDA’s Vaccine Adverse Event Reporting System (VAERS), “the stories
that people tell you are terrible and your heart goes out, but you have to look
for patterns in the data to determine whether a problem is really there.”
Especially important to the FDA, Ball explains, are “serious events that result
in life-threatening illness, hospitalization, or disability.” And here, he
says, no clear pattern emerged. “Only a small minority, 85 people or eight
percent, of the reported adverse events following LYMErix administration were
classified as serious, according to this definition,” states Ball. “Of this
group, we have not identified any clear patterns in the reports. The
neurological events were diverse and no single condition predominated. Events
involving stroke were reported, but these events are relatively common in the
older age group in which these events occurred. Only hypersensitivity
reactions, which are uncommonly reported, can be plausibly linked to the
vaccine because of their specific timing and clinical features.”
As to the risk of arthritis, the main concern expressed by
the theoretical work, or the retriggering of Lyme itself, Ball says that, based
on his study of the VAERS reports, no disturbing patterns could be found. “If
there is an effect, it is pretty small,” Ball adds, “and the VAERS system may
not be sensitive enough to pick it out.” To dig deeper, the FDA is planning internal
studies of HLA types and cellular reactivity to OspA. On labeling issues,
including warnings about the possible risk of the arthritis gene or prior Lyme,
the FDA can only say it is “working closely with the sponsor,” but not whether
changes will be made.
Stephen Sheller, the Philadelphia attorney representing
some 250 LYMErix vaccinees in personal injury suits against GlaxoSmithKline,
says Ball is manipulating data “by focusing almost exclusively on ‘serious’
events that result in hospitalization, permanent disability, or death, while
discounting the far more prevalent ‘severe’ event. I’ve been contacted by
hundreds of individuals whose lives have been drastically affected by a chronic
inflammatory process which is neither life-threatening nor requires hospitalization,
and whose permanence has not yet been determined,” Sheller explains. “These
people don’t meet the requirements of the FDA standard, but they do usually fit
the definition of the ‘Grade 3 Severe’ adverse event, defined as a problem that
prevents normal everyday activities, and approved by the FDA for the human
clinical trials of LYMErix. In a young child, for instance, this kind of
reaction would prevent attendance at school or day care, and would cause
parents to seek medical advice. I believe the FDA and GSK have information
demonstrating the true rate of Grade 3 Severe adverse reactions in both adult
and/or pediatric clinical trials to be in excess of 20 percent.” Spearheading a
class action suit seeking labeling changes for LYMErix, Sheller says “this information
must be fully and clearly disclosed to the medical community and to consumers
at once.”
Glaxo insists the vaccine is safe.
His fight with GlaxoSmithKline appears headed to court. “Based
on all our scientific evidence we believe the lawsuits to be without merit and
will defend against them,” states GlaxoSmithKline spokesperson Hogan. “All the evidence
to date from clinical trials and post marketing data establishes LYMErix to be
safe and effective. Over 15,000 people took part in the clinical trials, and
GSK has distributed over 1.3 million doses representing some 400,000 vaccinees,”
Hogan states. (Sheller argues that no more than 100,000 have completed all
three doses.)
“There is no scientific evidence that individuals with HLA
DR4 genotype are at increased risk of developing adverse events from the
product. The company was aware of this theoretical issue and, indeed, this
matter was examined in study participants in clinical trials,” Hogan goes on.
As to Sheller’s assertion that 20 percent of those in the pediatric trial
suffered Grade 3 adverse reaction, she clarifies: “Approximately 20 percent of
the children who participated in the pediatric clinical studies did report
adverse events that were characterized as ‘severe,’ a term that was defined in
the study protocols as ‘preventing normal daily activity.’ But the vast
majority of these reports involved localized injection site events such as
soreness, pain, or swelling that prevented the children from throwing a ball or
playing with others for a limited period of time following vaccination.” Hogan
also notes that “in a study in which 4,087 healthy children between the ages of
4 and 18 were vaccinated, arthritis was no more frequent in those who received
the vaccine than in those who received the placebo.”
For those investigating LYMErix outside the FDA-pharma
circle, the questions just mount. Is the vaccine sparking a devastating
autoimmune reaction that places a third of its recipients at risk for something
much worse, much less treatable, than Lyme disease? Is it igniting asymptomatic
Lyme disease (an entity researchers now say may be as pervasive as the
symptomatic kind), revealing infection with the Bb spirochete to be persistent
or far more common than generally thought? Do the bizarre Western blot patterns
reflect a raging, expansive immune response to the OspA molecule, as Paul
Fawcett believes, suggesting that Lyme disease pathology is still
misunderstood? Or are the bands merely artifacts, testament to gross misinterpretation
of lab results by the field’s leading lights going back years? Are the answers
even knowable in the face of what could be the ultimate nightmare scenario - vaccine
trials performed according to a disease definition that is incomplete,
arbitrary, or wrong? Perhaps most pertinent, why are we asking these questions
now, after the product’s release?
The problem may stem from the race to market LYMErix.
Some insight comes from Alan Barbour, professor of
infectious disease at the University of California at Irvine, and one of two
inventors on the OspA patent that was filed in 1988 by Symbicom AB, a small
Swedish biotech company (now part of AstraZeneca). Though Barbour himself did
not work on the vaccine, he recalls the race to market between two companies,
SmithKline Beecham and Pasteur Merieux Connaught , now Aventis Pasteur (which eventually
dropped out). “That race would be an intriguing topic for an article in the New
Yorker magazine,” he states.
A result of that competition, says one scientist close to
the action, was pressure to complete clinical trials so the vaccine could move
through the approval process. “And in retrospect,” he says, “the approval
itself was rushed, mainly because it was not known how often booster
immunizations would be needed and what the consequences of getting or not
getting the booster would be.”
Government watchdogs say the problem may be conflict of
interest, an issue recently investigated by the General Accounting Office, an
arm of Congress. In a two-part report
released this month (posted online at www.gao.gov/new.items/d01755.pdf
and www.gao.gov/new.items/d01787r.pdf), the GAO found no
profound conflict, stating that “federal agencies generally meet requirements
for disclosure and review of financial interests related to Lyme disease.” Yet
patient advocacy groups hold that, while not illegal, the potential conflicts
of interest on the part of decision makers are of concern. According to “Conflicts
of Interest in Lyme Disease,” a report from the Lyme Disease Association to
which this reporter contributed, the Dearborn panel setting the disease
definition had particular potential for bias. Indeed, the nine voting
consultants hired by CDC included a scientist holding the patent for OspA; the
inventor of the canine Lyme vaccine, Lymevac; the CDC scientist named as
inventor of the “P37/FlaA protein antigen,” with potential for use in next
generation vaccines and diagnostic tests; and Allen Steere, who was both an
author of the study used to generate the case definition and lead investigator
for clinical trials of the vaccine.
The problem may be conflicts of interest within the FDA.
As to the FDA panel that approved LYMErix in 1998, the
report highlights a State University of New York at Stony Brook scientist given
voting rights by the FDA. According to the official transcript, this researcher
disclosed a consulting relationship with the pharmaceutical manufacturer and
received a waiver. However, the transcript does not mention that the scientist
and his colleague, also a researcher at Stony Brook and a voting member of the panel,
were principals of a company with a product line directly dependent on the
availability of the OspA vaccine.
Moreover, the LDA adds, the government and corporate
entities with vested interest in LYMErix and associated Lyme disease products
are vast. U.S. government agencies,
including the CDC, the National Institutes of Health, and the Department of
Defense own partial rights to revenue from more than a third of the 56 U.S.
patents identified as especially significant for Lyme disease vaccines and
tests. What’s more, GSK may not be the only company with revenue rights to
LYMErix. Also poised to derive benefit based on possible interest in the patent
are multinational life science giants Aventis and AstraZeneca.
Attorney Stephen Sheller, meanwhile, compares the LYMErix
situation to the handling of the diet drugs fen-phen and Redux. “These drugs
caused heart valve problems in hundreds of thousands of people before industry
or the FDA chose to act in September of 1997 to protect consumer safety.” In
fact, Sheller notes, a recent editorial in The Lancet documented private FDA communications
that apparently “subverted official procedures” and “suppressed scientific
debate and open review” within the agency in the case of another
GlaxoSmithKline drug, Lotronex. Hogan of GlaxoSmithKline counters that The
Lancet article is misleading. “As with all our medicines and vaccines, we have
and will continue to work closely with FDA, in line with all regulatory
requirements and obligations,” she states. Sheller, however, believes that “the
conduct criticized in The Lancet might be repeating itself with the LYMErix
vaccine.”
But if the powers that be have been spinning Lyme disease
for profit, they have made a bumbling mistake: The hub of the so-called
strategy, the OspA protein, now wreaks havoc, careening through Western blots
like a zany free radical and bringing out more bands than Woodstock. Whether
these bands signal a true immune response or just decades of misinterpretation,
they demand that we cipher their meaning. In doing so, we’ll be forced to
rethink the Dearborn criteria, the meaning of Lyme disease, and the clinical
trials that propelled the vaccine through approval at FDA.
In the end, the problems of LYMErix may be rooted in
something far less organized than insidious - the hubris of medical science,
which has sold its soul to industry for the funding it needs to survive. To be
true to itself, science must acknowledge the gray areas, but to fit the needs
of business, it must deal in black and white. The Nobel Prize-winning
geneticist Barbara McClintock put it best. To do real science, she said,
scientists must have “a dialog with nature.” But to send a product down the FDA
pipeline, it is the outcome, not the dialog, that counts. Experimental design
and disease definition created in the shadows of the drug approval process must,
by McClintock’s standard of science, be forever flawed.
Pamela Weintraub is a former staff writer at Discover,
former editor-in-chief of Omni Internet, and the author of 15 books on health
and science.
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children since 1982.”
KWilliams Note: This is a long article but well worth the
time to read it.
The Bitter Feud over LYMErix
from BiomedNet :The Bitter Feud over LYMErix: Big Pharma
Takes on the Wrong
Little Osp
by Pamela Weintraub
While Glaxo insists that LYMErix is safe and effective,
the questions continue to mount. Is the vaccine provoking a raging, destructive
immune response? Is it turning asymptomatic Lyme into symptomatic forms of infection?
Is the disease definition itself arbitrary or wrong? And, finally, why are
these questions being asked now, after LYMErix has already been released?
---- Heading to Bethesda this past January for the Food
and Drug
Administration’s (FDA) meeting on the Lyme disease vaccine
LYMErix, I
expected a somber and orderly affair. Instead, for the
price of gas and
tolls from New York, I bought a ringside seat at a
raucous, riotous, and
bitter free-for-all worthy of Jerry Springer. Before the
meeting was
through, enraged FDA panel members questioning the
manufacturer,
GlaxoSmithKline, would alternately yell and laugh at the
company’s experts,
sometimes making such pointed fun of them I thought I was
at a roast. When
the FDA advisors were done, a lineup of furious, litigious
patients - the
“LYMErix vaccine victims” - delivered testimony both
shocking and
heartbreakingly sad. Yet in the end, LYMErix was left
standing. Without
asking for so much as a label change, the FDA charged
GlaxoSmithKline with
the task of submitting more data and validating the
vaccine’s worth. Was
there a method to this madness? The answers, I would
learn, lay in the
politics of drug approvals, a protracted debate about Lyme
disease, and the
bizarre saga of a molecule called OspA.
The most common vector-borne illness in the United States,
Lyme disease, is caused by the spirochete bacterium Borrelia burgdorferi (Bb),
and is spread by the Ixodes tick. About 16,000 new cases a year are reported to
the Centers for Disease Control and Prevention (CDC), a figure the CDC itself estimates
may represent 10 to 20 percent of those meeting its surveillance criteria,
although no recent study pinpoints the number exactly. With about 100,000 new
cases a year meeting the CDC’s strict standard, and an uncertain number of
infected individuals the agency says fall outside those parameters, this group
presents an important health concern. The reason is that while Lyme disease is
usually easily cured if treated early on, late or partial treatment can leave
patients extremely ill or even disabled, their arthritic, neuropsychiatric, or
gastrointestinal symptoms lasting for months to years.
The problem is compounded by debates over who qualifies
for diagnosis at all. The question is so difficult because Bb bacteria are
elusive, quickly leaving the bloodstream for tissue of the joints or brain.
Tests must, therefore, detect the organism indirectly through measurement of an
immune response that varies according to bacterial strain, the infected
individual, and stage of the disease. Because there were so many different
tests and diagnostic standards in the early 1990s, chaos reigned. All agreed
the uncertainty called for new, more accurate testing. And no one wanted to settle
the confusion through standardization more than SmithKline Beecham, at the time
the parent company for LYMErix. Without an official definition, after all, the
company could not tell the difference between adverse event and vaccine
failure. Without a definition, it would be impossible to conduct clinical
trials or move a product toward approval at the FDA.
The case definition includes a two-step diagnostic test.
To resolve the matter, the company, the CDC, and the FDA
got together in the spring of 1994 and agreed upon a case definition, including
a two-tier diagnostic test based on measurement of antibody response in the
blood. In the first step, an ELISA (enzyme-linked immunoabsorbent assay),
scientists looked for antibodies responsive to a mixture of whole-cell Bb
spirochetes. Because the mixture
included not just proteins specific to the microbe, but others found more
widely, the scientists adopted a second, confirmatory test, a Western blot that
detected a smaller, more specific set of antigens; these antigens (and the
Western blot bands that represented them) were derived from a statistical
analysis of patients in a study conducted by the vaccine’s chief investigator,
Allen Steere, the Yale University rheumatologist who first recognized Lyme
disease in Connecticut and now heads the Rheumatology and Immunology Department
at the New England Medical Center, Tufts University School of Medicine.
Five months later, in October, the same two-step
serological standard was adopted for surveillance and research purposes in
Dearborn, Michigan, at the Second National Conference on Lyme Disease Testing,
sponsored by the Association of State and Territorial Public Health Laboratory
Directors and the CDC. The most divisive part of the two-step diagnostic
standard - now called the Dearborn criteria - was elimination from the Western
blot of two Bb proteins, outer surface protein A (OspA), from which LYMErix was
made, and outer surface protein B (OspB), the intended component of next-generation
vaccines. For the vaccine trials, this made sense. In a universe of the
vaccinated, testing for OspA antibodies would only serve to blur the line
between inoculation and disease. But removal of OspA and OspB for other
purposes was viewed with alarm by many practitioners, who knew these proteins
were specific to Lyme disease and sometimes the only markers present in those
with late-stage disease.
Many of the sickest patients no longer meet the standard.
“The CDC said the standard was not to be used for
diagnosis,” said Nick Harris, president of IgeneX, a California reference
laboratory that tests for vector-borne diseases, “but they did not seem to
realize how difficult they were making that choice for local physicians, who
look to CDC definitions for guidance and take test results at face value -
positive or negative - without reading between the lines. Without OspA or OspB
to serve as markers, many of the sickest patients no longer met any diagnostic standard,”
Harris says. “By excluding these patients from diagnosis, we excluded them from
treatment as well.”
One of the most political molecules in the history of
science, OspA has, since those early days, become a cause celebre in the
embattled world of Lyme disease. Was OspA removed from the Dearborn definition
by power players who callously disregarded the sickest of the sick to enable a
vaccine to be developed, as many angered physicians believe to this day? Or, as
asserted by the CDC and the Dearborn voting panel, was the definition used in
both venues because it was, in fact, the most precise?
War Room at Versailles: Concerns over approval were
legion.
Whatever the answer, it was under the umbrella of the
Dearborn criteria that LYMErix journeyed through the product pipeline and
finally received a pass from FDA scientists in the Versailles Room of the
Bethesda Holiday Inn in May of 1998. But the stamp of approval was about as ambivalent
as members of the committee had ever seen. In fact, despite the go-ahead,
concerns were legion. Some panel members wondered whether the OspA vaccine
would prevent accurate diagnosis of Lyme disease caught after protection wore
off. Others worried that LYMErix might cause relapses in those with previously
diagnosed Lyme disease, or worsen symptoms in those with current Lyme disease.
The biggest concern was voiced by the chief investigator, Allen Steere.
Findings from his lab at Tufts University suggested the possibility that
LYMErix could cause a particularly onerous form of treatment-resistant Lyme arthritis
in people with a gene called HLA-DR4, present in about 30 percent of the U.S.
population and linked to severe rheumatoid arthritis. Published a few months
later in the journal Science, Steere’s evidence, while circumstantial, showed a
striking resemblance between a portion of the OspA molecule and the human
protein, LFA-1. In genetically susceptible individuals, Steere’s theory went, T
cells primed to attack OspA might also recognize and attack human cells lined
with the “molecular mimic,” LFA-1. The
result, Steere suggested, might be autoimmune disease, in which T-cells continued
their attack on the mimic even when OspA was gone. [1].
In the end, the committee signed off, reluctantly,
declaring a leap into the unknown. The group’s sentiment was best expressed by
panel member David Karzon, professor at Vanderbilt University Medical Center: “Those
who did the trial,” he said, “have unearthed some very interesting sinister possibilities
that may or may not be real.”
Given this turbulent history and the hailstorm of lawsuits
that have followed the vaccine’s commercial distribution, it’s no surprise that
this past January, when FDA panelists reconvened in the Versailles Room on the issue
of LYMErix, they were prepared to joust.
There is no sign of autoimmune disease - in mice.
Plentiful ammo was provided by the sponsor (now, following
a merger, called GSK, or GlaxoSmithKline.) To cast doubt on the genetic risk
factor, for instance, GSK scientists had inoculated arthritis-prone mice with
OspA and found no sign of autoimmune disease. Isn’t this study “irrelevant,”
several panel members asked, since the mice had no analog to the human mimic in
question, the protein LFA-1. Glaxo also reviewed a safety study conducted at an
HMO. Unfortunately, the vaccine had had such bad press, the study coordinator
said, that the uptake had been slow - while 25,000 participants were required
for completion, the company had only 2,800 participants to date. How would the
sponsor get so many additional participants in the year remaining, asked a
panel member, “when it is possible that a hearing like this will make people
less comfortable and doctors less comfortable, and there will be a gigantic
falloff. Do you have any idea what is going on?” Finally, the company touted a
pregnancy registry with “no unexpected findings” and only 4 miscarriages out of
13. “You make it sound as though you find no consequences. I don’t consider
that . . . no pattern of anything,” the Mayo Clinic’s Michael O’Fallon fumed.
The comments “really disturb me,” he said. That was when a tall, well-dressed
man swept up to the podium from somewhere in the back and motioned the
presenting scientists away. It was time for damage control, and David Wheadon,
vice president of regulatory affairs at GSK, took charge. “Certainly
spontaneous abortion, within the context of pregnancy, in an overall
population, is not something that is unexpected,” Wheadon told the panel, “and
I think that was, indeed, what was intended to be said.”
Twenty “vaccine victims” told their stories.
The LYMErix vaccine victims could not have engineered it
better if they had written the Glaxo script themselves - the panel was primed
to hear their stories, 20 in all. There was Emily Biegel, who addressed the
panel for her husband, John, vaccinated in April and May of 1999. “Some of you
may have seen him come in with a walker,” she said. An active outdoorsman
before vaccination, John has since been through four hospitalizations, atrophy,
insulin dependence, compression fractures, tremors, and 25 plasmaphoresis treatments.
He is positive for HLA-DR4.
Jenny Marra, a New Jersey hospice nurse positive for
HLA-DR4, said she had been living with “severe joint and muscle pain since
vaccination in 1999. SmithKline did not
include a warning about the potential risk for this information in the product
labeling or inform the health care providers of this concern. Had I known this
I personally would not have taken the vaccine.” Physicians aware of the
political controversy, she added, are turning the LYMErix vaccine victims away “with
statements like, ‘I don’t want to get involved.’”
A “twilight zone” exists between patient testimony and the
sponsor’s denial. Karen Burke, the
mother of two toddlers from the Pocono Mountains of Pennsylvania, said that her
husband, the vigorous owner of a construction business, got his second dose of
LYMErix in July of 1999. By October, he couldn’t roll over in bed. “My standing
joke with him is, honey, at least when our kids are big enough to go to Disney
World you’ll be well enough to sit in a wheel chair, and we’ll get to the front
of the line. It’s not funny, but you have to have some fun in your life,” Burke
said.
Benjamin Luft, a panel member from the Department of
Medicine University Hospital and Medical Center Health Sciences Center at the
State University of New York at Stony Brook, described the “twilight zone” of
the “disconnect” between the patient testimony and the sponsor’s denial of significant
adverse events.
Would he be tempted to try this new vaccine. “The answer,”
said O’Fallon, was emphatically “No!”
“My concern is greater than it was before,” said Patricia
Ferrieri, University of Minnesota Medical School, Minneapolis, a longtime panel
member and the person who chaired the FDA meeting on LYMErix in 1998. “Are we
going to be able to resolve these issues expeditiously, or should you put a moratorium
on the vaccine until you are able to very critically examine what we have. . .
. I’ve never had to say this before,” she told the FDA scientists in the room.
But “in all of the years I’ve been on the committee, I’ve never heard this type
of concern iterated without agency response that has satisfied the
dissatisfying. . . . I consider what we’re dealing with today to be very, very
serious, and I would like to throw back to you the need to reexamine how this
fits into your mission and in the public health realm. There are too many ifs
here for us to feel secure that the answers will be forthcoming . . . you have
to examine where you are and what we owe to the public.”
A metaphor for science-gone-wrong among the tick disease
crowd at the annual Lyme Disease Foundation Conference this past April in
Farmington, Connecticut, LYMErix was, as expected, omnipresent - mentioned in
talk after talk, it functioned as data, as anecdote, as the proverbial wrench
in the works. In fact, the news coming out at the conference and elsewhere
around the country was bizarre. In physician offices, in diagnostic labs, and
now in clinical and controlled studies, LYMErix recipients without any known exposure
to Bb and no symptoms of Lyme disease were testing Dearborn positive. What’s
more, those who once had Lyme seemed to be relapsing into the symptoms of the
disease.
Researchers report the first controlled cases of
arthritis.
Paul Fawcett, director of the immunology laboratories at
the duPont Hospital for Children in Wilmington, Delaware, and a noted expert on
Lyme disease serology, says he’d observed the ability of the OspA vaccine to
provoke a wide range of Borrelia-specific bands on Western blots well before
the product reached market, as patients involved in clinical trials appeared
for routine Lyme disease tests. Fascinated by the phenomenon, he coordinated a study
of 20 adult volunteers, all employees of the hospital, who received three
vaccine doses each and submitted blood for analysis.
As it turned out, the elaborate banding patterns showed up
in all but one subject in Fawcett’s experimental group. In fact, the banding
was so robust that 30 days after the second dose of vaccine, the only two
commercial Western blots then approved by the FDA were “rendered virtually
useless for diagnostic purposes.” On one of the FDA-approved tests, for
instance, he found that OspA vaccinees tested with “antigens covering the whole
length of the strip, so that they were positive for Lyme disease by CDC
criteria. These people were so
reactive,” adds Fawcett, “that they often showed 15 to 20 bands,” far more than
the minimum requirement of five. The other FDA-approved Western blot, he notes,
“showed several bands below the OspA region and one dark gray smear of
reactivity at OspA and above.”
What’s more, Fawcett found that the odd patterns were
sometimes accompanied by adverse events. Two of the 20 in his study - one
physician and one therapist - developed severe arthritic pain, and the strange
symptom, not generally seen in Lyme disease itself, of swelling hands. “There’s
absolutely no question these are the result of the vaccine,” Fawcett states. His feeling was only strengthened in yet
another study, this one of children participating in LYMErix clinical trials.
Here, he found the vaccine could literally retrigger or worsen symptoms of the
disease. In one instance, a 16-year old presenting with severe, recurrent
arthritis had been infected at around the time of his third LYMErix dose. “This
was a vaccine failure,” says Fawcett, treatable with antibiotics, “but LYMErix
apparently worsened the course of the disease.” In another instance, a
six-year-old vaccinee with previous, neurological Lyme disease but no evidence
of current infection experienced a full-blown return of symptoms as his banding
pattern bloomed.
What could be going on? Describing himself as a “fan of
data,” Fawcett reviewed his findings and concluded the only explanation was a “hyperactivation”
of the immune system after exposure to the vaccine. “This test group was clean,”
he says of his adult trial, “with absolutely no serological evidence of prior
exposure to B. burgdorferi at baseline. Part of what we see could be
cross-reactivity, with OspA stimulating antibodies that match, even if
imperfectly, the Borrelia burgdorferi bands on the Western blot. But that can’t
be all of it.” The rest, Fawcett theorizes, “may be a generalized, nonspecific,
broad-spectrum activation of the immune system.” It is this phenomenon, he
notes, that would account for adverse events.
LYMErix may retrigger “cured” cases.
A study from Sam Donta, professor of infectious disease at
Boston University School of Medicine, suggests that LYMErix can retrigger old,
presumably “cured” cases of Lyme. Donta says he was alerted to the possibility
after the vaccine hit the market and he began to see, within his own practice, LYMErix
recipients who appeared to have the symptoms of chronic Lyme disease, most
often reported after the third shot. Donta found that these patients tended to
test positive for Lyme bacteria proteins other than Osp-A on Western blots.
Moreover, treating them with antibiotics, he found most got well, just as he
would expect in bona fide cases of the disease. In a formal study of 50 such
patients, 25 within his own practice, Donta has found the observations hold.
Why does he believe these adverse events represent
reactivation of previous Lyme disease instead of the autoimmune reaction
suggested by Steere? “Because in cases
where patients have had Lyme before, the flare-ups induced by the vaccine
caused the same types of symptoms in the same location of the body, revealing a
disease fingerprint specific to each patient, and generally observed in those
who relapse. Either they coincidentally got Lyme disease during the series of
vaccinations, or they had the disease already,” Donta adds. The latter seems
more likely, he says, “because patients have responded to antibiotics after
suffering from their vaccine reaction for months or years.”
Providing a third perspective is rheumatologist Philip J.
Molloy, medical director of Imugen, the Massachusetts diagnostic laboratory
identified by many in the mainstream as the sine qua non for diagnosing
vector-borne disease. Molloy’s investigation, published last year in Clinical
Infectious Diseases, concludes that the problem is not the vaccine, but the
Western blot itself [2]. Like everyone else, Molloy found that vaccination led
a complex pattern of multiple bands, including CDC diagnostic bands, on Western
blots, making it difficult to determine which bands came from the vaccine and
which ones from infection. “It was possible to tell whether or not they had
been vaccinated,” says David Persing, vice president of research for Corixa,
who did the study with Molloy, “but not whether they had Lyme.”
“Dearborn is irrelevant, an artifact.”
To resolve the problem, the researchers have patented an
OspA-less strain of Bb, which they now use to make vaccine-specific ELISAs and
Western blots. “We know the bands that
show up are due to infection,” says Molloy, “when they show up on Western blot
strips made without OspA.” While Molloy says the phenomenon “has yet to be
fully explained,” the theory he favors is degradation of OspA into smaller
fragments and buildup of OspA into larger particles, resulting in Western blot
tests with a diversity of bands that seem to confirm the disease. One
interesting implication of the finding, he adds, is that the banding pattern
chosen at Dearborn may “represent an immune response to OspA, which is being ‘counted’
several times, while other bands presumed to be present are not really there at
all.” In fact, says Molloy, “Dearborn is irrelevant, an artifact of the Western
blot strip” misinterpreted by experts for years. Many of the bands the CDC
considers diagnostic for Lyme disease, he adds, may often appear in reaction to
antibodies for OspA - the very molecule removed as statistically insignificant
in 1994. “We’re working on finding more appropriate banding patterns for our
own tests,” he adds.
Defending the accuracy of the serological criteria adopted
at Dearborn, Ned Hayes, chief of epidemiology at the Bacterial Zoonoses Branch
of the Division of Vector-borne Infectious Diseases at the CDC, says that “the two-stage
testing has close to 100 percent sensitivity in patients with Lyme arthritis
and appears to be somewhat less sensitive in patients with late neurologic
disease.” Moreover, adds Hayes, “we believe that experienced laboratories are
able to discriminate between vaccination and infection in most cases through
careful interpretation of the blot pattern.”
There may be a lot more Lyme out there.
“If the CDC is correct and Dearborn is relevant, then the
vaccine may be triggering an immune response to Borrelia burgdorferi in people
we never recognized as infected with the spirochete, although they were. It
could mean there is a lot more Lyme out there than we ever realized,” says
Harris of IgeneX. “But, if Imugen is right, we need to go back to the drawing
board and determine a new definition for the disease.”
Fawcett takes a middle ground, disputing the notion that
latent infection emerges, but contending the hyperactive banding patterns
represent an immune reaction of serious concern. “This indicates not only that
the vaccine is immunologically reactive,” he says, “but also that the disease
pathology is far more complex than we have understood. Forgive me for being a
scientist,” Fawcett adds, “but these OspA bands are the most interesting thing
to come along in Lyme disease in years.”
As for GlaxoSmithKline, communications director Carmel
Hogan says the company cannot add to the debate about the banding patterns
right now. “We would need more time,” she states, “for our scientists to study
the papers and reports in depth.”
In June 2001, five months after the meeting in Bethesda,
LYMErix is now in data-gathering mode - one aimed at determining whether it
causes irreversible autoimmune disease or other adverse events. Yet the
concerns expressed by the panel members have not been provided to patients, who
must be inoculated with LYMErix to enable the review. According to Robert Ball,
director of the FDA’s Vaccine Adverse Event Reporting System (VAERS), “the stories
that people tell you are terrible and your heart goes out, but you have to look
for patterns in the data to determine whether a problem is really there.”
Especially important to the FDA, Ball explains, are “serious events that result
in life-threatening illness, hospitalization, or disability.” And here, he
says, no clear pattern emerged. “Only a small minority, 85 people or eight
percent, of the reported adverse events following LYMErix administration were
classified as serious, according to this definition,” states Ball. “Of this
group, we have not identified any clear patterns in the reports. The neurological
events were diverse and no single condition predominated. Events involving
stroke were reported, but these events are relatively common in the older age
group in which these events occurred. Only hypersensitivity reactions, which
are uncommonly reported, can be plausibly linked to the vaccine because of
their specific timing and clinical features.”
As to the risk of arthritis, the main concern expressed by
the theoretical work, or the retriggering of Lyme itself, Ball says that, based
on his study of the VAERS reports, no disturbing patterns could be found. “If
there is an effect, it is pretty small,” Ball adds, “and the VAERS system may
not be sensitive enough to pick it out.” To dig deeper, the FDA is planning internal
studies of HLA types and cellular reactivity to OspA. On labeling issues,
including warnings about the possible risk of the arthritis gene or prior Lyme,
the FDA can only say it is “working closely with the sponsor,” but not whether
changes will be made.
Stephen Sheller, the Philadelphia attorney representing
some 250 LYMErix vaccinees in personal injury suits against GlaxoSmithKline,
says Ball is manipulating data “by focusing almost exclusively on ‘serious’
events that result in hospitalization, permanent disability, or death, while
discounting the far more prevalent ‘severe’ event. I’ve been contacted by
hundreds of individuals whose lives have been drastically affected by a chronic
inflammatory process which is neither life-threatening nor requires hospitalization,
and whose permanence has not yet been determined,” Sheller explains. “These
people don’t meet the requirements of the FDA standard, but they do usually fit
the definition of the ‘Grade 3 Severe’ adverse event, defined as a problem that
prevents normal everyday activities, and approved by the FDA for the human
clinical trials of LYMErix. In a young child, for instance, this kind of
reaction would prevent attendance at school or day care, and would cause
parents to seek medical advice. I believe the FDA and GSK have information
demonstrating the true rate of Grade 3 Severe adverse reactions in both adult
and/or pediatric clinical trials to be in excess of 20 percent.” Spearheading a
class action suit seeking labeling changes for LYMErix, Sheller says “this information
must be fully and clearly disclosed to the medical community and to consumers
at once.”
Glaxo insists the vaccine is safe.
His fight with GlaxoSmithKline appears headed to court. “Based
on all our scientific evidence we believe the lawsuits to be without merit and
will defend against them,” states GlaxoSmithKline spokesperson Hogan. “All the evidence
to date from clinical trials and post marketing data establishes LYMErix to be
safe and effective. Over 15,000 people took part in the clinical trials, and
GSK has distributed over 1.3 million doses representing some 400,000 vaccinees,”
Hogan states. (Sheller argues that no more than 100,000 have completed all
three doses.)
“There is no scientific evidence that individuals with HLA
DR4 genotype are at increased risk of developing adverse events from the
product. The company was aware of this theoretical issue and, indeed, this
matter was examined in study participants in clinical trials,” Hogan goes on.
As to Sheller’s assertion that 20 percent of those in the pediatric trial
suffered Grade 3 adverse reaction, she clarifies: “Approximately 20 percent of
the children who participated in the pediatric clinical studies did report
adverse events that were characterized as ‘severe,’ a term that was defined in
the study protocols as ‘preventing normal daily activity.’ But the vast
majority of these reports involved localized injection site events such as
soreness, pain, or swelling that prevented the children from throwing a ball or
playing with others for a limited period of time following vaccination.” Hogan
also notes that “in a study in which 4,087 healthy children between the ages of
4 and 18 were vaccinated, arthritis was no more frequent in those who received
the vaccine than in those who received the placebo.”
For those investigating LYMErix outside the FDA-pharma
circle, the questions just mount. Is the vaccine sparking a devastating
autoimmune reaction that places a third of its recipients at risk for something
much worse, much less treatable, than Lyme disease? Is it igniting asymptomatic
Lyme disease (an entity researchers now say may be as pervasive as the
symptomatic kind), revealing infection with the Bb spirochete to be persistent
or far more common than generally thought? Do the bizarre Western blot patterns
reflect a raging, expansive immune response to the OspA molecule, as Paul
Fawcett believes, suggesting that Lyme disease pathology is still
misunderstood? Or are the bands merely artifacts, testament to gross misinterpretation
of lab results by the field’s leading lights going back years? Are the answers
even knowable in the face of what could be the ultimate nightmare scenario - vaccine
trials performed according to a disease definition that is incomplete,
arbitrary, or wrong? Perhaps most pertinent, why are we asking these questions
now, after the product’s release?
The problem may stem from the race to market LYMErix.
Some insight comes from Alan Barbour, professor of
infectious disease at the University of California at Irvine, and one of two
inventors on the OspA patent that was filed in 1988 by Symbicom AB, a small
Swedish biotech company (now part of AstraZeneca). Though Barbour himself did
not work on the vaccine, he recalls the race to market between two companies,
SmithKline Beecham and Pasteur Merieux Connaught , now Aventis Pasteur (which eventually
dropped out). “That race would be an intriguing topic for an article in the New
Yorker magazine,” he states.
A result of that competition, says one scientist close to
the action, was pressure to complete clinical trials so the vaccine could move
through the approval process. “And in retrospect,” he says, “the approval
itself was rushed, mainly because it was not known how often booster
immunizations would be needed and what the consequences of getting or not
getting the booster would be.”
Government watchdogs say the problem may be conflict of
interest, an issue recently investigated by the General Accounting Office, an
arm of Congress. In a two-part report
released this month (posted online at www.gao.gov/new.items/d01755.pdf
and www.gao.gov/new.items/d01787r.pdf), the GAO found no
profound conflict, stating that “federal agencies generally meet requirements
for disclosure and review of financial interests related to Lyme disease.” Yet
patient advocacy groups hold that, while not illegal, the potential conflicts
of interest on the part of decision makers are of concern. According to “Conflicts
of Interest in Lyme Disease,” a report from the Lyme Disease Association to
which this reporter contributed, the Dearborn panel setting the disease
definition had particular potential for bias. Indeed, the nine voting
consultants hired by CDC included a scientist holding the patent for OspA; the
inventor of the canine Lyme vaccine, Lymevac; the CDC scientist named as
inventor of the “P37/FlaA protein antigen,” with potential for use in next
generation vaccines and diagnostic tests; and Allen Steere, who was both an
author of the study used to generate the case definition and lead investigator
for clinical trials of the vaccine.
The problem may be conflicts of interest within the FDA.
As to the FDA panel that approved LYMErix in 1998, the
report highlights a State University of New York at Stony Brook scientist given
voting rights by the FDA. According to the official transcript, this researcher
disclosed a consulting relationship with the pharmaceutical manufacturer and
received a waiver. However, the transcript does not mention that the scientist
and his colleague, also a researcher at Stony Brook and a voting member of the panel,
were principals of a company with a product line directly dependent on the
availability of the OspA vaccine.
Moreover, the LDA adds, the government and corporate
entities with vested interest in LYMErix and associated Lyme disease products
are vast. U.S. government agencies,
including the CDC, the National Institutes of Health, and the Department of
Defense own partial rights to revenue from more than a third of the 56 U.S.
patents identified as especially significant for Lyme disease vaccines and
tests. What’s more, GSK may not be the only company with revenue rights to
LYMErix. Also poised to derive benefit based on possible interest in the patent
are multinational life science giants Aventis and AstraZeneca.
Attorney Stephen Sheller, meanwhile, compares the LYMErix
situation to the handling of the diet drugs fen-phen and Redux. “These drugs
caused heart valve problems in hundreds of thousands of people before industry
or the FDA chose to act in September of 1997 to protect consumer safety.” In
fact, Sheller notes, a recent editorial in The Lancet documented private FDA communications
that apparently “subverted official procedures” and “suppressed scientific
debate and open review” within the agency in the case of another
GlaxoSmithKline drug, Lotronex. Hogan of GlaxoSmithKline counters that The
Lancet article is misleading. “As with all our medicines and vaccines, we have
and will continue to work closely with FDA, in line with all regulatory
requirements and obligations,” she states. Sheller, however, believes that “the
conduct criticized in The Lancet might be repeating itself with the LYMErix
vaccine.”
But if the powers that be have been spinning Lyme disease
for profit, they have made a bumbling mistake: The hub of the so-called
strategy, the OspA protein, now wreaks havoc, careening through Western blots
like a zany free radical and bringing out more bands than Woodstock. Whether
these bands signal a true immune response or just decades of misinterpretation,
they demand that we cipher their meaning. In doing so, we’ll be forced to
rethink the Dearborn criteria, the meaning of Lyme disease, and the clinical
trials that propelled the vaccine through approval at FDA.
In the end, the problems of LYMErix may be rooted in
something far less organized than insidious - the hubris of medical science,
which has sold its soul to industry for the funding it needs to survive. To be
true to itself, science must acknowledge the gray areas, but to fit the needs
of business, it must deal in black and white. The Nobel Prize-winning
geneticist Barbara McClintock put it best. To do real science, she said,
scientists must have “a dialog with nature.” But to send a product down the FDA
pipeline, it is the outcome, not the dialog, that counts. Experimental design
and disease definition created in the shadows of the drug approval process must,
by McClintock’s standard of science, be forever flawed.
Pamela Weintraub is a former staff writer at Discover,
former editor-in-chief of Omni Internet, and the author of 15 books on health
and science.
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