Re: lymerix question

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Date: 03/27/05

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Date: 27 Mar 2005 13:20:05 -0800

Excerpt:P

"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.""

Magazine: Feature 3
http://www.astralgia.com/magazine/bitterfeud.htm

FEATURE 3

The Bitter Feud over LYMErix
Big Pharma Takes on the Wrong Little Osp

by Pamela Weintraub

Posted July 6, 2001 · Issue 106

--------------------------------------------------------------------------------

Abstract

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.

How did LYMErix gain FDA approval?
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."

And the Bands Play On

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.

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 to 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.

Has medical science sold its soul?
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.
Cary Barnhard grew up in New Jersey, where his senior class voted him
"most unique." He maintains that honor is a polite way of being voted
"most likely to need therapy." After a few misadventures in the music
industry, he started pretending to be a graphic artist. Eventually it
became the truth.

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Endlinks

Borrelia Pathogenesis Research in the Post-Genomic and Post-Vaccine Era
- reviews recent data about the parasite that causes Lyme disease. From
Current Opinion in Microbiology, 2000, 3:86-92. Full text available
from BioMedNet.

Targeting Lyme Disease Bacterium - a brief report of a second major
Borrelia antigen, OspC. From Trends in Biochemical Sciences, 2001,
26:4:222. Full text available from BioMedNet.

Safety and Immunogenicity of a Recombinant Borrelia burgdorferi Outer
Surface Protein A Vaccine Against Lyme Disease in Healthy Children and
Adolescents: A Randomized Controlled Trial - abstract of the study,
published in July 2001 in Pediatrics, buttressing GlaxoSmithKline's
position.

The Prevention of Lyme Disease with Vaccine - concludes that the
vaccine is a safe and effective method of preventing Lyme disease. From
the March 21, 2001 issue of Vaccine.

New Biopharmaceuticals in the USA: Trends in Development and Marketing
Approvals 1995-1999 - examines trends in the development and approval
process for biopharmaceuticals, including LYMErix.

Current Status and Future Trends in Vaccine Regulation: USA - provides
an overview of the current regulatory process and future trends. From
Vaccine, 2001, 19:13-14:1567-1572.

Lyme Disease: Introduction - the Centers for Disease Control site
covers the history, prevention, treatment, diagnosis, and epidemiology
of Lyme disease, including a section on vaccine recommendations.

Vector Ecology Laboratory - covers current research on tick ecology and
tick-borne pathogens.

Tick Research Laboratory - contains lots of information on ticks and
Lyme disease.