|
Uproar over a little-known preservative, thimerosal, jostles U.S.
hepatitis B vaccination policy In 1997, when Frank Pallone, a Democratic
congressman from New Jersey, attached a simple amendment to an FDA
reauthorization bill, he could not have predicted that it would
cause such a commotion two years later. His amendment ran just 133
words. It gave FDA two years to "compile a list of drugs and foods
that contain intentionally introduced mercury compounds and . [to]
provide a quantitative and qualitative analysis of the mercury compounds
in the list.."
The bill later evolved into the landmark FDA Modernization Act
of 1997 (FDAMA) and was signed into law on November 21, 1997. Pallone's
amendment undoubtedly sprang from his long interest in environmental
causes. But he had unwittingly set into motion a chain of events
that would, two years later, bring turmoil to the immunization policy
world and fears of harm to the nation's hepatitis B control effort.
Facts about thimerosal and mercury
Thimerosal is a water-soluble, cream-colored crystalline powder.
It is 49.6% mercury by weight. In the human body, thimerosal is
metabolized to ethylmercury and thiosalicylate. The literature on
thimerosal metabolism and excretion is limited and old. Case reports
have demonstrated toxicity after massive overdoses. Toxicological
information on the chief metabolite of thimerosal, ethylmercury,
is extremely limited.
During the recent controversy over the safety of thimerosal in
vaccines, toxicologists have assumed that the toxicity of ethylmercury
is equivalent to the toxicity of methylmercury. The toxicity of
methylmercury is complex and depends on the type, level, and duration
of exposure. The primary environmental exposure is through consumption
of predator fish. A 6-ounce can of tuna fish contains an average
of 17 micrograms of mercury.
A pediatric dose of hepatitis B vaccine contains 12.5 micrograms.
The major toxicity of mercury is manifested in the central nervous
system. Forty years ago, when women at Minamata Bay, Japan, ate
fish contaminated with methylmercury from pollutants, their children
were exposed to high levels in utero and were born with severe developmental
and neurological disorders. Methylmercury poisoning also occurred
in Iraq following consumption of seed grain that had been treated
with a fungicide containing methylmercury.
In both the Japanese and Iraqi episodes, exposures to methylmercury
were very high. Two population-based studies are often cited as
the basis for calculations on the neurotoxicity of mercury in utero.
In the first, a study from the Seychelles, infants were exposed
to mercury in utero when their mothers ate a high daily consumption
of methylmercury-containing fish. The mothers had mean mercury levels
in hair of 6.8 ppm. No developmental defects were detected. In the
second, a study from the Faroe Islands, infants were born to mothers
with mean hair levels of 4.3 ppm.
In contrast to the Seychelles mothers, these mothers were exposed
to mercury through intermittent "bolus" consumption of pilot whale
meat. Lower scores on memory, attention, and language tests were
associated with methylmercury exposure in the children (see Mercury
Study Report to Congress, EPA, 1997).
Thimerosal, old soldier under a cloud
At first glance, someone looking for a controversy would not choose
thimerosal. It has been used as a vaccine preservative since the
1930s, and, until recently, it has generally been viewed as a safe,
reliable, and somewhat drab defender against bacterial and fungal
contamination. The compound garners only one short paragraph in
the 1249-page Plotkin and Orenstein reference book, Vaccines 3rd
Edition (1999). Thimerosal is sometimes added to vaccines during
manufacturing as a guarantee against production-related contamination.
Its greatest value, however, is in the field, where it acts as a
fail-safe against imperfect aseptic handling. It is especially valuable
for multidose vaccine vials, in which the re-entry of needles greatly
increases the risk of bacterial introduction.
Thimerosal's only competitor, 2-phenoxyethanol, is less effective
than thimerosal in suppressing potential contaminants like Pseudomonas
aeruginosa, E. coli, and Staph. aureus, according to data presented
by Dr. Stanley Plotkin at an August workshop on thimerosal safety
held at the National Institutes of Health. The problem with thimerosal
is that it contains 49.6% mercury by weight. At high exposure levels,
mercury causes neurotoxicity in humans, especially in fetuses and
small infants whose brains are still developing.
But because of thimerosal's long track record as a defender against
vaccine contamination disasters, discarding it is not easy. CBER
mercury analysis triggered fears Over a year went by before the
FDAMA mercury study got any public attention at FDA. Finally, on
December 14, 1998, just 11 months before the congressional deadline,
the agency published a notice in the Federal Register requesting
manufacturers to provide data on mercury content. The agency published
a second, more specific request on April 29, 1999.
The work of analyzing the vaccine data fell to FDA's Center for
Biologics Evaluation & Research (CBER). Officials at CBER were aware
that thimerosal had surfaced as a safety issue in Europe. In June
1999, the "European FDA", called the Agency for the Evaluation of
Medicinal Products (EMEA), completed an 18-month inquiry into the
risks and benefits of using thimerosal in vaccines. EMEA concluded
that "although there is no evidence of harm caused by the level
of exposure from vaccines, it would be prudent to promote the general
use of vaccines without thimerosal.."
One of CBER's first tasks was to simply add up the total amount
of mercury given to children through vaccines in the US immunization
schedule. Although it may seem surprising that CBER had not done
this before, CBER's mission, to ensure the purity, potency, safety,
and efficacy of individual products, would never have required such
an analysis. CBER researchers soon confirmed that thimerosal was
present in over 30 licensed vaccines in the US in concentrations
of 0.003% to 0.01%. According to the agency's calculations, an infant
six months old who got all vaccine doses on schedule would receive
75 micrograms of mercury from three doses of DTaP, 75 micrograms
from three doses of Hib, and 37.5 micrograms from three doses of
hepatitis B vaccine - a total of 187.5 micrograms of mercury.
But was this enough mercury to worry about? The analysts next tried
to compare the calculated mercury intake with federal guidelines
for safe mercury intake, but they immediately ran into difficulty.
Thimerosal is metabolized in humans to ethylmercury, but all guidelines
for safe mercury intake relate only to methylmercury. No guideline
exists for the ethyl compound. Indeed, the literature on ethylmercury
toxicity is so scant that toxicologists do not even know whether
ethylmercury is more or less toxic than its methyl cousin. Left
with no choice, CBER analysts assumed that the toxicity of the ethyl
compound is equivalent to the methyl compound.
Armed with this assumption, they compared the mercury intake from
vaccines in children six months old, 187.5 micrograms, to the suggested
safe limits for methylmercury intake published by three federal
agencies: EPA, FDA, and the Agency for Toxic Substances and Disease
Registry (ATSDR). It was then that they made a remarkable discovery
- the mercury intake through vaccination in the first six months
of life exceeded the limit set by EPA.
Sharpening a double-edged sword
The CBER analysts were concerned. Millions of American children
under six months old had apparently received, and were continuing
to receive, an amount of mercury from vaccines that exceeded a federal
guideline. The finding was potentially serious, but it was muddled
by several factors. First, the three federal agencies that publish
mercury intake guidelines, EPA, FDA, and ATSDR, disagree about the
safe limit. EPA's limit is significantly lower than the FDA and
ATSDR guidelines. The intake of mercury from vaccination exceeded
only the EPA guideline.
Second, EPA's guideline (called the EPA reference dose, or RfD)
is truly cautious. It is based on a single episode of methylmercury
poisoning in Iraq in which 81 children were exposed to high levels
of mercury in utero. EPA calculated the RFD by determining the dose
that produced a 10% prevalence of adverse neurological effects in
the affected children, such as late walking, late talking, and abnormal
neurological scores. The agency then placed a 95% confidence interval
around this dose and divided the lower bound of the interval by
an "uncertainty factor" of 10 to arrive at the RFD CBER's finding
was also clouded by important differences in the nature of exposure
between the Iraqi children and children exposed through vaccination.
The Iraqi children sustained long-term daily prenatal exposures,
while vaccinated children have intermittent intramuscular doses
later in life, as infants. No one, however, could tell CBER exactly
how these exposure differences might affect the potential neurotoxicity
of mercury.
AAP sounds an alarm
In mid-June, CBER's findings came to attention of Dr. Neal A. Halsey,
Director of the Johns Hopkins Institute for Vaccine Safety. Halsey
is a pediatrician and a highly respected vaccine expert. When he
learned of the CBER findings, he was finishing up a four-year term
as chairperson of the AAP Committee on Infectious Diseases, the
committee that determines AAP vaccination policy and edits the renowned
Red Book. Long before he heard about the thimerosal findings, Halsey
had become worried about the progress of vaccination protest groups
in the US
They had chalked up significant successes in discrediting childhood
vaccination. Five months earlier, a network television program had
seriously questioned the nation's hepatitis B vaccination policy
see Hepatitis Control Report, Winter 1998-99 issue). In May, Congress
had held a contentious hearing on the dangers of vaccination (see
Hepatitis Control Report, Spring 1999 issue). News media and political
groups had picked up the anti-vaccination chant.
Halsey feared that the tide was turning against childhood vaccination,
with potentially dangerous consequences. Halsey confirmed CBER's
calculations and did his own research on mercury, consulting with
experts around the country. He became convinced that the findings
were worthy of alarm, and he worried that if they became public
prematurely, vaccination protesters would use them to stage yet
another attack on the nation's immunization programs. Halsey met
with officials at CBER on June 22nd and then called Dr. Walter Orenstein,
director of CDC's National Immunization Program (NIP). Eight days
later, NIP staff flew to Washington to meet with FDA, AAP, and vaccine
manufacturers.
From the start, Halsey and his colleagues at AAP, including the
new chairperson of the Infectious Diseases Committee, Dr. Jon Abramson,
took a strong proactive stance. They argued that physicians should
be told - soon - about the amount of mercury in vaccines and the
conflict with a federal guideline. Hectic negotiations led to AAP-CDC
compromise, but differences lived on CDC was surprised by the urgent
and undoubting position taken by Halsey and his colleagues at AAP.
CDC officials argued that there was no need for precipitous action.
They pointed out that no child was known to be harmed from thimerosal,
and they were loath to undermine confidence in existing vaccines
by labeling some vaccines "bad" (thimerosal-containing) and some
"good" (thimerosal-free). But, in further discussions through the
first few days of July, it became clear that Halsey and AAP would
not retreat - they believed that immediate action was needed. Within
AAP, the issue ascended quickly from Halsey's committee to the executive
board.
AAP executives felt that their members needed more than just information
about thimerosal - they also needed a way to reduce mercury exposure
in their tiny patients. They feared that pediatricians who continued
to administer thimerosal-containing vaccines could face a flurry
of lawsuits, perhaps claiming that children had acquired learning
disabilities from mercury exposure. The discussions quickly veered
toward pushing vaccine doses back from the first six months of life
to a later time, when infants' bodies were larger and better able
to tolerate mercury. Delaying vaccinations against diphtheria-tetanus-pertussis
or Hemophilus influenza type b was not practical or could expose
children to serious infections.
It soon became evident that the delayed vaccine would have to be
hepatitis B. Only two single-antigen pediatric hepatitis B vaccines
exist on the US market, Engerix-B (SmithKline Beecham) and Recombivax
HB (Merck). Both contain thimerosal and 12.5 micrograms of mercury
per 0.5 ml dose. AAP pressed CDC to agree to a delay of the hepatitis
B vaccination series, usually started at birth, for children born
to hepatitis B surface antigen (HBsAg)-seronegative mothers. The
Academy argued that the delay would only be temporary, because both
Merck and SmithKline Beecham had promised that they could quickly
shift manufacturing to thimerosal-free vaccine, perhaps in just
a few months.
FDA had already promised to review applications for thimerosal-free
hepatitis B vaccine rapidly - within 30 days. At the CDC Hepatitis
Branch in Atlanta, Dr. Harold Margolis, Chief of the Branch, and
staff epidemiologist Dr. Eric Mast saw trouble. They and other hepatitis
B control advocates had worked hard since 1991 to make infant vaccination
routine, and it had become a cornerstone of the CDC-ACIP strategy
to eliminate hepatitis B transmission in the US The strategy was
working - hepatitis B rates had fallen consistently since the policy
was implemented.
Margolis and Mast worried that delaying the routine birth dose,
even temporarily, would cause hepatitis B vaccination rates to slide.
Furthermore, once the policy was changed, it could be difficult
to switch back. States were already under pressure from vaccination
protest groups to drop hepatitis B vaccination school entry requirements
(see Hepatitis Control Report, Winter 1998-99 issue). Margolis and
Mast began working furiously to build a case against delaying hepatitis
B vaccination. The CDC hepatitis group felt that AAP had not sufficiently
accounted for the burden of hepatitis B virus (HBV) infection during
childhood.
Mast had estimates showing that, in the years before routine vaccination
began, 45,000 HBV infections had occurred annually in children less
than 10 years old. Of those, 33,000 were in children of HBsAg-seronegative
mothers. CDC also had data from the 1998 National Immunization Survey
suggesting that a delay in the birth dose would decrease hepatitis
B vaccination completion rates by 15% - perhaps even more in infants
born to high-risk mothers.
Negotiations continued with AAP nearly around the clock. Everyone
was becoming exhausted. AAP insisted on a six-month delay of hepatitis
B vaccination for infants of HBsAg-negative moms. CDC resisted.
As the groups continued negotiations over days, worries increased
that the story would leak to the press in an uncontrolled way, triggering
a general vaccination scare. "Everyone worried that, with the vaccination
protest groups looking over our shoulders, if they got the sense
that some [toxicological] standard was broken, all hell would break
loose," said a senior official who worked on the issue.
Speaking later, AAP's Abramson said, "AAP and CDC diverged on the
hepatitis B issue. It was a matter of how safe do you want to be?
. Our perspective was let the individual pediatrician make a judgment
for each family. CDC was looking at it from a public health perspective."
Finally, after a week of late night meetings involving the AAP executive
board, Surgeon General Dr. David Satcher, CDC Director Dr. Jeffrey
Koplan and other CDC officials, FDA, the manufacturers, and others,
the exhausted group struck a compromise.
An AAP-USPHS joint statement was issued on July 7 at 4:15 PM (see
www.aap.org/advocacy/releases/jointvacc.htm). The statement said
in part: Clinicians and parents can take advantage of the flexibility
within the existing schedule for infants born to HBsAg-negative
women to postpone the first dose of hepatitis B vaccine from birth
until two to six months of age when the infant is considerably larger.
Pre-term infants born to HBsAg-negative mothers should similarly
receive hepatitis B vaccine, but ideally not until they reach term
gestational age and a weight of at least 2.5 kilograms. Because
of the substantial risk of disease, there is no change in the recommendations
for infants of HBsAg-positive mothers or of mothers whose status
is unknown.
Also, in populations where HBsAg screening of pregnant women is
not routinely performed, vaccination of all infants at birth should
be maintained, as is currently recommended. A few days later, AAP
issued an "Interim Report to Clinicians" sharpening its own position:
At this time, the only thimerosal-free hepatitis B vaccine available
(COMVAX) also contains Hib vaccine (PRP-OMP). The product is not
approved for use before 6 weeks of age because of decreased response
to the Hib component. For that reason, where available, this thimerosal-free
vaccine may be given to infants born to HBsAg negative women beginning
at the two months visit. If thimerosal-free vaccine is not available,
hepatitis B virus vaccination should be initiated at 6 months of
age.. CDC issued its own supplemental guidance on July 14 (see http://www.cdc.gov/nip/news/thimerosal-guidance.htm),
saying: Many hospitals have instituted policies to vaccinate all
children at birth regardless of HBsAg status as a means of ensuring
that all the infants of HBsAg positive women and infants of women
with an unknown HBsAg status are vaccinated at birth.
These hospitals should continue current policies until procedures
are or can be put in place to guarantee the proper management of
all births to prevent perinatal HBV transmission.. CDC also said
"hepatitis B vaccination at birth should be continued for infants
born to HBsAg-negative mothers belonging to populations at risk
for early childhood HBV infections, including Asian Pacific Islanders,
immigrant populations from countries in which HBV is of high or
intermediate endemicity., and households with persons with chronic
HBV infection." The AAP and CDC policies remain slightly at odds.
AAP prefers that infants of HBsAg-seropositive moms be delayed until
two months if COMVAX is available, or until six months if it is
not. CDC prefers that hepatitis B vaccine be administered according
to the current recommendations of the ACIP, which allow vaccination
to begin at two months .
Reaction in the real world In the weeks after the AAP and CDC statements
were issued, state health departments reacted in a variety of ways.
At least one state, New Hampshire, recommended no change in the
hepatitis B vaccination schedule. At the other extreme, New Mexico
opted for a full one-year delay. Most states have adopted a 2- or
a 2-6 month delay for infants of HBsAg-seronegative women, and many
of those states recommend COMVAX at two months.
Some physicians have criticized the new recommendations. "I can't
believe the Academy doesn't think it has stubbed its toe on this
one," said one prominent Texas pediatrician who is a member of AAP.
"It's too much too fast. I mean, it's crazy." Dr. Paul Offit, chief
of infectious disease at the Children's Hospital of Philadelphia
and a member of ACIP, told The Philadelphia Inquirer that the fear
of trace mercury in vaccines was "a theoretical and unproven problem
which has been elevated to a level of importance that doesn't make
sense."
Others have taken the opposite view - some leaders within AAP believe
that the Academy did not go far enough to protect infants against
mercury. But pediatricians in both camps feel obligated to follow
the new policies for fear of legal liability if they diverge. Informal
surveys indicate that hospitals have changed their hepatitis B vaccination
policies rapidly to comply with the new recommendations, often on
orders from their legal departments.
The consequences have not always been good. Dr. Barbara Watson,
chief of immunization at the Philadelphia City Health Department,
told attendees at the August NIH thimerosal workshop that she personally
knew of three infants of HBsAg-seropositive mothers who missed being
vaccinated in hospital because of confusion caused by the policy
change. At the August NIH workshop, Dr. Eric Mast showed a CDC analysis
estimating that 246 infants of HBsAg-seronegative mothers and 200
infants of mothers with unknown HBsAg status would become infected
nationwide as a result of the new policy, assuming it lasted six
months and produced a 15% to 25% drop in the newborn vaccination
rate.
The aftermath
The nation's most well-known vaccination protester is pleased with
the change in hepatitis B vaccination policy. Barbara Loe Fisher,
President of the National Vaccine Information Center in Vienna,
Virginia, said in a press release that the new policy "will result
in the deaths and injury of fewer babies.. Eliminating mercury from
childhood vaccines is an important safety initiative and we hope
that further evaluation of the cumulative toxic effects of other
vaccine ingredients, such as aluminum used as an adjuvant, will
also be undertaken .."
But a physician from WHO, Dr. John Clements, said at the NIH workshop
that "the US has gone on its due process to identify a problem and
correct it. But there is a knock-on effect which the world must
bear as a consequence." Clements pointed out that only multidose,
multipuncture vaccine vials can be used in developing countries
because of cost and cold-chain considerations. Removing thimerosal
from these vials is not an option for WHO, at least for the next
several years, he said.
The foreseeable future
The long-term effect of the controversy on hepatitis B vaccination
rates remains murky. Vaccine manufacturers have agreed to provide
a plan to eliminate or reduce the mercury content of vaccines as
soon as possible (see editor's postscript). AAP and CDC plan to
monitor immunization practices, immunization coverage, and vaccine
preventable disease levels. ACIP will take up the thimerosal issue
at its October meeting. In an August interview, Dr. Halsey defended
the thimerosal decision-making process used by AAP and CDC. It would
not have been possible to deal with thimerosal in the usual public
forums like ACIP, Halsey said, because the presence of vaccination
protesters would have made rational discussion hopeless. Deliberations
were handled in the only way possible, he said.
But Halsey acknowledged that many of his immunization colleagues
are angry with him and miffed about the way the issue was handled.
Halsey said he does not believe that delaying the first dose of
hepatitis B vaccine in HBsAg-seronegative mothers will have a major
impact. He does worry, however, about the effects, real and perceived,
that mercury may have on vaccinated infants. He pointed out that,
to truly assess infants' exposure to mercury, the intake from thimerosal
must be added to the intake from all other sources, especially maternal
fish consumption. For infants born to women with high mercury consumption,
he said, "no one knows what dose of mercury, if any, from vaccines
is safe.. We can say there is no evidence of harm, but the truth
is no one has looked."
http://www.hepatitiscontrolreport.com/vol/v4n21.html
| 