Thimerosal in Vaccines Questions and Answers
Vaccines are safe?
FDA's Center for Biologics Evaluation and Research is responsible for
regulating vaccines in the U.S. Before new vaccines are licensed, they
are tested extensively for safety in the laboratory, in animals, and in
successive stages of human clinical trials called
phases. When a
new vaccine is first tested in humans, a sponsor (a vaccine
manufacturer, academic investigator or other individual or organization)
must first submit an Investigational New Drug Application to FDA. If
data at any stage of clinical development raise significant concerns
regarding the safety of the product, FDA may request additional
information or may halt ongoing or planned studies.
Phase 1 studies typically enroll less than 20 participants and are designed to look for very common adverse events.
Phase 2
studies may include up to several hundred individuals and are designed
to look at the overall safety profile of the vaccine for local reactions
such as redness and swelling at the injection site as well as general
side effects that may occur with some vaccines such as fever. For
phase 3
studies, the sample size is often determined by the number required to
establish efficacy of the new vaccine, which may be in the thousands or
tens of thousands of subjects.
Phase 3 studies are usually of
sufficient size to detect less common adverse events, such as those
occurring at rates of 1 in 100 to 1 in 1000. For vaccines given
concomitantly with other vaccines under the routine immunization
schedules, the safety of new vaccines typically is studied with
concurrent administration of these other vaccines. In addition, FDA
carefully reviews information on the manufacturing process of new
vaccines, and testing is performed on individual lots for safety and
potency. If product development is successful, the completion of all
three phases of clinical development can be followed by submission of a
Biologics License Application (BLA).
Following FDA's review of a license application for a new indication,
the sponsor and FDA usually present their findings to an expert
advisory committee in an open public meeting for comment and advice. The
advisory committee provides advice to FDA on approval or disapproval.
Vaccine approval also requires the provision of adequate information
(labeling) to health care providers and the public on the vaccine's
proper use, including its potential benefits and risks, and its
indications and contraindications.
The safety of new vaccines continues to be monitored following
licensure in several ways. The Vaccine Adverse Event Reporting System,
co-administered by FDA and CDC, is a national passive surveillance
system for the collection of all reports of adverse events following
vaccination. As a spontaneous reporting system, VAERS has several
limitations including under-reporting, incompleteness of reports, lack
of consistent diagnostic criteria, and the inability in most cases to
establish a cause and effect relationship.
VAERS is useful, however, for
raising "red-flags" and subsequently generating hypotheses that can be
tested further in controlled clinical trials or epidemiological studies.
As part of a post-licensure commitment, FDA often asks the manufacturer
to conduct additional clinical studies (sometimes called
phase 4
studies), to further evaluate safety, and to provide this information
to FDA in a timely manner. In addition, controlled epidemiological
studies may be conducted using pre-established large-linked databases,
which have improved ability to evaluate whether rare adverse events are
caused by vaccination. One such system is the Vaccine Safety Datalink,
administered by the CDC.
What are preservatives and why are they added to vaccines?
Preservatives are compounds that kill or prevent the growth of
microorganisms, such as bacteria or fungi. They are used in vaccines to
prevent bacterial or fungal growth in the event that the vaccine is
accidentally contaminated, as might occur with repeated puncture of
multi-dose vials. Vaccines, both in the United States and throughout
other parts of the world, are commonly packaged in multi-dose vials. In
some cases, preservatives are added during manufacture to prevent
microbial growth; with changes in manufacturing technology, however, the
need to add preservatives during the manufacturing process has
decreased markedly.
Preservatives have been used in vaccines for over 70 years. The
requirement for a preservative in multi-dose, multi-entry vials was
placed into the Code of Federal Regulations (21 CFR 610.15) in January
1968. There are exceptions to this requirement for preservative,
primarily involving the live-attenuated viral vaccines.
The general need for preservatives in multi-dose vials has been
underscored by cases in which multi-dose vials that did not contain
preservatives become contaminated during use and caused fatal infections
in vaccine recipients; cf. the Narrative Section on Thimerosal.
What is thimerosal?
Thimerosal is a preservative that has been used in some vaccines
since the 1930's, when it was first introduced by Eli Lilly Company. It
is 49.6% mercury by weight and is metabolized or degraded into
ethylmercury and thiosalicylate. At concentrations found in vaccines, it
meets the requirements for a preservative as set forth by the
United States Pharmacopeia;
that is, it kills the specified challenge organisms and is able to
prevent the growth of the challenge fungi. Prior to its introduction in
the 1930's, data were available in several animal species and humans
providing evidence for its safety and effectiveness as a preservative.
Since then, thimerosal has a long record of safe and effective use
preventing bacterial and fungal contamination of vaccines, with no ill
effects established other than minor local reactions at the site of
injection.
As a vaccine preservative, thimerosal is used in concentrations of
0.003% to 0.01%. A vaccine containing 0.01% thimerosal as a preservative
contains 50 micrograms of thimerosal per 0.5 ml dose or approximately
25 micrograms of mercury per 0.5 mL dose. The use of mercury-containing
preservatives in vaccines has declined markedly since 1999.
FDA is continuing its efforts toward reducing or removing thimerosal
from all existing vaccines. Much progress has been made to date. FDA has
been actively working with manufacturers, particularly those that
manufacture childhood vaccines, to reach the goal of eliminating
thimerosal from vaccines, and has been collaborating with other PHS
agencies to further evaluate the potential health effects of thimerosal.
In this regard, all vaccines routinely recommended for children 6 years
of age or younger and marketed in the U.S. contain no thimerosal or
only trace amounts (1 microgram or less mercury per dose), with the
exception of inactivated influenza vaccine, which was first recommended
by the Advisory Committee on Immunization Practices in 2004 for routine
use in children 6 to 23 months of age.
What has FDA done to address the issue of mercury containing preservatives in vaccines?
Under the FDA Modernization Act (FDAMA) of 1997, FDA carried out a
comprehensive review of the use of thimerosal in childhood vaccines.
Conducted in 1999, this review found no evidence of harm from the use of
thimerosal as a vaccine preservative, other than local hypersensitivity
reactions.
As part of the FDAMA review, FDA evaluated the amount of mercury an infant might receive in the form of
ethylmercury
from vaccines under the U.S. recommended childhood immunization
schedule and compared these levels with existing guidelines for exposure
to
methylmercury, as there are
no existing guidelines for ethylmercury, the metabolite of thimerosal.
At the time of this review in 1999, the maximum cumulative exposure to
mercury from vaccines in the recommended childhood immunization schedule
was within acceptable limits for the methylmercury exposure guidelines
set by FDA, Agency for Toxic Substances and Disease Registry (ATSDR),
and the World Health Organization (WHO). However, depending on the
vaccine formulations used and the weight of the infant, some infants
could have been exposed to cumulative levels of mercury during the first
six months of life that exceeded EPA recommended guidelines for safe
intake of methylmercury. As a precautionary measure, the Public Health
Service (including FDA, National Institutes of Health [NIH], Centers for
Disease Control and Prevention [CDC] and Health Resources and Services
Administration [HRSA]) and the American Academy of Pediatrics issued a
Joint Statement, urging vaccine manufacturers to reduce or eliminate
thimerosal in vaccines as soon as possible. The U.S. Public Health
Service agencies have collaborated with various investigators to
initiate further studies to better understand any possible health
effects from exposure to thimerosal in vaccines.
Available data has been reviewed in several public forums including
the Workshop on Thimerosal, held in Bethesda in August 1999 and
sponsored by the National Vaccine Advisory Committee, two meetings of
the Advisory Committee on Immunization Practices of the CDC, held in
October 1999 and June 2000, and by the Institute of Medicine's
Immunization Safety Review Committee in July 2001 and February 2004.
Data reviewed did not demonstrate convincing evidence of toxicity from
doses of thimerosal used in vaccines. In case reports of accidental
high-dose exposures in humans to thimerosal or ethyl mercury toxicity
was demonstrated only at exposures that were 100 or 1000 times that
found in vaccines.
In its report of October 1, 2001, the IOM's Immunization Safety
Review Committee concluded that the evidence is inadequate to either
accept or reject a causal relationship between thimerosal exposure from
childhood vaccines and the neurodevelopmental disorders of autism,
attention deficit hyperactivity disorder (ADHD), and speech or language
delay. At that time the committee's conclusion was based on the fact
that there were no published epidemiological studies examining the
potential association between thimerosal-containing vaccines and
neurodevelopmental disorders. The Committee did conclude that the
hypothesis that exposure to thimerosal-containing vaccines could be
associated with neurodevelopmental disorders was biologically plausible.
However, additional studies were needed to establish or reject a causal
relationship. The Committee stated that the effort to remove thimerosal
from vaccines was "a prudent measure in support of the public health
goal to reduce mercury exposure of infants and children as much as
possible."
In 2004, the IOM's Immunization Safety Review Committee again
examined the hypothesis that vaccines, specifically the MMR vaccines and
thimerosal containing vaccines, are causally associated with autism. In
this report, the committee incorporated new epidemiological evidence
from the U.S., Denmark, Sweden, and the United Kingdom, and studies of
biologic mechanisms related to vaccines and autism that had become
available since its report in 2001. The committee concluded that this
body of evidence favors rejection of a causal relationship between
thimerosal-containing vaccines and autism, and that hypotheses generated
to date concerning a biological mechanism for such causality are
theoretical only. Further, the committee stated that the benefits of
vaccination are proven and the hypothesis of susceptible populations is
presently speculative, and that widespread rejection of vaccines would
lead to increases in incidences of serious infectious diseases like
measles, whooping cough and Hib bacterial meningitis
FDA is continuing its efforts toward reducing or removing thimerosal
from all existing vaccines. Much progress has been made to date. FDA has
been actively working with manufacturers, particularly those that
manufacture childhood vaccines, to reach the goal of eliminating
thimerosal from vaccines, and has been collaborating with other PHS
agencies to further evaluate the potential health effects of thimerosal.
Since 2001, all vaccines recommended for children 6 years of age and
younger have contained either no thimerosal or only trace amounts, with
the exception of inactivated influenza vaccines, which are marketed in
both the preservative-free and thimerosal-preservative-containing
formulations. Thimerosal-preservative free influenza vaccine licensed
for use in children six to 59 months of age is available in limited
supply. Nevertheless, FDA is in discussions with manufacturers of
influenza vaccine regarding their capacity to increase the supply of
vaccine without thimerosal as a preservative. Additionally, new
pediatric vaccines that have received licensure do not contain
thimerosal.
Why did FDA wait until mandated by Congress under FDAMA 1997 to examine the use of preservatives containing mercury?
Several factors led to examination of mercury-containing
preservatives in childhood vaccines. Over the past decade there has been
increased attention focused on the health effects of human exposure to
mercury, particularly methyl mercury. In 1994, the EPA revised its
Reference Dose (RfD) for methylmercury exposure, lowering its guideline
for safe exposure from 0.3 to 0.1 microgram per kilogram body weight per
day. Prospective studies (in the Seychelles, Faroe Islands and others)
of the effects of low dose exposure to methylmercury in the diet were
published , and some of these studies raised concern that
neurodevelopmental outcomes in children may be subtly affected when
their mothers were exposed to methylmercury from dietary sources at
levels that were previously thought to be safe. Also in the 1990's, the
CDC's Advisory Committee on Immunization Practices (ACIP) and other
recommending bodies added new vaccines (e.g., hepatitis B, Hib), some of
which contained thimerosal as a preservative, to the routine childhood
immunization schedule. Additionally, beginning in 1996, the replacement
of whole cell DTP-Hib combination vaccines with separately administered
DTaP and Hib vaccines increased the amount of thimerosal that some
infants might have received (depending on vaccine formulation(s)
received). In light of efforts by various federal agencies to decrease
human exposure to mercury from various sources, and the potential
increase in infant exposure to thimerosal from vaccines, FDA undertook
review of this issue.
Thus, while enactment of FDAMA 1997 provided an official mechanism
for review of this issue, the use of thimerosal as a preservative in
vaccines had already begun to be considered by FDA. During the past ten
years, FDA has provided informal and formal advice to manufacturers
recommending that new vaccines under development be formulated without
thimerosal as a preservative.
FDA had previously reviewed thimerosal use in biological products,
including vaccines, in 1976. This review evaluated exposure to
thimerosal from biological products using the 1974 American Academy of
Pediatrics "Red Book" immunization schedule and concluded that, with the
exception of long term immune globulin replacement therapy, "no
dangerous quantity of mercury is likely to be received from biologic
products in a lifetime." Of note, immune globulin products licensed in
the U.S. no longer use thimerosal as a preservative.
What progress has been made towards the goal of eliminating thimerosal from vaccines?
Great progress has been made in removing thimerosal from vaccines.
Manufacturers have been able to accomplish this goal through changing
their manufacturing processes, including a switch from multi-dose vials,
which generally require a preservative, to single-dose vials or
syringes. Since 2001, all vaccines manufactured for the U.S. market and
routinely recommended for children ≤ 6 years of age have contained no
thimerosal or only trace amounts (≤ 1 microgram of mercury per dose
remaining from the manufacturing process), with the exception of
inactivated influenza vaccine. In addition, all of the routinely
recommended vaccines that had been previously manufactured with
thimerosal as a preservative (some formulations of DTaP, Haemophilus
influenzae b conjugate (Hib), and hepatitis B vaccines) had reached the
end of their shelf life by January 2003.
In the past, prior to the initiative to reduce or eliminate
thimerosal from childhood vaccines, the maximum cumulative exposure to
mercury via routine childhood vaccinations during the first six months
of life was 187.5 micrograms. With the introduction of
thimerosal-preservative-free formulations of DTaP, hepatitis B, and Hib,
the maximum cumulative exposure from these vaccines decreased to less
than three micrograms of mercury in the first 6 months of life. With the
addition of influenza vaccine to the recommended vaccines, an infant
could receive a thimerosal-containing influenza vaccine at 6 and 7
months of age. This would result in a maximum exposure or 28 micrograms
via routine childhood vaccinations. This level is well below the EPA
calculated exposure guideline for methylmercury of 65 micrograms for a
child in the 5th percentile body weight during the first 6 months of
life.
Currently, all hepatitis vaccines manufactured for the U.S. market
contain either no thimerosal or only trace amounts. Also, DT, Td, and
Tetanus Toxoid vaccines are now available in formulations that contain
no thimerosal or only trace amounts
Furthermore, all new vaccines licensed since 1999 are free of
thimerosal as a preservative. Inactivated influenza vaccine was added to
the routinely recommended vaccines for children 6 to 23 months of age
in 2004. FDA has approved thimerosal–preservative free formulations
(containing either no or only trace amounts of thimerosal) for the
inactivated influenza vaccines manufactured by Sanofi Pasteur and
Chiron. These influenza vaccines continue to be marketed in both the
preservative free and thimerosal-preservative containing formulations.
In addition, in August 2005, FDA licensed GlaxoSmithKline's inactivated
influenza vaccine, which contains 1.25 micrograms mercury per dose. Of
the three licensed inactivated influenza vaccines, Sanofi Pasteur's
Fluzone is the only one approved for use in children down to 6 months of
age. Chiron's Fluvirin is approved for individuals 4 years of age and
older, and GSK's Fluarix is approved for individuals 18 years of age and
older. The live attenuated influenza vaccine (FluMist, manufactured by
MedImmune), which contains no thimerosal, is approved for individuals 5
to 49 years of age. For the 2005-2006 season, Sanofi Pasteur was able to
manufacture up to 8 million doses of thimerosal-preservative free
influenza vaccine. Based on an estimated annual birth cohort in the
United States of 4 million, there are 6 million infants and children
between the ages of 6 and 23 months, most of whom would need two doses
each. Thus, the amount of thimerosal-preservative-free vaccine that is
available based on current manufacturing capacity is well below the
number of doses needed to fully vaccinate this age group. FDA is in
discussions with manufacturers of influenza vaccine regarding their
capacity to further increase the supply of preservative-free
formulations.
Why are some vaccines noted to be
"thimerosal-free" while some are "thimerosal-reduced"? What is the
difference between "thimerosal-free" and "preservative-free"?
Thimerosal may be added at the end of the manufacturing process to
act as a preservative to prevent bacterial or fungal growth in the event
that the vaccine is accidentally contaminated, as might occur with
repeated puncture of multi-dose vials. When thimerosal is used as
preservative in vaccines, it is present in concentrations up to 0.01%
(50 micrograms thimerosal per 0.5 mL dose or 25 micrograms mercury per
0.5 mL dose). In some cases, thimerosal is used during the manufacturing
process and is present in small amounts in the final vaccine (1
micrograms mercury or less per dose).
The term "preservative-free" indicates that no preservative
(thimerosal or otherwise) is used in the vaccine; however, traces used
during the manufacturing process may be present in the final
formulation. For example, some vaccines may be preservative-free but may
contain traces of thimerosal (1 micrograms mercury or less per dose);
in such settings, this information is noted in the package insert.
Similarly, the term "thimerosal-reduced" usually indicates that
thimerosal is not added as a vaccine preservative, but trace amounts (1
micrograms mercury per dose or less) may remain from use in the
manufacturing process. Such trace amounts are not felt to be clinically
significant, nor would they result in exposure exceeding any federal
guideline for mercury exposure. Vaccines may be termed "thimerosal-free"
if no thimerosal can be measured; i.e., thimerosal content is below the
limit of detection.
Why is exposure to mercury a concern?
Mercury is an element that is dispersed widely around the earth. Most
of the mercury in the water, soil, plants and animals is found as
inorganic mercury salts. Mercury accumulates in the aquatic food chain,
primarily in the form of the methylmercury, an organomercurial.
Methylmercury is more easily absorbed and is less readily eliminated
from the body than inorganic mercury. Exposure to one chemical with
mercury, i.e., methylmercury, has been shown to pose a variety of health
risks to humans. Extremely high levels, such as that observed in
poisoning episodes in Japan and Iraq has caused neurological damage and
death. The fetus is considered more sensitive to health effects of
methylmercury than adults. In recent years some studies have found
adverse health effects of methylmercury at levels previously thought to
be safe. Other studies, however, have shown conflicting results.
It is important to note that the preservative thimerosal contains
ethylmercury, a related though distinct chemical from methylmercury.
Moreover, recent studies in animal models exposed to thimerosal
containing vaccines or oral methylmercury suggest that methylmercury may
not be a suitable reference to assess the risk from exposure to
thimerosal (Burbacher et al, 2005). In addition, data from studies in
human infants that were given routine immunizations with
thimerosal-containing vaccines showed that mercury levels in blood and
urine were uniformly below safety guidelines for methyl mercury and that
unlike methylmercury excretory profiles, infants excreted significant
amounts of mercury in stool after thimerosal (ethylmercury) exposure,
thus removing mercury from their bodies (Pichichero ME, et al, 2002).
I understand that the Institute of Medicine
(IOM) has reviewed the issue of thimerosal in vaccines. What were the
IOM's findings?
In its report of October 1, 2001, the IOM's Immunization Safety
Review Committee concluded that the evidence is inadequate to either
accept or reject a causal relationship between thimerosal exposure from
childhood vaccines and the neurodevelopmental disorders of autism,
attention deficit hyperactivity disorder (ADHD), and speech or language
delay. At that time the committee's conclusion was based on the fact
that there were no published epidemiological studies examining the
potential association between thimerosal containing vaccines and
neurodevelopmental disorders. The Committee did conclude that the
hypothesis that exposure to thimerosal-containing vaccines could be
associated with neurodevelopmental disorders was biologically plausible.
However, additional studies were needed to establish or reject a causal
relationship.
The Committee believed that the effort to remove thimerosal from
vaccines was "a prudent measure in support of the public health goal to
reduce mercury exposure of infants and children as much as possible."
Furthermore, in this regard, the Committee urged that "full
consideration be given to removing thimerosal from any biological
product to which infants, children, and pregnant women are exposed."
In 2004, the IOM's Immunization Safety Review Committee again
examined the hypothesis that vaccines, specifically the MMR vaccines and
thimerosal containing vaccines, are causally associated with autism. In
this report, the committee incorporated new epidemiological evidence
from the U.S., Denmark, Sweden, and the United Kingdom, and studies of
biologic mechanisms related to vaccines and autism that had become
available since its report in 2001. The committee concluded that this
body of evidence favors rejection of a causal relationship between
thimerosal-containing vaccines and autism, and that hypotheses generated
to date concerning a biological mechanism for such causality are
theoretical only. Further, the committee stated that the benefits of
vaccination are proven and the hypothesis of susceptible populations is
presently speculative, and that widespread rejection of vaccines would
lead to increases in incidences of serious infectious diseases like
measles, whooping cough and Hib bacterial meningitis.
The IOM urged that "full consideration be
given to removing thimerosal from any biological product to which
infants, children, and pregnant women are exposed" (IOM 2001). Routine
administration of influenza vaccine is recommended in pregnant women,
yet currently available U.S. licensed influenza vaccines contain
thimerosal. Why are pregnant women receiving influenza vaccine
containing thimerosal?
This issue was reviewed by the CDC's Advisory Committee on
Immunization Practices (ACIP) in 1999 and again in 2001. At that time,
the ACIP recommended no changes in the influenza vaccination guidelines,
including those for children and pregnant women. The ACIP stated that
"because pregnant women are at increased risk for influenza
complications and because a substantial safety margin has been
incorporated into health guidance values for organic mercury exposure,
the benefit of influenza vaccine outweighs the potential risks for
thimerosal". Furthermore, in its most recent recommendation regarding
prevention and control of influenza the ACIP stated "The risks for
severe illness from influenza infection are elevated among both young
children and pregnant women, and both groups benefit from vaccination by
preventing illness and death from influenza. In contrast, no
scientifically conclusive evidence exists of harm from exposure to
thimerosal preservative-containing vaccine, whereas evidence is
accumulating of lack of any harm resulting from exposure to such
vaccines. Therefore, the benefits of influenza vaccination outweigh the
theoretical risk, if any, for thimerosal exposure through vaccination"
(MMWR 54 [RR08]: 1-40, 2005). Nonetheless, FDA is in discussions with
manufacturers of influenza vaccine encouraging them to further increase
the supply of preservative-free formulations.
Is it safe for children to receive an influenza vaccine that contains thimerosal?
Yes. There is no convincing evidence of harm caused by the small
doses of thimerosal preservative in influenza vaccines, except for minor
effects like swelling and redness at the injection site.
Recent research suggests that healthy children under the age of 2 are
more likely than older children and as likely as people over the age of
65 to be hospitalized with flu complications. Therefore, vaccination
with thimerosal-preservative containing influenza vaccine and
thimerosal-reduced influenza vaccine is encouraged when feasible in
children, including those that are 6-23 months of age.
Is it safe for pregnant women to receive an influenza vaccine that contains thimerosal?
Yes. A study of influenza vaccination examining over 2,000 pregnant
women demonstrated no adverse fetal effects associated with influenza
vaccine. Case reports and limited studies indicate that pregnancy can
increase the risk for serious medical complications of influenza. One
study found that out of every 10,000 women in their third trimester of
pregnancy during an average flu season, 25 will be hospitalized for flu
related complications.
Additionally, influenza-associated excess deaths among pregnant women
have been documented during influenza pandemics. Because pregnant women
are at increased risk for influenza-related complications and because a
substantial safety margin has been incorporated into the health
guidance values for organic mercury exposure, the benefits of
thimerosal–reduced influenza vaccine or thimerosal-preservative
containing influenza vaccine outweighs the theoretical risk, if any, of
thimerosal.
You have said that thimerosal is no longer
used as a preservative in vaccines routinely recommended for children 6
years or less of age, with the exception of influenza vaccine. What is
being done about the thimerosal content of other vaccines and other
biological products given to infants, children, and pregnant women?
FDA is continuing its efforts to reduce the exposure of infants,
children, and pregnant women to mercury from vaccines. FDA is in
discussions with manufacturers of influenza vaccine regarding their
capacity to further increase the supply of preservative-free
formulations. Of note, all hepatitis B vaccines for the U.S., including
for adults, are now available only as thimerosal-free or
thimerosal-reduced containing formulations.
Tetanus and Diphtheria toxoids (Td) which is indicated for children 7
years of age or older and adults, is now also available in
thimerosal-free formulations. In addition, all vaccines licensed since
1999 with the exception of inactivated influenza vaccine have not
contained thimerosal as a preservative. Also, all immune globulin
preparations including hepatitis B immune globulin, and Rho(D) immune
globulin preparations are manufactured without thimerosal.
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