- Questions about Vaccine Safety
- Institute of Medicine (IOM) Findings
- Questions about Thimerosal in Vaccine regarding Infants, Children, and Pregnant Women
How does FDA evaluate vaccines to make sure they 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 (see Table 3).
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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