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 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.
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 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.
| Vaccine | Tradename (Manufacturer)* | Thimerosal Status Concentration**(Mercury) | Approval Date for Thimerosal Free or Thimerosal / Preservative Free (Trace Thimerosal)*** Formulation |
|---|---|---|---|
| DTaP | Infanrix (GSK) | Free | Never contained more than a trace of thimerosal, approval date for thimerosal-free formulation 9/29/00 |
| DTaP | Daptacel (AP) | Free | Never contained Thimerosal |
| DTaP | Tripedia (AP) | Trace(<0.3 µg Hg/0.5mL dose) | 03/07/01 |
| DTaP-HepB-IPV | Pediarix (GSK) | Trace (<0.0125 µg Hg/0.5mL dose) | Never contained more than a Trace of Thimerosal |
| Pneumococcal conjugate | Prevnar (WL) | Free | Never contained Thimerosal |
| Inactivated Poliovirus | IPOL (AP) | Free | Never contained Thimerosal |
| Varicella (chicken pox) | Varivax (M) | Free | Never contained Thimerosal |
| Mumps, measles, and rubella | M-M-R-II (M) | Free | Never contained Thimerosal |
| Hepatitis B | Recombivax HB (M) | Free | 08/27/99 |
| Hepatitis B | Engerix B (GSK) | Trace (<0.5 µg Hg/0.5mL dose) | 03/28/00 |
| Haemophilus influenzae type b conjugate (Hib) | ActHIB (AP)/OmniHIB (GSK) | Free | Never contained Thimerosal |
| Haemophilus influenzae type b conjugate (Hib) | PedvaxHIB (M) | Free | 08/99 |
| Haemophilus influenzae type b conjugate (Hib) | HibTITER, single dose (WL)1 | Free | Never contained Thimerosal |
| Hib/Hepatitis B combination | Comvax (M) | Free | Never contained Thimerosal |
| Influenza | Fluzone (AP) | 0.01% (12.5 µg/0.25 mL dose, 25 µg/0.5 mL dose)2 | |
| Influenza | Fluzone (AP)3(no thimerosal) | Free | 12/23/2004 |
| Influenza | Fluvirin (Chiron/Evans) | 0.01% (25 µg/0.5 mL dose) | |
| Influenza | Fluvirin (Chiron/Evans) (Preservative Free) | Trace (<1ug Hg/0.5mL dose) | 09/28/01 |
| Influenza, live | FluMist4 (MedImmune) | Free | Never contained Thimerosal |
Manufacturer abbreviations:
GSK = GlaxoSmithKline; WL = Wyeth Lederle; AP = Aventis Pasteur; M = Merck.
*Since this update, a biologics license application was approved for Rotavirus Vaccine, Tradename-RotaTeq (Merck), that is thimerosal free and never contained thimerosal.
** Thimerosal is approximately 50% mercury (Hg) by weight. A 0.01% solution (1 part per 10,000) of thimerosal contains 50 µg of Hg per 1 mL dose or 25 µg of Hg per 0.5 mL dose.
*** The term “trace” has been taken in this context to mean 1 microgram of mercury per dose or less.
- HibTiITER was also manufactured in thimerosal-preservative containing multidose vials but these were no longer available after 2002.
- Children 6 months old to less than 3 years of age receive a half-dose of vaccine, i.e., 0.25 mL; children 3 years of age and older receive 0.5 mL.
- A trace thimerosal containing formulation of Fluzone was approved on 9/14/02 and has been replaced with the formulation without thimerosal.
- FluMist is not indicated for children less than 5 years of age.
| Preservative | Vaccine Examples (Tradename; Manufacturer*) |
|---|---|
| Thimerosal | DT Td (several) TT (several) Influenza (several) |
| 2-phenoxyethanol and formaldehyde | IPV (IPOL; AP) DTaP (Daptacel; AP) |
| Phenol | Typhoid Vi Polysaccharide (Typhim Vi; AP) Pneumococcal Polysaccharide (Pneumovax 23; M) |
| Benzethonium chloride (Phemerol) | Anthrax (B) |
| 2-phenoxyethanol | DTaP (Infanrix; GSK) Hepatitis A (Havrix; GSK) Hepatitis A/Hepatitis B (Twinrix; GSK) |
*Manufacturer abbreviations:
GSK = Glaxo SmithKline; WL = Wyeth Lederle; AP = Aventis Pasteur; M = Merck; B=Bioport.
| Vaccine | Trade Name | Manufacturer | Thimerosal Concentration1 | Mercury |
|---|---|---|---|---|
| Anthrax | Anthrax vaccine | BioPort Corporation | 0 | 0 |
| DTaP | Tripedia2 | Aventis Pasteur, Inc | < 0.00012% | < 0.3 µg/0.5 mL dose |
| DTaP | Infanrix | GlaxoSmithKline | 0 | 0 |
| DTaP | Daptacel | Aventis Pasteur, Ltd | 0 | 0 |
| DTaP-HepB-IPV | Pediarix | GlaxoSmithKline | < 0.000005% | < 0.0125 µg/0.5 mL dose |
| DT | No Trade Name | Aventis Pasteur, Inc | < 0.00012% (single dose) | < 0.3 µg/0.5mL dose |
| DT | No Trade Name | Aventis Pasteur, Ltd3 | 0.01% | 25 µg/0.5 mL dose |
| Td | No Trade Name | Mass Public Health | 0.0033% | 8.3 µg/0.5 mL dose |
| Td | Decavac | Aventis Pasteur Inc | < 0.00012% | < 0.3 µg mercury/0.5 ml dose |
| Td | No Trade Name | Aventis Pasteur, Ltd | 0 | 0 |
| Adacel | Aventis Pasteur, Ltd | 0 | 0 | |
| Tdap | Boostrix | GlaxoSmithKline | 0 | 0 |
| No Trade Name | Aventis Pasteur Inc | 0.01% | 25 µg/0.5 mL dose | |
| Hib | ActHIB/OmniHIB4 | Aventis Pasteur, SA | 0 | 0 |
| Hib | HibTITER | Wyeth-Lederle | 0 | 0 |
| Hib | PedvaxHIB liquid | Merck | 0 | 0 |
| Hib/HepB | COMVAX5 | Merck | 0 | 0 |
| Hepatitis B | Engerix-B Pediatric/adolescent Adult |
GlaxoSmithKline | < 0.0002% < 0.0002% |
< 0.5 µg/0.5 mL dose <1µg/1 ml dose |
| Hepatitis B | Recombivax HB Pediatric/adolescent Adult (adolescent) Dialysis |
Merck | 0 0 0 |
0 0 0 |
| Hepatitis A | Havrix | GlaxoSmithKline | 0 | 0 |
| Hepatitis A | Vaqta | Merck | 0 | 0 |
| HepA/HepB | Twinrix | GlaxoSmithKline | < 0.0002% | < 1 µg/1mL dose |
| IPV | IPOL | Aventis Pasteur, SA | 0 | 0 |
| IPV | Poliovax | Aventis Pasteur, Ltd | 0 | 0 |
| Influenza | Fluzone6 | Aventis Pasteur, Inc | 0.01% | 25 µg/0.5 mL dose |
| Influenza | Fluvirin | Evans | 0.01% | 25 µg/0.5 ml dose |
| Influenza | Fluzone (no thimerosal) | Aventis Pasteur, Inc | 0 | 0 |
| Influenza | Fluvirin (Preservative Free) Evans | < 0.0004% | < 1 µg/0.5 mL dose | |
| Influenza | Fluarix | GlaxoSmithKline | < 0.0005% | < 1.25 µg/0.5 mL dose |
| Influenza | FluLaval | ID Biomedical Corporation of Quebec | 0.01% | 25 µg/0.5 ml dose |
| Influenza, live | FluMist | MedImmune | 0 | 0 |
| Japanese Encephalitis7 | JE-VAX | BIKEN | 0.007% | 35 µg/1.0mL dose 17.5 µg/0.5 mL dose |
| MMR | MMR-II | Merck | 0 | 0 |
| Meningococcal | Menomune A, C, AC and A/C/Y/W-135 | Aventis Pasteur, Inc | 0.01% (multidose) 0 (single dose) |
25 µg/0.5 dose 0 |
| Meningococcal | Menactra A, C, Y and W-135 | Aventis Pasteur, Inc | 0 | 0 |
| Pneumococcal | Prevnar (Pneumo Conjugate) | Lederle Laboratories | 0 | 0 |
| Pneumococcal | Pneumovax 23 | Merck | 0 | 0 |
| Rabies | IMOVAX | Aventis Pasteur, SA | 0 | 0 |
| Rabies | Rabavert | Chiron Behring | 0 | 0 |
| Typhoid Fever | Typhim Vi | Aventis Pasteur, SA | 0 | 0 |
| Typhoid Fever | Typhoid Ty21a | Berna Biotech, Ltd | 0 | 0 |
| Varicella | Varivax | Merck | 0 | 0 |
| Yellow Fever | Y-F-Vax | Aventis Pasteur, Inc | 0 | 0 |
- Thimerosal is approximately 50% mercury (Hg) by weight. A 0.01% solution (1 part per 10,000) of thimerosal contains 50 µg of Hg per 1 ml dose or 25 µg of Hg per 0.5 ml dose.
- Aventis Pasteur’s Tripedia may be used to reconstitute ActHib to form TriHIBit. TriHIBit is indicated for use in children 15 to 18 months of age.
- This vaccine is not marketed in the US.
- OmniHIB is manufactured by Aventis Pasteur but distributed by GlaxoSmithKline.
- COMVAX is not licensed for use under 6 weeks of age because of decreased response to the Hib component.
- Children under 3 years of age receive a half-dose of vaccine, i.e., 0.25 mL (12.5 µg mercury/dose.)
- JE-VAX is manufactured by BIKEN and distributed by Aventis Pasteur. Children 1 to 3 years of age receive a half-dose of vaccine, i.e., 0.5 mL (17.5 µg mercury/dose).
For more information, visit: http://www.fda.gov/cber/vaccine/thimfaq.htm#q3
