Indian J Med Res 124, July 2006, pp 5-8

Editorial
Vaccine preservatives: what is the big deal?

A vaccine consists of many parts, only one of which is the antigen by which it is known. Other components of the presentation may include, for instance, an adjuvant, a preservative or other ingredient. There may be components not stated on the information sheet that are classified as proprietary and therefore the manufacturers are not obliged to declare them. Thus, the effect the vaccine has on an individual may be influenced in various ways by each and all of these components. Preservatives, then, are just one of a number of additives to vaccines that are carefully regulated and which come under special scrutiny from time to time. Not all vaccines contain preservatives. Freezedried measles and BCG vaccines do not need a preservative because, if handled correctly, they are not in a liquid state long enough to become contaminated and overgrown with dangerous organisms such as Staphylococcus . Equally important, a preservative cannot be used in such vaccines as it would kill or damage the live organisms and render the vaccines useless. But multi-dose vials of liquid vaccines may have the rubber bung penetrated by a needle many times over a prolonged period of time. Should contamination occur during use, a preservative will minimize the risk to subsequent doses, inhibiting or preventing bacterial growth within the liquid vaccine. Those with a preservative and are in common use include triple (diphtheria-pertussis-tetanus) and hepatitis B vaccines. The most frequently used (but not the only) preservative is thiomersal (also called thimerosal in many North American-based products) - a product that depends on the mercury within its
5

molecule for its strong bacteria-killing properties. Thiomersal came into the public gaze in 1999 as the result of a study being undertaken to estimate how much mercury was being administered to children in North America through vaccines. To everyones surprise, the amount exceeded the allowed maximum according to environmental health permitted limits1,2. Vaccine safety studies At that time, there was little information on the toxicological profile of thiomersal, a compound containing mercury in the form of ethyl mercury. Instead, scientists assumed that it would have the same toxicology as methyl mercury, a chemical about which a great deal was known. For instance, methyl mercury used as an insecticide had been shown to be responsible for severe poisoning of a large number of people who had eaten grains contaminated with a mercury-based insecticide. Worse, mothers pregnant at the time gave birth to babies with foetal defects3. It was also known that cosmetics containing mercury were harmful. All in all, mercury had a bad reputation. Thiomersal, then, was judged guilty by association. Gradually over the ensuing years, evidence was accumulated that showed ethyl mercury actually had a different metabolic pathway in the human body compared with methyl mercury. Both were metabolized in the liver and excreted in the gut, but methyl mercury was reabsorbed and accumulated in the body. Ethyl mercury, on the other hand, was found to be passed in the stool and lost from the body, thus avoiding a cumulative effect4. The parameters previously set for methyl mercury were not directly applicable to ethyl mercury5.

INDIAN J MED RES, JULY 2006

Public and professional reactions While science took its laborious course in discovering more about the toxicological profile of thiomersal, events raced on. Soon after the initial scare (and before the metabolism of the compound was properly understood) professionals in North America blew the whistle, declaring vaccines containing thiomersal to be potentially dangerous. Such vaccines were soon withdrawn from use in the United States 6. However, vaccination of children went on almost without a hitch - the industry was able to switch to mono-dose presentations that did not require and did not contain a preservative. A range of professional bodies in Europe and Canada7,8 examined the evidence and declared (with certain minor variations) that vaccines containing thiomersal had not been shown to be damaging and could continue to be used. Most declared that over the medium to long haul, however, vaccine preparations containing thiomersal should be phased out. Encouraged by some journal articles, the public in North America and Europe began discussion whether thiomersal was the cause of an apparent rise in autism9. It was an appealing theory, there being no better alternative explanation for why children appeared to be developing autism in increasing

numbers. Thiomersal seemed tailor-made to fit the role of villain. Even when a number of authoritative papers were published and major commissioned reviews reported the chemical was not responsible10, a vocal minority preferred to cling to the theory. Epidemiological studies to the rescue The published literature prior to 1999 consists primarily of studies on the toxicology of methyl mercury and the clinical syndromes associated with topical application of medicinal compounds containing thiomersal. From 1999, there was a predictable increase in studies examining the neurodevelopmental effects of thiomersal. Of the 105 papers identified as containing the words thiomersal or thimerosal in their title, 31 papers were concerned with the chemical nature of thiomersal or its metabolism or were announcements by official organs such as National Paediatric Associations, and most of the remaining 74 were reviews. Only 12 publications were identified containing significant new data or new ways of analyzing existing data (Table)11-22. The first six were high quality studies that showed no clear link between neurodevelopmental disorders or autism and the receipt of vaccines containing thiomersal. For example, one of these studies examined a population-based cohort study of all children born in

Table. Primary epidemiological data sources investigating the possible link between receipt of vaccines containing thiomersal and the onset of neurodevelopmental conditions Authors Andrews et al11 Heron et al Hviid et al
12

Type of study Retrospective cohort Prospective cohort Retrospective cohort

14 15

Link with neurodevelopmental conditions None proved None proved None proved None proved Inconclusive - none proved

Possible but unproven association Tics None None None Tics Attention Deficit Disorder, speech and language None Various associations claimed

13

Madsen et al

Retrospective cohort Retrospective cohort

Verstraeten et al

Stehr-Green et al16 Geier & Geier et al

17-22

Ecological Retrospective cohort and ecological

None proved Link claimed in all six papers

Source: Clements CJ, McIntyre PB. When science is not enough - a risk/benefit profile of thiomersal-containing vaccines. Expert Opin Drug Safety 2006; 5 : 17-29. (Reproduced with permission)

CLEMENTS : VACCINE PRESERVATIVES

Denmark13 from 1990, until 1996 (N = 467, 450). In Denmark, childhood vaccines with and without thiomersal were in use and both vaccination status from a national register and autism diagnosis which is determined at a central clinic were available for the whole cohort. During 2,986,654 person-years, 440 children were identified as cases of autism and 787 with other autistic-spectrum disorders. The risk of autism and other autistic-spectrum disorders did not differ significantly between children vaccinated with thimerosal-containing vaccine and children vaccinated with thimerosal-free vaccine. Similarly, there was no evidence of a dose-response association of ethyl mercury for autism and for other autistic-spectrum disorders. The paper concluded that the results did not support a causal relationship between childhood vaccination with thimerosal-containing vaccines and the development of autistic-spectrum disorders. The seventh set of authors, Geier et al 17-22 , is particularly important because they have published six essentially similar papers with only minor variations. Each evaluated the effects of mercury from thimerosal-containing childhood vaccines on the prevalence of childhood neurodevelopmental disorders. Three of the studies used principally the Vaccine Adverse Events Reporting System (VAERS), a system designed as a passive reporting system providing early warnings of possible adverse events. It was not designed for, and cannot be used as an accurate database as the true denominator cannot be ascertained. This makes the statistical analysis in three of the studies uncertain. The Geier studies have also been critiqued by other authors23. For instance, the American Academy of Pediatrics declared that the study failed to show a connection between thimerosal and autism, indicating that it used data from the VAERS inappropriately and contained numerous conceptual and scientific flaws, omissions of fact, inaccuracies, and mis-statements24. It is worth noting that the six of Geier papers clearly fly in the face of the weight of scientific evidence, yet support a widely held public belief that thiomersal (in the quantities present in vaccines) is bad for children. Impact on non-industrialized countries The World Health Organization (WHO) has consistently provided a lead through the Global

Advisory Committee on Vaccine Safety25. Based on a lack of evidence concerning any damage to children who have received thiomersal-containing vaccines, WHO, on the advice of the committee, has encouraged countries to keep using the preservativecontaining vaccines. This position has been maintained and backed up by successive research and publications on the subject. One concern currently being addressed by WHO is the possibility that the brain of premature and newborn infants might be more at risk from mercury in vaccines than older infants26,27. Because most developing nations are still struggling to achieve or maintain high vaccination coverage, their focus has been on getting their children vaccinated to avoid life-threatening diseases. Reassured by the WHO reports, and not under pressure from the media or vocal parent groups, Ministries of Health have been able to continue using the preservative-containing vaccines without problems. In summary, there is an intuitive feeling that any type and any quantity of mercury is undesirable in the human body, particularly in infants and children. But respected authorities on the subject are satisfied that it is not only safe but also necessary for liquid vaccines in multi-dose vials to contain small amounts of preservative. The problem (if problem it is) may well ultimately solve itself - even in developing countries, more and more vaccines are being delivered as mono-dose polyvalent presentations that do not require a preservative. C. John Clements Centre for International Health The Macfarlane Burnet Institute for Medical Research & Public Health Ltd. GPO Box 2284, Commercial Road Melbourne, Australia e-mail: john@clem.com.au References
1. Mahaffey KR, Rice GE. An assessment of exposure to mercury in the United States: Mercury study report to Congress. US Environmental Protection Agency (1997) Document EPA-452/R-97-006.

INDIAN J MED RES, JULY 2006 14. Madsen KM, Lauritsen MB, Pedersen CB, Thorsen P, Plesner AM, Andersen PH, et al . Thimerosal and the occurrence of autism: negative ecological evidence from Danish population-based data. Pediatrics 2003; 112 : 604-6. 15. Verstraeten T, Davis RL, DeStefano F, Lieu TA, Rhodes PH, Black SB, et al . Vaccine Safety Datalink Team. Safety of thimerosal-containing vaccines: a two-phased study of computerized health maintenance organization databases. Pediatrics 2003; 112 : 1039-48. 16. Stehr-Green P, Tull P, Stellfeld M, Mortenson PB, Simpson D. Autism and thimerosal-containing vaccines: lack of consistent evidence for an association. Am J Prev Med 2003; 25 : 101-6. 17. Geier MR, Geier DA. Neurodevelopmental disorders after thimerosal-containing vaccines: a brief communication. Exp Biol Med (Maywood) 2003; 228 : 660-4. 18. Geier DA, Geier MR. A comparative evaluation of the effects of MMR immunization and mercury doses from thimerosalcontaining childhood vaccines on the population prevalence of autism. Med Sci Monit 2004; 10 : I33-9. 19. Geier DA, Geier MR. An assessment of the impact of thimerosal on childhood neurodevelopmental disorders. Pediatr Rehabil 2003; 6 : 97-102. 20. Geier DA, Geier MR. Thimerosal in childhood vaccines, neurodevelopmental disorders, and heart disease in the United States. J Am Physicians Surg 2003; 8 : 6-11. 21. Geier DA, Geier MR. A two-phase epidemiological study of the safety of thimerosal-containing vaccines: a followup analysis. Med Sci Monit 2005; 11 : CR 160-70. 22. Geier DA, Geier MR. Neurodevelopmental disorders following thiomersal-containing childhood immunizations: a follow-up analysis. Int J Toxicol 2004; 23 : 369-76. 23. Mann JR. Questions about thimerosal remain. Exp Biol Med (Maywood) 2003; 228 : 991-2. 24. American Academy of Pediatrics. Study fails to show a connection between thimerosal and autism. http:// www.aap.org/profed/thimaut-may03.htm accessed on May 28, 2006. 25. Global Advisory Committee on Vaccine Safety, 20-21 June 2002. Wkly Epidemiol Rec 2002; 77 : 389-94. http:// www.who.int/docstore/wer/pdf/2002/wer7747.pdf , accessed on May 28, 2006. 26. Stajich GV, Lopez GP, Harry SW, Sexson WR. Iatrogenic exposure to mercury after hepatitis B vaccination in preterm infants. J Pediatr 2000; 136 : 679-81. 27. Clements CJ. The evidence for the safety of thiomersal in newborn and infant vaccines. Vaccine 2004; 7 : 1854-61.

2. Clements CJ, Ball LK, Ball R, Pratt D. Thiomersal in vaccines. Lancet 2000; 355 : 1279-80. 3. Harada M. Minamata disease: Methyl mercury poisoning in Japan caused by environmental pollution. Crit Rev Toxicol 1995; 25 : 1-24. 4. Pichichero ME, Cernichiari E, Lopreiato J, Treanor J. Mercury concentrations and metabolism in infants receiving vaccines containing thiomersal: a descriptive study. Lancet 2002; 360 : 1737-41. 5. Action level for mercury in fish, shellfish, crustaceans, and other aquatic animals: Department of Health, Education, and Welfare (US), Food and Drug Administration. Federal Register 1979; 44 : 3990, January 19, 1979. 6. Centers for Disease Control and Prevention. Recommendations regarding the use of vaccines that contain thimerosal as a preservative. MMWR Morb Mortal Wkly Rep 1999; 48 : 996-8. 7. Exposure to thimerosal in vaccines used in Canadian infant immunization programs, with respect to risk of neurodevelopmental disorders. Canadian Communicable Disease Report, Canada, 28-09 , May 1, 2002. 8. The European Agency for the Evaluation of Medicinal Products Human Medicines Evaluation Unit London. EMEA Public Statement on Thiomersal in Vaccines for Human Use - Recent Evidence Supports Safety of Thiomersal Containing Vaccines. http://www.emea.eu.int/pdfs/human/press/pus/ 119404en.pdf accessed on May 28, 2006. 9. Bernard S, Enayati A, Redwood L, Roger H, Binstock T. Autism: a novel form of mercury poisoning. Med Hypotheses 2001; 56 : 462-71. 10. Immunization Safety Review Committee, Institute of Medicine. Immunization Safety Review: Vaccines and Autism. National Academy Press, Washington DC 2004. http://www.nap.edu/books/030909237X/html/ accessed on May 28, 2006. 11. Andrews N, Miller E, Grant A, Stowe J, Osborne V, Taylor B. Thimerosal exposure in infants and developmental disorders: a retrospective cohort study in the United Kingdom does not support a causal association. Pediatrics 2004; 114 : 584-91. 12. Heron J, Golding J, ALSPAC Study Team. Thimerosal exposure in infants and developmental disorders: a prospective cohort study in the United Kingdom does not support a causal association. Pediatrics 2004; 114 : 577-83. 13. Hviid A, Stellfeld M, Wohlfahrt J, Melbye M. Association between thimerosal-containing vaccine and autism. JAMA 2003; 290 : 1763-6.