Vaccine components and constituents: responding to consumer concerns

Thiomersal (sodium ethylmercuric thiosalicylate) is an organic compound containing ethylmercury that has been widely used as a vaccine preservative since the 1930s. Concerns have focused on its potential toxicity as a heavy metal, and its role in the claimed link between measles, mumps and rubella (MMR) vaccination and autism.5

A recent study assessed whether multiple vaccinations can lead to mercury accumulation.6 In full-term infants exposed to vaccines containing thiomersal, mercury concentrations detected in blood (range, 2.85–20.55 nmol/L) were well below the level thought to be associated with adverse effects. Additionally, ethylmercury appears to be eliminated via the gastrointestinal tract soon after exposure (estimated half-life, 7 days).6 Because the developing fetus and low birthweight babies are more vulnerable to toxic effects of mercury, it has been suggested that exposure to vaccines containing thiomersal at time of birth may pose some risk in very low birthweight premature infants.6 To minimise any potential risk, all vaccinations in the Australian Standard Vaccination Schedule for children younger than 5 years are now thiomersal-free or contain only trace amounts.7

In 1998, a case series was published describing 12 children with pervasive development disorder with gastrointestinal features.8 The report claimed that exposure to MMR vaccination may have been linked to emergence of behavioural symptoms. Since then, controversy has surrounded the potential association between MMR vaccine and autism, with thiomersal a suggested culprit. The original claims have been criticised for being based on uncontrolled, anecdotal associations, and more recently, some of the study authors have retracted their interpretation associating MMR vaccines with autism.9 Larger epidemiological studies have also failed to demonstrate an association between MMR vaccination or use of thiomersal-containing vaccines and autism.10

The mercury or thiosalicylate components of thiomersal may produce hypersensitivity reactions.11 Reactions are uncommon, even in those with sensitisation, and serious reactions are rare.

2-Phenoxyethanol is an alternative to thiomersal. One report describes generalised eczema occurring after vaccination where 2-phenoxyethanol was found to be the sensitising agent.12

Antibiotics such as neomycin and polymyxin B are often used to prevent bacterial contamination during vaccine manufacture;5 they may contribute to systemic allergic reactions, including anaphylaxis, or local skin reactions.13 Previous skin reactions to neomycin are not considered a risk factor for anaphylaxis and are not a contraindication for use of neomycin-containing vaccines.13 Neomycin concentrations may vary between vaccines, but most contain only residual amounts.14

Gelatin is a partially hydrolysed collagen, usually of bovine or porcine origin, and is one of many types of stabilisers added to vaccines.5 It may be responsible for some allergic reactions occurring after vaccination, with symptoms including urticaria, anaphylaxis, or local reactions.21 “Egg allergies” reported after MMR vaccination were found to occur in individuals with no sensitivity to egg,5 and were later found to represent gelatin sensitivity. However, the incidence of anaphylaxis to gelatin is low (about one case per 2 million doses).5

Egg-related allergy is common, particularly in children with asthma or general allergies, and may be as high as 40% in children with moderate to severe atopic dermatitis.21 The risk of egg-related allergy after vaccination depends on the presence of egg protein in the final product. For example, influenza vaccine is manufactured using the extra-embryonic fluids of chick embryos and contains measurable quantities of egg proteins.21 Although the National Health and Medical Research Council (NHMRC) immunisation guidelines state that “individuals with anaphylactic hypersensitivity to eggs should not be given influenza vaccine”,7 little evidence is available to identify the actual risk of serious allergic reactions in this context. In fact, one study reported that graded dosing of influenza vaccine in 27 patients with a history of anaphylactic reactions to egg ingestion was well tolerated and not associated with significant allergic reactions.22 Current guidelines and evidence suggest that patients with egg allergies, other than anaphyl-axis, may be vaccinated safely.7,22,23

MMR vaccine is developed using chick embryo fibroblast tissue, and the final commercial vaccine does not contain egg proteins. Egg allergy is not a contraindication;7 previous reports of allergy-related adverse events occurring after MMR vaccination have now been attributed to the presence of gelatin.5

Vaccine manufacture requires the production of organisms cultivated on an appropriate culture medium. A medium must provide nutrients such as proteins, albumin, polypeptides, and growth factors specific to the needs of the microbe. Animal sera are frequently added to culture media to provide nutrients for microbial growth. Bovine serum is primarily used, although serum from pigs, horses, rabbits or humans may also be used.24 Extensive filtering processes ensure that the final vaccine contains little, if any, of the original cell material. Some media are serum-free or may be of synthetic, semi-synthetic or yeast origin.

Some vaccines are manufactured using Saccharomyces cerevisiae (baker’s yeast). There are no reports of yeast-specific IgE detected in patients following exposure to vaccines manufactured using baker’s yeast. Currently, the risk of vaccines contributing to yeast allergy is theoretical.5

Cell lines refer to a specific population of cells that are maintained in culture for extended periods. Cells used in cell lines can undergo spontaneous and unlimited replication, producing an unlimited lifespan for the cells, and a cell source that is continuously available. This removes the need for ongoing harvesting. More than 5000 human and animal cell lines are available. Those used in vaccine manufacture include two diploid cell strains of human origin (MRC-5 and WI-38), simian-derived continuous and diploid cell lines, chick embryo and chick embryo fibro-blasts.14 Residual proteins from these cell lines may be present to a varying degree in the vaccines produced from them. However, vaccines undergo purification processes to remove cellular residuals and have maximum limits placed on their presence.14

Certain cell lines (human diploid cell lines WI-38 and MRC-5) were derived from embryonic tissue from three elective, medically indicated abortions conducted in the 1960s.25 This has raised concerns, with reports of some individuals with religious objections to abortion refusing vaccination because they feel this makes them complicit with the original act of abortion.26

Patients should be aware that cell lines are self-sustaining and are not the end therapeutic product; thus additional abortions are not needed to sustain vaccine manufacture.25,26 No human cells are actually present in the vaccine, and no abortions are conducted specifically for the purpose of harvesting cell lines. Ethicists at the US National Catholic Bioethics Center have concluded that the association between certain vaccines and abortion was non-complicit, and thus use of these vaccines is not contrary to a religious opposition to abortion.27

Some religious groups who have dietary restrictions for certain animal products may be concerned about their presence in vaccines. Ingestion of pork products is forbidden in Islam, and some Muslims may avoid medications that contain pork-derived products.28 However, Shariah law includes the principle of “transformation”, where objects can be changed into another object with totally different properties and character, and this can turn unclean objects into clean and permissible objects. Within such a ruling, gelatin made from an unclean animal may be clean and permissible to ingest.29

Jews and Seventh-day Adventists also consider pork to be unclean. However, Jewish law permits use of porcine-derived products in non-edible forms such as parenteral formulations, or binding agents in tablets.30 Similarly, pork-derived medical products are not prohibited for Seventh-day Adventists, although some individuals may prefer to avoid such products (Dr P Harrold, Associate Director of Adventist Health Ministries, South Pacific Division, personal communication, May 2005). Some strict vegetarians or vegans may also choose to avoid animal products in medications and vaccines; this is largely a personal choice and is likely to vary among individuals.

A number of issues indicate that vaccination was not a contri-buting factor in the cases of vCJD in the United Kingdom. Most of these people would have been vaccinated before the emergence of BSE in British cattle.31 Additionally, vaccines are used internationally, yet the outbreak of vCJD in humans was largely restricted to the UK. Gelatin is rated as a low-risk product. Bovine serum is not actually present in the final vaccine product, and the cells that contribute to the vaccine are not able to replicate prions.32

Despite administration of tens of millions of doses of vaccines manufactured using bovine-derived material, there are no reported cases of BSE transmission via human or animal vaccination. Because of these factors, the risk is considered theoretical.24,32-34 Australian reviews have concluded that vaccines used in Australia meet high safety standards and that any risk of vaccines being contaminated with BSE is extremely low. Australian, European and US regulatory bodies have developed guidelines for use of bovine material in vaccine manufacture to minimise risk of BSE transmission.24,32-34

Bovine material must be sourced from countries where no recorded cases of BSE have occurred and an appropriate system of monitoring and reporting of BSE in animals has been implemented. Alternatively, bovine material may be sourced from specific donor herds where animal health is routinely monitored.

Use of manufacturing processes, such as heat sterilisation and chemical treatment, reduces or removes BSE infectivity from bovine products.