Global Vaccine Safety

Global Advisory Committee on Vaccine Safety, 2-3 December 2004

The Global Advisory Committee on Vaccine Safety (GACVS) is an expert clinical and scientific advisory body established by WHO to deal independently and with scientific rigour with vaccine safety issues of potential global importance.1 GACVS held its eleventh meeting in Geneva, Switzerland, on 2-3 December 2004 and considered, inter alia, the following vaccine safety and policy issues.2

Safety of adjuvants

The Committee considered the safety of adjuvants used in vaccines. This hitherto neglected subject is becoming increasingly important given modern advances in vaccine development and manufacture. WHO is developing a web site to make available all relevant preclinical and clinical trial information pertaining to the safety of vaccine adjuvants. With the development of vaccines for malaria, human immunodeficiency virus (HIV), human papillomavirus and hepatitis B and of other complex modern vaccines, adjuvant safety has become a central issue. Increasingly in the future there will be a need in developing countries for surveillance of vaccine adjuvant safety following vaccine registration. This applies not only to new vaccines but also to vaccines already available and used for new indications. GACVS will participate in developing such safety surveillance.

Thiomersal: neurobehavioural studies in animal models

The Committee considered whether animal models could be applied in order to better understand the association, if any, between thiomersal (containing ethyl mercury) and neurobehavioural disorders in infants, children and adults receiving thiomersal-containing vaccines. It was noted that in the neuropathology of autism - one neurobehavioural disorder that has received much public attention - the characteristic features of increased brain weight, total brain volume, cortical grey matter volume and neuronal cell density in the limbic system, with a decreased number of Purkinje cells in the cerebellum and absence of gliosis were not consistent with an external toxic agent. There is no evidence in autism of neurodegeneration, a pathological feature that would be expected if the cause of the disease were toxic.

From an expert presentation made to the Committee and from several publications, it is clear that: (i) no precise animal model exists that closely mimics autism in humans, although animal models of deficit in social play do exist; (ii) in the models available, susceptibility to neurobehavioural disorders has a genetic basis; (iii) there are experimental data to suggest that there is a link between autoimmune deficiency and predisposition to autism (although this remains conjectural); and (iv) mice born to mothers infected with human influenza virus have developed neuropathologies similar to those described in association with autism.

The Committee further reviewed results published in the scientific literature analysing a potential neuropathological effect of ethyl mercury in various strains of mice. Although a particular autoimmune disease-sensitive strain of mice showed some neurological and behavioural changes following administration of thiomersal, it was concluded by the Committee that the general picture presented did not mimic autism in humans.

The Committee identified two ways to further investigate the safety of thiomersal: epidemiological studies on the effects of ethyl mercury and pharmacokinetic studies in infants. Little is known of any particular susceptibility to thiomersal toxicity in infants weighing less than 2.5 kg, and in malnourished infants. Epidemiological studies are in progress. Special consideration is being given to how predisposition to thiomersal toxicity in infants weighing less than 2.5 kg and in infants with malnutrition might be addressed.

Safety of residual cellular DNA in vaccines

The risks, if any, of residual cellular DNA in vaccines as a result of the production process are theoretically two in number: (i) transmission of latent viruses and other agents; and (ii) incorporation of cellular DNA into host genetic material. These are theoretical safety issues that need to be considered in the scientific decisions underpinning registration of vaccines produced in new cell substrates. GACVS noted that WHO will be setting up a Working Group to consider international specifications for the quantity of residual cellular DNA in vaccines from new cell substrates. The Committee has agreed to serve as a reference point for safety issues for this Working Group.

Transmissible spongiform encephalopathies

The implications for vaccine safety of the emergence of certain transmissible spongiform encephalopathies (TSEs) have received the attention of the Committee for several years. Animal products, for example gelatin, are used as an excipient in some vaccines. Although it is clear that the major risk of human exposure to TSEs such as bovine spongiform encephalopathy (BSE) is from food sources, and that the risk from vaccines remains theoretical, WHO has compiled precautionary regulatory guidelines. These guidelines define tissue infectivity categories and outline risk management strategies not only for vaccines but also for blood products and pharmaceutical products.

GACVS noted several developments. On the positive side: (i) the annual number of deaths from variant Creutzfeld Jacob disease (vCJD) in the United Kingdom, which has the highest global burden of known vCJD, is in decline; (ii) the availability of WHO reference preparations has enabled demonstration of increasing sensitivity in laboratory diagnostic detection methods, but it is clear that more needs to be achieved; and (iii) data are available to show that the gelatin manufacturing processes reduce the infective load of abnormal misfolded prion protein associated with TSEs (PrPTSE) spiked in starting material by several log orders. On the negative side, GACVS heard that: (i) transmission of vCJD by blood transfusion is possible; (ii) susceptibility to vCJD infection is not confined to the methionine homozygous prion protein gene (PRNP) genotypes; (iii) people with heterozygous PRNP genotypes, who constitute the majority of the population, may be clinically silent carriers of vCJD; and (iv) recent data show that transmission of PrPTSE has been detected in muscle tissue from some animals, and the issue of spread of TSE through the infection of small ruminants has been raised following demonstration of PrPTSE in a goat.

Given these developments there is a need to update the relevant parts of the WHO guidelines but not, at this stage, measures pertaining to vaccines. GACVS noted that surveillance systems are crucially important in developing countries and elsewhere where BSE undoubtedly exists but is not detected and reported. The Committee will be maintaining a watching brief on the situation.

Potential risk of vaccines produced in yeast

There is a theoretical risk of contamination of vaccines with yeast antigens with resultant mimicry between peptides of yeast and human myelin proteins. T-cells might be activated, with a resultant cross-reaction with myelin proteins. It has been suggested in the past that this might induce reactivity in patients with multiple sclerosis. However, in hepatitis B vaccine, for example, less than 1% of vaccine protein content is of yeast origin and there is no detectable immunogenicity. GACVS believes that the issue of mimicry should be considered with caution as there are few true examples in human disease of mimicry. Large amounts of yeast and adjuvants would be necessary for a reaction, and in general histocompatibility leukocyte antigen (HLA) binding studies are of uncertain significance. Humans are universally exposed to yeast in the environment and everyone will have antibodies against yeasts. Without a signal, there is little point at present in pursuing this theoretical concern. The data suggestive of a yeast-induced immune stimulation as a result of vaccine contamination are not convincing.

Safety of hexavalent vaccines

Two hexavalent diphtheria, tetanus, acellular pertussis, Haemophilus influenzae type B, poliovirus and hepatitis B (DTaP-Hib-IPV-HepB) combination vaccines were licensed and introduced in Europe in 2000. They have contributed to a significant increase in the infant vaccine coverage against hepatitis B in Austria, Germany, Italy and Switzerland. In late 2000, the description of a cluster of 3 cases of sudden unexplained death (SUD) in close temporal association with the administration of a hexavalent vaccine in southern Germany raised concern. The German and European licensing authorities convened several expert meetings to review available data on all identified cases of SUD following immunization with each of the two available hexavalent vaccines.

A retrospective analysis was performed, using available data from various sources, to compare the calculated number of expected cases with that of observed cases of SUD following hexavalent immunization within a 3-year period. This analysis concluded that there was no association between SUD and hexavalent vaccination in the first year of life. However, the observed number of 3 cases of SUD within 48 hours of administration of a booster dose of one particular brand of hexavalent vaccine exceeded the number of cases expected (0-1) in 700 000 children given a booster dose during the 3-year period analysed. Consequently, the European Medicines Agency's scientific committee, the Committee for Proprietary Medicinal Products (CPMP), concluded in December 2003 that this temporal relationship constituted a possible signal for this hexavalent vaccine, despite the limitations of the data sources and the methods used to calculate the expected numbers. The CPMP could find no plausible biological cause for such an association and recommended further studies to establish whether or not there is a risk.

The retrospective analysis was presented to GACVS, together with additional information. On the basis of all the available data, GACVS concluded that there is no evidence to support a causal association between the administration of hexavalent vaccines and SUD. In response to the potential signal observed in the second year of life, the Committee encouraged studies to be conducted that are designed to provide more powerful evidence on the presence or absence of an association. GACVS was informed that a retrospective analysis of the possible association of any deaths within the first 2 years of life with vaccination is currently being conducted in Italy. The Committee will review the results of the study at its next meeting in mid-2005.

Yellow fever

GACVS has previously reviewed the safety of yellow fever vaccines, with particular reference to viscerotropic disease and other serious adverse vents.3 To date, 23 confirmed or probable cases of viscerotropic disease following the use of 17D yellow fever vaccine have been reported globally with case onset from 1996. Altogether, 14 (61%) of the 23 cases have been fatal. All cases were reported after the primary yellow fever vaccination. Recent risk estimates for yellow fever vaccine-associated viscerotropic disease are consistent with previous estimates from the United States, ranging from 0.04 to 3 per million vaccine doses. A higher risk has been recognized in subjects aged over 60 years. Disease of the thymus gland has been recognized as a potential independent risk factor; 4 (17%) of the 23 known cases had a history of thymus disease. However, there is little knowledge of additional risk factors for viscerotropic disease because of its low incidence.

GACVS reiterates that particular care should be taken that the vaccine is received only by those travellers who are truly at risk of exposure to yellow fever. In addition, vaccine providers should give careful consideration to the risks and benefits for elderly travellers and should routinely enquire about a history of thymus disorder, irrespective of the age of the subject. Where a history of thymus disorder is reported, alternative prevention measures should be considered.

Vaccine Safety Net Project

The Vaccine Safety Net Project was launched in August 2003 to address unbalanced and misleading information about vaccine safety propagated on the Internet. As part of this project, GACVS researched and approved a set of criteria for good information practices for vaccine safety web sites Since the setting of the criteria, WHO has evaluated a number of web sites providing vaccine safety information for their adherence to the "credibility" and "content" criteria. Sites meeting these criteria are listed on the WHO immunization safety web site ( immunization_safety/safety_quality/approved_vaccine_safety_websites/en/). The priority for the project during the coming months is to expand the network to a wide range of non-English language sites and also to sites in regions across the world.

Modus operandi of the GACVS

The modus operandi of the Committee, the scope of its work and recent decisions, recommendations and actions have been published in the latest issue of the American Journal of Public Health.4

1 See No. 41, 1999, pp. 337-338.
2 GACVS invited additional experts to present evidence and participate in the discussions on thiomersal, safety of residual cellular DNA in vaccines, transmissible spongiform encephalopathies, potential risk of vaccines produced in yeast and safety of hexavalent vaccines.
3 See No. 3, 2004, pp. 16-20.
4 A global perspective on vaccine safety and public health: the Global Advisory Committee on Vaccine Safety. American Journal of Public Health, 2004, 94:1926-1931.