Global Vaccine Safety

Global Advisory Committee on Vaccine Safety, 20–21 June 2002

The Global Advisory Committee on Vaccine Safety (GACVS) was established in 1999 by WHO to respond promptly, efficiently, independently (of WHO), and with scientific rigour to vaccine safety issues of potential global importance. The Committee meets twice a year on a regular basis.

GACVS is a scientific and clinical advisory body that aims to provide a reliable and independent assessment of vaccine safety issues through:

  • Review of the latest knowledge in all fields, from basic science to epidemiology, of any aspect of vaccine safety of global or national interest, in close collaboration with all parties involved, including experts from national administrations, academia, and industry.
  • Determination of causal relationships between vaccines and/or their components and adverse events attributed to them.
  • Creation, where necessary, of ad hoc specialist teams with a mandate to monitor and evaluate any major concerns regarding a suggested association of vaccines and adverse events and to commission appropriate research on purported associations.

Membership of GACVS includes experts from around the world in the fields of epidemiology, internal medicine, paediatrics, infectious diseases, pharmacology and toxicology, public health, immunology and autoimmunity, and drug regulation and safety.

The principles that the committee has developed in its approach to causality assessment have been previously published in the WER.1

GACVS held its sixth meeting at WHO headquarters, Geneva, Switzerland, on 20–21 June 2002. The main conclusions of the meeting were as follows:

Safety of thiomersal-containing vaccines

In 1999, concerns were raised in the United States of America regarding exposure to mercury following immunization with thiomersal-containing vaccines. This was based on the calculation that the cumulative amount of mercury in infant immunization schedules potentially exceeds the recommended threshold set by a USA government agency for methyl mercury. However, thiomersal contains ethyl mercury, not methyl mercury.

Expert advice and data presented to GACVS indicate that the pharmacokinetics of ethyl and methyl mercury are quite different. In particular, the half-life of ethyl mercury is short (less than 1 week) compared with that of methyl mercury (1.5 months). Thus, exposure to ethyl mercury in blood is relatively brief. Ethyl mercury is actively excreted via the gut, whereas methyl mercury accumulates in the body. Two independent epidemiological studies have recently been completed in the United Kingdom. One was funded by WHO (analysis of the General Practice Research Database (GPRD)), the other by the United Kingdom Department of Health (analysis of the data set of the Avon Longitudinal Study of Pregnancy and Childhood (ALSPAC). The GPRD analysis suggests that there is no association between developmental delay, particularly adverse neurological developmental outcomes or behavioural problems, and thiomersal-containing diptheria–pertussis–tetanus (DPT) vaccines given at 2, 3, and 4 months of age. These findings are supported by the ALSPAC results. These studies give further support to the safety in infants of thiomersal-containing vaccines in the amounts used in existing vaccines.

On this basis, GACVS concluded that there is currently no evidence of mercury toxicity in infants, children, or adults exposed to thiomersal in vaccines. It also concluded that there is no reason to change current immunization practices with thiomersal-containing vaccines on the grounds of safety.

Hepatitis B vaccine and leukaemia

An abstract presented at the April 2002 meeting of the American Association for Cancer Research reported an association between hepatitis B vaccine and acute lymphocytic leukaemia in 334 children in northern California. The investigators suggested that thiomersal may play a role since its effects were more likely to occur with repeated dosing. The authors pointed out that the results should be interpreted with caution. The research suggested a link only between thiomersal in the hepatitis B vaccine and leukaemia. Other childhood vaccines containing thiomersal were not implicated.

Ethyl mercury, as thiomersal, is excreted rapidly from the body, mostly disappearing within 5–6 days. Such brief exposure to minute amounts of mercury is unlikely to be a sufficient carcinogenic stimulus to trigger childhood leukaemia. There is no other documented association between mercury and any human cancer, leukaemia, lymphoma, or other malignant or pre-malignant disease. In animal studies, cancer has been associated only with metal carcinogens involving continual or repeated exposure.

GACVS concluded that the suggestion of an association between hepatitis B vaccine and acute lymphocytic leukaemia, from one source and based on small numbers, was not convincing. The purported association might equally be explained by the design of the study concerned, which did not preclude the chance of statistical bias; the result does not provide a convincing causal link. Furthermore, since an association cannot be disregarded on the basis of available evidence, the Committee resolved that the matter should be kept under review. At this stage, the risk, if any, must be regarded as tentative at best and weighed against the proven benefits of hepatitis B immunization.

It is nonetheless important that the association with hepatitis B vaccine be further investigated using appropriate and robust epidemiological methods. In that regard, additional research is being conducted by the US Centers for Disease Control and Prevention (CDC) using the Vaccine Safety Datalink.

GACVS will continue to review the evidence and any epidemiological data that may emerge from ongoing studies and evaluate the possibility of analysing other registries.

Hepatitis B vaccine and multiple sclerosis

Hepatitis B vaccine has been used extensively in France in recent years, with more than 20 million persons being vaccinated. Several case reports have raised concerns that hepatitis B immunization may be linked to new cases or relapses of multiple sclerosis (MS). In response to public and professional concern, the French Ministry of Health on 1 October 1998 temporarily suspended the school-based adolescent hepatitis B vaccine programme. France maintained the recommendations for universal infant immunization and administration of the vaccine to adults at special risk, and reiterated their support for adolescent vaccination. This decision was misunderstood and interpreted as a ban on hepatitis B immunization, generating widespread concern in other countries.

Three possible theories explain the link between MS and hepatitis B vaccine: 1) coincidence, due to the large number of hepatitis B vaccine doses administered, many to individuals in the age groups in which MS first occurs; 2) “triggering”, an increased risk of demyelination following hepatitis B vaccine that would act as a “trigger” in individuals predisposed to develop MS or other central nervous system demyelinating disease; and 3) a true causal association between hepatitis B vaccination and MS or other demyelinating disease.

By 2001, more than 700 cases of central demyelinating diseases with a close match to the natural epidemiological distribution of MS had been reported to the French authorities, the majority in adult females. The time delay between the last dose of vaccine and the onset of neurological symptoms was from 1 day to 5 years (median: 60 days). No cases were reported among children < 25 months, despite vaccination of 1.8 million babies. Overall, 9 epidemiological studies have been carried out to estimate the risk (if any) of an association between vaccination with hepatitis B vaccine and a first attack or relapse of MS. None of the initial studies, despite a slightly elevated odds ratio, showed a statistically significantly increase in risk; the most recent studies do not indicate any excess risk. Analysis of data from spontaneous reports and epidemiological studies does not support a causal relationship between MS and hepatitis B vaccine. The most likely explanation is a coincidental association.

The conclusions of a recent report of the United States Institute of Medicine on an association between hepatitis B vaccine and demyelinating neurological disorders also did not support a causal relationship between hepatitis B vaccine administered to adults and MS or relapse of MS. GACVS has concluded that there is no reason to suggest a change in the recommendations for universal infant and adolescent immunization coverage with hepatitis B vaccine.

Aluminium-containing vaccines and macrophagic myofasciitis

In France, biopsies of deltoid muscle from patients with a variety of complaints have revealed, in a few cases, the presence of a minute inflammatory focus of macrophages with associated necrosis, called macrophagic myofasciitis (MMF). These localized lesions have been shown to contain aluminium salts. Since the location of the lesions in the deltoid muscle coincides with the usual injection site for vaccines, it would appear that these microscopic lesions are related to immunization. In addition, scientists from the Groupe d’études et de recherche sur les maladies musculaires acquises et dysimmunitaires (GERMMAD) have suggested that vaccination and localized MMF lesions may be associated with a multi-system disorder. However, it remains possible that the finding is only coincidental.

WHO initiated a broad consultation on the issue in September 19992, on the advice of GACVS, with experts, GERMMAD scientists, and interested pharmaceutical companies. It was important to determine why macrophagic inflammation persists in a small number of subjects following immunization, and whether this histological lesion may or may not be responsible for generalized symptoms in some patients. These questions can be resolved only by epidemiological studies comparing individuals with and without the lesion. In 1999, WHO recommended that a study be undertaken to establish whether or not there is an association between local MMF lesions and any generalized illness. This study is now in progress.

Preliminary results of animal studies conducted in monkeys and rats to examine the long-term persistence of aluminium and histopathological changes at the vaccine injection site, as well as comparative studies of macrophagic function in healthy subjects and patients with MMF, further support the idea that MMF may represent a simple marker of vaccination with long-term persistence of aluminium at the injection site and minute local inflammatory response to it, without other symptoms or consequences.

The most recent evidence suggests that there is no reason to conclude that administration of aluminium-containing vaccines poses a health risk or to change current vaccination practice. The issue will be further considered when the results of the ongoing epidemiological study become available.

Bell palsy following intranasal vaccination

Results from a case–control study and a case-series analysis indicate a significantly increased risk of Bell palsy developing following intranasal immunization with a new vaccine. This inactivated influenza vaccine, composed of influenza antigens in a virosomal formulation with E. coliderived LT adjuvant, was licensed in Switzerland in October 2000. Following spontaneous reports of Bell palsy, the company decided not to market the vaccine during the following season.

In general, the etiology and pathogenesis of Bell palsy remain inadequately understood. The greater risk of Bell palsy following immunization with this vaccine may be due to specific vaccine components such as LT toxin, influenza antigens or virosomes, or simply to use of the intranasal administration route. It is thus possible that such complications of vaccine administration may also apply to other nasal vaccines. GACVS therefore recommends that any novel vaccine for nasal administration should be tested on a sufficiently large number of subjects before licensing and submitted to active post-marketing surveillance studies. Since the average time to onset of Bell palsy following intranasal immunization with this new vaccine was as much as 60–90 days, GACVS recommends that the follow-up period in the context of clinical trials should be routinely extended to 3 months following administration of a new intranasal vaccine.

Potential adverse impact of routine vaccination on child survival

A study in Guinea-Bissau published in the British Medical Journal in December 2000 suggested a nonspecific effect of routine vaccination that might influence survival in infants, either negatively or positively, depending upon the vaccine. Increased mortality was reported in children vaccinated with DPT in the 6 months following vaccination. Female gender was suggested as a modifier of the outcome.

GACVS reviewed this issue and urged WHO to arrange for testing of the hypothesis on different data sets from different countries where vaccination data, death, and other factors possibly influencing mortality had been recorded. Following an open call for proposals, WHO funded or cofunded studies in Bangladesh, Burkina Faso, Indonesia, and Papua New Guinea.

Analysis of those studies was completed: all of them showed reduced mortality in the children vaccinated with all of the vaccines. In particular, the studies showed no negative effect of DPT vaccination and no difference between males and females. Preliminary results of an independent analysis conducted to test the hypothesis on another six data sets have been communicated to GACVS. None of these confirmed the observations from Guinea- Bissau with respect to the DPT vaccine.

GACVS concluded that the evidence is sufficient to reject the hypothesis for an increased nonspecific mortality following vaccination.

For the discussions on thiomersal, Bell palsy, viral hepatitis B and MS, and MMF and aluminium-containing vaccines, GACVS invited additional experts to participate in the discussions.

1 See No. 41, 1999, pp. 337–340.
2 See No 12, 2001, pp. 85–89.