Global Vaccine Safety

Global Advisory Committee on Vaccine Safety, 1-2 December 2005

Published in the WHO Weekly Epidemiological Record on 13 January 2006

The Global Advisory Committee on Vaccine Safety (GACVS), an expert clinical and scientific advisory body reporting to WHO, was established to deal with vaccine safety issues of potential global importance independently and with scientific rigour.1 GACVS held its thirteenth meeting in Geneva, Switzerland, on 1–2 December 2005. The following issues, inter alia, were considered.

Vaccine Safety Net

An update was provided on the current status of the Vaccine Safety Net Project.2 The project aims to improve global dissemination, via the Internet, of information on vaccine safety in accordance with good information practices. Since the launch of the project in August 2004, more than 20 organizations providing information on vaccine safety have joined the network. Member sites include Dutch, English, French, German, Italian and Spanish languages. International medical organizations, national and regional governments, professional medical associations and WHO-associated bodies are represented.

The main activities during 2005 included strengthening of the process for site evaluation and expansion of the network in Europe. During 2006, the network will extend to sites in regions and countries beyond Canada, the United States and western Europe. Activities will include promotion of awareness of the project.

Safety issues associated with pandemic influenza vaccines

In the event of an influenza pandemic, protective influenza vaccines will be urgently required. WHO is promoting vaccination strategies that economize on the use of antigens to address the current global shortage of influenza vaccines for epidemics and pandemics. That would entail development and licensing of novel antigen-sparing vaccine formulations. Evaluation of safety and efficacy of new vaccines is likely to be especially challenging since the vaccines might not be available until after the pandemic had started. There would be public health demand for a vaccine to be made available as soon as possible. Advanced planning of safety and efficacy evaluation would be essential, with collaborative collection and evaluation of data, and rapid communication of conclusions.

The GACVS agreed to act as a resource for WHO if such a situation were to arise. The Committee made the following recommendations: develop pharmacovigilance guidelines to enable rapid assessment of pandemic influenza vaccines; promote the extension of such guidelines to evaluate seasonal influenza vaccines; develop an authoritative review of the safety and efficacy of inactivated influenza vaccines with adjuvants. It would be assured that regulators from developing countries are included in WHO meetings to promote regulatory collaboration on pandemic influenza vaccine issues and that lessons from the past, such as those from swine influenza vaccine, are taken into account.

Safety of adjuvants

Adjuvant safety and the use of preclinical models to assess adjuvant safety were due to be discussed at the WHO conference on adjuvants on 4–8 December 2005. A WHO web site on adjuvants in clinical evaluation including adjuvant safety, with a database of clinical trials, will be made available shortly.

Since a squalene-containing adjuvant is already used for one already licensed flu vaccine, and is also a candidate adjuvant for pandemic influenza vaccines, it would be important to assure the safety of squalene in that context. An authoritative information source on adjuvants, including a review of the scientific data to support adjuvant safety for vaccines that might be used in pandemic influenza vaccine, should be developed.

Rotavirus vaccine safety

The Committee was asked to consider whether the use of tetravalent rhesus reassortant rotavirus vaccine (commercially known as RotaShield®) might be associated with a significantly lower risk of vaccine-induced intussusception if immunization is completed before 2 months of age. This had been suggested in a recent publication of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, United States, in the Journal of Infectious Diseases.

The Committee studied a re-analysis of the original case-control study data from the United States Centers for Disease Control and Prevention (CDC), which showed a lower relative risk of intussusception in infants immunized before 60 days of age than those immunized later in infancy. The authors concluded that the relative risk of intussusception might be substantially reduced if a neonatal immunization schedule is used rather than the vaccination strategy in older infants that had been used in the introduction of the vaccine in the United States. It was suggested to the Committee that an age-dependent risk of intussusception might also apply to the 2 novel rotavirus vaccines that are currently in advanced development. The Committee noted that although the point estimates of relative risk differed between older and younger infants, the confidence intervals on the estimates overlapped substantially and the differences were not statistically significant.

Representatives from CDC, who where involved with the initial analysis and investigation of the association between RotaShield® and intussusception, presented the Committee with a re-analysis of the initial data set. The CDC confirmed a high relative risk in infants immunized after day 60. Too few children had been immunized before day 60 in the CDC studies to assess adequately the hypothesis of a lower relative risk in younger infants. No efficacy data are available using a neonatal schedule for any of the rotavirus vaccines.

The Committee concluded as follows:

  • The studies provide clarification and confirmation of a high risk of RotaShield®-associated intussusception in infants immunized after day 60.
  • The available evidence is not sufficient to conclude that the use of RotaShield® at an age less than 60 days is associated with a lower relative risk of intussusception.
  • Even strict recommendations for adherence to an early immunization schedule would be extremely difficult to implement in the field in many countries.

The Committee will continue to review the safety data of new rotavirus vaccines from clinical trials and post-marketing surveillance. It noted that the possibility of an age-dependent risk of intussusception should be taken into account in assessing rotavirus vaccines.

Subacute sclerosing panencephalitis and measles vaccination

The Committee reviewed the epidemiology of subacute sclerosing panencephalitis (SSPE) and the purported relationship between measles immunization and the occurrence of SSPE. The deliberations were considerably helped by a commissioned report presented by experts from the Health Protection Agency (HPA) of the United Kingdom. The meeting was joined by experts from the Division of Viral and Rickettsial Diseases, CDC National Center for Infectious Diseases (NCID), who agreed with the general conclusions and recommendations from the HPA experts. Evidence was provided that the true incidence of SSPE is approximately 4–11 cases per 100 000 cases of measles, although with measles infection acquired very early in life the risk may be higher (18 per 100 000 cases). A risk as high as 27.9 SSPE cases per 100 000 cases of measles has been cited. In many countries with good measles control, an increasing age at onset of SSPE has been observed attributable to cases that acquired measles infection at a time when the disease was more prevalent.

Available epidemiological data are consistent with a directly protective effect of vaccine against SSPE mediated by preventing measles. In countries with good measles control through vaccination, a decline in new SSPE cases is seen a few years after the decline in measles incidence. However, given the latency of SSPE following natural measles infection, it would take at least 5 years before an impact on SSPE incidence is seen, and more than 10 years before a large decrease is seen. Even with the elimination of measles, cases of SSPE may still occur 20 to 30 years after the last measles cases because of the skew of the latency distribution. Re-emergence of SSPE cases has been seen after outbreaks of measles following a period of good measles control. Available epidemiological data, in line with virus genotyping data, do not suggest that measles vaccine virus can cause SSPE. Furthermore, epidemiological data do not suggest that the administration of measles vaccine can accelerate the course of SSPE or trigger SSPE in an individual who would have developed the disease at a later time without immunization. Neither can the vaccine lead to the development of SSPE where it would not otherwise have occurred in a person who has already a benign persistent wild measles infection at the time of vaccination.

For situations where cases of SSPE occur in vaccinated individuals who have no previous history of natural measles infection, the available evidence points to natural measles infection as the cause of SSPE, not vaccine.

Chronic fatigue syndrome and hepatitis B vaccination

The Committee considered the possible association between hepatitis B vaccination and chronic fatigue syndrome that had been reported in Canada. A thorough literature review of the issue was commissioned. The review revealed that only 3 case-control studies had examined the issue and that all 3 studies had limitations. The Committee concluded that, based on the evidence available, there are no grounds to support the association.

Conjugate meningococcal vaccine and Guillain-Barré Syndrome

Several cases of Guillain-Barré Syndrome (GBS) were recently reported in the United States following the introduction of a tetravalent conjugated meningococcal vaccine. More than 2.5 million doses of this vaccine had been distributed in the United States at the time of these reports. Although a temporal relationship to vaccination prompted an alert by CDC and the Food and Drug Administration, the number of cases reported was similar to what would normally have been expected in this population. Accordingly, no change to vaccination recommendations was proposed. This information has been included in vaccine information sheets and the package insert for the vaccine. Similarly, the GACVS recommended no change in vaccination policies based on these reports.

Modus operandi of the Committee

The scope of the Committee’s work, recent decisions, recommendations and actions, as well as its modus operandi, have been published in the American Journal of Public Health.3

1. See No. 41, 1999, pp. 337-338.

2. See websites/en/

3. 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.