Global Vaccine Safety

Global Advisory Committee on Vaccine Safety, 29-30 November 2006

Published in the WHO Weekly Epidemiological Record on 19 January 2007

The Global Advisory Committee on Vaccine Safety (GACVS), an expert clinical and scientific advisory body, was established by WHO to deal with vaccine safety issues of potential global importance independently from WHO and with scientific rigour.1 GACVS held its fifteenth meeting in Geneva, Switzerland, on 29–30 November 2006.2 The committee discussed a number of general issues relevant to all vaccines as well as a number of vaccine-specific issues. Discussions of vaccine-specific issues pertained both to long-standing vaccines as well as to new vaccines or vaccines still under development. The following issues, among others, were considered.

General issues

Monitoring vaccine safety

At previous meetings3, 4, the GACVS requested that global vaccine pharmacovigilance be strengthened, particularly within the context of the WHO Programme for International Drug Monitoring. Aspects in particular need of attention include data transmission by countries, assurance of data quality, and the processing and analysis of data, including timely signal detection and action. As a result of the above-mentioned request, a subgroup of 6 GACVS members was formed to work closely with the secretariat to ensure that the initiative continues to move forward in a timely fashion.4 A report of the subgroup’s activities was presented to the full committee. The specific terms of reference of this subgroup are: to advise WHO regarding the development of a high-quality system for reporting, detecting, analysing and communicating adverse events following immunization (AEFI) at a global level; and to advise WHO, the WHO Collaborating Centre for International Drug Monitoring based in Uppsala, Sweden, (known as the Uppsala Monitoring Centre or UMC) and Member States on specific issues relating to implementing activities aimed at achieving the first goal. To achieve this goal, specific objectives and deliverables have been agreed upon, and these will be undertaken by the subgroup over the next couple of years. A high priority will be to raise the profile and awareness of pharmacovigilance within the immunization community using existing WHO networks and other means.

A report on a visit to Uppsala by representatives of the secretariat and subgroup was presented. Key areas for action include: (i) increasing vaccine-specific expertise at the UMC through the creation of a position dedicated to vaccine safety; (ii) assisting in the recruitment of additional volunteer expert reviewers who can assess potential vaccine safety signals; and (iii) engaging scientific experts to consider what types of methods are best for detecting vaccine safety signals. Deficiencies with respect to vaccines in the anatomical therapeutic chemical and defined daily dose (ATC/DDD) classification and WHO’s Drug Dictionary need to be addressed. A programme of work is planned to review and propose modifications appropriate to vaccines to the ATC/DDD; these proposals will be presented to the WHO Collaborating Centre for Drug Statistics Methodology, Oslo, Norway, at its forthcoming meeting.

Report of the WHO Expert Committee on Biological Standardization

The work of the WHO Expert Committee on Biological Standardization was summarized. The committee establishes global norms and standards that help define biological medicinal products of assured quality, including the quality, efficacy and safety specifications that are used for prequalification of vaccines.

The committee met most recently during 23–27 October 2006. At that meeting, 3 new written standards were established: for human papillomavirus vaccines, for meningococcal A conjugate vaccine, and for the regulatory expectations for stability evaluations of vaccines. The committee also established 15 new reference preparations, which are global measurement standards that guide manufacturers and regulatory authorities on the activity of biological medicines. Finally, the committee endorsed a number of new projects in the area of quality standards and commented on a number of regulatory issues, including regulatory preparedness for pandemic influenza vaccines and the licensing of vaccines procured through United Nations agencies.

During discussion of the committee’s report, GACVS noted that developing processes to share safety information from clinical trials of vaccines would be beneficial and requested that the secretariat explore ways to do this.

Safety of vaccine formulations

This session stemmed from a recommendation made at the last GACVS meeting that the committee should start looking proactively into the real and perceived safety of preservatives and other inactive ingredients in vaccine formulations. The limited information provided about excipients, in contrast to the active components, in vaccines was highlighted. This is a challenge for drug regulators and industry in the areas of quality assurance, and it is likewise a challenge for health professionals in terms of communicating risks. The infrequent administration of vaccines makes it unlikely that small amounts of excipients are toxic. However, this may change with the development of therapeutic vaccines, which might be administered repeatedly. A mechanism must be established to secure more information about detailed vaccine formulations and to rigorously review the safety of excipients.

A GACVS subgroup was established to examine this issue in further detail. The subgroup will report on its work, including identifying priorities and establishing a listing of excipients and conceivable adverse effects, at the June 2007 meeting of the committee.

Vaccinating adolescents and young adults: problems with coincidental pathologies and safety assessments

There is likely to be an increased focus on the vaccination of adolescents both for new vaccines, such as human papillomavirus vaccines, and for some previously available vaccines. The committee was presented with preliminary modelling work performed using health utilization data from a health maintenance organization (a type of private health insurer) in the United States. This work indicates there is a high likelihood of the coincidental occurrence of various pathologies in close proximity to vaccinations. This is especially the case for gynaecological and autoimmune disorders, and such observations may lead to public concern about vaccine safety. The committee recognized that this issue deserves more attention. Countries moving towards introducing vaccines aimed at adolescents and young adults should endeavour to secure population-specific and age-specific baseline rates of specific conditions in the relevant age-group (for example, rates of autoimmune disease). This will assist any investigation of safety issues that may surface. Any signal generated by surveillance will require thorough investigation using appropriate epidemiological methods before conclusions can be drawn.

Issues associated with specific vaccines

Safety of mumps vaccine strains

At the request of the immunization Strategic Advisory Group of Experts (SAGE), the committee was asked to update the 2003 comprehensive review of the safety of mumps vaccine strains, paying particular attention to the risk of vaccine-derived meningitis. A review of the safety profile based on an updated literature search and data provided by some vaccine manufacturers was presented to the committee.

Similar to its previous review,5 GACVS noted that cases of aseptic meningitis and estimates of incidence rates have been reported following the use of Urabe, Leningrad–Zagreb, Hoshino, Torii, and Miyahara strains from various surveillance systems and epidemiological studies. Given the variability in the quality of these studies and in the methods used, no clear conclusion on differences in risk between these vaccine strains can be drawn. The data up to now have revealed low rates of aseptic meningitis and no cases of virologically proven meningitis following the use of Jeryl–Lynn and RIT 4385 strains. There is only limited information about the Leningrad-3 strain. No data were available to assess the safety of the S79 strain.

Mass vaccination campaigns using mumps–measles–rubella vaccine that contained mumps vaccine strains associated with an increased risk of aseptic meningitis have resulted in clusters of adverse events that disrupted programmes. Recognition of the clustering of cases of aseptic meningitis has potentially been enhanced during mass immunization campaigns due to increased sensitivity of AEFI surveillance. This has been observed with Urabe and Leningrad–Zagreb strains. As of the date of this meeting, all reported cases of vaccine-derived mumps meningitis have recovered. Some of these were laboratory diagnosed cases and had little, if any, clinically significant disease. Despite the occurrence of these cases, the perceived risk–benefit ratio of utilization of the Urabe and Leningrad–Zagreb mumps vaccines over several years in routine programmes in developing countries has been considered acceptable. However, if mumps vaccine strains that have been associated with an increased risk of aseptic meningitis are to be used in mass campaigns, immunization programmes should implement appropriate strategies for communicating risk and managing cases in order to handle possible reports of clusters of aseptic meningitis.

Further studies undertaken to compare the safety profile of different mumps vaccine strains should be carefully designed to discriminate between potential strain variability and age-specific risk in different populations. Standardization of case definitions and quantification of severity will help in interpreting results.

GACVS is pleased with the steps taken to establish a repository of mumps vaccine virus strains at the National Institute for Biological Standards and Control, Potters Bar, England, and urges the acceleration of work to gain insight into the biological determinants of risk from the different strains. The committee requests to be informed of any new data pertaining to the safety of mumps vaccines so that a better assessment can be made of the risk of aseptic meningitis or other conditions associated with specific strains.

Safety of BCG vaccine in HIV-infected children

The committee has reviewed the policy on the use of bacille Calmette–Guérin (BCG) vaccination for children infected with HIV in light of new evidence. Data from retrospective studies from Argentina and South Africa indicate there is a substantiated higher risk of disseminated BCG disease developing in children infected with HIV who are vaccinated at birth and who later developed AIDS. The reported risk associated with vaccinating HIV-infected children may outweigh the benefits of preventing severe tuberculosis, especially since the protective effect of BCG against tuberculosis in HIV-infected children is not known.

WHO currently recommends administering a single dose of BCG vaccine to all infants living in areas where tuberculosis is highly endemic as well as to infants and children at particular risk of exposure to tuberculosis in countries with low endemicity. BCG vaccine is contraindicated in people with impaired immunity, and WHO does not recommend BCG vaccination for children with symptomatic HIV infection.

GACVS concluded that the recent findings indicated there is a high risk of disseminated BCG disease developing in HIV-infected infants and therefore BCG vaccine should not be used in children who are known to be HIV infected.

The committee recognizes the difficulty in identifying infants infected with HIV at birth in settings where diagnostic and treatment services for mothers and infants are limited. In such situations, BCG vaccination should continue to be given at birth to all infants regardless of HIV exposure, especially considering the high endemicity of tuberculosis in populations with high HIV prevalence. Close follow up of infants known to be born to HIV-infected mothers and who received BCG at birth is recommended in order to provide early identification and treatment of any BCG-related complication. In settings with adequate HIV services that could allow for early identification and administration of antiretroviral therapy to HIV-infected children, consideration should be given to delaying BCG vaccination in infants born to mothers known to be infected with HIV until these infants are confirmed to be HIV negative.

Update on Menantra® and Guillain-Barré syndrome

An update on the reported occurrence of Guillain-Barré syndrome (GBS) after vaccination with a tetravalent conjugated meningococcal vaccine (Menactra®)6 in the United States was presented. As of September 2006, a total of 17 cases had been reported to the US Vaccine Adverse Event Reporting System as occurring within 6 weeks after vaccination. Analysis of the data suggests that there may be a small increased risk (1.25 cases per million doses distributed; 95% confidence interval, 0.058–5.993) of GBS after vaccination with Menactra®, but this finding should be viewed with caution, given the limitations of the reporting system and the uncertainty regarding background incidence rates of GBS.

Pandemic influenza vaccines

The committee discussed plans for the global monitoring of the safety of pandemic influenza vaccine. The committee emphasized the importance of developing a robust network of contact points to share information and pilot the system during seasonal influenza immunization. The network is intended to ensure that Member States have rapid and timely access to safety information concerning pandemic and seasonal influenza vaccines, to provide access to dedicated resources able to address urgent queries, and to initiate and coordinate relevant responses. A web-based platform to support the collection and dissemination of information to relevant stakeholders in Member States is being developed. The formation of this influenza vaccine safety network should be carefully planned and should consider the possible limitations imposed by the pandemic.

Recognizing that the availability of several global surveillance systems for communicable diseases, drugs or vaccines may be relevant to certain aspects of monitoring the safety of pandemic influenza vaccines, the global post-marketing surveillance network aims to coordinate resources and supplement areas not sufficiently addressed. Although the system is being developed for pandemic influenza vaccines, it would initially use seasonal influenza vaccine safety monitoring as a proxy. A subgroup of GACVS will be formed to pursue this goal in connection with the series of WHO regulatory preparedness workshops on human vaccines for pandemic influenza.

Safety of Japanese encephalitis vaccination in India

GACVS considered the report from an Indian expert panel that assessed the reported cases of serious adverse events following immunization campaigns with the live, attenuated SA 14-14-2 Japanese encephalitis vaccine in 4 Indian states during the summer of 2006. These campaigns reached >9.3 million children aged between 1 year and 15 years. A total of 65 serious adverse events were reported, 22 of which were fatal. Most serious adverse events were considered to be unrelated to the vaccine. A total of 2 clusters of encephalitis-like syndromes were identified after immunization, 1 probably representing cases of natural Japanese encephalitis and another classified as acute encephalopathy syndrome of unknown etiology; thorough investigation into possible alternative etiologies has not been conducted.

The committee considered that the overall number of reported serious adverse events appeared low for the target population and that the type of clustering of encephalopathy and encephalitis cases made it unlikely that they were related to the vaccine. However, a better definition of cases of serious adverse events, using standard case classifications, such as the Brighton Collaboration definitions, and more active case investigation would be valuable. GACVS recommended that future immunization campaigns should be accompanied by strengthened AEFI monitoring and investigation activities.

Safety of pneumococcal conjugate vaccine

At the request of SAGE, the committee reviewed the safety of pneumococcal conjugate vaccines. A comprehensive review of all evidence on the safety of pneumococcal conjugate vaccines was conducted and presented. Data from 62 studies, including randomized controlled trials and post-marketing studies, were included in the review. While there has been a weak and inconsistent signal of increases in reactive airway conditions in some studies, these apparent effects have not been consistently observed.

The evidence on the safety of the 7-valent pneumococcal conjugate vaccine and other pneumococcal conjugate vaccines is reassuring. Reports since the licensure of the 7-valent pneumococcal conjugate vaccine in 2000 and widespread use in the United States and, more recently, in Canada and some European countries, have not identified any major safety concerns. There is substantial evidence that when introduced into developing countries, the presently available pneumococcal conjugate vaccines will have a considerable impact on pneumococcal disease and overall infant mortality. Nevertheless, as with the introduction of any new vaccine, it will be important to conduct surveillance for possible rare and unexpected effects.

Modus operandi of the committee and additional information

In addition to publications in the Weekly Epidemiological Record, the scope of the committee’s work and past decisions, recommendations and actions, as well as its modus operandi, have been published in the American Journal of Public Health.7 More information about the topics discussed in this article as well as the committee’s terms of reference can be found on the GACVS web site at The committee agreed to discuss further the safety of vaccine formulations and to update its review of the safety of human papillomavirus and rotavirus vaccines at its next meeting in June 2007.

  • See No. 41, 1999, pp.337-338
  • GACVS invited additional experts to present evidence and participate in the discussions on the safety of mumps vaccine strains, the safety of Japanese encephalitis vaccine in India, the vaccination of adolescents and young adults including problems associated with coincidental pathologies in terms of safety assessments, and the review of safety of conjugate pneumococcal vaccine.
  • See No. 28, 2005, pp. 242–247.
  • See No. 28, 2006, pp. 273–278.
  • See No. 32, 2003, pp 282–284.
  • See No. 2, 2006, pp. 15–18.
  • 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.