Global Vaccine Safety

Global Advisory Committee on Vaccine Safety, 12-13 June 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 sixteenth meeting in Geneva, Switzerland, on 12–13 June 2007.2 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, 5 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 prompt data transmission by countries, assurance of data quality, and the processing and analysis of data, including timely signal detection and action. As a result, a GACVS subgroup 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 and the outcome of its 11 June 2007 meeting were presented to the full Committee. Most of the subgroup meeting was spent reviewing issues raised by the secretariat (emergency response to crises involving adverse events following immunization (AEFI); potential utility of invoking the International Health Regulations (IHR) as a way to facilitate WHO investigation of serious AEFI in different settings; and an initiative to develop a Global Vaccine Safety Datalink project). It was agreed that development of an emergency response protocol should be pursued, but that invoking the IHR to investigate AEFI should probably be employed only in rare and special circumstances; WHO will further deliberate on how this might be implemented before a final decision is made. Enthusiastic support was expressed for WHO participation in the Global Vaccine Safety Datalink project. The inclusion of vaccine pharmacovigilance sessions at 2 international meetings – the 4th Biennial Conference on Signal Detection and Interpretation in Pharmacovigilance (London, UK, 14–15 June 2007) and the 7th International Society of Pharmacovigilance (Bournemouth, UK, 21–24 October 2007) – was also highlighted.

Safety of vaccine formulations

This session stemmed from a recommendation made at a previous GACVS meeting4 that the Committee should start looking proactively into the actual and perceived safety of preservatives and other non-antigenic ingredients found in vaccine formulations. A GACVS subgroup was established to examine this issue in further detail. The subgroup briefly reported on its work and presented the agreed terms of reference, proposed methodology and list of priority action items. The subgroup’s goal is to advise WHO, through the GACVS, on issues relating to the potential adverse effects of vaccines due to non-antigenic components and to propose strategies on how to deal with such concerns. The specific terms of reference are: (i) to provide advice on ways to capture AEFI that are due to, or suspected to be due to, components of a vaccine formulation other than the antigenic components. The latter might be categorized as (a) substances that are intended to be part of the final formulation (e.g. adjuvant, preservative, stabilizers) and (b) substances that are used in the manufacturing process but that may be present in the final formulation in residual amounts (e.g. formaldehyde, toxins, viral growth media/substrate); (ii) to provide recommendations on how to evaluate such concerns through specific scientific investigations; (iii) to identify issues related to non-antigenic components of vaccines that impact on public health programmes; (iv) to advise on proactive communication strategies to address real and unfounded concerns about vaccine formulations in order to prevent inappropriate loss of confidence in immunization programmes.

The attribution of an AEFI to a particular vaccine ingredient is a complex process that may involve the evaluation of many factors, including the complexity of the formulation, and manufacturing, storage and handling processes as well as administration and host-related factors. Regulatory authorities would benefit from background scientific documents that could describe the safety profile of the non-antigenic vaccine constituents. Standardized definitions for and use of terminologies such as “residuals”, “adjuvants”, and “contaminants” would also be useful.

Operational strategies were presented for discussion with the GACVS, including specific events that should trigger subgroup actions. A draft framework for categorizing vaccine constituents was presented and suggestions for refinement received. As a next step, the subgroup will prioritize constituents for review.

Issues associated with specific vaccines

Mumps vaccine virus strain repository

GACVS was updated on the status of the repository of mumps vaccine virus strains. Following a request from WHO, the WHO reference repository at the National Institute for Biological Standards and Control (NIBSC), Potters Bar, UK, has been provided with samples of different mumps vaccine virus strains used by 5 manufacturers in their vaccines. The main objective of this repository is to serve as a source of well-documented strains for further investigation of their genetic characteristics and neurovirulence profile. The immediate need is to improve quality control of mumps vaccines by introducing a more consistent and precise neurovirulence assay. The rat-based neurovirulence test (RNVT) developed at the Center for Biologics Evaluation and Research (CBER) in the USA has shown potential advantages compared with the existing monkey neurovirulence model. Mumps vaccine virus strains in the repository are scheduled to be tested at NIBSC and CBER to establish validity criteria for the RNVT. As a result, a future scoring system is anticipated to determine the degree of neurovirulence of each strain. In view of the variability that has been observed in different epidemiological studies, this might provide some useful insights to help discriminate the potential of a strain to cause aseptic meningitis. GACVS acknowledged the collaboration provided by manufacturers who responded to the request for samples and continues to encourage other manufacturers to provide additional vaccine virus strains to the repository.

Safety of BCG vaccines

Currently, a number of vaccine strains of bacille Calmette-Guérin (BCG) are being used worldwide. These vaccines differ in their genetic, physical and chemical properties. Data reviewed by GACVS indicate that they also differ in terms of their reactogenicity and immunogenicity profile when given to infants and children. However, the data are insufficient to make recommendations on whether one strain should be preferred over the other.

The Committee also reviewed data from a study conducted in the Pasteur Institute, Paris, to assess the sensitivities of different BCG strains to antibiotics. All strains examined (Russian BCG-I (SI India and BB-NCIPD Bulgaria), Tokyo- 172-1, Danish 1331, Glaxo ST 1077, Connaught and Moreau RDJ) were sensitive to isoniazid, rifampicin, ethambutol, and streptomycin. The strains were all resistant to pyrazinamide and D-cycloserine, which is consistent with prior studies. These findings also support the current practice of not recommending the use of pyrazinamide or D-cycloserine for the treatment of disseminated BCG disease.

GACVS was presented with a summary of ongoing modelling work to weigh the benefits and risks of delayed BCG vaccination in HIV-positive infants, and noted that careful consideration will be needed of how the results can be translated into vaccination policy. It will be important that any policy recommendations deriving from that work are formulated in such a way that they are applicable in the context of routine vaccination programmes. It was also emphasized that the model should take into account regional differences in terms of the epidemiology, management, and policies around HIV and tuberculosis (TB).

GACVS recommended that the WHO Working Group on BCG vaccines as well as the Vaccine subcommittee of the Stop TB Partnership, be consulted for broader discussion on the clinical relevance of using different BCG vaccines, taking into account other issues including vaccine quality control and genetic diversity of different strains. The Committee emphasized that the most important safety consideration with regard to vaccination policy is the potential for disseminated BCG disease in immunocompromised children with specific vaccine strains, rather than reactogenicity in the general target population.

Safety of human papillomavirus vaccine

At the request of the Strategic Advisory Group of Experts on immunization (SAGE), the Committee reviewed the safety of human papillomavirus (HPV) vaccines.

A review of available evidence of the safety of both the 4-valent HPV (Gardasil®) and the 2-valent HPV (Cervarix®) vaccines was presented. Data from pre-licensure randomized controlled trials and post-licensure surveillance reports from the 2 vaccine manufacturers as well as from the European Medicines Evaluation Agency, the United States Food and Drug Administration (FDA) and the United States Centers for Disease Control and Prevention (CDC) were included in the review.

The current evidence on the safety of HPV vaccines is reassuring. The reviewed data covered local and systemic events in short-term, and long-term events up to 6 years after vaccination, including pregnancy events. A common observation was the occurrence of injection site reaction and muscle pain. During adolescent vaccine campaigns, some mass sociogenic illnesses such as post-vaccination dizziness and syncope have been reported. These events have been prevented by observing adolescents for 15 minutes post-vaccination and encouraging good hydration. No concerns with the safety profile were identified.

As with the introduction of any new vaccine, it will be important to conduct surveillance to identify possible, rare unexpected adverse effects, especially as good-quality information on the rates of a variety of diseases before widespread vaccine introduction is generally lacking in the target age group for HPV vaccination (i.e. 9 to 26 years). Also, careful surveillance for specific adverse effects during pregnancy will be important as the target group includes females of reproductive age.

The Committee was advised of studies that are planned, mostly in developed countries, to monitor the occurrence of adverse effects of HPV vaccination. The Committee considered that it would be highly desirable if the protocols for these studies were to be made publicly available to encourage the conduct of similar studies in other locations, including developing countries. The evaluation of adverse effects, especially the long-term events and also the effectiveness of the HPV vaccine, would be greatly facilitated if national registers were maintained of all those who are vaccinated. This is planned in some countries, and the extension of this practice in other locations must be encouraged.

Update on Menactra® and Guillain-Barré syndrome

An update was presented on the reported occurrence of Guillain-Barré syndrome (GBS) after vaccination with a tetravalent conjugated meningococcal vaccine (Menactra®)5 in the USA. To date, more than 12 million doses have been delivered in the USA. As of 30 April 2007, a total of 19 cases of GBS, occurring within 6 weeks of vaccination, had been reported to the US Vaccine Adverse Event Reporting System (VAERS). Analysis of the data could not exclude a slightly increased risk of GBS after vaccination, but this finding should be reviewed with caution given the limitation of the reporting system and the uncertainty of the background rate of GBS and its potential for seasonal fluctuation. The manufacturer of the vaccine is planning further studies to evaluate the possible risk of GBS following vaccination with Menactra®.

Safety of rotavirus vaccines

Data were presented by the manufacturers of RotaTeq® and Rotarix® rotavirus vaccines as well as by the CDC and the FDA. Data related mainly to the risk of intussusception, which had been identified as associated with a previous rotavirus vaccine. In addition, information was presented on Kawasaki disease following vaccination, for which there was limited, not statistically significant, evidence of an increased risk observed in a clinical trial for 1 of the 2 products.

With respect to Rotarix®, there was no evidence from any of the studies, which included over 30 000 vaccinees in trials and worldwide usage, with about 5 million doses distributed, that there was an excess incidence of intussusceptions. Those cases of intussusception that were reported did not show a pattern with regard to the time of onset following vaccination consistent with a causal relationship. The overall numbers of cases reported were much less than would have been expected based on applying rates for the normal incidence of intussusception to a population of the size vaccinated.

With respect to RotaTeq®, a large (>30 000) trial (the REST study) has been reported, and an observational cohort of 44 000 vaccinated children is planned. Most data relate to developed countries, especially in the post-marketing studies and spontaneous reporting. There is no evidence that the rate of intussusceptions is raised above background rates, and it is certainly much less than the rate previously observed with the vaccine that was withdrawn following an association with intussusception. The VAERS spontaneous reporting data also show a lower than expected rate of intussusception.

The REST study had 5 cases of Kawasaki disease in the vaccinated group compared with 1 in the placebo group. These cases were quite young, and it is not clear whether this rate in the vaccinated group is higher than expected. Detailed data on background incidence of Kawasaki disease are not well determined. The time to occurrence in vaccinated children does not show a pattern, but the number of reports is too low for a detailed assessment. The focus of the post-marketing surveillance has been largely targeted at intussusception, and there are few data on Kawasaki disease.

GACVS concluded that with regard to intussusception, the data, particularly those from developed countries, are reassuring. It was noted, however, that the present data relate mainly to vaccines administered to young children at the recommended age. It remains important that intussusception should be monitored in developing countries as rotavirus vaccines are introduced, especially because infants are likely to present for their first dose of vaccine at slightly older ages, on average, than is the case in developed countries.

With respect to the rare cases of Kawasaki disease that have been observed, while the evidence is at best a hint of a signal, the data do not yet permit a full evaluation of a possible risk. Kawasaki disease is not easy to diagnose in infancy and may not be reported if there is no suspicion that it could be caused by a vaccine. There is a need for careful assessment of Kawasaki disease in the existing data and to ensure that ongoing and future studies incorporate surveillance for Kawasaki disease following vaccination.6

Influenza vaccines: update

GACVS was presented with a detailed account of the investigation of 4 reported deaths following the administration of a seasonal influenza vaccine in Israel in 2006. These reports were rapidly investigated and none of the findings supported a causal relationship between the deaths and immunization. Nonetheless, a significant decrease in vaccine uptake was noted, underscoring communication challenges in responding to vaccine safety concerns.

A brief description of allergic events occurring after administration of Grippol®, a polyoxidonium adjuvanted split virus influenza vaccine produced in the Russian Federation, was presented. There is a paucity of information regarding these events, and WHO could not secure additional information on the investigation. As such, it is unclear if events reported in the media were compatible with expected rates of allergic reactions or represented an increase and possibly some manufacturing problems. GACVS nevertheless recommends that countries using this vaccine put in place a surveillance system for the upcoming influenza season so that its safety profile can be better characterized. Improved information sharing regarding the safety profile of influenza vaccines is critical for pandemic influenza preparedness.

An update on Flumist®, a cold adapted live attenuated influenza vaccine, was presented. Studies with Flumist® in young children demonstrate efficacy against circulating H1N1 and H3N2 strains, including H3N2 strains that are antigenically dissimilar to the strain included in the annual vaccine. Efficacy has also been demonstrated against circulating B strains, although in some studies the protection against B strains is less impressive. Of note, however, was a significantly increased incidence of medically significant wheezing episodes within 42 days of vaccination among children aged 6–23 months. The manufacturer has applied to extend the indication to children less than 5 years of age, and this matter remains under review by the respective national regulatory authority.

An update on the activities of the subgroup on influenza vaccines, initiated at the November 2006 GACVS meeting,5 was also presented. Its terms of reference are: (i) to provide WHO, through GACVS, with medical, scientific and public health advice relating to post-marketing surveillance of seasonal and pandemic influenza vaccines within the scope of pandemic influenza preparedness planning; (ii) to review topics related to influenza vaccine safety surveillance in detail and to formulate recommendations and statements for GACVS. The specific terms of reference are: (i) to assist WHO in the preparation of an appropriate pharmacovigilance strategy and plan; (ii) to assess and respond to the anticipated risks associated with pandemic influenza vaccines at an international level based on experience gained with seasonal influenza vaccines; (iii) to advise on the post-marketing surveillance approach described in the WHO Guidelines on Regulatory Preparedness for Human Pandemic Influenza Vaccines (section 4); (iv) to advise on the development of operational post-marketing surveillance guidelines for seasonal and pandemic influenza vaccines; (v) to advise on the tools to assess national capacity to monitor safety of seasonal and pandemic influenza vaccines; (vi) to advise WHO on the formation of a pilot global post-marketing surveillance network aimed at providing rapid and timely access to safety information concerning seasonal and pandemic influenza vaccines; (vii) to contribute to development and revisions of GACVS web pages on the safety of influenza vaccines;7 and (viii) to address other specific issues related to seasonal or pandemic influenza vaccines identified and referred by GACVS, as appropriate.

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.8 More information about the topics discussed in this article as well as the Committee’s terms of reference and the work of its subgroups can be found on the GACVS web site at http://www.who.int/vaccine_safety/en/. The Committee tentatively agreed to particularly focus, at its next meeting scheduled for 12–13 December 2007, on the following: updated review of the safety of the live attenuated SA 14-14-2 Japanese encephalitis vaccine; review of the safety of the meningococcal meningitis B vaccine; to review the safety of vaccination in immunocompromised individuals; GBS in relation to vaccination in general.

  • See No. 41, 1999, pp. 337–338.
  • GACVS invited additional experts to present evidence with respect to the safety of bacille Calmette-Guérin (BCG) vaccine, Menactra® and Guillain-Barré syndrome, safety of human papillomavirus vaccines, safety of influenza vaccines and safety of rotavirus vaccines. Depending on the session, these experts were affiliated with the Institut Pasteur Paris, the United States Food and Drug Administration, the Israeli Ministry of Health; the United States Centers for Disease Control and Prevention, the European Medicines Evaluation Agency, and the manufacturers of human papillomavirus and rotavirus vaccines.
  • See No. 28, 2005, pp. 242–247.
  • See No. 28, 2006 pp. 273–278.
  • See No 3, 2007, pp. 18–24.
  • In June 2007, the US Food and Drug Administration (FDA) (http://www.fda.gov/cber/products/rotateq.htm) approved a label change based on the reports of Kawasaki disease but did not make any changes to its indications for use of RotaTeq®, nor did the agency issue new or revised warnings or precautions. In its announcement of the label change, the FDA stated that cases reported to date were no more frequent those that could be expected to occur by coincidence and that health-care practitioners and parents should remain confident in using RotaTeq®. Likewise, the US Centers for Disease Control and Prevention did not make any changes to its recommendations regarding the use of RotaTeq®.
  • The endorsement of influenza vaccines related web content remains with GACVS in its full membership and the Web content reflects deliberations by the full Committee.
  • 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.
Share