Global Vaccine Safety

Global Advisory Committee on Vaccine Safety, 6-7 June 2006

Published in the WHO Weekly Epidemiological Record on 7 July 2006

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 fourteenth meeting in Geneva, Switzerland, on 6–7 June 2006.2 The following issues, inter alia, were considered.

Vaccine safety monitoring and the WHO Programme for International Drug Monitoring

The report3 of the WHO Consultation on global monitoring of adverse events following immunization (AEFI) held in Geneva on 9–10 January 2006 at the request of the GACVS4 was presented and discussed by the Committee. The recommendations were endorsed, with emphasis placed on ensuring that vaccine pharmacovigilance is strengthened within the WHO Programme for International Drug Monitoring with respect to data transmission by countries, assurance of data quality, and the processing and analysis of data, including timely signal detection and action. A working subgroup of 6 GACVS members was formed to ensure that the initiative continues to move forward in a timely fashion. Terms of reference and an action plan will be developed and initiated by the working group in conjunction with the WHO secretariat in the coming months and a progress report submitted to GACVS at its November 2006 meeting.

Post-marketing surveillance of rotavirus vaccines

WHO is developing a generic protocol for post-marketing surveillance of rotavirus vaccine safety that can be adapted for implementation at the country level. This protocol will be made available before the end of 2006 and covers monitoring of intussusception as well as other potential safety issues, including other gastrointestinal symptoms, the potential effect of malnutrition as well as shedding and transmission of vaccine virus strains. WHO will also support the post-marketing surveillance of rotavirus vaccine safety through a network of sentinel countries.

The Committee noted that plans are under way, under the leadership of the United States Centers for Disease Control and Prevention, to develop and make available a protocol for the post-marketing surveillance of the impact of rotavirus vaccines. It strongly recommended that introduction of rotavirus vaccines should be associated with careful consideration of post-marketing surveillance at country level and securing its funding as an essential part of immunization programmes.

Safety of squalene

Squalene is a component of some adjuvants that is added to vaccines to enhance the immune response. A naturally occurring substance found in plants, animals and humans, squalene is synthesized in the liver and circulates in the human bloodstream. It is also found in a variety of foods, cosmetics, over-the-counter medications and health supplements. Squalene is commercially extracted from fish oil – in particular shark-liver oil – and is purified from this source when used in pharmaceutical products and vaccines.

Squalene alone is not an adjuvant, but emulsions of squalene with surfactants enhance the immune response when added to antigens. MF59, a proprietary adjuvant containing squalene, is included in a seasonal subunit influenza vaccine licensed by the Italian regulatory authority in 1997 and subsequently by several other countries. The vaccine contains about 10 mg of squalene per dose. Over 22 million doses have been distributed since that time. Reported rates of adverse events and local reactogenicity are not in excess of those that would be expected with other inactivated seasonal flu vaccines, suggesting that squalene in this vaccine poses no significant risk. This vaccine has been administered primarily to individuals aged 65 years and older, for whom the vaccine was licensed.

Several experimental vaccines, including some pandemic flu vaccines, malaria vaccines, and various viral and bacterial vaccines, are also being developed with squalene-containing adjuvants, with the intention of enhancing immunogenicity and thereby efficacy. Clinical studies of squalene-containing vaccines have been performed in infants and neonates without evidence of safety concerns.

A link between the health problems of Gulf-War veterans and possible presence of squalene in vaccines received by these soldiers has been suggested. One published report has suggested that some army veterans who received anthrax vaccines developed anti-squalene antibodies and that these antibodies caused disabilities. However, squalene was not added to the vaccines administered to these veterans, nor was it used in the manufacturing process. Various papers have been published outlining the technical deficiencies in that original report.

Most adults, particularly older ones, irrespective of their history of vaccination, have naturally occurring antibodies reacting with squalene. In a clinical trial, immunization with the licensed influenza vaccine containing squalene did not affect the frequency or titre of anti-squalene antibodies.

The Committee concurred that fears of squalene in vaccine-inducing pathological anti-squalene antibodies are unfounded. It did note, however, that the experience of squalene-containing vaccines has been primarily in older age-groups and recommended that as squalene-containing vaccines are introduced in other age-groups, careful post-marketing follow up to detect any vaccine-related adverse events needs to be performed.

Immunogenic overload

The GACVS acknowledges that supposed “immune overload” as a result of infant immunization is a parental and societal concern that may limit confidence in and thus affect immunization programmes. It noted that the concept of immune overload was ill defined – but the available evidence was reviewed and discussed. Vaccine interference (i.e. the limitation of specific vaccine-induced immune responses as a result of combined, simultaneous or successive vaccinations) is a recognized phenomenon that may result from a variety of immunological mechanisms. It is important to recognize when this phenomenon occurs and to adjust the recommended immunization schedule accordingly. The Committee specifically discussed issues such as the influence of vaccine schedules on the protective responses that may be induced (vaccine administration in early infancy or at a later age, schedules accelerated or extended over a longer period of time) and of the effect of factors such as malnutrition or exposure to environmental pathogens/antigens that may differ in various country settings.

The Committee recognizes the difficulty in communicating complex scientific knowledge and the usefulness of studies addressing public concerns. It concluded that additional epidemiological studies assessing the presence of an association between vaccination and recurrent infant infections or atopic dermatitis would be welcome. Demonstrating the absence of such risks would reinforce the confidence of health-care providers, if not the public at large, in infant immunization.

The available evidence reviewed by GACVS does not support the hypothesis that vaccines, as currently used, weaken or harm the immune system. Surveillance should continue, and changes in vaccine schedules or introduction of new vaccines may provide opportunities to perform randomized studies to identify any possible harm posed by infant vaccines or to strengthen the evidence indicating a lack of harm. This is of crucial importance in helping national authorities respond to public concerns and support immunization programmes.

Safety of pandemic influenza vaccines

At its request, GACVS was presented with historical experience from the 1976 swine influenza A (H1N1) outbreak and vaccination efforts initiated at the time in the United States. A number of lessons learnt from this experience should be taken into consideration in preparation for a potential pandemic. Vaccines from different manufacturers may behave differently in terms of safety or immunogenicity due to use of different viral strains, formulation or manufacturing processes. Possible high-risk shortcuts in response to a potential emergency would be difficult to justify prior to the actual occurrence of the emergency. Effectiveness of pandemic vaccines will not be known before the pandemic and possibly only after it is over. In addition, unexpected adverse events, whether coincidental or vaccine-related, will occur that may lead to anxiety and may affect vaccine uptake. It will be important to try to obtain appropriate baseline data in different age groups before the use of the vaccines or the onset of pandemic, to conduct a careful and independent regulatory review, updated, as new information becomes available. In this respect, WHO could play a critical role in assisting Member States and reviewing data from various sources for the evaluation of the available safety evidence. Clear communication on risks and benefits of immuno-prophylaxis is critical. A comprehensive set of the lessons and action points can be accessed on the web site at

The GACVS reviewed possible actions to overcome obstacles relating to the use of newly formulated vaccines for emergency use, some of which will contain new adjuvants. These include strengthening rapid detection systems for identification of AEFIs, testing and improving existing national and global networks for sharing of such information, and strong national regulatory oversight of the production facilities. The Committee was informed of a process initiated for the development of post-marketing surveillance protocols for pandemic influenza vaccine. The protocol and international information-sharing should be tested and harmonized during the forthcoming and subsequent influenza seasons. WHO’s role in gathering information on the safety profile of candidate pandemic vaccines from clinical trials should be enhanced. With regard to efficacy and safety testing, use of individual and cluster randomized trials was discussed from both practical and ethical standpoints. Such trials offer best quality of evidence and should be considered in the situation of limited vaccine supply. Internationally coordinated preparatory work for these trials should start immediately, as little time would be available for putting the needed infrastructure in place after the start of the pandemic.

Pregnant women are considered at special risk for influenza infection based on morbidity and mortality from previous pandemic events and from intense influenza seasons. The Committee reviewed the use of inactivated seasonal flu vaccine in 2003 5 and concluded that the risk–benefit of influenza vaccination during all stages of pregnancy should be reconsidered, given the high risk to the mother – and thus to the fetus – of the disease itself, and the likely small risk to mother and fetus of the inactivated influenza vaccine. There are currently no data on the safety profile of candidate pandemic influenza vaccines when administered during pregnancy. Where appropriate (e.g. with use of novel adjuvants), reproductive toxicity studies using animal models should be conducted. It is expected that inadvertent immunization during pregnancy may occur during the pre-pandemic phase of vaccine use. These pregnancies should be followed up and pregnancy outcomes (with or without adverse events) reported to pharmacovigilance centres. Pregnancy and congenital malformation registries should be scrutinized for ability to provide information on immunization events during pregnancy and linked to other databases enabling the review of safety outcomes in mothers and infants exposed to pandemic influenza vaccine during pregnancy.

Safety issues of varicella vaccines

As part of its systematic effort to review potential safety issues of all vaccines, including new vaccines and vaccines still under development, GACVS reviewed the accumulated experience with respect to the use of varicella vaccine.

Safety issues with varicella vaccination are unique given that both the wild and vaccine-virus strains establish latency in humans. In the United States, universal childhood immunization has been under way since 1995, with about 50 million doses administered. Data collected through passive surveillance in the United States (VAERS) are valuable in assessing the safety of vaccination against varicella. In the United States, since introduction of varicella immunization, there has been a clear decrease in morbidity and mortality caused by varicella. The vaccine coverage for the age group 19–35 months in 2004 was estimated to be 88%. About 50% of all AEFI reports received at VAERS are in children aged 12–24 months. In 70% of reports, varicella vaccine was given concomitantly with other vaccines.

Some potential safety issues are common to other live attenuated viral vaccines including the effect of vaccination on pregnant women inadvertently immunized as well as the risk of secondary transmission of the attenuated virus vaccine strain from vaccinees to their contacts. To date, the data provide no cause for concern.

The rate of reported adverse events following concomitant administration of varicella and measles, mumps and rubella (MMR) vaccine is in line with what would be expected based on the administration of MMR or varicella vaccine administered alone.

An important safety issue related to the varicella vaccine is the impact on the epidemiology of herpes zoster both in vaccinees as well as in individuals previously infected with wild-type varicella. Mathematical models have predicted that the limited circulation of wild virus as a result of ongoing universal varicella immunization programmes could lead to an increased incidence of herpes zoster for many years before an eventual decline over decades. The US data do not show signs of such an increase after 11 years of observation. However, given the natural history of reactivation, it is likely that decades of observation will be required before any conclusions can be drawn regarding the long-term impact on herpes zoster epidemiology.

In view of the potential impact of these long-term effects, it is recommended that any countries planning to introduce varicella vaccine programmes should collect baseline data on the age-specific incidence of herpes zoster. These observations should be shared and continuously reviewed.

Modus operandi of the Committee and additional information

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.6 More information in relation to the above-mentioned topics and others can be found on the GACVS web site at n

  • See No. 41, 1999, pp. 337-338
  • GACVS invited additional experts to present evidence and participate in the discussions on post-marketing surveillance of newly introduced vaccines, with focus on rotavirus, safety of squalene, potential immunogenic overload resulting from concomitant vaccination with too many antigens, safety of pandemic influenza vaccines and safety issues of varicella vaccines.
  • See No. 27, 2006, pp. 261-265
  • See No. 28, 2005, pp. 242-247
  • See No. 79, 2004, pp. 16-20
  • 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.