Global Vaccine Safety

Global Advisory Committee on Vaccine Safety, 3–4 December 2009

Published in the WHO Weekly Epidemiological Record on 29 January 2010

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 twenty-first meeting in Geneva, Switzerland, during 3–4 December 2009.2 The Committee reviewed the safety of pandemic A (H1N1) influenza vaccines and the safety profile of a meningococcus A conjugate vaccine that will soon be deployed in sub-Saharan Africa. The Committee also discussed the use of bacille Calmette–Guérin (BCG) vaccine in areas with a high prevalence of infection with human immunodeficiency virus (HIV) and reviewed progress with global monitoring of adverse events following immunization (AEFI).

Safety of pandemic A (H1N1) influenza vaccines

Since its emergence in March 2009, influenza A (H1N1) 2009 virus has caused significant morbidity and mortality. For example, the United States Centers for Disease Control and Prevention (CDC) estimates that in the USA there have been about 100 000 hospitalizations and nearly 4000 deaths caused by pandemic (H1N1) 2009 virus during the period April to 17 October 2009. In response to the pandemic, >30 pandemic (H1N1) 2009 vaccines have been developed and licensed. Since September 2009, >50 countries have implemented immunization programmes targeting various populations. These populations include health-care workers, children, pregnant women, and individuals with certain underlying medical conditions, including chronic lung disease, diabetes, and heart disease, as well as those whose immune systems are compromised.3,4

From 21 September to 2 December 2009, tens of millions of doses of the pandemic (H1N1) 2009 vaccine were administered, thereby providing the basis for this first safety review by the GACVS. The review is mainly based on passive surveillance data.5 Under the coordination of WHO, there is an unprecedented, ongoing exchange of safety information among regulatory and public health authorities from many countries around the world.

Pandemic influenza vaccines include live attenuated vaccines, inactivated unadjuvanted vaccines (split, sub-unit virion, or whole virion) and inactivated adjuvanted vaccines (split or sub-unit virion). At the time of the GACVS review, it was estimated that nearly 150 million vaccine doses had been distributed in many countries around the world. Approximately 30% of those 150 million doses are adjuvanted vaccines. No unexpected safety concerns have been identified for any of the pandemic (H1N1) 2009 vaccines. Product labelling for each vaccine contains a summary of expected side-effects.6

In the ongoing immunization campaigns, deaths in temporal association with vaccination have been reported in many countries. Given the large number of people who have been vaccinated, it is expected that deaths that were unrelated to vaccination would occur in temporal association with vaccination.7 Investigation of deaths that have been reported after immunization have identified that the cause of death has been unrelated to vaccination in all but a few instances. There have been a few individual reports of deaths associated with anaphylactic reactions to vaccination.

Immediate hypersensitivity reactions have been reported after the use of all types of pandemic (H1N1) 2009 vaccines. These events include urticaria, angioedema and anaphylaxis, with reactions ranging from mild to serious. The overall reporting rates for anaphylaxis range from 0.1 to 1.0 per 100 000 doses distributed. Anaphylaxis is a known, potentially life-threatening adverse effect of all vaccines and is a very rare event. Nonetheless, immunization providers must be prepared to recognize and appropriately treat such reactions.8

Although some cases of Guillain–Barré syndrome have been reported after receipt of pandemic (H1N1) 2009 vaccines, the evidence to date is reassuring, with no increase in reporting rates above what is expected, based on background rates. Active surveillance for GBS has been instituted in several countries and should provide additional information by the first quarter of 2010.

Concerns have been raised about the use of adjuvanted pandemic vaccines in patients with immune disorders, such as immunodeficiency, autoimmune disorders and solid organ transplants. To date, post-marketing surveillance has not found evidence for causality of any safety issues in such patients. Viral infections, such as influenza, can lead to severe complications in immunocompromised patients. Thus, the benefit of pandemic (H1N1) 2009 vaccines, adjuvanted or unadjuvanted, far outweighs the potential risks in these patients.

Programmatic errors have also been reported, including erroneously administering other drugs instead of vaccine, or errors in mixing adjuvant and antigen components as required for some of the vaccines. Immunization programmes should take appropriate measures to prevent such errors. In summary, GACVS concluded that:

  • Ten weeks into the worldwide immunization campaign against pandemic (H1N1) 2009, the GACVS reviewed the safety of pandemic (H1N1) 2009 vaccines currently in use. To date, the safety data are reassuring.
  • Most of the adverse events that have been reported after immunization have not been serious. To date, no unexpected safety concerns have been identified.
  • Reporting mechanisms have been enhanced. Ongoing vaccine safety monitoring (pharmacovigilance) is critical, including regular information-sharing with WHO by national regulatory and health authorities. Most of the safety information to date is from passive surveillance. Data from active surveillance will be assessed as they become available.3

Review of safety profile on meningococcal A conjugate vaccine from clinical trials

The Committee was given an overview of the MenAfriVacTM vaccine clinical safety data and risk management plan. This is a lyophilized meningitis A conjugate vaccine developed by the Meningitis Vaccine Project. Each dose of 0.5ml vaccine contains: PsA10 µg, TT conjugate 10–33 µg, aluminium phosphate adjuvant 0.3mg Al3+ and thiomersal 0.01%. Four clinical trials have evaluated the reactogenicity and safety of MenAfriVacTM , and 2 additional trials are ongoing. The phase I study was conducted in 18–34 year-old volunteers in India; Phase II and II/III studies, to assess the safety and immunogenicity of the vaccine, were performed in 1–29 year-old people in Africa and India. To date, a total of 1126 subjects have been followed to evaluate the safety and immunogenicity of the MenAfriVacTM vaccine.

The subjects in the trials were followed for AEFI for at least 1 month after vaccination and for serious adverse events up to at least 1 year after vaccination. MenAfriVacTM vaccine did not cause any adverse reactions beyond 4 days post immunization; the adverse events observed were comparable between study and control vaccine groups, except for injection site tenderness which was more common (13%) among those in the MenAfriVacTM vaccine group. No particular safety concerns were identified in any of the age groups evaluated. None of the 137 serious adverse events (including 14 deaths) reported in the vaccine studies were assessed to be related to the study vaccines.

The Committee highlighted issues yet to be addressed with respect to use of the vaccine. These included the need for booster doses, their effect on carriage, interactions with EPI if given to infants and the possibility of serotype replacement. There are no data on the effects of the vaccine in special groups such as those HIV-infected and those severely malnourished.

The Committee also reviewed the safety profile of other meningococcal conjugate vaccines. Pre- and post-licensure data for meningococcal conjugate vaccines have not shown marked differences between the vaccines, and reported serious adverse events are rare. Based on potential safety signals that were identified with other meningococcal conjugate vaccines, the pharmacovigilance for the meningococcal A conjugate vaccine should pay specific attention to anaphylactic reactions, severe cutaneous reactions, nephrotic syndrome, meningitis-like symptoms, myocarditis and Guillain–Barré syndrome. These other vaccines differed from MenAfriVacTM with respect to the excipients in the vaccine, particularly aluminium phosphate and thiomersal. Establishment of proactive pharmacovigilance, with a risk management programme that includes safety evaluation during a phased roll-out, should therefore be an essential component of introduction plans for this new vaccine.

The Committee concluded that available data for MenAfriVacTM vaccine do not indicate any special cause for concern. However, further studies, particularly post-marketing surveillance, are needed to better assess the safety profile of the vaccine.

Use of BCG vaccine in HIV-infected infants

Additional data from studies in Argentina and South Africa confirm the significantly high risk of disseminated BCG (dBCG) disease in HIV-positive infants, with rates approaching 1%. Other studies have shown that infection with HIV severely impairs the BCG-specific T-cell responses during the first year of life. Thus, BCG may therefore provide little, if any, protection against tuberculosis in HIV-infected infants. Considering the significant risk of dBCG disease, these data strongly support the WHO recommendation of not giving BCG to children who are known to be infected with HIV. Additional data suggest that highly active antiretroviral therapy (HAART) may reduce the rate of dBCG disease and that this benefit may be greater than the increased frequency of the immune reconstitution inflammatory syndrome that is observed in BCG-vaccinated HIV-infected children receiving HAART.

The new data do not provide arguments for modifying the current policy recommended by WHO,9 which has also been supported by recent statements from the International Union Against Tuberculosis and Lung Disease and the Childhood TB Subgroup of the WHO DOTS Expansion Working Group.10 The operational difficulties in implementing the WHO recommendations were noted, in particular the delayed vaccination approach,11 which might be possible to implement only in situations where: good TB and HIV surveillance systems for pregnant women and infants existed; where strategies for the prevention of mother-to-child transmission of HIV were operating optimally and were closely linked to well functioning EPI programmes with good follow-up of all infants; and in situations where HAART coverage for mothers and children is high.

Disseminated BCG diseases have mainly been reported from Argentina and South Africa, countries that use the Pasteur and Danish strains respectively. Countries with good HIV and tuberculosis reporting systems, such as Brazil and Thailand, have not reported dBCG cases to the extent that the other 2 countries have. These last 2 countries use less reactogenic BCG vaccines (i.e. Japanese and Moreau vaccines) and whether strain is important in the genesis of dBCG in HIV infected children merits further evaluation.

Strengthening global monitoring of adverse events following immunization

Recommendations from the 2006 WHO Consultation on Global Monitoring of AEFI emphasized the need for strengthening vaccine pharmacovigilance within the WHO Programme for International Drug Monitoring with respect to data quality in AEFI reporting, data transmission by countries, and the processing and analysis of data, including timely signal detection and action.

A previously identified key area for action by the subgroup on AEFI Monitoring was to consider what types of methods are best for detecting vaccine safety signals. To facilitate this, the Uppsala Monitoring Centre (UMC) – the WHO Collaborating Centre for International Drug Monitoring – has provided access to their complete dataset. Preliminary analyses were done using data on vaccines alone as well as including data on both drugs and vaccines and stratifying analyses by age. GACVS reviewed the preliminary analyses and was encouraged by the potential of using this system for signal detection. Further work on methodology is required and will be further reviewed by GACVS in 2010.

The proliferation of vaccine products in the past decade, which are often not clearly identified in AEFI reports, has made interpretation of AEFI reports increasingly complex. In addition, there is a need to include non-antigenic vaccine components in safety assessments. Current vaccine nomenclature and conventional classification systems do not provide adequate differentiation of vaccine products. Therefore, GACVS has recommended, as a priority, the development of a vaccine dictionary that will allow differentiation of different formulations of vaccines from different manufacturers. UMC and WHO propose to include in the database additional vaccine characteristics, including antigen production and strain, dosage amount, carrier protein, adjuvants, non-antigenic components, generic abbreviation and market authorization holder. The dictionary structure is expected to be finalized by early 2010 and the full dictionary released by autumn 2010.

Progress continues to be made in the development of the WHO Global Network for Postmarketing Surveillance of Prequalified Vaccines. This project provides a direct means to increase the quantity and quality of AEFI data submitted to UMC. Additionally, the experience and knowledge gained in planning, initiating, supporting and maintaining this project will provide valuable insight into potential needs, gaps, barriers and strengths related to AEFI reporting by other countries, and will inform strategic decisions in refining the workplan of the Subgroup on AEFI Monitoring for the next 2 years.

  • See No. 41, 1999, pp. 337–338.
  • GACVS invited additional experts to present evidence on the safety of meningitis conjugate vaccines. These experts included people affiliated with the Ministry of Health, the Agence pour la Médecine Préventive, Ouagadougou (Burkina Faso) and the Programme for Appropriate Technology in Health, Ferney-Voltaire (France).
  • See No. 30, 2009, pp. 301–308.
  • See No. 49, 2009, pp. 505–516.
  • Passive surveillance refers to a system designed to collect adverse events that follow vaccination. This type of surveillance typically relies on health professionals noting and reporting to the appropriate authority adverse events that occur in individuals after vaccination. This system relies on spontaneous reporting by health-care staff. By contrast, active surveillance is a mechanism through which specific health conditions are monitored through a systematic and continuous review of medical records.
  • The Committee noted the recent warning from the European Medicines Agency (EMEA), after review of data from an ongoing clinical trial submitted by the manufacturer, that a higher proportion of young children may experience fever after their second dose of an adjuvanted pandemic influenza vaccine, Pandemrix, than after their first dose. The EMEA recommended that prescribers and parents should monitor the temperature of the vaccinated child and, if necessary, take measures to lower the fever. Additional information is available at: (accessed January 2010).
  • Black S et al. Importance of background rates of disease in assessment of vaccine safety during mass immunisation with pandemic H1N1 influenza vaccines. Lancet, 2009 (doi:10.1016/S0140-6736(09)61877–8).
  • The Public Health Agency of Canada identified a higher-than-normal rate of anaphylaxis (4.1/100 000 doses distributed) linked to one particular lot of the adjuvanted pandemic (H1N1) 2009 vaccine. Pending further investigation of adverse event reports linked to the lot, unused vaccines from this lot were withdrawn from use on 24 November 2009.
  • See No. 3, 2007, p. 22.
  • International Journal of Tuberculosis and Lung Disease, 2008;12:1376–1379.
  • The current WHO recommendation is that for infants born to HIV-infected mothers where early HIV diagnostic testing can be performed, BCG can be deferred until diagnostic testing results are available.