Safety of pandemic A (H1N1) influenza vaccines
Since its emergence in March 2009, pandemic influenza A (H1N1) 2009 virus has caused significant morbidity and mortality globally. For example, in the United States the pandemic A (H1N1) 2009 virus is estimated to have caused 61 million cases of illness, 274 000 hospitalizations, and 12 470 deaths between April 2009 and April 2010.1 In response to the pandemic, over 30 pandemic A (H1N1) 2009 vaccines were licensed worldwide: these included live attenuated vaccines; inactivated unadjuvanted vaccines (split, subunit virion or whole virion); and inactivated adjuvanted vaccines (split or subunit virion). Between September 2009 and June 2010, >350 million doses of vaccine were administered, targeting various populations.
As of 6 June 2010, more than 214 countries had reported laboratory-confirmed cases of pandemic A (H1N1) 2009 influenza, including at least 18 156 deaths. Younger age groups have been disproportionately affected by the pandemic virus and have had higher mortality from the disease than from seasonal influenza. Pregnant women have been disproportionately represented in admissions to intensive care units. Although older age groups have had lower rates of infection than with seasonal influenza, their hospitalization rates and mortality rates have been high.
Most of the safety information about pandemic influenza vaccines has been derived from passive surveillance, but there has been some active surveillance for specific conditions or circumstances for which it was thought, a priori, that there might be an increased risk (such as Guillain–Barré syndrome) or when the vaccine has been used for specific groups of patients (for example, in pregnant women or people who are immunocompromised).
Since the initiation of vaccination campaigns, WHO has coordinated an unprecedented and continuing exchange of safety information among regulatory and public health authorities from many countries. Follow-up of vaccinated populations continues, and additional data on safety are expected later in 2010. In order to establish reliably the risk–benefit balance of the vaccines, these findings should be considered along with additional observations on the impact of the pandemic disease itself. An interim assessment of the potential risks (or signals) of adverse reactions evaluated in different countries and geographical areas for several different products is given below.
In the United States, where an estimated 65 million people were vaccinated with inactivated unadjuvanted vaccines and 17 million individuals were vaccinated with live attenuated vaccine, no signals of unexpected side-effects were detected through passive surveillance. The occurrence of Guillain–Barré syndrome in people who had been vaccinated was evaluated through several different active surveillance systems, one of which yielded a weak signal; further analyses are under way. Preliminary analysis suggests that if an increase in the risk of Guillain–Barré in those vaccinated is confirmed, the risk may be approximately 1 case/1 000 000 doses, which is similar to the risk reported during some years with seasonal trivalent, inactivated, unadjuvanted vaccine. In addition, there were weak signals of thrombocytopenia and Bell’s palsy; these are also being investigated.
In Japan, approximately 18 million individuals were vaccinated with 21 million doses of inactivated unadjuvanted vaccine. Safety was monitored primarily through passive surveillance. Cases of interstitial lung disease, thrombocytopenia, idiopathic thrombocytopenic purpura and allergic purpura following immunization were evaluated, but were not considered to represent new safety issues.
As of April 2010, China reported that 97 million people, representing 7% of the population, had been vaccinated with locally produced, inactivated, unadjuvanted vaccines. Safety has been monitored through passive surveillance. The rate of adverse events following immunization was about 8.6/100 000 doses administered. The reported rate for serious reactions was around 1/100 000 doses administered; the majority of these reactions were Schönlein–Henoch purpura, anaphylactic shock, laryngeal oedema and febrile convulsions. The number of cases of Guillain–Barré reported was not higher than expected. Although deaths following vaccination were reported, these were found to result from underlying conditions.
In Canada, an estimated 12.5 million people were vaccinated with inactivated vaccine adjuvanted with AS03. Passive surveillance detected a signal for allergic events; this is being investigated.
In the European Economic Area, at least 38.5 million people were vaccinated with 1 of 3 authorized vaccines marketed in the area. These vaccines included: inactivated unadjuvanted whole virion vaccine; inactivated subunit vaccine adjuvanted with MF59; and inactivated split-virus vaccine adjuvanted with AS03. Additional vaccines were authorized nationally, and when these are included >46 million people are estimated to have been vaccinated. The safety of vaccines has been monitored at the European level using passive surveillance; adverse events following immunization have been reported to EudraVigilance (which covers products authorized by the European Union). After thorough evaluation of spontaneous reports, no new safety issues have been identified.
GACVS reached the following conclusions:
- Reporting mechanisms for adverse events following immunization with pandemic A (H1N1) 2009 influenza vaccines have been enhanced in many countries. Continuing to monitor vaccine safety (maintaining pharmacovigilance) is critical; monitoring should include regular information-sharing with WHO by national regulatory and health authorities. Most of the safety information has been derived from passive surveillance. Data from active surveillance will be assessed as they become available.
- The safety profile of the pandemic A (H1N1) 2009 influenza vaccines noted above is 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.
- Active surveillance for Guillain–Barré syndrome is under way in a number of countries, and analyses are pending in many of these. So far, the risk of Guillain–Barré syndrome, if any, appears to be no greater than has been reported previously for some seasonal, trivalent, inactivated influenza vaccines.
- Active surveillance of pregnancy outcomes also continues. So far, available data on the safety of the vaccines are reassuring.
- It is critical to strengthen adverse event reporting following immunization, which relies on existing infrastructure for ongoing pharmacovigilance. Prospectively agreed-upon case definitions for adverse events (e.g. for anaphylaxis, Guillain–Barré syndrome, convulsions) are also important because they facilitate global comparisons of safety profiles of vaccines used in different countries.
- Updated CDC estimates of 2009 H1N1 influenza cases, hospitalizations and deaths in the United States, April 2009 – April 10, 2010. United States Centers for Disease Control and Prevention. (http://www.cdc.gov/h1n1flu/pdf/CDC_2009_H1N1_Est_PDF_May_4_10_fulltext.pdf). InformationE-mailPrint