Safety of adjuvanted pandemic influenza A (H1N1) 2009 vaccinesBMJ 2011; 343 doi: http://dx.doi.org/10.1136/bmj.d4159 (Published 12 July 2011) Cite this as: BMJ 2011;343:d4159
- Frank DeStefano, director1,
- Claudia Vellozzi, deputy director1,
- Lawrence B Schonberger, assistant director for public health2,
- Robert T Chen, HIV vaccine and special studies team leader3
- 1Immunization Safety Office (MS-D26), Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention (CDC), Atlanta, GA 30333, USA
- 2Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, CDC, Atlanta, GA, USA
- 3Division of HIV/AIDS Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, CDC, Atlanta, GA, USA
Guillain-Barré syndrome has been a focus of safety monitoring since the report in 1976 of an increased risk of almost one extra case per 100 000 influenza vaccinations of swine origin.1 Subsequent studies have shown either no increased risk or a slightly increased risk (1-2 per million vaccinees) after vaccination for seasonal flu.2 The spread of the 2009 pandemic influenza A (H1N1) virus, which contained genes of swine origin, resulted in the development and widespread use of influenza A (H1N1) monovalent vaccines (2009 H1N1 vaccines).3 These included formulations containing oil in water adjuvants that had not previously been widely used in flu vaccines in Europe. Although available evidence suggested that the adjuvanted vaccines had acceptable safety profiles,3 data on the risk of rare adverse events, such as Guillain-Barré syndrome, were limited.
In the linked study (doi:10.1136/bmj.d3908), Dieleman and colleagues report the first data on adjuvanted 2009 H1N1 vaccines and the risk of Guillain-Barré syndrome from a case-control study conducted in five European countries.4 Overall, the results suggest that if there was an increased risk associated with the adjuvanted 2009 H1N1 vaccines studied, it was considerably smaller than that seen with the 1976 swine flu vaccines. Whether there was an increased risk, however, is not clear.
Although the study used a common protocol and data collection instruments, countries differed substantially in case ascertainment, subject enrollment, and sources of data on vaccinations and other potential risk factors, as well as specific vaccine brands. The results varied considerably by country—the unadjusted odds ratios from four countries ranged from 1.3 to 9.5 (data from one country were limited and not included in the analysis).
Adjustment for influenza-like illness or upper respiratory tract infection strongly influenced the results, although these data were available for only three of the countries. Adjustment for both of these respiratory illnesses decreased all the odds ratios (range 1.1-1.8) and all 95% confidence intervals overlapped 1.0 in the individual country analyses, as well as the pooled analyses. Further adjustment for receipt of seasonal flu vaccine either did not change or further decreased (to less than 1.0 in some analyses) the odds ratio estimates. In sub-analyses restricted to people without preceding respiratory illnesses the unadjusted odds ratios were between 1.9 and 2.5 (with 95% confidence intervals that overlapped 1.0) but decreased to 1.2 after adjustment for preceding seasonal flu vaccination.
Although respiratory (and other) infections have often been associated with Guillain-Barré syndrome, respiratory illnesses have not previously been identified as strong confounding factors for the association between seasonal flu vaccines and the syndrome. Perhaps confounding by these respiratory illnesses was more apparent for the 2009 H1N1 vaccines in Dieleman and colleagues’ study because vaccination occurred concurrently with circulation of pandemic H1N1 virus, whereas in typical flu seasons vaccination occurs before widespread circulation of the virus. The study also had some puzzling findings on seasonal flu vaccine. In the data from the United Kingdom, the 2009-10 seasonal flu vaccine (unadjuvanted) was associated with an increased risk of Guillain-Barré syndrome. This is surprising given that a previous analysis using the same UK database found no evidence of an increased risk associated with seasonal flu vaccines administered from 1990 to 2005.5
The finding that adjuvanted 2009 H1N1 vaccines were not associated with a substantially increased risk of Guillain-Barré syndrome is consistent with the results published to date on unadjuvanted 2009 H1N1 vaccines. These include studies from spontaneous reporting systems in the United States and China,6 7 in which reported rates of the syndrome after receipt of unadjuvanted H1N1 vaccines were lower than the expected background rates. Although spontaneous reporting systems are subject to under-reporting, these results suggest that there was not a large increased risk of the syndrome. A large epidemiological study of unadjuvanted H1N1 vaccine in the US found a small increased risk of less than one excess case per million vaccinations, although respiratory illnesses were not controlled for.8 Other studies of H1N1 vaccines and risk of the syndrome have been conducted in the US and internationally,4 9 but their results have not yet been published.
Although pandemic influenza A (H1N1) 2009 monovalent vaccines are no longer being used, data on their safety are relevant to current clinical practice because the H1N1 strain in the pandemic vaccine has been incorporated into the currently recommended trivalent seasonal vaccine. Most of the trivalent seasonal flu vaccines currently used in Europe do not contain an adjuvant, and no adjuvanted flu vaccines are used in the US. Nonetheless, the safety findings on adjuvanted flu vaccines will be important if such vaccines become more common in the future, whether in seasonal flu vaccines or for the next pandemic.
Cite this as: BMJ 2011;343:d4159
Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.
Provenance and peer review: Commissioned; not externally peer reviewed.