Early estimates of seasonal influenza Vaccine effectiveness in Europe among target group for vaccination, 2011/12: I-MOVE, a multicentre case-control study
Kissling E, Valenciano M for the I-MOVE case–control studies team. Euro Surveill. 2012;17(15):pii=20146. http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20146
A rapid communication published on April 12th 2012 describes the early results of the annual multicentre case-control study undertaken by the ECDC sponsored I-MOVE consortium whose work is coordinated by an Epiconcept team.(1) This work is based on eight influenza sentinel surveillance networks (in France, Hungary, Ireland, Italy, Poland, Portugal, Romania and Spain) working to a common agreed protocol.(2) The studies have been conducted annually since 2007/8 to provide estimates of influenza vaccine effectiveness (VE) in Europe, including during the 2009 pandemic. Publications from these and related studies that have appeared in peer-review journals are listed on the I-MOVE web-site.
This particular publication describes a study of influenza-like illness (ILI) cases up to week 7/2012 among European risk groups for vaccination. Laboratory confirmed A(H3) influenza cases were compared to negative controls. An adjusted VE was calculated using logistic regression models adjusting for a number of potential confounding factors: age groups (10 year age bands), sex, week of onset of symptoms, chronic disease (at least one), hospitalisations associated with the chronic disease in the last 12 months and practitioner visits in the last 12 months. The final analysis included 530 individuals, after excluding individuals with missing information on 2011/12 seasonal vaccination, on hospitalisations for chronic disease in the previous year and on practitioner visits in the previous year. The early European season was dominated by A(H3N2) viruses and the crude unadjusted VE against A(H3N2) was 42.9% (with 95% Confidence Intervals 10.3%-63.6%) while the adjusted VE against A(H3N2) was 43% with wide 95% Confidence Intervals from -0.4% to 67.7%).(1)
ECDC Comment (12 April 2012):
The influenza viruses to which the public are exposed to each season differ from year to year both in their mix and the genetic and antigenic features of the virus sub-types. The influenza vaccines are often adjusted to try to keep up with the genetic / antigenic change.(3) Hence the ability of vaccines to prevent infection varies from season to season and has to be monitored. Studies like the one described here are measuring effectiveness in vaccine target groups using observational methods since it is impractical to assess efficacy each season (see Glossary of Terms). Also most authorities consider that it would be unacceptable to conduct placebo-controlled trials among those in risk groups as it would mean potentially leaving unprotected people at higher risk of severe disease and death. A number of countries outside of Europe (Australia, Canada, New Zealand and the USA) also use this monitoring mechanism annually.
A difficulty of the observational methods is that it is impossible to entirely eliminate bias and so to know how closely the results from these approaches are to what efficacy studies would show if those could be undertaken. It also needs to be noted that the outcome here, though it is laboratory confirmed infection, is usually mild disease. There is no information on less common outcomes like severe disease or death associated with influenza infection for which vaccine effectiveness may be higher or lower. What should never be done is to measure effectiveness against influenza-like-illness of unknown etiology which will always result in spuriously low estimates.
This season has been especially interesting since in February the WHO strain selection meeting that makes recommendations on vaccines for the Northern Hemisphere in 2012-2013 observed an imperfect antigenic match between the circulating A(H3N2) virus and the vaccines used in the autumn.(4) Although such imperfect matches of viruses and vaccine components do not necessarily mean a loss of effectiveness it does make it more likely.(3) The adjusted estimates by Kissling et al for 2011-12 are over ten points lower than what was observed in 2010-11 in Europe.(5) But that was against a different virus mix dominated by A(H1N1)pdm09. Also, the 2011-12 estimates have wideconfidence limits and do not differ statistically from last season. However the low observed vaccine effectiveness this season is credible given other Northern Hemisphere observations. Vaccine effectiveness data are not yet available for 2011-12 in North America but In the United States an increase in influenza-positive paediatric patients infected by A(H3N2) presenting to a major metropolitan hospital in the Pacific North West has been noted as vaccine failures.(6) There are also other relevant data from Europe. A publication from Spain described influenza outbreaks in nursing homes with high vaccination coverage in Navarre, Spain, in the season 2011/12 (7) and there are anecdotal results from elsewhere. Another pertinent observation is an excess mortality among older people in some European countries during the winter season. Though it has to be emphasised that other respiratory viruses as well as a seasonal predominance of A(H3N2) (compared to A(H1N1)pdm09 which rarely affects older people) and cold weather could all have contributed more to this observation than any fall in vaccine effectiveness.(8)
The observed fall in effectiveness this season is not necessarily due entirely to the imperfect antigenic match. Given the late start to the season it could simply be that immunity from vaccination in the early autumn has waned with time.(1,6) But a more likely explanation is the emergence of antigenically drifted A(H3N2) variants. Support for this comes both from the observation of the WHO Collaborating Centres and the impression in the I-MOVE work of heterogeneity of viruses and vaccine effectiveness estimates by country and some suggestion of waning of the latter over time this season. What is therefore needed is careful post-season studies comparing the distribution in time and place of drifted viruses with the final observed vaccine effectiveness. Another consequence of these heterogeneities in Europe is that at the end of season the estimates of overall vaccines effectiveness may vary more by country that in the 2009 pandemic and the 2010-2011 season.
As has been noted by Osterholm et al (9). and is emphasised by ECDC the effectiveness of seasonal influenza vaccines is unacceptably low. While vaccination remains the most effective single way of protecting individuals, families and communities, an effectiveness of only at best 70% is not what is needed or expected by the public or practitioners. Indeed that 70%, which came from the pandemic vaccines, is very much a ‘top of the range’ estimate with an excellent antigenic fit and vaccines that were usually adjuvanted.(10) It is disappointing that many of the seasonal vaccines that are used may be little improved in their effectiveness from what was used three decades ago. The case for more investment in better seasonal vaccines using public and industry resources is unanswerable.
Finally these findings have implications for the Southern Hemisphere temperate countries whose influenza season will begin in three months or less. They have been immunising with the same vaccines as used by the Northern Hemisphere (the updated vaccines will only become available at the end of the European summer). The same applies for Equatorial Countries, where influenza transmission is more continuous. Where A(H3N2) predominates clinicians will need to be more aware of the possibility of vaccine failures and to consider early use of antivirals and other therapies in immunised as well as unimmunised persons with influenza like symptoms.
Glossary of Terms
Vaccine effectiveness–likelihood of a vaccine preventing infection+ when it is used in practice usually determined by well-designed observational studies allowing for possible confounding factors.
Vaccine efficacy* –estimate of the likelihood of a vaccine preventing infection+ under optimal circumstances – for example as determined in randomised controlled trials.
Serological efficacy# –proportion of persons immunised with a vaccine whose blood shows the pre-agreed rise in antibodies. Used for licensing and regulatory purposes.
* Last JM, Dictionary of epidemiology International Epidemiological Association, Oxford University Press 4th edition 2001.
# The European Agency for the Evaluation of Medicinal Products (EMEA). Note for guidance on harmonisation of requirements for influenza vaccines. Committee for proprietary medicinal products 1997; CPMP/BWP/214/96. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideine/2009/09/WC500003945.pdf
+ In studies on influenza vaccines effectiveness or efficacy ‘infection’ should be defined as ‘laboratory-confirmed influenza infection’
- Kissling E, Valenciano M for the I-MOVE case–control studies team Early estimates of seasonal influenza Vaccine effectiveness in Europe among target group for vaccination, 2011/12: I-MOVE, a multicentre case-control study Euro Surveill. 2012;17(15):pii=20146. http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20146
- ECDC Technical Document Protocol for case-control studies to measure influenza vaccine effectiveness in the European Union and European Economic Area Member States. Revised version November 2009 http://ecdc.europa.eu/en/publications/Publications/0907_TED_Influenza_AH1N1_Measuring_Influenza_Vaccine_Effectiveness_Protocol_Case_Control_Studies.pdf
- Gerdil C. The annual production cycle for influenza vaccine. Vaccine 2003; 21: 1776-9. Link Here
- WHO – Recommended composition of influenza virus vaccines for use in the 2012-2013 northern hemisphere influenza season February 2012. Available online: http://www.who.int/influenza/vaccines/virus/recommendations/201202_recommendation.pdf
- Kissling E , Valenciano M , Cohen JM , Oroszi B , Barret A-S , et al. 2011 I-MOVE Multi-Centre Case Control Study 2010-11: Overall and Stratified Estimates of Influenza Vaccine Effectiveness in Europe. PLoS ONE 6(11): e27622. doi:10.1371/journal.pone.0027622
- Wilson J. Influenza in Previously Vaccinated Children (USA Pacific Northwest) ProMed April 5th 2012. http://www.promedmail.org/direct.php?id=20120406.1092588
- Castilla J, Cía F, Zubicoa J, Reina G, Martínez-Artola V, Ezpeleta C. Influenza outbreaks in nursing homes with high vaccination coverage in Navarre, Spain, 2011/12. Euro Surveill. 2012;17(14):pii=20141. Available online: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20141
- Mazick A, Gergonne B, Nielsen J, Wuillaume F, Virtanen MJ, Fouillet A, Uphoff H, Sideroglou T, Paldy A, Oza A, Nunes B, Flores-Segovia VM, Junker C, McDonald SA, Green HK, Pebody R, Mølbak K. Excess mortality among the elderly in 12 European countries, February and March 2012. Euro Surveill. 2012;17(14):pii=20138. Available online: http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20138
- Osterholm MT, Kelley NS, Sommer A, et al. Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis The Lancet Infectious Diseases, Volume 12, Issue 1, Pages 36 - 44, January 2012 doi:10.1016/S1473-3099(11)70295-
- Valenciano M Kissling E, Cohen J-M, Oroszi B, Barret AS, Rizzo C et al Estimates of Pandemic Influenza Vaccine Effectiveness in Europe, 2009–2010: Results of Influenza Monitoring Vaccine Effectiveness in Europe (I-MOVE) Multicentre Case-Control Study. Plos Medicine PLoS Med 8(1): e1000388. doi:10.1371/ journal.pmed.1000388 http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1000388