Vaccine 33 (2015) 1099–1101

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Short communication

Impact of influenza vaccination on mortality in the French elderly population during the 2000–2009 period Isabelle Bonmarin ∗ , Emmanuel Belchior, Daniel Lévy-Bruhl Institut de veille sanitaire, 12 rue du val d’Osne, 94415 Saint Maurice cedex, France

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Article history: Received 4 November 2014 Received in revised form 29 December 2014 Accepted 8 January 2015 Available online 17 January 2015 Keywords: Influenza Mortality Vaccine effectiveness Immunization

a b s t r a c t With declining influenza vaccine coverage in the elderly in recent years in France, we aimed at assessing the benefits of seasonal influenza vaccination, based on available data for observed mortality, vaccine coverage and vaccine effectiveness. To estimate the annual number of deaths avoided by vaccination in the people aged 65 years or more, we used the following three elements: an estimate of vaccine effectiveness against all-cause mortality (based on the “difference-in-differences” approach which reduces the usual bias seen in observational studies), French mortality data and vaccine coverage data. We estimated an annual average of 2000 deaths currently avoided through vaccination and a vaccine effectiveness of 35% against influenza-attributable deaths. Around 2650 vaccinations are needed to prevent a death among the elderly. Communicating these results should help restoring at-risk populations’ confidence in influenza vaccination. © 2015 Elsevier Ltd. All rights reserved.

1. Background Annual influenza vaccination has been recommended for persons 65 years old and over since 2000 in France. Estimated coverage in this population was between 60% and 65% until 2009. The negative perception of the A(H1N1) vaccination campaign in 2009 led to a further decrease in vaccination coverage to 50%. One of the reasons for this suboptimal coverage is growing health professional and public scepticism about influenza vaccine effectiveness (VE), especially in the elderly. We hypothesised that an improved assessment of the vaccine’s benefits would allow strengthening the active promotion of annual influenza vaccination before the season begins. Very few data on VE from clinical trials are available and results from observational studies are controversial and heterogeneous. It is difficult to disentangle the contribution of real differences in effectiveness according to place and season from the impact of methodological issues inherent to such studies. Indeed, one of the main flaws of observational studies measuring influenza vaccine effectiveness is related to selection bias whereby high-risk patients who drive influenza mortality are less likely to be vaccinated than

∗ Corresponding author: Tel.: +33 1 41 79 67 97; fax: +33 1 41 79 68 72. E-mail addresses: [email protected] (I. Bonmarin), [email protected] (E. Belchior), [email protected] (D. Lévy-Bruhl). http://dx.doi.org/10.1016/j.vaccine.2015.01.023 0264-410X/© 2015 Elsevier Ltd. All rights reserved.

their healthier targeted counterparts. This trend has been described in a recent study by Fireman et al. [1]. They have shown how this bias led to an overestimation of vaccine effectiveness and have proposed a new approach, called “difference-in-differences”, to overcome this problem when measuring VE against all-cause mortality. In short, it consists in computing VE as the difference in VE estimates between the epidemic and non-epidemic periods, this latter estimate being actually a measurement of the indication bias. We used the VE value estimated with this new approach, French all-cause mortality data and influenza vaccine coverage data to estimate the average annual number of deaths avoided by vaccination, the VE against influenza deaths and the number of vaccinations needed to avoid a death among the elderly in France.

2. Methods 2.1. Step 1: number of deaths avoided by vaccination (DAV ) We estimated the number of influenza-attributable deaths avoided by influenza vaccination each season (DAV-S ) during the epidemic period using the estimate of vaccine effectiveness against all-cause mortality (VEAC ), the observed number of all-cause deaths during the epidemic period (DObs-S ) and the vaccine coverage (VCS ) that same season, based on the combination of two simple equations, as follows:

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I. Bonmarin et al. / Vaccine 33 (2015) 1099–1101

If we apply in a population an influenza vaccine of effectiveness against all-cause mortality VEAC with a coverage VCS , the percentage reduction of the mortality induced each season is measured by VEAC × VCS . Therefore, if the all-cause mortality during the annual influenza epidemic period in the absence of vaccination is DNV-S , the mortality prevented by vaccination DAV-S is given by the formula: DAV-S = DNV-S × (VEAC × VCs )

(1)

On the other hand, the mortality expected without vaccination is the sum of the observed number of all-cause deaths (DObs-S ) during an influenza epidemic period and the mortality prevented by vaccination (DAV-S ). DNV-S = DAV-S + DObs-S

(2)

Substituting in Eq. (1), DNV-S by its value in Eq. (2) yields DAV-S = (DAV-S + DObs-S ) × (VEAC × VCS ) => DAV-S [(1 − (VEAC × VCS )] = DObs-S × VEAC × VCS If the value of at least one of two parameters VEAC and VCs differs from 100%, it comes DAV-S = DObs-S × VEAC × VCS /[1 − (VEAC × VCS )]

(3)

2.4.2. Influenza vaccine coverage in elderly (VC) Influenza vaccine coverage data came from the Social Security Scheme database. To measure coverage, we evaluated the rate of used free-vaccination vouchers provided to all the elderly population aged 65 years or more, from 2007 to 2009. This data was complemented with other data from different surveys covering 2001–2006. We estimated a seasonal vaccine coverage (VCS ) increase from 60% in 2000–2001 to 63% in 2008–2009 with an average of 62% (VC9 ) over the nine seasons. 2.4.3. All-cause deaths during influenza epidemic period (DObs ) The national comprehensive registry of deaths provided the weekly number of all-cause deaths among people ≥65 years old, from week 27/2000 to week 05/2009 (http://www. cepidc.inserm.fr/site4/). We identified weeks belonging to an influenza epidemic period, as defined by the réseau Sentinelles, a French network of general practitioners involved in influenza surveillance (http://www.sentiweb.org). Their epidemic threshold is based on a periodic regression model [2]. We calculated the number of allcause deaths occurring during the epidemic period each season (DObs-S ) and a seasonal average over the nine seasons (DObs9 ).

This last formula was applied for each season in the 2000–2009 period. We then averaged the nine seasonal results to obtain the yearly average number of influenza-attributable deaths avoided during the epidemic period (DAV9 ). We then calculated the number of average influenzaattributable deaths avoided (DAV-VC ) according to different hypothetical vaccine coverage (VC) values based on Eq. (1). The number of all-cause deaths expected with no vaccination (DNV9 ) was computed trough Eq. (2), by adding the average numbers of influenza-attributable deaths avoided and of observed all causesdeaths (DAV9 + DObs9 ).

2.4.4. Influenza-attributable deaths and population figures Over the 9 years and for each calendar week (from 1 to 52/53), we compared the average number of all-cause deaths occurring when a given week fell within the influenza epidemic period and when it did not. The difference was assumed to be due to influenza. We summed the weekly differences to obtain the average number of influenza-attributable deaths occurring per season (DFlu9 ). The “Institut national de la statistique et des études économiques” (Insee) provided population figures for those 65 years old and over.

2.2. Step 2: Vaccine effectiveness against influenza-attributable death (VEFlu )

3. Results

Vaccine effectiveness against influenza-attributable deaths (VEFlu ) was estimated from Eq. (1), applied to influenza-attributable mortality instead of all-causes mortality. VEFlu =

DAV9 (DFluNv × VC9 )

with DFluNv , the mortality attributable to influenza during the annual influenza epidemic period in the absence of vaccination, estimated as the sum of yearly average number of influenzaattributable deaths observed (DFlu9 ) and avoided (DAV9 ) over the nine seasons. 2.3. Step 3: number of vaccinations required to avoid a death (NNV) The number of vaccinations needed to avoid a death (NNV) was estimated using the formula defining NNV: NNV =

1 (VEFlu × DFluNv /population)

The average number of observed all-cause deaths during the epidemic period (DObs9 ) was 85,411 and the average number of influenza-attributable deaths (DFlu9 ) was estimated at 9025, i.e. 11% of the number of all-cause deaths during the epidemic period. The number of influenza-attributable deaths avoided by vaccination (DAV-S ) during the epidemic period varied from 1809 to 3016 according to the season, with a mean of 2485 [95%CI: 369–4591]. It varied according to the vaccine coverage (Table 1). The average number of influenza-attributable deaths expected in the absence of vaccination (DFluNv ) was 11,510 [95%CI: 9394–13,616]. Vaccine effectiveness to avoid an influenza-attributable death (VEFlu ) was estimated at 35% [95%CI: 6–55%]. To avoid a death, an average of 2647 vaccinations [95%CI: 1722–14,204] were needed.

Table 1 Impact of influenza vaccination coverage on deaths avoided and deaths observed among persons aged 65 years or more during epidemic period, France, influenza seasons 2000-2009. Vaccine coverage

Death avoided (DAV )

2.4. Sources of data N

2.4.1. For VE against all-cause mortality (VEAC ) We used the value for vaccine effectiveness against all-cause mortality from the American publication quoted above [1]: 4.6% [95%CI: 0.7–8.3]

0% 52% 2013-14 VC estimate 62% Average from 2000-2009 75% WHO objective

0 2102 2493 3032

Death observed (DObs )

95% IC

N

320–3794 379–4497 461–5472

11,510 9408 9018 8478

I. Bonmarin et al. / Vaccine 33 (2015) 1099–1101

4. Discussion Our study confirms previous results for the number of influenzaattributable deaths in the French elderly population and the capacity of influenza vaccination to prevent a significant part of this burden. We estimated that approximately 9000 influenzaattributable deaths occur among the elderly each year, accounting for 11% of all-cause deaths during influenza seasons. Although we estimated vaccine effectiveness against influenza mortality at only 35%, this nonetheless translates, for a vaccine coverage of 62%, into almost 2500 avoided deaths each season among people aged 65 years or more, due to the large number of influenza deaths. The study has several limitations: - We used a simple method to estimate the number of influenzaattributable deaths. If other epidemics follow the same seasonal pattern as influenza, our estimate for influenza-attributable deaths could have been overestimated, leading to an underestimation of the true VE against influenza deaths. This may be for instance the case for diseases sharing with influenza similar meteorological determinants. - The present study used the value for VE against all-cause mortality estimated in a study in the United States of America (USA) covering 1996–2005. However, circulating influenza viruses may have been different in the USA and France during this period, leading to different true VE values against all-cause mortality in each country. Furthermore, despite the efforts to control for the indication bias in the American study, through the use of the “differences of differences” methodology, some residual confounding may have still been present in the measurement of VE. - The range of the estimated number of influenza-attributable deaths avoided by influenza vaccination is wide (369–4591), due to the wide confidence interval of the all-cause mortality VE estimate [0.7–8.3%]. This reinforces the need for more precise estimate of vaccine effectiveness. - The method used assumes that influenza vaccination targeted to high risk subjects has only direct effects on vaccinated individuals. There may an indirect effect (herd protection) induced by vaccinating a significant proportion of the elderly.

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If this is the case, our calculation has underestimated the number of avoided deaths and overestimated the number needed to vaccinate to prevent a death. Despite these limitations, our result of an average annual 9000 influenza deaths is consistent with other influenza-attributable death estimates. Regression models performed in France yielded estimates of 7670 deaths among the ≥75 years old age group, from 1980 to 1990 [3], and 11,000 deaths during A(H3N2) dominant seasons as opposed to 1370 deaths at other times among the ≥65 years old age group, from 1997 to 2009 [4]. It is also similar to North American results [5] with a mortality rate at 98.3/100,000 among the ≥65 years old age group, corresponding to about 10,500 deaths in France. The method used allows producing, in a simple way, a gross estimate of the impact of influenza vaccination on deaths. It should help reassure decision makers, health professionals and the general public about the benefits of seasonal vaccination of high-risk individuals.

Conflict of interest The authors declare that there are no conflicts of interest. References [1] Fireman B, Lee J, Lewis N, Bembom O, van der Laan M, Baxter R. Influenza vaccination and mortality: differentiating vaccine effects from bias. Am J Epidemiol 2009;170(5 (Sep 1)):650–6. [2] Costagliola D, Flahault A, Galinec D, Garnerin P, Menares J, Valleron AJ. A routine tool for detection and assessment of epidemics of influenza-like syndromes in France. Am J Public Health 1991;81(1):97–9. [3] Carrat F, Valleron AJ. Influenza mortality among the elderly in France, 1980–90: how many deaths may have been avoided through vaccination? J Epidemiol Community Health 1995;49(4 (Aug)):419–25. [4] Lemaitre M, Carrat F, Rey G, Miller M, Simonsen L, Viboud C. Mortality burden of the 2009 A/H1N1 influenza pandemic in France: comparison to seasonal influenza and the A/H3N2 pandemic. PLoS ONE 2012;7(9): e45051. [5] Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ, et al. Mortality associated with influenza and respiratory syncytial virus in the United States. J Am Med Assoc 2003;289(2 (Jan 8)):179–86.

Impact of influenza vaccination on mortality in the French elderly population during the 2000-2009 period.

With declining influenza vaccine coverage in the elderly in recent years in France, we aimed at assessing the benefits of seasonal influenza vaccinati...
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