G Model JVAC-15083; No. of Pages 1
ARTICLE IN PRESS Vaccine xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Letter to the Editor
Reply: Cochrane rearranged To the Editor, Although we support evidence-based vaccine evaluations, we strongly disagree with the conclusion of Beyer et al. that their reanalysis “. . . provides evidence of the effectiveness of influenza vaccination of the elderly” [1]. This conclusion is challenged by four key issues that were not addressed by the authors. First, some studies used in this reanalysis were methodologically flawed because the investigators used seroconversion to define influenza infection. Vaccinated individuals are significantly less likely to seroconvert when infected with influenza virus; therefore, true infections are missed. This well-recognized source of bias leads to a significant overestimation of vaccine efficacy [2]. The review by Beyer et al. did not address this potential bias. Second, biological vaccine efficacy as described by Beyer et al. is based on previously published work on the relationship between clinical protection and HI titers. They defined clinical protection as “identical to . . . or above the cut-off level for seroprotection” [3]. This implies that HI is a well-defined correlate of protection. However, according to the Food and Drug Administration, “a specific HI antibody titer associated with protection against culture-confirmed influenza illness has not been identifed” [2]. Clinical trials have reported seroprotection in over 90% of vaccine recipients and yet culture/RT-PCR—confirmed influenza VE was much lower (in the 50–60% range) [3]. These findings indicate that using HI as the primary correlate of protection will substantially overestimate VE. Third, the authors acknowledge that estimates of VE against allcause mortality are biased; however, they did not fully consider the degree of this bias. Using more sophisticated methods that adjusted for unmeasured confounding, Fireman and colleagues found that influenza vaccine yielded an 8.5% reduction in mortality due to cardiovascular or respiratory disease in people ≥65 years old [4]. This is substantially lower than the mean of 28% reported by Beyer et al., which suggests uncontrolled confounding with overestimation of VE in their meta-analysis. Fourth, recent, high-quality observational studies using the test-negative design have highlighted the limited effectiveness of influenza vaccines against laboratory-confirmed influenza in adults ≥60 years of age. During the 2012–2013 influenza season, VE for adults ≥65 years of age in the U.S. Flu VE Network was 27% for all strains and only 9% (non-significant) for H3N2, despite well-matched H3N2 strains [5]. Interim estimates from Europe, Canada, and the United States were remarkably similar for effectiveness against H3N2 in 2012–2013, and 2011–2012 influenza season results from Europe demonstrated similar low VE for adults
≥60 years of age. These findings are not consistent with conclusions Beyer et al. We agree that substantial challenges exist when conducting influenza vaccine efficacy and effectiveness studies, such as conducting studies during seasons with low influenza activity, which can result in non-significant VE estimates with wide confidence intervals. However, the data used by Beyer et al. have many additional limitations. The conclusions of their study, therefore, cannot be substantiated and do not provide additional evidence that influenza vaccine is even moderately effective in the elderly. References [1] Beyer WEP, McElhaney J, Smith DJ, Arnold S Monto, Jonathan S Nguyen-Van-Tam, Albert DME Osterhaus. Cochrane re-arranged: support for policies to vaccinate elderly people against influenza. Vaccine 2013;31(50):6030–3. [2] Osterholm MT, Kelley NS, Manske JM, Balllering KS, Leighton TR, Moore KM. The compelling need for game-changing influenza vaccines: an analysis of the influenza vaccine enterprise and recommendations for the future. University of Minnesota: Center for Infectious Disease Research and Policy; 2012 www.cidrap.umn.edu [3] Jackson LA, Gaglani MJ, Keyserling HL, Balser J, Bouveret N, Fries L, Treanor JJ. Safety, efficacy, and immunogenicity of an inactivated influenza vaccine in healthy adults: a randomized, placebo-controlled trial over two influenza seasons. BMC Infect Dis 2010;10(1):71. [4] 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):650–6. [5] Jackson L, Jackson ML, Phillips CH, Joyce B, Edward AB, Deanna C, Sarah K, et al. Interim adjusted estimates of seasonal influenza vaccine effectiveness – United States, February 2013. MMWR 2013;62(7):119–23.
Michael T. Osterholm ∗ Nicholas S. Kelley Center for Infectious Disease Research and Policy, University of Minnesota, Minneapolis, MN 55355, United States Edward A. Belongia Marshfield Clinic Research Foundation, Marshfield, WI 54449, United States Lisa A. Jackson Michael L. Jackson Group Health Research Institute, Seattle, WA 98101, United States ∗ Corresponding
author. Tel.: +1 612 626 6770. E-mail address: [email protected] (M.T. Osterholm) 18 November 2013 Available online xxx
0264-410X/$ – see front matter © 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.vaccine.2014.01.097
Please cite this article in press as: http://dx.doi.org/10.1016/j.vaccine.2014.01.097
Osterholm
MT,
et
al.
Reply:
Cochrane
rearranged.
Vaccine
(2014),
ARTICLE IN PRESS Vaccine xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Letter to the Editor
Reply: Cochrane rearranged To the Editor, Although we support evidence-based vaccine evaluations, we strongly disagree with the conclusion of Beyer et al. that their reanalysis “. . . provides evidence of the effectiveness of influenza vaccination of the elderly” [1]. This conclusion is challenged by four key issues that were not addressed by the authors. First, some studies used in this reanalysis were methodologically flawed because the investigators used seroconversion to define influenza infection. Vaccinated individuals are significantly less likely to seroconvert when infected with influenza virus; therefore, true infections are missed. This well-recognized source of bias leads to a significant overestimation of vaccine efficacy [2]. The review by Beyer et al. did not address this potential bias. Second, biological vaccine efficacy as described by Beyer et al. is based on previously published work on the relationship between clinical protection and HI titers. They defined clinical protection as “identical to . . . or above the cut-off level for seroprotection” [3]. This implies that HI is a well-defined correlate of protection. However, according to the Food and Drug Administration, “a specific HI antibody titer associated with protection against culture-confirmed influenza illness has not been identifed” [2]. Clinical trials have reported seroprotection in over 90% of vaccine recipients and yet culture/RT-PCR—confirmed influenza VE was much lower (in the 50–60% range) [3]. These findings indicate that using HI as the primary correlate of protection will substantially overestimate VE. Third, the authors acknowledge that estimates of VE against allcause mortality are biased; however, they did not fully consider the degree of this bias. Using more sophisticated methods that adjusted for unmeasured confounding, Fireman and colleagues found that influenza vaccine yielded an 8.5% reduction in mortality due to cardiovascular or respiratory disease in people ≥65 years old [4]. This is substantially lower than the mean of 28% reported by Beyer et al., which suggests uncontrolled confounding with overestimation of VE in their meta-analysis. Fourth, recent, high-quality observational studies using the test-negative design have highlighted the limited effectiveness of influenza vaccines against laboratory-confirmed influenza in adults ≥60 years of age. During the 2012–2013 influenza season, VE for adults ≥65 years of age in the U.S. Flu VE Network was 27% for all strains and only 9% (non-significant) for H3N2, despite well-matched H3N2 strains [5]. Interim estimates from Europe, Canada, and the United States were remarkably similar for effectiveness against H3N2 in 2012–2013, and 2011–2012 influenza season results from Europe demonstrated similar low VE for adults
≥60 years of age. These findings are not consistent with conclusions Beyer et al. We agree that substantial challenges exist when conducting influenza vaccine efficacy and effectiveness studies, such as conducting studies during seasons with low influenza activity, which can result in non-significant VE estimates with wide confidence intervals. However, the data used by Beyer et al. have many additional limitations. The conclusions of their study, therefore, cannot be substantiated and do not provide additional evidence that influenza vaccine is even moderately effective in the elderly. References [1] Beyer WEP, McElhaney J, Smith DJ, Arnold S Monto, Jonathan S Nguyen-Van-Tam, Albert DME Osterhaus. Cochrane re-arranged: support for policies to vaccinate elderly people against influenza. Vaccine 2013;31(50):6030–3. [2] Osterholm MT, Kelley NS, Manske JM, Balllering KS, Leighton TR, Moore KM. The compelling need for game-changing influenza vaccines: an analysis of the influenza vaccine enterprise and recommendations for the future. University of Minnesota: Center for Infectious Disease Research and Policy; 2012 www.cidrap.umn.edu [3] Jackson LA, Gaglani MJ, Keyserling HL, Balser J, Bouveret N, Fries L, Treanor JJ. Safety, efficacy, and immunogenicity of an inactivated influenza vaccine in healthy adults: a randomized, placebo-controlled trial over two influenza seasons. BMC Infect Dis 2010;10(1):71. [4] 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):650–6. [5] Jackson L, Jackson ML, Phillips CH, Joyce B, Edward AB, Deanna C, Sarah K, et al. Interim adjusted estimates of seasonal influenza vaccine effectiveness – United States, February 2013. MMWR 2013;62(7):119–23.
Michael T. Osterholm ∗ Nicholas S. Kelley Center for Infectious Disease Research and Policy, University of Minnesota, Minneapolis, MN 55355, United States Edward A. Belongia Marshfield Clinic Research Foundation, Marshfield, WI 54449, United States Lisa A. Jackson Michael L. Jackson Group Health Research Institute, Seattle, WA 98101, United States ∗ Corresponding
author. Tel.: +1 612 626 6770. E-mail address: [email protected] (M.T. Osterholm) 18 November 2013 Available online xxx
0264-410X/$ – see front matter © 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.vaccine.2014.01.097
Please cite this article in press as: http://dx.doi.org/10.1016/j.vaccine.2014.01.097
Osterholm
MT,
et
al.
Reply:
Cochrane
rearranged.
Vaccine
(2014),
