Correlates of Protection against Influenza in the Elderly: Results from an Influenza Vaccine Efficacy Trial

Andrew J Dunning, Carlos A DiazGranados, Timothy Voloshen, Branda Hu, Victoria A Landolfi, H Keipp Talbot, Andrew J Dunning, Carlos A DiazGranados, Timothy Voloshen, Branda Hu, Victoria A Landolfi, H Keipp Talbot

Abstract

Although a number of studies have investigated and quantified immune correlates of protection against influenza in adults and children, data on immune protection in the elderly are sparse. A recent vaccine efficacy trial comparing standard-dose with high-dose inactivated influenza vaccine in persons 65 years of age and older provided the opportunity to examine the relationship between values of three immunologic assays and protection against community-acquired A/H3N2 influenza illness. The high-dose vaccine induced significantly higher antibody titers than the standard-dose vaccine for all assays. For the hemagglutination inhibition assay, a titer of 40 was found to correspond with 50% protection when the assay virus was antigenically well matched to the circulating virus--the same titer as is generally recognized for 50% protection in younger adults. A dramatically higher titer was required for 50% protection when the assay virus was a poor match to the circulating virus. With the well-matched virus, some protection was seen at the lowest titers; with the poorly matched virus, high levels of protection were not achieved even at the highest titers. Strong associations were also seen between virus neutralization test titers and protection, but reliable estimates for 50% protection were not obtained. An association was seen between titers of an enzyme-linked lectin assay for antineuraminidase N2 antibodies and protection; in particular, the proportion of treatment effect explained by assay titer in models that included both this assay and one of the other assays was consistently higher than in models that included either assay alone. (This study has been registered at ClinicalTrials.gov under registration no. NCT01427309.).

Copyright © 2016 Dunning et al.

Figures

FIG 1
FIG 1
Protection curves for the A/Victoria/361/2011 HAI assay using the circulating virus against A/H3N2 illness by three laboratory-confirmed influenza (LCI) case definitions (defn.), showing titers for 50% and 80% protection, with 95% CIs.

References

    1. Zhou H, Thompson WW, Viboud CG, Ringholz CM, Cheng PY, Steiner C, Abedi GR, Anderson LJ, Brammer L, Shay DK. 2012. Hospitalizations associated with influenza and respiratory syncytial virus in the United States, 1993-2008. Clin Infect Dis 54:1427–1436. doi:10.1093/cid/cis211.
    1. Quandelacy TM, Viboud C, Charu V, Lipsitch M, Goldstein E. 2014. Age- and sex-related risk factors for influenza-associated mortality in the United States between 1997-2007. Am J Epidemiol 179:156–167. doi:10.1093/aje/kwt235.
    1. Haq K, McElhaney JE. 2014. Immunosenescence: influenza vaccination and the elderly. Curr Opin Immunol 29:38–42. doi:10.1016/j.coi.2014.03.008.
    1. McElhaney JE, Beran J, Devaster JM, Esen M, Launay O, Leroux-Roels G, Ruiz-Palacios GM, van Essen GA, Caplanusi A, Claeys C, Durand C, Duval X, El Idrissi M, Falsey AR, Feldman G, Frey SE, Galtier F, Hwang SJ, Innis BL, Kovac M, Kremsner P, McNeil S, Nowakowski A, Richardus JH, Trofa A, Oostvogels L; for the Influence65 Study Group . 2013. AS03-adjuvanted versus non-adjuvanted inactivated trivalent influenza vaccine against seasonal influenza in elderly people: a phase 3 randomised trial. Lancet Infect Dis 13:485–496. doi:10.1016/S1473-3099(13)70046-X.
    1. DiazGranados CA, Dunning AJ, Kimmel M, Kirby D, Treanor J, Collins A, Pollak R, Christoff J, Earl J, Landolfi V, Martin E, Gurunathan S, Nathan R, Greenberg DP, Tornieporth NG, Decker MD, Talbot HK. 2014. Relative efficacy of high-dose trivalent influenza vaccine compared to standard-dose vaccine in adults 65 years of age and older. N Engl J Med 371:635–645. doi:10.1056/NEJMoa1315727.
    1. Plotkin SA, Orenstein WA, Offit PA (ed). 2013. Vaccines, 6th ed W.B. Saunders, London, United Kingdom.
    1. Sasaki S, Sullivan M, Narvaez CF, Holmes TH, Furman D, Zheng NY, Nishtala M, Wrammert J, Smith K, James JA, Dekker CL, Davis MM, Wilson PC, Greenberg HB, He XS. 2011. Limited efficacy of inactivated influenza vaccine in elderly individuals is associated with decreased production of vaccine-specific antibodies. J Clin Investig 121:3109–3119. doi:10.1172/JCI57834.
    1. Goodwin K, Viboud C, Simonsen L. 2006. Antibody response to influenza vaccination in the elderly: a quantitative review. Vaccine 24:1159–1169. doi:10.1016/j.vaccine.2005.08.105.
    1. Falsey AR, Treanor JJ, Tornieporth N, Capellan J, Gorse GJ. 2009. Randomized, double-blind controlled phase 3 trial comparing the immunogenicity of high-dose and standard-dose influenza vaccine in adults 65 years of age and older. J Infect Dis 200:172–180. doi:10.1086/599790.
    1. Frey SE, Reyes MR, Reynales H, Bermal NN, Nicolay U, Narasimhan V, Forleo-Neto E, Arora AK. 2014. Comparison of the safety and immunogenicity of an MF59-adjuvanted with a non-adjuvanted seasonal influenza vaccine in elderly subjects. Vaccine 32:5027–5034. doi:10.1016/j.vaccine.2014.07.013.
    1. Tsang P, Gorse GJ, Strout CB, Sperling M, Greenberg DP, Ozol-Godfrey A, DiazGranados C, Landolfi V. 2014. Immunogenicity and safety of Fluzone intradermal and high-dose influenza vaccines in older adults ≥65 years of age: a randomized, controlled, phase II trial. Vaccine 32:2507–2517. doi:10.1016/j.vaccine.2013.09.074.
    1. Mannino S, Villa M, Apolone G, Weiss NS, Groth N, Aquino I, Boldori L, Caramaschi F, Gattinoni A, Malchiodi G, Rothman KJ. 2012. Effectiveness of adjuvanted influenza vaccination in elderly subjects in northern Italy. Am J Epidemiol 176:527–533. doi:10.1093/aje/kws313.
    1. de Jong JC, Palache AM, Beyer WE, Rimmelzwaan GF, Boon AC, Osterhaus AD. 2003. Haemagglutination-inhibiting antibody to influenza virus. Dev Biol (Basel) 115:63–73.
    1. Coudeville L, Bailleux F, Riche B, Megas F, André P, Ecochard R. 2010. Relationship between haemagglutination-inhibiting antibody titres and clinical protection against influenza: development and application of a Bayesian random-effects model. BMC Med Res Methodol 10:18. doi:10.1186/1471-2288-10-18.
    1. Hobson D, Curry RL, Beare AS, Ward-Gardner A. 1972. The role of serum haemagglutination-inhibiting antibody in protection against challenge infection with influenza A2 and B viruses. J Hyg (Lond) 70:767–777. doi:10.1017/S0022172400022610.
    1. Black S, Nicolay U, Vesikari T, Knuf M, Del Giudice G, Della Cioppa G, Tsai T, Clemens R, Rappuoli R. 2011. Hemagglutination inhibition antibody titers as a correlate of protection for inactivated influenza vaccines in children. Pediatr Infect Dis J 30:1081–1085. doi:10.1097/INF.0b013e3182367662.
    1. Reber A, Katz J. 2013. Immunological assessment of influenza vaccines and immune correlates of protection. Expert Rev Vaccines 12:519–536. doi:10.1586/erv.13.35.
    1. Cheng LW, Huang SW, Huang LM, Chang LY, Shao PL, Kiang D, Wang JR. 2012. Comparison of neutralizing and hemagglutination-inhibiting antibody responses for evaluating the seasonal influenza vaccine. J Virol Methods 182:43–49. doi:10.1016/j.jviromet.2012.03.004.
    1. Couch RB, Atmar RL, Franco LM, Quarles JM, Wells J, Arden N, Niño D, Belmont JW. 2013. Antibody correlates and predictors of immunity to naturally occurring influenza in humans and the importance of antibody to the neuraminidase. J Infect Dis 207:974–981. doi:10.1093/infdis/jis935.
    1. Centers for Disease Control and Prevention. 2013. Influenza activity–United States, 2012-13 season and composition of the 2013-14 influenza vaccine. MMWR Morb Mortal Wkly Rep 62:473–479.
    1. World Health Organization. 2013. Recommended composition of influenza virus vaccines for use in the 2013-2014 northern hemisphere influenza season. Wkly Epidemiol Rec 88:101–114.
    1. Prentice RL. 1986. A case-cohort design for epidemiologic cohort studies and disease prevention trials. Biometrika 73:1–11. doi:10.1093/biomet/73.1.1.
    1. Lambre CR, Terzidis H, Greffard A, Webster RG. 1990. Measurement of anti-influenza neuraminidase antibody using a peroxidase-linked lectin and microtiter plates coated with natural substrates. J Immunol Methods 135:49–57. doi:10.1016/0022-1759(90)90255-T.
    1. Couzens L, Gao J, Westgeest K, Sandbulte M, Lugovtsev V, Fouchier R, Eichelberger M. 2014. An optimized enzyme-linked lectin assay to measure influenza A virus neuraminidase inhibition antibody titers in human sera. J Virol Methods 210C:7–14.
    1. Qin L, Gilbert PB, Corey L, McElrath MJ, Self SG. 2007. A framework for assessing immunological correlates of protection in vaccine trials. J Infect Dis 196:1304–1312. doi:10.1086/522428.
    1. Gilbert PB, Qin L, Self SG. 2008. Evaluating a surrogate endpoint at three levels, with application to vaccine development. Stat Med 27:4758–4778. doi:10.1002/sim.3122.
    1. Prentice RL. 1989. Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med 8:431–440. doi:10.1002/sim.4780080407.
    1. Lin DY, Fleming TR, De Gruttola V. 1997. Estimating the proportion of treatment effect explained by a surrogate marker. Stat Med 16:1515–1527.
    1. Dunning AJ. 2006. A model for immunological correlates of protection. Stat Med 25:1485–1497. doi:10.1002/sim.2282.
    1. Dunning AJ, Kensler J, Coudeville L, Bailleux F. 2015. Some extensions in continuous models for immunological correlates of protection. BMC Med Res Methodol 15:107. doi:10.1186/s12874-015-0096-9.
    1. Hosmer DW, Lemeshow S. 2000. Applied logistic regression. Wiley Interscience, Hoboken, NJ.
    1. DiazGranados CA, Dunning AJ, Jordanov E, Landolfi V, Denis M, Talbot HK. 2013. High-dose trivalent influenza vaccine compared to standard dose vaccine in elderly adults: safety, immunogenicity and relative efficacy during the 2009-2010 season. Vaccine 31:861–866. doi:10.1016/j.vaccine.2012.12.013.
    1. Cate TR, Rayford Y, Niño D, Winokur P, Brady R, Belshe R, Chen W, Atmar RL, Couch RB. 2010. A high dosage influenza vaccine induced significantly more neuraminidase antibody than standard vaccine among elderly subjects. Vaccine 28:2076–2079. doi:10.1016/j.vaccine.2009.12.041.
    1. Plotkin SA. 2013. Complex correlates of protection after vaccination. Clin Infect Dis 56:1458–1465. doi:10.1093/cid/cit048.
    1. Gentile D, Doyle W, Whiteside T, Fireman P, Hayden FG, Skoner D. 1998. Increased interleukin-6 levels in nasal lavage samples following experimental influenza A virus infection. Clin Diagn Lab Immunol 5:604–608.
    1. Memoli MJ, Czajkowski L, Reed S, Athota R, Bristol T, Proudfoot K, Fargis S, Stein M, Dunfee RL, Shaw PA, Davey RT, Taubenberger JK. 2015. Validation of the wild-type influenza A human challenge model H1N1pdMIST: an A(H1N1)pdm09 dose-finding investigational new drug study. Clin Infect Dis 60:693–702. doi:10.1093/cid/ciu924.
    1. Lambert LC, Fauci AS. 2010. Influenza vaccines for the future. N Engl J Med 363:2036–2044. doi:10.1056/NEJMra1002842.
    1. Monto AS, Petrie JG, Cross RT, Johnson E, Liu M, Zhong W, Levine M, Katz JM, Ohmit SE. 2015. Antibody to influenza virus neuraminidase: an independent correlate of protection. J Infect Dis 212:1191–1199. doi:10.1093/infdis/jiv195.
    1. Murphy BR, Kasel JA, Chanock RM. 1972. Association of serum anti-neuraminidase antibody with resistance to influenza in man. N Engl J Med 286:1329–1332. doi:10.1056/NEJM197206222862502.
    1. Johansson BE, Pokorny BA, Tiso VA. 2002. Supplementation of conventional trivalent influenza vaccine with purified viral N1 and N2 neuraminidases induces a balanced immune response without antigenic competition. Vaccine 20:1670–1674. doi:10.1016/S0264-410X(01)00490-X.
    1. Bosch BJ, Bodewes R, de Vries RP, Kreijtz JH, Bartelink W, van Amerongen G, Rimmelzwaan GF, de Haan CA, Osterhaus AD, Rottier PJ. 2010. Recombinant soluble, multimeric HA and NA exhibit distinctive types of protection against pandemic swine-origin 2009 A(H1N1) influenza virus infection in ferrets. J Virol 84:10366–10374. doi:10.1128/JVI.01035-10.

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