1,071
Views
75
CrossRef citations to date
0
Altmetric
Review

Influenza immunology evaluation and correlates of protection: a focus on vaccines

&
Pages 967-976 | Received 11 Jan 2016, Accepted 07 Mar 2016, Published online: 25 Mar 2016

References

  • Onions D, Egan W, Jarrett R, et al. Validation of the safety of MDCK cells as a substrate for the production of a cell-derived influenza vaccine. Biologicals. 2010;38(5):544–51.
  • Montomoli E, Capecchi B, Hoschler K. Correlates of Protection Against Influenza. In: Ag SB, editor. Influenza Vaccines for the Future. Basel: Springer: 2011.
  • Sridhar S, Brokstad KA, Cox RJ. Influenza Vaccination Strategies: Comparing Inactivated and Live Attenuated Influenza Vaccines. Vaccines (Basel). 2015;3(2):373–389.
  • Manini I, Domnich A, Amicizia D, et al. Flucelvax (Optaflu) for seasonal influenza. Expert Rev Vaccines. 2015;14(6):789–804.
  • Hobson D, Curry RL, Beare AS, et al. The role of serum haemagglutination-inhibiting antibody in protection against challenge infection with influenza A2 and B viruses. J Hyg (Lond). 1972;70(4):767–777.
  • CPMP. Note for guidance on harmonisation of requirements for influenza vaccines. London: The European Agency for the Evaluation of Medicinal Products; 1997.
  • Plotkin SA, Gilbert PB. Nomenclature for immune correlates of protection after vaccination. Clin Infect Dis. 2012;54(11):1615–1617.
  • Qin L, Gilbert PB, Corey L, et al. A framework for assessing immunological correlates of protection in vaccine trials. J Infect Dis. 2007;196(9):1304–1312.
  • Hannoun C, Megas F, Piercy J. Immunogenicity and protective efficacy of influenza vaccination. Virus Res. 2004;103(1–2):133–138.
  • Plotkin SA. Vaccines: correlates of vaccine-induced immunity. Clin Infect Dis. 2008;47(3):401–409.
  • Al-Khayatt R, Jennings R, Potter CW. Interpretation of responses and protective levels of antibody against attenuated influenza A viruses using single radial haemolysis. J Hyg (Lond). 1984;93(2):301–312.
  • de Jong JC, Palache AM, Beyer WE, et al. Haemagglutination-inhibiting antibody to influenza virus. Dev Biol (Basel). 2003;115:63–73.
  • Coudeville L, Bailleux F, Riche B, et al. Relationship between haemagglutination-inhibiting antibody titres and clinical protection against influenza: development and application of a bayesian random-effects model. BMC Med Res Methodol. 2010;10:18.
  • Coudeville L, Andre P, Bailleux F, et al. A new approach to estimate vaccine efficacy based on immunogenicity data applied to influenza vaccines administered by the intradermal or intramuscular routes. Hum Vaccin. 2010;6(10):841–848.
  • Black S, Nicolay U, Vesikari T, et al. Hemagglutination inhibition antibody titers as a correlate of protection for inactivated influenza vaccines in children. Pediatr Infect Dis J. 2011;30(12):1081–5.
  • Granström M, Voordouw AC. Registration of influenza vaccines for children in Europe. Vaccine. 2011;29(43):7572–7575.
  • Ohmit SE, Petrie JG, Cross RT, et al. Influenza hemagglutination-inhibition antibody titer as a correlate of vaccine-induced protection. J Infect Dis. 2011;204(12):1879–1885.
  • Van Els C, Mjaaland S, Naess L, et al. Fast vaccine design and development based on correlates of protection (COPs). Hum Vaccin Immunother. 2014;10(7):1935–1948.
  • Katz JM, Hancock K, Xu X. Serologic assays for influenza surveillance, diagnosis and vaccine evaluation. Expert Rev Anti Infect Ther. 2011;9(6):669–683.
  • Wood JM, Melzack D, Newman RW, et al. A single radial haemolysis assay for antibody to H5 haemagglutinin. Int Congress Ser. 2001;1219:761–766.
  • Soema PC, Kompier R, Amorij JP, et al. Current and next generation influenza vaccines: Formulation and production strategies. Eur J Pharm Biopharm. 2015;94:251–63.
  • Goodeve A, Potter CW, Clark A, et al. A graded-dose study of inactivated, surface antigen influenza B vaccine in volunteers: reactogenicity, antibody response and protection to challenge virus infection. J Hyg (Lond). 1983;90(1):107–115.
  • WHO. Serological detection of avian influenza A(H7N9) virus infections by modified horde red blood cells haemagglutination-inhibition assay. China: World Health Organization; 2013. p. 1–11.
  • Reber A, Katz J. Immunological assessment of influenza vaccines and immune correlates of protection. Expert Rev Vaccines. 2013;12(5):519–536.
  • Wood JM, Montomoli E, Newman RW, et al. Collaborative study on influenza vaccine clinical trial serology - part 2: reproducibility study. Pharmeur Bio Sci Notes. 2011;2011(1):36–54.
  • Stephenson I, Heath A, Major D, et al. Reproducibility of serologic assays for influenza virus A (H5N1). Emerg Infect Dis. 2009;15(8):1252–1259.
  • Noah DL, Hill H, Hines D, et al. Qualification of the hemagglutination inhibition assay in support of pandemic influenza vaccine licensure. Clin Vaccine Immunol. 2009;16(4):558–566.
  • Beyer WE, Palache AM, Lüchters G, et al. Seroprotection rate, mean fold increase, seroconversion rate: which parameter adequately expresses seroresponse to influenza vaccination? Virus Res. 2004;103(1–2):125–132.
  • Beyer WE, Palache AM, Sprenger MJ, et al. Effects of repeated annual influenza vaccination on vaccine sero-response in young and elderly adults. Vaccine. 1996;14(14):1331–1339.
  • Schild GC, Pereira MS, Chakraverty P. Single-radial-hemolysis: a new method for the assay of antibody to influenza haemagglutinin. Applications for diagnosis and seroepidemiologic surveillance of influenza. Bull World Health Organ. 1975;52(1):43–50.
  • Morley PS, Hanson LK, Bogdan JR, et al. The relationship between single radial hemolysis, hemagglutination inhibition, and virus neutralization assays used to detect antibodies specific for equine influenza viruses. Vet Microbiol. 1995;45(1):81–92.
  • Clarke M, Boustred J, Seagroatt V, et al. The use of single-radial-haemolysis for rubella antibody studies. J Hyg (Lond). 1977;79(3):355–364.
  • Callow KA, Beare AS. Measurement of antibody to influenza virus neuraminidase by single radial hemolysis in agarose gels. Infect Immun. 1976;13(1):1–8.
  • Trombetta CM, Perini D, Vitale L, et al. Validation of Single Radial Haemolysis assay: A reliable method to measure antibodies against influenza viruses. J Immunol Methods. 2015;422:95–101.
  • Farrohi K, Farrohi FK, Noble GR, et al. Evaluation of the single radial hemolysis test for measuring hemagglutinin- and neuraminidase-specific antibodies to H3N2 influenza strains and antibodies to influenza B. J Clin Microbiol. 1977;5(3):353–360.
  • Fulton RE, DiNinno VL, Frank RI, et al. Single radial hemolysis test for quantitation of complement-fixing antibodies to non-hemagglutinating viruses. J Clin Microbiol. 1984;20(2):248–254.
  • Goodeve AC, Jennings R, Potter CW. The use of the single radial haemolysis test for assessing antibody response and protective antibody levels in an influenza B vaccine study. J Biol Stand. 1983;11(4):289–296.
  • Rowe T, Abernathy RA, Hu-Primmer J, et al. Detection of antibody to avian influenza A (H5N1) virus in human serum by using a combination of serologic assays. J Clin Microbiol. 1999;37(4):937–943.
  • Delem A. Serum SRH antibody level as a measure of the immunity against natural and artificial A/Victoria/3/75 infections. Dev Biol Stand. 1977;39:391–396.
  • Wood JM, Gaines-Das RE, Taylor J, et al. Comparison of influenza serological techniques by international collaborative study. Vaccine. 1994;12(2):167–174.
  • Kayali G, Setterquist SF, Capuano AW, et al. Testing human sera for antibodies against avian influenza viruses: horse RBC hemagglutination inhibition vs. microneutralization assays. J Clin Virol. 2008;43(1):73–78.
  • WHO. Recommendations and laboratory procedures for detection of avian influenza A(H5N1) virus in specimens from suspected human cases. Geneva: World Health Organization; 2007. p. 1–28.
  • Wagner R, Göpfert C, Hammann J, et al. Enhancing the reproducibility of serological methods used to evaluate immunogenicity of pandemic H1N1 influenza vaccines-an effective EU regulatory approach. Vaccine. 2012;30(27):4113–4122.
  • Veguilla V, Hancock K, Schiffer J, et al. Sensitivity and specificity of serologic assays for detection of human infection with 2009 pandemic H1N1 virus in U.S. populations. J Clin Microbiol. 2011;49(6):2210–2215.
  • WHO. Manual for the laboratory diagnosis and virological surveillance of influenza. 2011. p. 1–137.
  • van der Velden MV, Aichinger G, Pöllabauer EM, et al. Cell culture (Vero cell) derived whole-virus non-adjuvanted H5N1 influenza vaccine induces long-lasting cross-reactive memory immune response: homologous or heterologous booster response following two dose or single dose priming. Vaccine. 2012;30(43):6127–6135.
  • Ansaldi F, Bacilieri S, Amicizia D, et al. Antigenic characterisation of influenza B virus with a new microneutralisation assay: comparison to haemagglutination and sequence analysis. J Med Virol. 2004;74(1):141–146.
  • Stephenson I, Das RG, Wood JM, et al. Comparison of neutralising antibody assays for detection of antibody to influenza A/H3N2 viruses: an international collaborative study. Vaccine. 2007;25(20):4056–4063.
  • Howard MK, Sabarth N, Savidis-Dacho H, et al. H5N1 whole-virus vaccine induces neutralizing antibodies in humans which are protective in a mouse passive transfer model. PLoS One. 2011;6(8):e23791.
  • Ehrlich HJ, Muller M, Oh HM, et al. A clinical trial of a whole-virus H5N1 vaccine derived from cell culture. N Engl J Med. 2008;358(24):2573–2584.
  • Cox RJ, Pedersen G, Madhun AS, et al. Evaluation of a virosomal H5N1 vaccine formulated with Matrix M™ adjuvant in a phase I clinical trial. Vaccine. 2011;29(45):8049–8059.
  • Galli G, Medini D, Borgogni E, et al. Adjuvanted H5N1 vaccine induces early CD4+ T cell response that predicts long-term persistence of protective antibody levels. Proc Natl Acad Sci U S A. 2009;106(10):3877–3882.
  • Allwinn R, Geiler J, Berger A, et al. Determination of serum antibodies against swine-origin influenza A virus H1N1/09 by immunofluorescence, haemagglutination inhibition, and by neutralization tests: how is the prevalence rate of protecting antibodies in humans? Med Microbiol Immunol. 2010;199(2):117–121.
  • Miller E, Hoschler K, Hardelid P, et al. Incidence of 2009 pandemic influenza A H1N1 infection in England: a cross-sectional serological study. Lancet. 2010;375(9720):1100–1108.
  • Hakim H, Allison KJ, Van De Velde LA, et al. Immunogenicity and safety of inactivated monovalent 2009 H1N1 influenza A vaccine in immunocompromised children and young adults. Vaccine. 2012;30(5):879–885.
  • Adamson WE, McGregor EC, Kavanagh K, et al. Population exposure to a novel influenza A virus over three waves of infection. J Clin Virol. 2011;52(4):300–303.
  • Verschoor CP, Singh P, Russell ML, et al. Microneutralization assay titres correlate with protection against seasonal influenza H1N1 and H3N2 in children. PLoS One. 2015;10(6):e0131531.
  • Tsang TK, Cauchemez S, Perera RA, et al. Association between antibody titers and protection against influenza virus infection within households. J Infect Dis. 2014;210(5):684–692.
  • Trombetta CM, Perini D, Mather S, et al. Overview of Serological Techniques for Influenza Vaccine Evaluation: Past, Present and Future. Vaccines. 2014;2(4):707–734.
  • Carnell GW, Ferrara F, Grehan K, et al. Pseudotype-based neutralization assays for influenza: a systematic analysis. Front Immunol. 2015;6:161.
  • Zakay-Rones Z. Human influenza vaccines and assessment of immunogenicity. Expert Rev Vaccines. 2010;9(12):1423–1439.
  • McCullers JA, Huber VC. Correlates of vaccine protection from influenza and its complications. Hum Vaccin Immunother. 2012;8(1):34–44.
  • Kilbourne ED, Couch RB, Kasel JA, et al. Purified influenza A virus N2 neuraminidase vaccine is immunogenic and non-toxic in humans. Vaccine. 1995;13(18):1799–1803.
  • Kilbourne ED, Laver WG, Schulman JL, et al. Antiviral activity of antiserum specific for an influenza virus neuraminidase. J Virol. 1968;2(4):281–288.
  • Schulman JL, Khakpour M, Kilbourne ED. Protective effects of specific immunity to viral neuraminidase on influenza virus infection of mice. J Virol. 1968;2(8):778–786.
  • Kilbourne ED, Johansson BE, Grajower B. Independent and disparate evolution in nature of influenza A virus hemagglutinin and neuraminidase glycoproteins. Proc Natl Acad Sci U S A. 1990;87(2):786–790.
  • Johansson BE, Bucher DJ, Kilbourne ED. Purified influenza virus hemagglutinin and neuraminidase are equivalent in stimulation of antibody response but induce contrasting types of immunity to infection. J Virol. 1989;63(3):1239–1246.
  • Couch RB, Atmar RL, Franco LM, et al. Antibody correlates and predictors of immunity to naturally occurring influenza in humans and the importance of antibody to the neuraminidase. J Infect Dis. 2013;207(6):974–981.
  • Rockman S, Brown LE, Barr IG, et al. Neuraminidase-inhibiting antibody is a correlate of cross-protection against lethal H5N1 influenza virus in ferrets immunized with seasonal influenza vaccine. J Virol. 2013;87(6):3053–3061.
  • Monto AS, Petrie JG, Cross RT, et al. Antibody to Influenza Virus Neuraminidase: an Independent Correlate of Protection. J Infect Dis. 2015;212(8):1191–1199.
  • Lambré CR, Terzidis H, Greffard A, et al. Measurement of anti-influenza neuraminidase antibody using a peroxidase-linked lectin and microtitre plates coated with natural substrates. J Immunol Methods. 1990;135(1–2):49–57.
  • EMA. Report from scientific workshop on serology assays and correlates of protection for influenza vaccines. London: European Medicines Agency; 2010. p. 1–32.
  • Fritz R, Sabarth N, Kiermayr S, et al. A vero cell-derived whole-virus H5N1 vaccine effectively induces neuraminidase-inhibiting antibodies. J Infect Dis. 2012;205(1):28–34.
  • Murphy BR, Tierney EL, Barbour BA, et al. Use of the enzyme-linked immunosorbent assay to detect serum antibody responses of volunteers who received attenuated influenza A virus vaccines. Infect Immun. 1980;29(2):342–347.
  • Turner R, Lathey JL, Van Voris LP, et al. Serological diagnosis of influenza B virus infection: comparison of an enzyme-linked immunosorbent assay and the hemagglutination inhibition test. J Clin Microbiol. 1982;15(5):824–829.
  • Alvarez MM, López-Pacheco F, Aguilar-Yañez JM, et al. Specific recognition of influenza A/H1N1/2009 antibodies in human serum: a simple virus-free ELISA method. PLoS One. 2010;5(4):e10176.
  • Jennings R, Smith T, Potter CW. Use of the enzyme-linked immunosorbent assay (ELISA) for the estimation of serum antibodies in an influenza virus vaccine study. Med Microbiol Immunol. 1981;169(4):247–258.
  • Cox RJ, Brokstad KA, Ogra P. Influenza virus: immunity and vaccination strategies. Comparison of the immune response to inactivated and live, attenuated influenza vaccines. Scand J Immunol. 2004;59(1):1–15.
  • Thomas PG, Keating R, Hulse-Post DJ, et al. Cell-mediated protection in influenza infection. Emerg Infect Dis. 2006;12(1):48–54.
  • Soema PC, van Riet E, Kersten G, et al. Development of cross-protective influenza a vaccines based on cellular responses. Front Immunol. 2015;6:237.
  • Svitek N, Taracha EL, Saya R, et al. Analysis of the Cellular Immune Responses to Vaccines. Methods Mol Biol. 2016;1349(p):247–262.
  • Coughlan L, Lambe T. Measuring Cellular Immunity to Influenza: Methods of Detection, Applications and Challenges. Vaccines (Basel). 2015;3(2):293–319.
  • WHO. Correlates of vaccine-induced protection: methods and implications. Geneva: World Health Organization; 2013. p. 1–65.
  • Podda A. The adjuvanted influenza vaccines with novel adjuvants: experience with the MF59-adjuvanted vaccine. Vaccine. 2001;19(17–19):2673–2680.
  • Beyer WE, Palache AM, de Jong JC, et al. Cold-adapted live influenza vaccine versus inactivated vaccine: systemic vaccine reactions, local and systemic antibody response, and vaccine efficacy. A meta-analysis. Vaccine. 2002;20(9–10):1340–1353.
  • Barrett PN, Berezuk G, Fritsch S, et al. Efficacy, safety, and immunogenicity of a Vero-cell-culture-derived trivalent influenza vaccine: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet. 2011;377(9767):751–759.
  • De Donato S, Granoff D, Minutello M, et al. Safety and immunogenicity of MF59-adjuvanted influenza vaccine in the elderly. Vaccine. 1999;17(23–24):3094–3101.
  • Vesikari T, Groth N, Karvonen A, et al. MF59-adjuvanted influenza vaccine (FLUAD) in children: safety and immunogenicity following a second year seasonal vaccination. Vaccine. 2009;27(45):6291–6295.
  • Gasparini R, Pozzi T, Montomoli E, et al. Increased immunogenicity of the MF59-adjuvanted influenza vaccine compared to a conventional subunit vaccine in elderly subjects. Eur J Epidemiol. 2001;17(2):135–140.
  • Pellegrini M, Nicolay U, Lindert K, et al. MF59-adjuvanted versus non-adjuvanted influenza vaccines: integrated analysis from a large safety database. Vaccine. 2009;27(49):6959–6965.
  • Knuf M, Leroux-Roels G, Rümke H, et al. Immunogenicity and safety of cell-derived MF59®-adjuvanted A/H1N1 influenza vaccine for children. Hum Vaccin Immunother. 2015;11(2):358–376.
  • Oh CE, Lee J, Kang JH, et al. Safety and immunogenicity of an inactivated split-virus influenza A/H1N1 vaccine in healthy children from 6 months to <18 years of age: a prospective, open-label, multi-center trial. Vaccine. 2010;28(36):5857–5863.
  • Knuf M, Leroux-Roels G, Rümke HC, et al. Safety and immunogenicity of an MF59-adjuvanted A/H1N1 pandemic influenza vaccine in children from three to seventeen years of age. Vaccine. 2015;33(1):174–181.
  • Nolan T, Bravo L, Ceballos A, et al. Enhanced and persistent antibody response against homologous and heterologous strains elicited by a MF59-adjuvanted influenza vaccine in infants and young children. Vaccine. 2014;32(46):6146–6156.
  • Knuf M, Leroux-Roels G, Rümke HC, et al. Immunogenicity and tolerability of an MF59-adjuvanted, egg-derived, A/H1N1 pandemic influenza vaccine in children 6–35 months of age. Pediatr Infect Dis J. 2014;33(12):e320–9.
  • Nolan T, Izurieta P, Lee BW, et al. Heterologous prime-boost vaccination using an AS03B-adjuvanted influenza A(H5N1) vaccine in infants and children<3 years of age. J Infect Dis. 2014;210(11):1800–1810.
  • Örtqvist A, Bennet R, Hamrin J, et al. Long term effectiveness of adjuvanted influenza A(H1N1)pdm09 vaccine in children. Vaccine. 2015;33(22):2558–2561.
  • Izurieta P, Uy-Aragon MJ, Dramé M, et al. Assessment of Prime-boost Vaccination Using an AS03B-adjuvanted Influenza A (H5N1) Vaccine: A Randomized Trial in Children of Three to Less Than Eighteen Years of Age. Pediatr Infect Dis J. 2016;35(2):e35–47.
  • Garcia-Sicilia J, Arístegui J, Omeñaca F, et al. Safety and persistence of the humoral and cellular immune responses induced by 2 doses of an AS03-adjuvanted A(H1N1)pdm09 pandemic influenza vaccine administered to infants, children and adolescents: Two open, uncontrolled studies. Hum Vaccin Immunother. 2015;11(10):2359–2369.
  • Gillard P, Giet D, Heijmans S, et al. Long-term outcome of the humoral and cellular immune response of an H5N1 adjuvanted influenza vaccine in elderly persons: 2-year follow-up of a randomised open-label study. Trials. 2014;15:419.
  • Reisinger KS, Holmes SJ, Pedotti P, et al. A dose-ranging study of MF59(®)-adjuvanted and non-adjuvanted A/H1N1 pandemic influenza vaccine in young to middle-aged and older adult populations to assess safety, immunogenicity, and antibody persistence one year after vaccination. Hum Vaccin Immunother. 2014;10(8):2395–2407.
  • Frey SE, Reyes MR, Reynales H, et al. Comparison of the safety and immunogenicity of an MF59®-adjuvanted with a non-adjuvanted seasonal influenza vaccine in elderly subjects. Vaccine. 2014;32(39):5027–5034.
  • Greenberg DP, Robertson CA, Noss MJ, et al. Safety and immunogenicity of a quadrivalent inactivated influenza vaccine compared to licensed trivalent inactivated influenza vaccines in adults. Vaccine. 2013;31(5):770–776.
  • Beran J, Peeters M, Dewé W, et al. Immunogenicity and safety of quadrivalent versus trivalent inactivated influenza vaccine: a randomized, controlled trial in adults. BMC Infect Dis. 2013;13:224.
  • Wang L, Chandrasekaran V, Domachowske JB, et al. Immunogenicity and Safety of an Inactivated Quadrivalent Influenza Vaccine in US Children 6–35 Months of Age During 2013–2014: Results From A Phase II Randomized Trial. J Pediatric Infect Dis Soc. 2015:pii:piv041. [Epub ahead of print]
  • Langley JM, Wang L, Aggarwal N, et al. Immunogenicity and Reactogenicity of an Inactivated Quadrivalent Influenza Vaccine Administered Intramuscularly to Children 6 to 35 Months of Age in 2012–2013: A Randomized, Double-Blind, Controlled, Multicenter, Multicountry, Clinical Trial. J Pediatric Infect Dis Soc. 2015;4(3):242–251.
  • Tinoco JC, Pavia-Ruz N, Cruz-Valdez A, et al. Immunogenicity, reactogenicity, and safety of inactivated quadrivalent influenza vaccine candidate versus inactivated trivalent influenza vaccine in healthy adults aged ≥18 years: a phase III, randomized trial. Vaccine. 2014;32(13):1480–1487.
  • Ambrose CS, Wu X, Belshe RB. The efficacy of live attenuated and inactivated influenza vaccines in children as a function of time postvaccination. Pediatr Infect Dis J. 2010;29(9):806–811.
  • Belshe RB, Edwards KM, Vesikari T, et al. Live attenuated versus inactivated influenza vaccine in infants and young children. N Engl J Med. 2007;356(7):685–696.
  • Hoft DF, Babusis E, Worku S, et al. Live and inactivated influenza vaccines induce similar humoral responses, but only live vaccines induce diverse T-cell responses in young children. J Infect Dis. 2011;204(6):845–853.
  • Clements ML, Betts RF, Tierney EL, et al. Serum and nasal wash antibodies associated with resistance to experimental challenge with influenza A wild-type virus. J Clin Microbiol. 1986;24(1):157–160.
  • Petrie JG, Ohmit SE, Johnson E, et al. Efficacy studies of influenza vaccines: effect of end points used and characteristics of vaccine failures. J Infect Dis. 2011;203(9):1309–1315.
  • CHMP. Guideline on influenza vaccines prepared from viruses with the potential to cause a pandemic and intended for use outside of the core dossier context. London: European Medicines Agency. EMEA/CHMP/VWP/263499/2006; 2006. p. 1–11.
  • Report. FDA/NIH/WHO public workshop on immune correlates of protection against influenza A viruses in support of pandemic vaccines development, Bethesda, Maryland, US, December 10–11, 2007. 2007. Vaccine.
  • EMA. Guideline on influenza vaccines. Non-clinical and clinical module. Draft. London: European Medicines Agency; 2014.
  • Powers DC, Kilbourne ED, Johansson BE. Neuraminidase-specific antibody responses to inactivated influenza virus vaccine in young and elderly adults. Clin Diagn Lab Immunol. 1996;3(5):511–516.
  • Sandbulte MR, Jimenez GS, Boon AC, et al. Cross-reactive neuraminidase antibodies afford partial protection against H5N1 in mice and are present in unexposed humans. PLoS Med. 2007;4(2):e59.
  • McElhaney JE. Influenza vaccine responses in older adults. Ageing Res Rev. 2011;10(3):379–388.
  • Impagliazzo A, Milder F, Kuipers H, et al. A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen. Science. 2015;349(6254):1301–6.
  • Yassine HM, Boyington JC, McTamney PM, et al. Hemagglutinin-stem nanoparticles generate heterosubtypic influenza protection. Nat Med. 2015;21(9):1065–70.
  • Chen Z, Kim L, Subbarao K, et al. The 2009 pandemic H1N1 virus induces anti-neuraminidase (NA) antibodies that cross-react with the NA of H5N1 viruses in ferrets. Vaccine. 2012;30(15):2516–2522.
  • Easterbrook JD, Schwartzman LM, Gao J, et al. Protection against a lethal H5N1 influenza challenge by intranasal immunization with virus-like particles containing 2009 pandemic H1N1 neuraminidase in mice. Virology. 2012;432(1):39–44.
  • Osterhaus A, Fouchier R, Rimmelzwaan G. Towards universal influenza vaccines? Philos Trans R Soc Lond B Biol Sci. 2011;366(1579):2766–2773.
  • Kreijtz JH, de Mutsert G, van Baalen CA, et al. Cross-recognition of avian H5N1 influenza virus by human cytotoxic T-lymphocyte populations directed to human influenza A virus. J Virol. 2008;82(11):5161–5166.
  • Sridhar S, Begom S, Bermingham A, et al. Cellular immune correlates of protection against symptomatic pandemic influenza. Nat Med. 2013;19(10):1305–1312.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.