The adaptive immune response to influenza virus infection is multifaceted and complex, involving antibody and cellular responses at both systemic and mucosal levels. Immune responses to natural infection with influenza virus in humans are relatively broad and long-lived, but influenza viruses can escape from these responses over time owing to their high mutation rates and antigenic flexibility. Vaccines are the best available countermeasure against infection, but vaccine effectiveness is low compared with other viral vaccines, and the induced immune response is narrow and short-lived. Furthermore, inactivated influenza virus vaccines focus on the induction of systemic IgG responses but do not effectively induce mucosal IgA responses. Here, I review the differences between natural infection and vaccination in terms of the antibody responses they induce and how these responses protect against future infection. A better understanding of how natural infection induces broad and long-lived immune responses will be key to developing next-generation influenza virus vaccines.
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World Health Organization. Influenza (seasonal). WHO https://www.who.int/en/news-room/fact-sheets/detail/influenza-(seasonal) (2018).
Krammer, F. et al. Influenza. Nat. Rev. Dis. Primers 4, 3 (2018).
Subbarao, K. Avian influenza H7N9 viruses: a rare second warning. Cell Res. 28, 1–2 (2018).
Krammer, F. Emerging influenza viruses and the prospect of a universal influenza virus vaccine. Biotechnol. J. 10, 690–701 (2015).
Palese, P. Influenza: old and new threats. Nat. Med. 10, S82–87 (2004).
Smith, G. et al. Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic. Nature 459, 1122–1125 (2009).
Guan, Y. et al. The emergence of pandemic influenza viruses. Protein Cell 1, 9–13 (2010).
Saunders-Hastings, P. R. & Krewski, D. Reviewing the history of pandemic influenza: understanding patterns of emergence and transmission. Pathogens 5, 66 (2016).
Gasparini, R., Amicizia, D., Lai, P. L. & Panatto, D. Clinical and socioeconomic impact of seasonal and pandemic influenza in adults and the elderly. Hum. Vaccin. Immunother. 8, 21–28 (2012).
Smith, W., Andrewes, C. H. & Laidlaw, P. P. A virus obtained from influenza patients. Lancet 222, 66–68 (1933).
Hobson, D., Curry, R. L., Beare, A. S. & Ward-Gardner, A. The role of serum haemagglutination-inhibiting antibody in protection against challenge infection with influenza A2 and B viruses. J. Hyg. (Lond.) 70, 767–777 (1972).
Doud, M. B. & Bloom, J. D. Accurate measurement of the effects of all amino-acid mutations on influenza hemagglutinin. Viruses 8, 155 (2016). This study explores the antigenic flexibility of influenza virus HA using a library of single amino acid mutants.
Heaton, N. S., Sachs, D., Chen, C. J., Hai, R. & Palese, P. Genome-wide mutagenesis of influenza virus reveals unique plasticity of the hemagglutinin and NS1 proteins. Proc. Natl Acad. Sci. USA 110, 20248–20253 (2013). This paper explores the antigenic flexibility of influenza virus using a five-amino-acid insertion library.
Kirkpatrick, E., Qiu, X., Wilson, P. C., Bahl, J. & Krammer, F. The influenza virus hemagglutinin head evolves faster than the stalk domain. Sci. Rep. 8, 10432 (2018).
Gerdil, C. The annual production cycle for influenza vaccine. Vaccine 21, 1776–1779 (2003).
de Jong, J. C., Beyer, W. E., Palache, A. M., Rimmelzwaan, G. F. & Osterhaus, A. D. Mismatch between the 1997/1998 influenza vaccine and the major epidemic A(H3N2) virus strain as the cause of an inadequate vaccine-induced antibody response to this strain in the elderly. J. Med. Virol. 61, 94–99 (2000).
Xie, H. et al. H3N2 mismatch of 2014–2015 northern hemisphere influenza vaccines and head-to-head comparison between human and ferret antisera derived antigenic maps. Sci. Rep. 5, 15279 (2015).
Wrammert, J. et al. Rapid cloning of high-affinity human monoclonal antibodies against influenza virus. Nature 453, 667–671 (2008).
Wu, N. C. & Wilson, I. A. Structural insights into the design of novel anti-influenza therapies. Nat. Struct. Mol. Biol. 25, 115–121 (2018).
van de Sandt, C. E., Bodewes, R., Rimmelzwaan, G. F. & de Vries, R. D. Influenza B viruses: not to be discounted. Future Microbiol. 10, 1447–1465 (2015).
Tan, J., Asthagiri Arunkumar, G. & Krammer, F. Universal influenza virus vaccines and therapeutics: where do we stand with influenza B virus? Curr. Opin. Immunol. 53, 45–50 (2018).
Bodewes, R. et al. In vitro assessment of the immunological significance of a human monoclonal antibody directed to the influenza a virus nucleoprotein. Clin. Vaccine Immunol. 20, 1333–1337 (2013).
Wang, M. et al. Antibody dynamics of 2009 influenza A (H1N1) virus in infected patients and vaccinated people in China. PLOS ONE 6, e16809 (2011).
Nachbagauer, R. et al. Defining the antibody cross-reactome directed against the influenza virus surface glycoproteins. Nat. Immunol. 18, 464–473 (2017). This study characterizes the breadth of the immune response to HA and NA in three animal models and humans across all HA subtypes.
Li, Z. N. et al. IgM, IgG, and IgA antibody responses to influenza A(H1N1)pdm09 hemagglutinin in infected persons during the first wave of the 2009 pandemic in the United States. Clin. Vaccine Immunol. 21, 1054–1060 (2014).
Monto, A. S. et al. Antibody to influenza virus neuraminidase: an independent correlate of protection. J. Infect. Dis. 212, 1191–1199 (2015). This paper describes NA-specific antibody titres as an independent correlate of protection against influenza virus infection in humans.
Lewnard, J. A. & Cobey, S. Immune history and influenza vaccine effectiveness. Vaccines (Basel) 6, 28 (2018). This interesting review discusses pre-existing immunity to influenza virus and its effects on vaccination.
Nachbagauer, R. et al. Age dependence and isotype specificity of influenza virus hemagglutinin stalk-reactive antibodies in humans. mBio 7, e01996–15 (2016).
Baz, M. et al. Seroconversion to seasonal influenza viruses after A(H1N1)pdm09 virus infection, Quebec, Canada. Emerg. Infect. Dis. 18, 1132–1134 (2012).
Krammer, F. & Palese, P. Influenza virus hemagglutinin stalk-based antibodies and vaccines. Curr. Opin. Virol. 3, 521–530 (2013).
Gerhard, W., Yewdell, J., Frankel, M. E. & Webster, R. Antigenic structure of influenza virus haemagglutinin defined by hybridoma antibodies. Nature 290, 713–717 (1981).
Webster, R. G. & Laver, W. G. Determination of the number of nonoverlapping antigenic areas on Hong Kong (H3N2) influenza virus hemagglutinin with monoclonal antibodies and the selection of variants with potential epidemiological significance. Virology 104, 139–148 (1980).
Skehel, J. J. et al. A carbohydrate side chain on hemagglutinins of Hong Kong influenza viruses inhibits recognition by a monoclonal antibody. Proc. Natl Acad. Sci. USA 81, 1779–1783 (1984).
Wang, Q., Cheng, F., Lu, M., Tian, X. & Ma, J. Crystal structure of unliganded influenza B virus hemagglutinin. J. Virol. 82, 3011–3020 (2008).
Medina, R. A. et al. Glycosylations in the globular head of the hemagglutinin protein modulate the virulence and antigenic properties of the H1N1 influenza viruses. Sci. Transl Med. 5, 187ra170 (2013).
Margine, I. et al. H3N2 influenza virus infection induces broadly reactive hemagglutinin stalk antibodies in humans and mice. J. Virol. 87, 4728–4737 (2013).
Sui, J. et al. Wide prevalence of heterosubtypic broadly neutralizing human anti-influenza A antibodies. Clin. Infect. Dis. 52, 1003–1009 (2011).
Throsby, M. et al. Heterosubtypic neutralizing monoclonal antibodies cross-protective against H5N1 and H1N1 recovered from human IgM+memory B cells. PLOS ONE 3, e3942 (2008).
Ekiert, D. C. & Wilson, I. A. Broadly neutralizing antibodies against influenza virus and prospects for universal therapies. Curr. Opin. Virol. 2, 134–141 (2012).
Dreyfus, C. et al. Highly conserved protective epitopes on influenza B viruses. Science 337, 1343–1348 (2012).
Corti, D. et al. A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutinins. Science 333, 850–856 (2011).
Chen, Y. Q. et al. Influenza infection in humans induces broadly cross-reactive and protective neuraminidase-reactive antibodies. Cell 173, 417–429 (2018). This study describes the first NA-specific antibodies isolated from humans and characterizes differences between natural infection with influenza virus and vaccination.
Pica, N. et al. Hemagglutinin stalk antibodies elicited by the 2009 pandemic influenza virus as a mechanism for the extinction of seasonal H1N1 viruses. Proc. Natl Acad. Sci. USA 109, 2573–2578 (2012).
Yu, X. et al. Neutralizing antibodies derived from the B cells of 1918 influenza pandemic survivors. Nature 455, 532–536 (2008).
Fisman, D. N. et al. Older age and a reduced likelihood of 2009 H1N1 virus infection. N. Engl. J. Med. 361, 2000–2001 (2009).
Hancock, K. et al. Cross-reactive antibody responses to the 2009 pandemic H1N1 influenza virus. N. Engl. J. Med. 361, 1945–1952 (2009).
Kendal, A. P. et al. Laboratory-based surveillance of influenza virus in the United States during the winter of 1977–1978. I. Periods of prevalence of H1N1 and H3N2 influenza A strains, their relative rates of isolation in different age groups, and detection of antigenic variants. Am. J. Epidemiol. 110, 449–461 (1979).
Babu, T. M. et al. Population serologic immunity to human and avian H2N2 viruses in the United States and Hong Kong for pandemic risk assessment. J. Infect. Dis. 218, 1054–1060 (2018).
Miller, M. S. et al. Neutralizing antibodies against previously encountered influenza virus strains increase over time: a longitudinal analysis. Sci. Transl Med. 5, 198ra107 (2013).
Miller, M. S. et al. 1976 and 2009 H1N1 influenza virus vaccines boost anti-hemagglutinin stalk antibodies in humans. J. Infect. Dis. 207, 98–105 (2012).
Krammer, F. et al. NAction! How can neuraminidase-based immunity contribute to better influenza virus vaccines? mBio 9, e02332–17 (2018).
Johansson, B. E., Moran, T. M. & Kilbourne, E. D. Antigen-presenting B cells and helper T cells cooperatively mediate intravirionic antigenic competition between influenza A virus surface glycoproteins. Proc. Natl Acad. Sci. USA 84, 6869–6873 (1987).
Wohlbold, T. J. & Krammer, F. In the shadow of hemagglutinin: a growing interest in influenza viral neuraminidase and its role as a vaccine antigen. Viruses 6, 2465–2494 (2014).
Rajendran, M. et al. Analysis of anti-influenza virus neuraminidase antibodies in children, adults, and the elderly by ELISA and enzyme inhibition: evidence for original antigenic sin. mBio 8, e02281–16 (2017).
Haaheim, R. Single-radial-complement-fixation: a new immunodiffusion technique. 2. Assay of the antibody response to the internal antigens (MP and NP) of influenza A virus in human sera after vaccination and infection. Dev. Biol. Stand. 39, 481–484 (1977).
Black, R. A., Rota, P. A., Gorodkova, N., Klenk, H. D. & Kendal, A. P. Antibody response to the M2 protein of influenza A virus expressed in insect cells. J. Gen. Virol. 74, 143–146 (1993).
Sukeno, N. et al. Anti-nucleoprotein antibody response in influenza A infection. Tohoku J. Exp. Med. 128, 241–249 (1979).
de Boer, G. F., Back, W. & Osterhaus, A. D. An ELISA for detection of antibodies against influenza A nucleoprotein in humans and various animal species. Arch. Virol. 115, 47–61 (1990).
Reiche, S. et al. High inter-individual diversity of point mutations, insertions, and deletions in human influenza virus nucleoprotein-specific memory B cells. PLOS ONE 10, e0128684 (2015).
Cretescu, L., Beare, A. S. & Schild, G. C. Formation of antibody to matrix protein in experimental human influenza A virus infections. Infect. Immun. 22, 322–327 (1978).
Joassin, L., Reginster, M. & Vaira, D. Anti M-protein antibody response to type A or B natural influenza detected by solid phase enzyme linked immunosorbent assay and by complement fixation. Arch. Virol. 76, 15–23 (1983).
Vanderven, H. A. et al. What lies beneath: antibody dependent natural killer cell activation by antibodies to internal influenza virus proteins. EBioMedicine 8, 277–290 (2016). This interesting paper characterizes the FcR-mediated effector functions of antibodies to NP and M1.
Jegaskanda, S. et al. Induction of H7N9-cross-reactive antibody-dependent cellular cytotoxicity antibodies by human seasonal influenza A viruses that are directed toward the nucleoprotein. J. Infect. Dis. 215, 818–823 (2017).
Feng, J. et al. Influenza A virus infection engenders a poor antibody response against the ectodomain of matrix protein 2. Virol. J. 3, 102 (2006).
Grandea, A. G. et al. Human antibodies reveal a protective epitope that is highly conserved among human and nonhuman influenza A viruses. Proc. Natl Acad. Sci. USA 107, 12658–12663 (2010).
Zhong, W. et al. Serum antibody response to matrix protein 2 following natural infection with 2009 pandemic influenza A(H1N1) virus in humans. J. Infect. Dis. 209, 986–994 (2014).
Khurana, S. et al. Antigenic fingerprinting of H5N1 avian influenza using convalescent sera and monoclonal antibodies reveals potential vaccine and diagnostic targets. PLOS Med. 6, e1000049 (2009).
Krejnusová, I. et al. Antibodies to PB1-F2 protein are induced in response to influenza A virus infection. Arch. Virol. 154, 1599–1604 (2009).
Yodsheewan, R. et al. Human monoclonal ScFv specific to NS1 protein inhibits replication of influenza viruses across types and subtypes. Antiviral Res. 100, 226–237 (2013).
Thathaisong, U. et al. Human monoclonal single chain antibodies (HuScFv) that bind to the polymerase proteins of influenza A virus. Asian Pac. J. Allergy Immunol. 26, 23–35 (2008).
Reynolds, H. Y. Immunoglobulin G and its function in the human respiratory tract. Mayo Clin. Proc. 63, 161–174 (1988).
Spiekermann, G. M. et al. Receptor-mediated immunoglobulin G transport across mucosal barriers in adult life: functional expression of FcRn in the mammalian lung. J. Exp. Med. 196, 303–310 (2002).
Pakkanen, S. H. et al. Expression of homing receptors on IgA1 and IgA2 plasmablasts in blood reflects differential distribution of IgA1 and IgA2 in various body fluids. Clin. Vaccine Immunol. 17, 393–401 (2010).
Suzuki, T. et al. Relationship of the quaternary structure of human secretory IgA to neutralization of influenza virus. Proc. Natl Acad. Sci. USA 112, 7809–7814 (2015).
Ekiert, D. C. et al. Cross-neutralization of influenza A viruses mediated by a single antibody loop. Nature 489, 526–532 (2012).
DiLillo, D. J., Palese, P., Wilson, P. C. & Ravetch, J. V. Broadly neutralizing anti-influenza antibodies require Fc receptor engagement for in vivo protection. J. Clin. Invest. 126, 605–610 (2016). This paper shows the importance of Fc–FcR interactions for protection mediated by HA stalk-reactive antibodies.
Henry Dunand, C. J. et al. Both neutralizing and non-neutralizing human H7N9 influenza vaccine-induced monoclonal antibodies confer protection. Cell Host Microbe 19, 800–813 (2016). This interesting manuscript describes non-neutralizing human HA-reactive antibodies that protect against infection with H7N9 virus.
Couch, R. B. 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. 207, 974–981 (2013).
Ohmit, S. E., Petrie, J. G., Cross, R. T., Johnson, E. & Monto, A. S. Influenza hemagglutination-inhibition antibody titer as a correlate of vaccine-induced protection. J. Infect. Dis. 204, 1879–1885 (2011).
Brandenburg, B. et al. Mechanisms of hemagglutinin targeted influenza virus neutralization. PLOS ONE 8, e80034 (2013).
Chai, N. et al. Two escape mechanisms of influenza A virus to a broadly neutralizing stalk-binding antibody. PLOS Pathog. 12, e1005702 (2016).
Tan, G. S. et al. Characterization of a broadly neutralizing monoclonal antibody that targets the fusion domain of group 2 influenza a virus hemagglutinin. J. Virol. 88, 13580–13592 (2014).
Ekiert, D. C. et al. Antibody recognition of a highly conserved influenza virus epitope. Science 324, 246–251 (2009).
Verschoor, C. P. et al. Microneutralization assay titres correlate with protection against seasonal influenza H1N1 and H3N2 in children. PLOS ONE 10, e0131531 (2015).
Tsang, T. K. et al. Association between antibody titers and protection against influenza virus infection within households. J. Infect. Dis. 210, 684–692 (2014).
Trombetta, C. M., Perini, D., Mather, S., Temperton, N. & Montomoli, E. Overview of serological techniques for influenza vaccine evaluation: past, present and future. Vaccines (Basel) 2, 707–734 (2014).
Trombetta, C. M., Remarque, E. J., Mortier, D. & Montomoli, E. Comparison of hemagglutination inhibition, single radial hemolysis, virus neutralization assays, and ELISA to detect antibody levels against seasonal influenza viruses. Influenza Other Respir. Viruses 12, 675–686 (2018).
Wohlbold, T. J. et al. Hemagglutinin stalk- and neuraminidase-specific monoclonal antibodies protect against lethal H10N8 influenza virus infection in mice. J. Virol. 90, 851–861 (2015).
Yang, X. et al. A beneficiary role for neuraminidase in influenza virus penetration through the respiratory mucus. PLOS ONE 9, e110026 (2014).
Schultz-Cherry, S. & Hinshaw, V. S. Influenza virus neuraminidase activates latent transforming growth factor beta. J. Virol. 70, 8624–8629 (1996).
Memoli, M. J. et al. Evaluation of antihemagglutinin and antineuraminidase antibodies as correlates of protection in an influenza A/H1N1 virus healthy human challenge model. mBio 7, e00417–16 (2016).
Dilillo, D. J., Tan, G. S., Palese, P. & Ravetch, J. V. Broadly neutralizing hemagglutinin stalk-specific antibodies require FcγR interactions for protection against influenza virus in vivo. Nat. Med. 20, 143–151 (2014).
Terajima, M. et al. Complement-dependent lysis of influenza a virus-infected cells by broadly cross-reactive human monoclonal antibodies. J. Virol. 85, 13463–13467 (2011).
Tan, G. S. et al. Broadly-reactive neutralizing and non-neutralizing antibodies directed against the H7 influenza virus hemagglutinin reveal divergent mechanisms of protection. PLOS Pathog. 12, e1005578 (2016).
Leon, P. E. et al. Optimal activation of Fc-mediated effector functions by influenza virus hemagglutinin antibodies requires two points of contact. Proc. Natl Acad. Sci. USA 113, E5944–E5951 (2016). This study describes the two-contact model for FcR-mediated effector functions of antibodies towards influenza virus antigens.
Cox, F. et al. HA antibody-mediated FcγRIIIa activity is both dependent on FcR engagement and interactions between HA and sialic acids. Front. Immunol. 7, 399 (2016).
Wohlbold, T. J. et al. Broadly protective murine monoclonal antibodies against influenza B virus target highly conserved neuraminidase epitopes. Nat. Microbiol. 2, 1415–1424 (2017).
Jacobsen, H. et al. Influenza virus hemagglutinin stalk-specific antibodies in human serum are a surrogate marker for in vivo protection in a serum transfer mouse challenge model. mBio 8, e01463–17 (2017).
El Bakkouri, K. et al. Universal vaccine based on ectodomain of matrix protein 2 of influenza A: Fc receptors and alveolar macrophages mediate protection. J. Immunol. 186, 1022–1031 (2011).
Ramos, E. L. et al. Efficacy and safety of treatment with an anti-M2e monoclonal antibody in experimental human influenza. J. Infect. Dis. 211, 1038–1044 (2014).
Lamere, M. W. et al. Regulation of antinucleoprotein IgG by systemic vaccination and its effect on influenza virus clearance. J. Virol. 85, 5027–5035 (2011).
LaMere, M. W. et al. Contributions of antinucleoprotein IgG to heterosubtypic immunity against influenza virus. J. Immunol. 186, 4331–4339 (2011).
García-Sastre, A. Induction and evasion of type I interferon responses by influenza viruses. Virus Res. 162, 12–18 (2011).
Ehrlich, H. J. et al. Pre-vaccination immunity and immune responses to a cell culture-derived whole-virus H1N1 vaccine are similar to a seasonal influenza vaccine. Vaccine 30, 4543–4551 (2012).
Fritz, R. et al. A vero cell-derived whole-virus H5N1 vaccine effectively induces neuraminidase-inhibiting antibodies. J. Infect. Dis. 205, 28–34 (2012).
van der Velden, M. V. 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 30, 6127–6135 (2012).
Beyer, W. E. P., Palache, A. M. & Osterhaus, A. D. M. E. Comparison of serology and reactogenicity between influenza subunit vaccines and whole virus or split vaccines: a review and meta-analysis of the literature. Clin. Drug Investig. 15, 1–12 (1998).
Oxford, J. S., Schild, G. C., Potter, C. W. & Jennings, R. The specificity of the anti-haemagglutinin antibody response induced in man by inactivated influenza vaccines and by natural infection. J. Hyg. (Lond.) 82, 51–61 (1979).
Wohlbold, T. J. et al. Vaccination with adjuvanted recombinant neuraminidase induces broad heterologous, but not heterosubtypic, cross-protection against influenza virus infection in mice. mBio 6, e02556 (2015).
Couch, R. B. et al. Randomized comparative study of the serum antihemagglutinin and antineuraminidase antibody responses to six licensed trivalent influenza vaccines. Vaccine 31, 190–195 (2012).
Cox, R. J. & Brokstad, K. A. The postvaccination antibody response to influenza virus proteins. APMIS 107, 289–296 (1999).
Moody, M. A. et al. H3N2 influenza infection elicits more cross-reactive and less clonally expanded anti-hemagglutinin antibodies than influenza vaccination. PLOS ONE 6, e25797 (2011).
Andrews, S. F. et al. Immune history profoundly affects broadly protective B cell responses to influenza. Sci. Transl Med. 7, 316ra192 (2015).
Fonville, J. M. et al. Antibody landscapes after influenza virus infection or vaccination. Science 346, 996–1000 (2014).
Zost, S. J. et al. Contemporary H3N2 influenza viruses have a glycosylation site that alters binding of antibodies elicited by egg-adapted vaccine strains. Proc. Natl Acad. Sci. USA 114, 12578–12583 (2017). This interesting paper shows the effect of egg adaptation on immune responses to different influenza virus vaccines.
Flannery, B. et al. Interim estimates of 2017–2018 seasonal influenza vaccine effectiveness - United States, February 2018. MMWR Morb. Mortal. Wkly Rep. 67, 180–185 (2018).
Krammer, F. & Palese, P. Advances in the development of influenza virus vaccines. Nat. Rev. Drug Discov. 14, 167–182 (2015).
Dunkle, L. M. & Izikson, R. Recombinant hemagglutinin influenza vaccine provides broader spectrum protection. Expert Rev. Vaccines 15, 957–966 (2016).
Dunkle, L. M. et al. Efficacy of recombinant influenza vaccine in adults 50 years of age or older. N. Engl. J. Med. 376, 2427–2436 (2017).
Su, F., Patel, G. B., Hu, S. & Chen, W. Induction of mucosal immunity through systemic immunization: phantom or reality? Hum. Vaccin. Immunother. 12, 1070–1079 (2016).
Barría, M. I. et al. Localized mucosal response to intranasal live attenuated influenza vaccine in adults. J. Infect. Dis. 207, 115–124 (2013).
Islam, S. et al. Influenza A haemagglutinin specific IgG responses in children and adults after seasonal trivalent live attenuated influenza vaccination. Vaccine 35, 5666–5673 (2017).
Johnson, P. R., Feldman, S., Thompson, J. M., Mahoney, J. D. & Wright, P. F. Comparison of long-term systemic and secretory antibody responses in children given live, attenuated, or inactivated influenza A vaccine. J. Med. Virol. 17, 325–335 (1985).
Ambrose, C. S., Wu, X., Jones, T. & Mallory, R. M. The role of nasal IgA in children vaccinated with live attenuated influenza vaccine. Vaccine 30, 6794–6801 (2012).
Belongia, E. A. et al. Waning vaccine protection against influenza A (H3N2) illness in children and older adults during a single season. Vaccine 33, 246–251 (2015).
Kissling, E. et al. Low and decreasing vaccine effectiveness against influenza A(H3) in 2011/12 among vaccination target groups in Europe: results from the I-MOVE multicentre case-control study. Euro Surveill. 18, 20390 (2013).
Kissling, E. et al. I-MOVE multicentre case-control study 2010/11 to 2014/15: is there within-season waning of influenza type/subtype vaccine effectiveness with increasing time since vaccination? Euro Surveill. 21, 30201 (2016).
Puig-Barberà, J. et al. Waning protection of influenza vaccination during four influenza seasons, 2011/2012 to 2014/2015. Vaccine 35, 5799–5807 (2017).
Ferdinands, J. M. et al. Intraseason waning of influenza vaccine protection: evidence from the US Influenza Vaccine Effectiveness Network, 2011–2012 through 2014–2015. Clin. Infect. Dis. 64, 544–550 (2017).
Petrie, J. G., Ohmit, S. E., Johnson, E., Truscon, R. & Monto, A. S. Persistence of antibodies to influenza hemagglutinin and neuraminidase following one or two years of influenza vaccination. J. Infect. Dis. 212, 1914–1922 (2015).
Petrie, J. G. et al. Modest waning of influenza vaccine efficacy and antibody titers during the 2007–2008 influenza season. J. Infect. Dis. 214, 1142–1149 (2016).
Wrammert, J. et al. Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection. J. Exp. Med. 208, 181–193 (2011).
Li, G. M. et al. Pandemic H1N1 influenza vaccine induces a recall response in humans that favors broadly cross-reactive memory B cells. Proc. Natl Acad. Sci. USA 109, 9047–9052 (2012).
Thomson, C. A. et al. Pandemic H1N1 influenza infection and vaccination in humans induces cross-protective antibodies that target the hemagglutinin stem. Front. Immunol. 3, 87 (2012).
Qiu, C. et al. Boosting heterosubtypic neutralization antibodies in recipients of 2009 pandemic H1N1 influenza vaccine. Clin. Infect. Dis. 54, 17–24 (2012).
Ellebedy, A. H. et al. Induction of broadly cross-reactive antibody responses to the influenza HA stem region following H5N1 vaccination in humans. Proc. Natl Acad. Sci. USA 111, 13133–13138 (2014).
Nachbagauer, R. et al. Induction of broadly reactive anti-hemagglutinin stalk antibodies by an H5N1 vaccine in humans. J. Virol. 88, 13260–13268 (2014). This study and that of Ellebedy et al. (2014) show that H5N1 virus vaccination induces HA stalk-specific antibodies in humans.
Krammer, F. et al. An H7N1 influenza virus vaccine induces broadly reactive antibody responses against H7N9 in humans. Clin. Vaccine Immunol. 21, 1153–1163 (2014).
Liu, L. et al. Induction of broadly cross-reactive stalk-specific antibody responses to influenza group 1 and group 2 hemagglutinins by natural H7N9 virus infection in humans. J. Infect. Dis. 215, 518–528 (2017).
Stadlbauer, D. et al. Vaccination with a recombinant H7 hemagglutinin-based influenza virus vaccine induces broadly reactive antibodies in humans. mSphere 2, e00502–17 (2017).
Stadlbauer, D., Nachbagauer, R., Meade, P. & Krammer, F. Universal influenza virus vaccines: what can we learn from the human immune response following exposure to H7 subtype viruses? Front. Med. 11, 471–479 (2017).
Andrews, S. F. et al. Preferential induction of cross-group influenza A hemagglutinin stem-specific memory B cells after H7N9 immunization in humans. Sci. Immunol. 2, eaan2676 (2017).
Erbelding, E. J. et al. A universal influenza vaccine: the strategic plan for the National Institute of Allergy and Infectious Diseases. J. Infect. Dis. 218, 347–354 (2018). This very informative manuscript describes plans by the US National Institute of Allergy and Infectious Diseases to develop a universal influenza virus vaccine.
Paules, C. I., Marston, H. D., Eisinger, R. W., Baltimore, D. & Fauci, A. S. The pathway to a universal influenza vaccine. Immunity 47, 599–603 (2017).
Paules, C. I., Sullivan, S. G., Subbarao, K. & Fauci, A. S. Chasing seasonal influenza - the need for a universal influenza vaccine. N. Engl. J. Med. 378, 7–9 (2018).
Krammer, F., García-Sastre, A. & Palese, P. Is it possible to develop a “universal” influenza virus vaccine? Potential target antigens and critical aspects for vaccine development. Cold Spring Harb. Perspect. Biol. 10, a028845 (2017).
Nachbagauer, R. & Krammer, F. Universal influenza virus vaccines and therapeutic antibodies. Clin. Microbiol. Infect. 23, 222–228 (2017). This review describes the universal influenza virus vaccine candidates that are in clinical trials.
Krammer, F. The quest for a universal flu vaccine: headless HA 2.0. Cell Host Microbe 18, 395–397 (2015).
Impagliazzo, A. et al. A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen. Science 349, 1301–1306 (2015).
Yassine, H. M. et al. Hemagglutinin-stem nanoparticles generate heterosubtypic influenza protection. Nat. Med. 21, 1065–1070 (2015).
Krammer, F., Pica, N., Hai, R., Margine, I. & Palese, P. Chimeric hemagglutinin influenza virus vaccine constructs elicit broadly protective stalk-specific antibodies. J. Virol. 87, 6542–6550 (2013).
Nachbagauer, R. et al. A chimeric haemagglutinin-based influenza split virion vaccine adjuvanted with AS03 induces protective stalk-reactive antibodies in mice. NPJ Vaccines 1, 16015 (2016).
Nachbagauer, R. et al. A universal influenza virus vaccine candidate confers protection against pandemic H1N1 infection in preclinical ferret studies. NPJ Vaccines 2, 26 (2017).
Carter, D. M. et al. Design and characterization of a computationally optimized broadly reactive hemagglutinin vaccine for H1N1 influenza viruses. J. Virol. 90, 4720–4734 (2016).
Wong, T. M. et al. Computationally optimized broadly reactive hemagglutinin elicits hemagglutination inhibition antibodies against a panel of H3N2 influenza virus cocirculating variants. J. Virol. 91, e01581–17 (2017).
Schepens, B., De Vlieger, D. & Saelens, X. Vaccine options for influenza: thinking small. Curr. Opin. Immunol. 53, 22–29 (2018).
Fink, A. L., Engle, K., Ursin, R. L., Tang, W. Y. & Klein, S. L. Biological sex affects vaccine efficacy and protection against influenza in mice. Proc. Natl Acad. Sci. USA 115, 12477–12482 (2018).
Fink, A. L. & Klein, S. L. The evolution of greater humoral immunity in females than males: implications for vaccine efficacy. Curr. Opin. Physiol. 6, 16–20 (2018).
Klein, S. L. & Pekosz, A. Sex-based biology and the rational design of influenza vaccination strategies. J. Infect. Dis. 209, S114–119 (2014).
Francis, T. On the doctrine of original antigenic sin. Proc. Am. Philos. Soc. 104, 572–578 (1960).
Lessler, J. et al. Evidence for antigenic seniority in influenza A (H3N2) antibody responses in southern China. PLOS Pathog. 8, e1002802 (2012).
Li, Y. et al. Immune history shapes specificity of pandemic H1N1 influenza antibody responses. J. Exp. Med. 210, 1493–1500 (2013).
Gostic, K. M., Ambrose, M., Worobey, M. & Lloyd-Smith, J. O. Potent protection against H5N1 and H7N9 influenza via childhood hemagglutinin imprinting. Science 354, 722–726 (2016). This interesting paper hypothesizes that imprinting might protect from severe infection with H5N1 virus or H7N9 virus.
Petrie, J. G. & Monto, A. S. Untangling the effects of prior vaccination on subsequent influenza vaccine effectiveness. J. Infect. Dis. 215, 841–843 (2017).
Zarnitsyna, V. I. et al. Masking of antigenic epitopes by antibodies shapes the humoral immune response to influenza. Philos. Trans. R Soc. B 370, 20140248 (2015).
Guthmiller, J. J. & Wilson, P. C. Harnessing immune history to combat influenza viruses. Curr. Opin. Immunol. 53, 187–195 (2018).
Cobey, S. & Hensley, S. E. Immune history and influenza virus susceptibility. Curr. Opin. Virol. 22, 105–111 (2017).
Angeletti, D. et al. Defining B cell immunodominance to viruses. Nat. Immunol. 18, 456–463 (2017). This report shows the immunodominance of antigenic sites in H1 HA in mice.
Liu, S. T. et al. Antigenic sites in influenza H1 hemagglutinin display species-specific immunodominance. J. Clin. Invest. 128, 4992–4996 (2018). This report shows the immunodominance of antigenic sites in H1 HA in several animal models and humans.
Broecker, F. et al. Immunodominance of antigenic site B in the hemagglutinin of the current H3N2 influenza virus in humans and mice. J. Virol. 92, e01100–18 (2018). This report shows the immunodominance of antigenic sites in H3 HA in several animal models and humans.
Sun, W. et al. Antibody responses toward the major antigenic sites of influenza B virus hemagglutinin in mice, ferrets and humans. J. Virol. 93, e01673–18 (2018). This report shows the immunodominance of influenza B virus antigenic sites in several animal models and humans.
Altman, M. O., Bennink, J. R., Yewdell, J. W. & Herrin, B. R. Lamprey VLRB response to influenza virus supports universal rules of immunogenicity and antigenicity. eLife 4, e07467 (2015).
Ellebedy, A. H. et al. Defining antigen-specific plasmablast and memory B cell subsets in human blood after viral infection or vaccination. Nat. Immunol. 17, 1226–1234 (2016).
Lau, D. et al. Low CD21 expression defines a population of recent germinal center graduates primed for plasma cell differentiation. Sci. Immunol. 2, eaai8153 (2017).
Lee, J. et al. Molecular-level analysis of the serum antibody repertoire in young adults before and after seasonal influenza vaccination. Nat. Med. 22, 1456–1464 (2016).
Schroeder, H. W. & Cavacini, L. Structure and function of immunoglobulins. J. Allergy Clin. Immunol. 125, S41–52 (2010).
El-Madhun, A. S., Cox, R. J. & Haaheim, L. R. The effect of age and natural priming on the IgG and IgA subclass responses after parenteral influenza vaccination. J. Infect. Dis. 180, 1356–1360 (1999).
Frasca, D. et al. Effects of age on H1N1-specific serum IgG1 and IgG3 levels evaluated during the 2011–2012 influenza vaccine season. Immun. Ageing 10, 14 (2013).
Manenti, A. et al. Comparative analysis of influenza A(H3N2) virus hemagglutinin specific IgG subclass and IgA responses in children and adults after influenza vaccination. Vaccine 35, 191–198 (2017).
Vidarsson, G., Dekkers, G. & Rispens, T. IgG subclasses and allotypes: from structure to effector functions. Front. Immunol. 5, 520 (2014).
Maurer, M. A. et al. Glycosylation of human IgA directly inhibits influenza A and other sialic-acid-binding viruses. Cell Rep. 23, 90–99 (2018).
Cox, M. M., Izikson, R., Post, P. & Dunkle, L. Safety, efficacy, and immunogenicity of Flublok in the prevention of seasonal influenza in adults. Ther. Adv. Vaccines 3, 97–108 (2015).
Berlanda Scorza, F. Advancing new vaccines against pandemic influenza in low-resource countries. Vaccine 35, 5397–5402 (2017).
Robertson, C. A. et al. Fluzone® high-dose influenza vaccine. Expert Rev. Vaccines 15, 1495–1505 (2016).
Tsai, T. F. Fluad®-MF59®-adjuvanted influenza vaccine in older adults. Infect. Chemother. 45, 159–174 (2013).
Isakova-Sivak, I. et al. Genetic bases of the temperature-sensitive phenotype of a master donor virus used in live attenuated influenza vaccines: A/Leningrad/134/17/57 (H2N2). Virology 412, 297–305 (2011).
Kiseleva, I. V. et al. PB2 and PA genes control the expression of the temperature-sensitive phenotype of cold-adapted B/USSR/60/69 influenza master donor virus. J. Gen. Virol. 91, 931–937 (2010).
Mossad, S. B. Demystifying FluMist, a new intranasal, live influenza vaccine. Cleve Clin. J. Med. 70, 801–806 (2003).
Manini, I. et al. Flucelvax (Optaflu) for seasonal influenza. Expert Rev. Vaccines 14, 789–804 (2015).
Talon, J. et al. Influenza A and B viruses expressing altered NS1 proteins: a vaccine approach. Proc. Natl Acad. Sci. USA 97, 4309–4314 (2000).
Mössler, C. et al. Phase I/II trial of a replication-deficient trivalent influenza virus vaccine lacking NS1. Vaccine 31, 6194–6200 (2013).
Bahl, K. et al. Preclinical and clinical demonstration of immunogenicity by mRNA vaccines against H10N8 and H7N9 influenza viruses. Mol. Ther. 25, 1316–1327 (2017).
Scorza, F. B. & Pardi, N. New kids on the block: RNA-based influenza virus vaccines. Vaccines (Basel) 6, E20 (2018). This excellent review discusses mRNA vaccines for influenza virus.
Lee, L. Y. Y., Izzard, L. & Hurt, A. C. A. Review of DNA vaccines against influenza. Front. Immunol. 9, 1568 (2018).
López-Macías, C. Virus-like particle (VLP)-based vaccines for pandemic influenza: Performance of a VLP vaccine during the 2009 influenza pandemic. Hum. Vaccin. Immunother. 8, 411–414 (2012).
Tregoning, J. S., Russell, R. F. & Kinnear, E. Adjuvanted influenza vaccines. Hum. Vaccin. Immunother. 14, 550–564 (2018).
Sebastian, S. & Lambe, T. Clinical advances in viral-vectored influenza vaccines. Vaccines (Basel) 6, E29 (2018).
Sano, K., Ainai, A., Suzuki, T. & Hasegawa, H. Intranasal inactivated influenza vaccines for the prevention of seasonal influenza epidemics. Expert Rev. Vaccines 17, 687–696 (2018).
Ma, J., Rubin, B. K. & Voynow, J. A. Mucins, mucus, and goblet cells. Chest 154, 169–176 (2017).
McAuley, J. L. et al. The cell surface mucin MUC1 limits the severity of influenza A virus infection. Mucosal Immunol. 10, 1581–1593 (2017).
Cohen, M. et al. Influenza A penetrates host mucus by cleaving sialic acids with neuraminidase. Virol. J. 10, 321 (2013).
The author thanks P. Wilson, A. Ellebedy and R. Nachbagauer for providing helpful comments and suggestions and J. Bragg for editing the manuscript. The author apologizes to all the colleagues whose great studies could not be cited here owing to space limitations. Work on influenza virus immunology and vaccines in the laboratory of F.K. is funded by the US National Institute of Allergy and Infectious Diseases (NIAID), the US Department of Defense, the Bill and Melinda Gates Foundation, PATH and GlaxoSmithKline. In particular, the author highlights support from the NIAID through the Centers of Excellence for Influenza Research and Surveillance (CEIRS), which has catalysed many of the recent significant advancements in the field.
- Zoonotic infections
Infections caused by an agent with an animal reservoir that can be transmitted from an animal to a human — for example, H5N1 or H7N9 influenza A viruses.
- Antigenic shift
Describes marked changes in the antigenicity of influenza viruses that are caused by the exchange of genomic segments encoding surface glycoproteins, usually involving a change from one virus subtype to another.
Infections caused by a new influenza virus subtype that spreads throughout the human population worldwide.
- Influenza virus epidemics
Seasonal outbreaks of influenza virus infection that typically occur during winter months.
- Population immunity
Also known as community immunity or herd immunity. Describes a situation in which a large proportion of the population is immune to a virus, thus limiting or completely inhibiting its spread, even to naive individuals.
- Correlate of protection
A measurable parameter that correlates with protection of an individual from infection and/or disease.
- Antigenic drift
Describes small changes in the antigenicity of influenza viruses that are usually caused by mutations in their surface glycoproteins, mostly in haemagglutinin (HA), leading to immune escape.
- Vaccine effectiveness
The ability of a vaccine to reduce disease and/or infection in the field, under non-optimal conditions.
Describes a phenomenon in which an antigen or epitope is preferentially targeted by the immune system compared with other antigens or epitopes.
- Haemagglutination inhibition assay
An assay that measures the ability of serum to block haemagglutination, which is the aggregation (agglutination) of red blood cells caused by influenza virus. The resulting haemagglutination inhibition titre is a correlate of protection for influenza virus that is accepted by many regulatory agencies.
A measurable increase (typically fourfold) in the titre of specific antibodies that is induced by vaccination or infection.
- Enzyme-linked immunosorbent assay
(ELISA). An assay that is used to detect the binding of antibody to antigens.
- Microneutralization assay
An assay that measures the ability of serum or antibodies to neutralize influenza virus.
Describes a phenomenon in which the first exposure to influenza virus during childhood leaves an immunological ‘imprint’, whereby subsequent exposures to antigenically different influenza virus strains boost responses to those epitopes that are shared between the two virus strains.
- Group 1 HA proteins
A phylogenetic cluster of influenza A virus haemagglutinin (HA) subtypes that includes H1, H2, H5, H6, H8, H9, H11, H12, H13, H16, H17 and H18.
- Glycan shielding
Shielding of epitopes from B cell receptors or antibodies by N-linked glycans.
- Group 2 HA proteins
A phylogenetic cluster of influenza A virus haemagglutinin (HA) subtypes that includes H3, H4, H7, H10, H14 and H15.
- Neuraminidase inhibition assays
Assays that measure the ability of antiserum to block the sialidase activity of neuraminidase (NA).
- Group 1 NA proteins
A phylogenetic cluster of influenza A virus neuraminidase (NA) subtypes that includes N1, N4, N5 and N8.
- Group 2 NA proteins
A phylogenetic cluster of influenza A virus neuraminidase (NA) subtypes that includes N2, N3, N6, N7 and N9.
- Fc receptor
(FcR). A receptor expressed on immune cells to which antibodies can bind via their crystallizable fragment (Fc) region. These receptors are important for antibody-dependent cell-mediated cytotoxicity and antibody-dependent cellular phagocytosis.
- Vaccine efficacy
The ability of a vaccine to reduce disease and/or infection in an ideal setting.
- Antibody-dependent cell-mediated cytotoxicity
(ADCC). The killing of infected cells by effector cells (for example, natural killer cells) via bound antibody.
- Antibody-dependent cellular phagocytosis
(ADCP). The phagocytosis of infected cells or virus by effector cells (for example, macrophages) via bound antibody.
- Complement-dependent lysis
The lysis of cells or viruses by complement via bound antibody.