Abstract
Although vaccines against influenza are widely available, control of the disease remains elusive. In part, this is due to the inability of current vaccines to induce durable, broadly protective immune responses. Prevention of influenza depends primarily on effective antibody responses that block virus entry. Following infection, high-affinity IgA antibodies are generated in the respiratory tract that lead to immune exclusion, while IgG prevents systemic spread. These are effective and long-lasting but also exert immune pressure. Mutation of the antigenic determinants of influenza therefore rapidly leads to emergence of novel variants that evade previously generated protective responses. Not only do vaccines suffer from this strain-specific limitation, but also they are suboptimal in their ability to induce durable immunity. However, recent evidence has demonstrated the possibility of inducing broadly cross-reactive antibody responses. Further understanding of the ways in which high-titer, long-lived antibody responses directed against such cross-reactive epitopes can be induced would lead to the development of novel vaccines that may remove the requirement for recurrent vaccination.
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Abt MC, Osborne LC, Monticelli LA et al (2012) Commensal bacteria calibrate the activation threshold of innate antiviral immunity. Immunity 37:158–170. doi:10.1016/j.immuni.2012.04.011
Ambrose CS, Levin MJ, Belshe RB (2011) The relative efficacy of trivalent live attenuated and inactivated influenza vaccines in children and adults. Influenza Other Respir Viruses 5:67–75. doi:10.1111/j.1750-2659.2010.00183.x
Asahi Y, Yoshikawa T, Watanabe I et al (2002) Protection against influenza virus infection in polymeric Ig receptor knockout mice immunized intranasally with adjuvant-combined vaccines. J Immunol 168:2930–2938. doi:10.4049/jimmunol.168.6.2930
Asahi-Ozaki Y, Yoshikawa T, Iwakura Y et al (2004) Secretory IgA antibodies provide cross-protection against infection with different strains of influenza B virus. J Med Virol 74:328–335. doi:10.1002/jmv.20173
Avnir Y, Tallarico AS, Zhu Q et al (2014) Molecular signatures of hemagglutinin stem-directed heterosubtypic human neutralizing antibodies against influenza A viruses. PLoS Pathog 10:e1004103. doi:10.1371/journal.ppat.1004103
Batista FD, Harwood NE (2009) The who, how and where of antigen presentation to B cells. Nat Rev Immunol 9:15–27. doi:10.1038/nri2454
Baumgarth N, Choi YS, Rothaeusler K et al (2008) B cell lineage contributions to antiviral host responses. Curr Top Microbiol Immunol 319:41–61
Belshe R, Mendelman P, Treanor J et al (1998) The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children. N Engl J Med 338:1405–1412
Bernasconi NL, Onai N, Lanzavecchia A (2003) A role for Toll-like receptors in acquired immunity: up-regulation of TLR9 by BCR triggering in naive B cells and constitutive expression in memory B cells. Blood 101:4500–4504. doi:10.1182/blood-2002-11-3569
Black S, Nicolay U, Vesikari T et al (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
Boyden AW, Legge KL, Waldschmidt TJ (2012) Pulmonary infection with influenza A virus induces site-specific germinal center and T follicular helper cell responses. PLoS ONE 7:e40733. doi:10.1371/journal.pone.0040733
Cao RG, Suarez NM, Obermoser G et al (2014) Differences in antibody responses between trivalent inactivated influenza vaccine and live attenuated influenza vaccine correlate with the kinetics and magnitude of interferon signaling in children. J Infect Dis jiu079. doi:10.1093/infdis/jiu079
Caton AJ, Brownlee GG, Yewdell JW, Gerhard W (1982) The antigenic structure of the influenza virus A/PR/8/34 hemagglutinin (H1 subtype). Cell 31:417–427. doi:10.1016/0092-8674(82)90135-0
Chen WH, Cross AS, Edelman R et al (2011) Antibody and Th1-type cell-mediated immune responses in elderly and young adults immunized with the standard or a high dose influenza vaccine. Vaccine 29:2865–2873. doi:10.1016/j.vaccine.2011.02.017
Choi S-M, Xie H, Campbell AP et al (2012) Influenza viral RNA detection in blood as a marker to predict disease severity in hematopoietic cell transplant recipients. J Infect Dis 206:1872–1877. doi:10.1093/infdis/jis610
Choi YS, Baumgarth N (2008) Dual role for B-1a cells in immunity to influenza virus infection. J Exp Med 205:3053–3064. doi:10.1084/jem.20080979
Chu VT, Berek C (2013) The establishment of the plasma cell survival niche in the bone marrow. Immunol Rev 251:177–188. doi:10.1111/imr.12011
Corti D, Suguitan AL, Pinna D et al (2010) Heterosubtypic neutralizing antibodies are produced by individuals immunized with a seasonal influenza vaccine. J Clin Invest 120:1663–1673. doi:10.1172/JCI41902 (41902 [pii])
Corti D, Voss J, Gamblin SJ et al (2011) A neutralizing antibody selected from plasma cells that binds to Group 1 and Group 2 influenza A hemagglutinins. Science. doi:10.1126/science.1205669 (science.1205669 [pii])
Couch RB, Kasel JA (1983) Immunity to influenza in man. Annu Rev Microbiol 37:529–549. doi:10.1146/annurev.mi.37.100183.002525
Ekiert DC, Bhabha G, Elsliger MA et al (2009) Antibody recognition of a highly conserved influenza virus epitope. Science 324:246–251. doi:10.1126/science.1171491 (1171491 [pii])
Fields BN, Knipe DM, Howley PM (2007) Fields’ virology, 5th edn. Knipe DM, Howley PM (editors-in-chief), Griffin DE (et al) (associate editors). Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia
Fink K (2012) Origin and function of circulating plasmablasts during acute viral infections. Front Immunol. doi:10.3389/fimmu.2012.00078
Garside P, Ingulli E, Merica R et al (1998) Visualization of specific B and T lymphocyte interactions in the lymph node. Science 281:96–99
Gerhard W, Mozdzanowska K, Furchner M et al (1997) Role of the B-cell response in recovery of mice from primary influenza virus infection. Immunol Rev 159:95–103
GeurtsvanKessel CH, Willart MAM, Bergen IM et al (2009) Dendritic cells are crucial for maintenance of tertiary lymphoid structures in the lung of influenza virus–infected mice. J Exp Med 206:2339–2349. doi:10.1084/jem.20090410
Grund S, Adams O, Wählisch S, Schweiger B (2011) Comparison of hemagglutination inhibition assay, an ELISA-based micro-neutralization assay and colorimetric microneutralization assay to detect antibody responses to vaccination against influenza A H1N1 2009 virus. J Virol Methods 171:369–373. doi:10.1016/j.jviromet.2010.11.024
Guihot A, Luyt C-E, Parrot A et al (2014) Low titers of serum antibodies inhibiting hemagglutination predict fatal fulminant influenza A(H1N1) 2009 infection. Am J Respir Crit Care Med. doi:10.1164/rccm.201311-2071OC
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
Henle W, Stokes Jr J, Shaw DR (1941) Passive immunization of mice against human influenza virus by the intranasal route. J Immunol 40:201–212
Hoft DF, Babusis E, Worku S et al (2011) Live and inactivated influenza vaccines induce similar humoral responses, but only live vaccines induce diverse T-Cell responses in young children. J Infect Dis 204:845–853. doi:10.1093/infdis/jir436
Huang K-YA, Li CK-F, Clutterbuck E et al (2014) Virus-specific antibody secreting cell, memory B-cell, and sero-antibody responses in the human influenza challenge model. J Infect Dis jit650. doi:10.1093/infdis/jit650
Jones PD, Ada GL (1986) Influenza virus-specific antibody-secreting cells in the murine lung during primary influenza virus infection. J Virol 60:614–619
King C, Tangye SG, Mackay CR (2008) T follicular helper (TFH) cells in normal and dysregulated immune responses. Annu Rev Immunol 26:741–766
Koutsonanos DG, Compans RW, Skountzou I (2013) Targeting the Skin for microneedle delivery of influenza vaccine. In: Katsikis PD, Schoenberger SP, Pulendran B (eds) Crossroads between innate and adaptive immunity IV. Springer, New York, pp 121–132
Kunisawa J, Nochi T, Kiyono H (2008) Immunological commonalities and distinctions between airway and digestive immunity. Trends Immunol 29:505–513. doi:10.1016/j.it.2008.07.008
Lee FE-H, Halliley JL, Walsh EE et al (2011) Circulating human antibody-secreting cells during vaccinations and respiratory viral infections are characterized by high specificity and lack of bystander effect. J Immunol 186:5514–5521. doi:10.4049/jimmunol.1002932
Li G-M, Chiu C, Wrammert J et al (2012) Pandemic H1N1 influenza vaccine induces a recall response in humans that favors broadly cross-reactive memory B cells. Proc Natl Acad Sci 109:9047–9052. doi:10.1073/pnas.1118979109
Liang B, Hyland L, Hou S (2001) Nasal-associated lymphoid tissue is a site of long-term virus-specific antibody production following respiratory virus infection of mice. J Virol 75:5416–5420. doi:10.1128/JVI.75.11.5416-5420.2001
McHeyzer-Williams LJ, Driver DJ, McHeyzer-Williams MG (2001) Germinal center reaction. Curr Opin Hematol 8:52–59
McHeyzer-Williams M, Okitsu S, Wang N, McHeyzer-Williams L (2012) Molecular programming of B cell memory. Nat Rev Immunol 12:24–34. doi:10.1038/nri3128
Mitnaul LJ, Matrosovich MN, Castrucci MR et al (2000) Balanced hemagglutinin and neuraminidase activities are critical for efficient replication of influenza A virus. J Virol 74:6015–6020
Moyron-Quiroz JE, Rangel-Moreno J, Hartson L et al (2006) Persistence and responsiveness of immunologic memory in the absence of secondary lymphoid organs. Immunity 25:643–654. doi:10.1016/j.immuni.2006.08.022
Moyron-Quiroz JE, Rangel-Moreno J, Kusser K et al (2004) Role of inducible bronchus associated lymphoid tissue (iBALT) in respiratory immunity. Nat Med 10:927–934. doi:10.1038/nm1091
Nichol KL, Nordin JD, Nelson DB et al (2007) Effectiveness of influenza vaccine in the community-Dwelling Elderly. N Engl J Med 357:1373–1381. doi:10.1056/NEJMoa070844
Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team et al (2009) Emergence of a novel swine-origin influenza A (H1N1) virus in humans. N Engl J Med 360:2605–2615. doi:10.1056/NEJMoa0903810
O’Hagan DT, Wack A, Podda A (2007) MF59 is a safe and potent vaccine adjuvant for flu vaccines in humans: what did we learn during its development? Clin Pharmacol Ther 82:740–744. doi:10.1038/sj.clpt.6100402
Ohmit SE, Petrie JG, Cross RT et al (2011) Influenza hemagglutination-inhibition antibody titer as a correlate of vaccine-induced protection. J Infect Dis 204:1879–1885
Okuno Y, Isegawa Y, Sasao F, Ueda S (1993) A common neutralizing epitope conserved between the hemagglutinins of influenza A virus H1 and H2 strains. J Virol 67:2552–2558
Pabst O (2012) New concepts in the generation and functions of IgA. Nat Rev Immunol 12:821–832. doi:10.1038/nri3322
Pape KA, Catron DM, Itano AA, Jenkins MK (2007) The humoral immune response is initiated in lymph nodes by B cells that acquire soluble antigen directly in the follicles. Immunity 26:491–502. doi:10.1016/j.immuni.2007.02.011
Pica N, Hai R, Krammer F et al (2012) Hemagglutinin stalk antibodies elicited by the 2009 pandemic influenza virus as a mechanism for the extinction of seasonal H1N1 viruses. Proc Natl Acad Sci 109:2573–2578. doi:10.1073/pnas.1200039109
Powell TJ, Peng Y, Berthoud TK et al (2013) Examination of influenza specific T cell responses after influenza virus challenge in individuals vaccinated with MVA-NP+M1 vaccine. PLoS ONE 8:e62778. doi:10.1371/journal.pone.0062778
Sangster MY, Riberdy JM, Gonzalez M et al (2003) An early CD4+ T cell–dependent immunoglobulin a response to influenza infection in the absence of key cognate T–B interactions. J Exp Med 198:1011–1021. doi:10.1084/jem.20021745
Sasaki S, Holmes TH, Albrecht RA et al (2014) Distinct cross-reactive B-cell responses to live attenuated and inactivated influenza vaccines. J Infect Dis jiu190. doi:10.1093/infdis/jiu190
Sasaki S, Jaimes MC, Holmes TH et al (2007) Comparison of the influenza virus-specific effector and memory B-cell responses to immunization of children and adults with live attenuated or inactivated influenza virus vaccines. J Virol 81:215–228. doi:10.1128/JVI.01957-06
Sasaki S, Sullivan M, Narvaez CF et al (2011) Limited efficacy of inactivated influenza vaccine in elderly individuals is associated with decreased production of vaccine-specific antibodies. J Clin Invest 121:3109–3119. doi:10.1172/JCI57834
Shaffer AL, Lin KI, Kuo TC et al (2002) Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. Immunity 17:51–62
Skehel JJ, Wiley DC (2000) Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin. Annu Rev Biochem 69:531–569. doi:10.1146/annurev.biochem.69.1.531
Steel J, Lowen AC, T Wang T et al (2010) Influenza virus vaccine based on the conserved hemagglutinin stalk domain. MBio. doi:10.1128/mBio.00018-10
Stephenson I, Heath A, Major D et al (2009) Reproducibility of serologic assays for influenza virus A (H5N1). Emerg Infect Dis 15:1250–1259. doi:10.3201/eid1508.081754
Sui J, Hwang WC, Perez S et al (2009) Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses. Nat Struct Mol Biol 16:265–273
Tamura S-I, Funato H, Hirabayashi Y et al (1991) Cross-protection against influenza A virus infection by passively transferred respiratory tract IgA antibodies to different hemagglutinin molecules. Eur J Immunol 21:1337–1344. doi:10.1002/eji.1830210602
Thompson CI, Barclay WS, Zambon MC, Pickles RJ (2006) Infection of human airway epithelium by human and avian strains of influenza A virus. J Virol 80:8060–8068. doi:10.1128/JVI.00384-06
Throsby M, van den Brink E, Jongeneelen M et al (2008) Heterosubtypic neutralizing monoclonal antibodies cross-protective against H5N1 and H1N1 recovered from human IgM+ memory B cells. PLoS One 3:e3942. doi:10.1371/journal.pone.0003942
Tricco AC, Chit A, Soobiah C et al (2013) Comparing influenza vaccine efficacy against mismatched and matched strains: a systematic review and meta-analysis. BMC Med 11:153. doi:10.1186/1741-7015-11-153
Van Riet E, Ainai A, Suzuki T, Hasegawa H (2012) Mucosal IgA responses in influenza virus infections; thoughts for vaccine design. Vaccine 30:5893–5900. doi:10.1016/j.vaccine.2012.04.109
Wang TT, Tan GS, Hai R et al (2010) Broadly protective monoclonal antibodies against H3 influenza viruses following sequential immunization with different hemagglutinins. PLoS Pathog 6:e1000796. doi:10.1371/journal.ppat.1000796
Wei CJ, Boyington JC, McTamney PM et al (2010) Induction of broadly neutralizing H1N1 influenza antibodies by vaccination. Science 329:1060–1064. doi:10.1126/science.1192517 (science.1192517 [pii])
Wrammert J, Koutsonanos D, Li G-M et al (2011) Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection. J Exp Med 208:181–193. doi:10.1084/jem.20101352
Wright PF, Sannella E, Shi JR et al (2008) Antibody responses after inactivated influenza vaccine in young children. Pediatr Infect Dis J 27:1004–1008. doi:10.1097/INF.0b013e31817d53c5
Yen H-L, Aldridge JR, Boon ACM et al (2009) Changes in H5N1 influenza virus hemagglutinin receptor binding domain affect systemic spread. Proc Natl Acad Sci 106:286–291. doi:10.1073/pnas.0811052106
Yewdell JW, Webster RG, Gerhard WU (1979) Antigenic variation in three distinct determinants of an influenza type A haemagglutinin molecule. Nature 279:246–248
Zaman K, Roy E, Arifeen SE et al (2008) Effectiveness of maternal influenza immunization in mothers and infants. N Engl J Med 359:1555–1564. doi:10.1056/NEJMoa0708630
Zinkernagel RM (2001) Maternal antibodies, childhood infections, and autoimmune diseases. N Engl J Med 345:1331–1335. doi:10.1056/NEJMra012493
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Chiu, C., Ellebedy, A.H., Wrammert, J., Ahmed, R. (2014). B Cell Responses to Influenza Infection and Vaccination. In: Oldstone, M., Compans, R. (eds) Influenza Pathogenesis and Control - Volume II. Current Topics in Microbiology and Immunology, vol 386. Springer, Cham. https://doi.org/10.1007/82_2014_425
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