Advertisement

Prospects for Broadly Protective Influenza Vaccines

  • John Jay Treanor
    Correspondence
    Address correspondence to: Tel.: +1 585 275 5871; fax: +1 585 442 9328
    Affiliations
    Department of Medicine, University of Rochester School of Medicine and Dentistry, Box 689, 601 Elmwood Avenue, Rochester, NY 14642, United States
    Search for articles by this author
      The development of vaccines that could provide broad protection against antigenically variant influenza viruses has long been the ultimate prize in influenza research. Recent developments have pushed us closer to this goal, and such vaccines may now be within reach. This brief review outlines the current approaches to broadly protective vaccines, and the probable hurdles and roadblocks to achieving this goal.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to American Journal of Preventive Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Andrewes C.
        • Smith W.
        Influenza: experiments on the active immunisation of mice.
        Br J Exp Path. 1937; 18: 43
        • Francis Jr., T.
        • Salk J.E.
        • Pearson H.E.
        • Brown P.N.
        Protective effect of vaccination against influenza.
        Proc Soc Exp Biol Med. 1944; 55: 104-105
        • Kilbourne E.D.
        • Smith C.
        • Brett I.
        • Pokorny B.A.
        • Johansson B.
        • Cox N.
        The total influenza vaccine failure of 1947 revisited: major intrasubtypic antigenic change can explain failure of vaccine in a post-World War II epidemic.
        Proc Natl Acad Sci USA. 2002; 99 ([Erratum appears in Proc Natl Acad Sci USA. 2003 Jan 21;100(2):764]): 10748-10752
        • Kilbourne E.D.
        • Loge J.P.
        Influenza A prime: a clinical study of an epidemic caused by a new strain of virus.
        Ann Intern Med. 1950; 33: 371-382
        • Reber A.
        • Katz J.
        Immunologic assessment of influenza vaccines and immune correlates of protection.
        Expert Rev Vaccines. 2013; 12: 519-536
        • Stephenson I.
        • Das R.G.
        • Wood J.M.
        • Katz J.M.
        Comparison of neutralising antibody assays for detection of antibody to influenza A/H3N2 viruses: an international collaborative study.
        Vaccine. 2007; 25: 4056-4063
        • Black S.
        • Nicolay U.
        • Mesikari T.
        • Knuf M.
        • DelGuidice G.
        • Cioppa G.
        • et al.
        Hemagglutination inhibition antibody titers as a correlate of protection for inactivated influenza vaccines in children.
        Pediatr Infect Dis J. 2011; 30: 1081-1085
        • Wilson I.A.
        • Cox N.J.
        Structural basis of immune recognition of influenza virus hemagglutinin.
        Annu Rev Immunol. 1990; 8: 737-771
        • Yewdell J.W.
        To dream the impossible dream: universal influenza vaccination.
        Curr Opin Virol. 2013; 3: 316-321
        • Kashyap A.K.
        • Steel J.
        • Oner A.F.
        • Dillon M.A.
        • Swale R.E.
        • Wall K.M.
        • et al.
        Combinatorial antibody libraries from survivors of the Turkish H5N1 avian influenza outbreak reveal virus neutralization strategies.
        Proc Natl Acad Sci USA. 2008; 105: 5986-5991
        • Wrammert J.
        • Koutsnanos D.
        • Li G.-M.
        • Edupuganti S.
        • Sui J.
        • Morrissey M.
        • et al.
        Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection.
        J Exp Med. 2011; 208: 191
        • Ekiert D.C.
        • Bhabha G.
        • Elsliger M.-A.
        • Friesen R.H.E.
        • Johngeneelen M.
        • Throsby M.
        • et al.
        Antibody recognition of a highly conserved influenza virus epitope.
        Science. 2009; 324: 246-251
        • Ekiert D.C.
        • Friesen R.H.E.
        • Bhabha G.
        • Kwaks T.
        • Jongeneelen M.
        • Yu W.
        • et al.
        A highly conserved neutralizing epitope on group 2 influenza.
        A Viruses Sci. 2011; 333: 843-850
        • Miller M.S.
        • Tsibane T.
        • Krammer F.
        • Hai R.
        • Rahmat S.
        • Basler C.F.
        • et al.
        1976 and 2009 H1N1 influenza virus vaccines boost anti-hemagglutinin stalk antibodies in humans.
        J Infect Dis. 2013; 207: 98-105
        • Nachbagauer R.
        • Wohlbold T.J.
        • Hirsh A.
        • Hai R.
        • Sjursen H.
        • Palese P.
        • et al.
        Induction of broadly reactive anti-hemagglutinin stalk antibodies by an H5N1 vaccine in humans.
        J Virol. 2014; 88: 13260-13268
        • Palese P.
        • Wang T.T.
        Why do influenza subtypes die out? A hypothesis.
        mBio. 2011; 2: e00150-e211
        • Krammer F.
        • Palese P.
        Influenza virus hemagglutinin stalk-based antibodies and vaccines.
        Curr Opin Virol. 2013; 3: 521-530
        • Sui J.
        • Sheehan J.
        • Hwang W.C.
        • Bankston L.A.
        • Burchett S.K.
        • Huang C.Y.
        • et al.
        Wide prevalence of heterosubtypic broadly neutralizing human anti-influenza A antibodies.
        Clin Infect Dis. 2011; 52: 1003-1009
        • Margine I.
        • Hai R.
        • Albrecht R.A.
        • Obermoser G.
        • Harrod A.
        • Banchereau J.
        • et al.
        H3N2 influenza virus infection induces broadly reactive hemagglutinin stalk antibodies in humans and mice.
        J Virol. 2013; 87: 4728-4737
        • Pica N.
        • Palese P.
        Towards a universal influenza virus vaccine: prospects and challenges.
        Annu Rev Med. 2013; 64: 189-202
        • Krammer F.
        • Pica N.
        • Hai R.
        • Margine I.
        • Palese P.
        Chimeric hemagglutinin influenza virus vaccine constructs elicit broadly protective stalk-specific antibodies.
        J Virol. 2013; 87: 6542-6550
        • Krammer F.
        • Margine I.
        • Hai R.
        • Flood A.
        • Hirsh A.
        • Tsvetnitsky V.
        • et al.
        H3 stalk-based chimeric hemagglutinin influenza virus constructs protect mice from H7N9 challenge.
        J Virol. 2014; 88: 2340-2343
        • Steel J.
        • Lowen A.C.
        • Wang T.T.
        • Yondola M.
        • Gao Q.
        • Hay K.
        • et al.
        Influenza virus vaccine based on the conserved hemagglutinin stalk domain.
        mBio. 2010; 1: e00018-10
        • Wang T.T.
        • Tan G.S.
        • Hai R.
        • Natalie P.
        • Ngai L.
        • Ekiert D.C.
        • et al.
        Vacccination with a synthetic peptide from the influenza virus hemagglutinin provides protection against distinct viral subtypes.
        Proc Natl Acad Sci USA. 2010; 107: 18979-18984
        • Lu Y.
        • Welsh J.P.
        • Swartz J.R.
        Production and stabilization of the trimeric influenza hemagglutinin stem domain for potentially broadly protective influenza vaccines.
        Proc Natl Acad Sci USA. 2014; 111: 125-130
        • Weaver E.A.
        • Rubrum A.M.
        • Webby R.J.
        • Barry M.A.
        Protection against divergent influenza H1N1 virus by a centralized influenza hemagglutinin.
        PLoS ONE. 2011; 6 ([Electronic Resource]): e18314
        • Giles B.M.
        • Ross T.M.
        A computationally optimized broadly reactive antigen (COBRA) based H5N1 VLP vaccine elicits broadly reactive antibodies in mice and ferrets.
        Vaccine. 2011; 29: 3043-3054
        • Giles B.M.
        • Bissel S.J.
        • DeAlmeida D.R.
        • Wiley C.A.
        • Ross T.M.
        Antibody breadth and protective efficacy are increased by vaccination with computationally optimized hemagglutinin but not with polyvalent hemagglutinin-based H5N1 virus-like particle vaccines.
        Clin Vaccine Immunol. 2012; 19: 128-139
        • Giles B.M.
        • Crevar C.J.
        • Carter D.M.
        • Bissel S.J.
        • Schultz-Cherry S.
        • Wiley C.A.
        • et al.
        A computationally optimized hemagglutinin virus-like particle vaccine elicits broadly reactive antibodies that protect nonhuman primates from H5N1 infection.
        J Infect Dis. 2012; 205: 1562-15710
        • Webster R.G.
        • Reay P.A.
        • Laver W.G.
        Protection against lethal influenza with neuraminidase.
        Virology. 1988; 164: 230-237
        • Kawaoka Y.
        • Krauss S.
        • Webster R.G.
        Avian-to-human transmission of the PB1 gene of influenza A viruses in the 1957 and 1968 pandemics.
        J Virol. 1989; 63: 4603-4608
        • Murphy B.R.
        • Kasel J.A.
        • Chanock R.M.
        Association of serum antineuraminidase antibody with resistance to influenza in man.
        N Engl J Med. 1972; 286: 1329-1332
        • Monto A.S.
        • Kendal A.P.
        Effect of neuraminidase antibody on Hong Kong influenza.
        Lancet. 1973; 7804: 623-625
        • Clements M.L.
        • Betts R.F.
        • Tierney E.L.
        • Murphy B.R.
        Serum and nasal wash antibodies associated with resistance to experimental challenge with influenza A wild-type virus.
        J Clin Microbiol. 1986; 24: 157-160
        • Johansson B.E.
        • Grajower B.
        • Kilbourne E.D.
        Infection-permissive immunization with influenza virus neuraminidase prevents weight loss in infected mice.
        Vaccine. 1993; 11: 1037-1039
        • Sandbulte M.R.
        • Westgeest K.B.
        • Gao J.
        • Xu X.
        • Klimov A.I.
        • Russell C.A.
        • et al.
        Discordant antigenic drift of neuraminidase and hemagglutinin in H1N1 and H3N2 influenza viruses.
        Proc Natl Acad Sci USA. 2011; 108: 20748-20753
        • Lambre C.R.
        • Terzidis H.
        • Greffard A.
        • Webster R.G.
        Measurement of anti-influenza neuraminidase antibody using a peroxidase-linked lectin and microtitre plates coated with natural substrates.
        J Immunol Methods. 1990; 135: 49-57
        • Cate T.R.
        • Rayford Y.
        • Nino D.
        • Winokur P.L.
        • Brady R.C.
        • Belshe R.
        • et al.
        A high dosage influenza vaccine induced significantly more neuraminidase antibody than standard vaccine amont elderly subjects.
        Vaccine. 2010; 28: 2076-2078
        • Laguio-Vila M.R.
        • Thompson M.G.
        • Reynolds S.
        • Spencer S.M.
        • Gaglani M.
        • Naleway A.
        • et al.
        Comparison of serum hemagglutinin and neuraminidase inhibition antiboides after 2010–2011 trivalent inactivated vaccination in healthcare personnel.
        Open Forum Infect Dis. 2015; : ofu115
        • Monto A.S.
        • Petrie J.G.
        • Cross R.T.
        • Johnson E.
        • Liu M.
        • Zhong W.
        • et al.
        Antibody to influenza virus neuraminidase: an independent correlate of protection.
        J Infect Dis. 2015; ([in press])
        • Johansson B.E.
        • Kilbourne E.D.
        Dissociation of influenza virus hemagglutinin and neuraminidase eliminates their intravirionic antigenic competion.
        J Virol. 1993; 67: 5721-5723
        • Johansson B.E.
        Immunization with influenza A virus hemagglutinin and neuraminidase produced in recombinant baculovirus results in a balanced and broadened immune response superior to conventional vaccine.
        Vaccine. 1999; 17: 2073-2080
        • Kilbourne E.D.
        • Couch R.B.
        • Kasel J.A.
        • Keitel W.A.
        • Cate T.R.
        • Quarles J.H.
        • et al.
        Purified influenza A virus N2 neuraminidase vaccine is immunogenic and non-toxic in humans.
        Vaccine. 1995; 13: 1799-1803
        • Fritz R.
        • Sabarth N.
        • Kiermayr S.
        • Hohenadl C.
        • Howard M.K.
        • Ilk R.
        • et al.
        A vero cell-derived whole-virus H5N1 vaccine effectively induces neuraminidase-inhibiting antibodies.
        J Infect Dis. 2012; 205: 28-34
        • Sandbulte M.R.
        • Jimenez G.S.
        • Boon A.C.M.
        • Smith Larry R.
        • Treanor J.J.
        • Webby R.J.
        Cross-reactive neuraminidase antibodies afford partial protection against H5N1 in mice and are present in unexposed humans.
        PLOS Med. 2007; 4: e59
        • Schiff G.
        • Kilbourne E.
        • Smith G.
        • Hackett C.
        • Manoff S.
        Phase 2 clinical evaluation of an influenza A virus recombinant N2 neuraminidase. In: options for the control of influenza IV.
        Crete. 2000;
        • Treanor J.J.
        • Tierney E.L.
        • Zebedee S.L.
        • Lamb R.A.
        • Murphy B.R.
        Passively transferred monoclonal antibody to the M2 protein inhibits influenza A virus replication in mice.
        J Virol. 1990; 64: 1375-1377
        • 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. 1993; 74: 143-146
        • Zhong W.
        • Reed C.
        • Blair P.J.
        • Katz J.M.
        • Hancock K.
        Serum antibody response to matrix 2 protein following natural infection with 2009 pandemic influenza A (H1N1) virus in humans.
        J Infect Dis. 2014; 209: 986-994
        • Jegerlehner A.
        • Schmitz N.
        • Storni T.
        • Bachmann M.F.
        • Influenza A.
        vaccine based on the extracellular domain of M2: weak protection mediated via antibody-dependent NK cell activity.
        J Immunol. 2004; 172: 5598-5605
        • Schmitz N.
        • Beerli R.R.
        • Bauer M.
        • Jegerlehner A.
        • Dietmeier K.
        • Maudrich M.
        • et al.
        Universal vaccine against influenza virus: linking TLR signaling to anti-viral protection.
        Eur J Immunol. 2012; 42: 863-869
        • Huleatt J.W.
        • Nakaar V.
        • Desai P.
        • Huang Y.
        • Hewitt D.
        • Jacobs A.
        • et al.
        Potent immunogenicity and efficacy of a universal influenza vaccine candidate comprising a recombinant fusion protein linking influenza M2e to the TLR5 ligand flagellin.
        Vaccine. 2008; 26: 201-214
        • Wang B.Z.
        • Gill H.S.
        • He C.
        • Ou C.
        • Wang L.
        • Wang Y.C.
        • et al.
        Microneedle delivery of an M2e-TLR5 ligand fusion protein to skin confers broadly cross-protective influenza immunity.
        J Controlled Release. 2014; 178: 1-7
        • Alvarez P.
        • Zylberman V.
        • Ghersi G.
        • Boado L.
        • Palacios C.
        • Goldbaum F.
        • et al.
        Tandem repeats of the extracellular domain of Matrix 2 influenza protein exposed in Brucella lumazine synthase decameric carrier molecule induce protection in mice.
        Vaccine. 2013; 31: 806-812
        • Neirynck S.
        • Deroo T.
        • Saelens X.
        • Vanlandschoot P.
        • Jou W.M.
        • Fiers W.
        A universal influenza A vaccine based on the extracellular domain of the M2 protein.
        Nat Med. 1999; 5: 1157-1163
        • Kim M.C.
        • Lee J.S.
        • Kwon Y.M.
        • Eunju O.
        • Lee Y.J.
        • Choi J.G.
        • et al.
        Multiple heterologous M2 extracellular domains presented on virus-like particles confer broader and stronger M2 immunity than live influenza A virus infection.
        Antiviral Res. 2013; 99: 328-335
        • Lee Y.N.
        • Kim M.C.
        • Lee Y.T.
        • Hwang H.S.
        • Cho M.K.
        • Lee J.S.
        • et al.
        AS04-adjuvanted virus-like particles containing multiple M2 extracellular domains of influenza virus confer improved protection.
        Vaccine. 2014; 32: 4578-4585
        • Wang L.
        • Hess A.
        • Chang T.Z.
        • Wang Y.C.
        • Champion J.A.
        • Compans R.W.
        • et al.
        Nanoclusters self-assembled from conformation-stabilized influenza M2e as broadly cross-protective influenza vaccines.
        Nanomedicine. 2014; 10: 473-482
        • Fiers W.
        • De Filette M.
        • El Bakkouri K.
        • Schepens B.
        • Roose K.
        • Schotsaert M.
        • et al.
        M2e-based universal influenza A vaccine.
        Vaccine. 2009; 27: 6280-6283
        • Ramos E.L.
        • Mitcham J.L.
        • Koller D.T.
        • Bonavia A.
        • Usner D.W.
        • Balaratnam G.
        • et al.
        Efficacy and safety of treatment with an anti-M2e monoclonal antibody in experimental human influenza.
        J Infect Dis. 2015; 211: 1038-1044
        • Wagner D.K.
        • Clements M.L.
        • Reimer C.B.
        • Snydr M.
        • Nelson D.L.
        • Murphy B.R.
        Analsyis of immunoglobulin G antibody responses after administration of live and inactivated influenza A vaccine indicates that nasal wash immunoglobulin G is a transudate from serum.
        J Clin Microbiol. 1987; 25: 559-562
        • Murphy B.R.
        • Clements M.L.
        The systemic and mucosal immune response of humans to influenza.
        Virus Curr Top Microbiol Immunol. 1989; 146: 107-116
        • Renegar K.B.
        • Small P.A.J.
        Passive transfer of local immunity to influenza virus by IgA antibody.
        J Immunol. 1991; 146: 1972-1978
        • Belshe R.B.
        • Gruber W.C.
        • Mendelman P.M.
        • Cho I.
        • Reisinger K.
        • Block S.L.
        • et al.
        Efficacy of vaccination with live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine against a variant (A/Sydney) not contained in the vaccine.
        J Pediatr. 2000; 136: 168-175
        • Mazanec M.B.
        • Kaetzel C.S.
        • Lamm M.E.
        • Fletcher D.
        • Nedrud J.G.
        Intracellular neutralization of virus by immunoglobulin A antibodies.
        Proc Natl Acad Sci USA. 1992; 89: 6901-6905
        • Tumpey T.M.
        • Renshaw M.
        • Clements J.D.
        • Katz J.M.
        Mucosal delivery of inactivated influenza vaccine induces B-cell-dependent heterosubtypic cross-protection against lethal influenza A H5N1 virus infection.
        J Virol. 2001; 75: 5141-5150
        • McMichael A.J.
        • Gotch F.M.
        • Noble G.R.
        • Beare P.A.S.
        Cytotoxic T-cell immunity to influenza.
        N Engl J Med. 1983; 309: 13-17
        • Forrest B.D.
        • Pride M.W.
        • Dunning A.J.
        • Rosario M.
        • Capeding Z.
        • Chotpitayasunondh T.
        • et al.
        Correlation of cellular immune responses with protection against culture-confirmed influenza virus in young children.
        Clin Vaccine Immunol. 2008; 15: 1042-1053
        • Wilkinson T.M.
        • Li C.K.F.
        • Chui C.S.C.
        • Hu8ang A.K.Y.
        • Perkins M.
        • Liebner J.C.
        • et al.
        Preexisting influenza-specific CD4+ T cells correlate with disease protection against influenza challenge in humans.
        Nat Med. 2012; 18: 274-280
        • Sridhar S.
        • Begom S.
        • Bermingham A.
        • Hoschler i
        • Adamson W.
        • Carman W.
        • et al.
        Cellular immune correlates of protection against symptomatic pandemic influenza.
        Nat Med. 2013; 19: 1305-1312
        • Moise L.
        • Terry F.
        • Ardito M.
        • Tassone R.
        • Latimer H.
        • Boyle C.
        • et al.
        Universal H1N1 influenza vaccine development: identification of consensus class II hemagglutinin and neuraminidase epitopes derived from strains circulating between 1980 and 2011.
        Hum Vaccines Immunother. 2013; 9: 1598-1607
        • Alexander J.
        • Bilsel P.
        • del Guercio M.F.
        • Marinkovic-Petrovic A.
        • Southwood S.
        • Stewart S.
        • et al.
        Identification of broad binding class I HLA supertype epitopes to provide universal coverage of influenza A virus.
        Hum Immunol. 2010; 71: 468-474
        • Alexander J.
        • Bilsel P.
        • del Guercio M.F.
        • Stewart S.
        • Marinkovic-Petrovic A.
        • Southwood S.
        • et al.
        Universal influenza DNA vaccine encoding conserved CD4+ T cell epitopes protects against lethal viral challenge in HLA-DR transgenic mice.
        Vaccine. 2010; 28: 664-672
        • Atsmon J.
        • Caraco Y.
        • Ziv-Sefer S.
        • Shaikevich D.
        • Abramov E.
        • Volokhov I.
        • et al.
        Priming by a novel universal influenza vaccine (Multimeric-001)-a gateway for improving immune response in the elderly population.
        Vaccine. 2014; 32: 5816-5823
        • Kwon J.S.
        • Yoon J.
        • Kim Y.J.
        • Kang K.
        • Woo S.
        • Jung D.I.
        • et al.
        Vaccinia-based influenza vaccine overcomes previously induced immunodominance hierarchy for heterosubtypic protection.
        Eur J Immunol. 2014; 44: 2360-2369
        • Hemann E.A.
        • Kang S.M.
        • Legge K.L.
        Protective CD8 T cell-mediated immunity against influenza A virus infection following influenza virus-like particle vaccination.
        J Immunol. 2013; 191: 2486-2494
        • Furuya Y.
        Return of inactivated whole-virus vaccine for superior efficacy.
        Immunol Cell Biol. 2012; 90: 571-578
        • Keitel W.A.
        • Campbell J.D.
        • Treanor J.J.
        • Walter E.
        • Patel S.M.
        • He F.
        • et al.
        Safety and immunogenicity of an inactivated influenza A/H5N1 vaccine given without or with aluminum hydroxide to healthy adults: results of a phase I-II randomized clinical trial.
        J Infect Dis. 2008; 198: 1309-1316
        • Atmar R.L.
        • Keitel W.A.
        • Patel S.M.
        • Katz J.M.
        • She D.
        • El Sahly H.
        • et al.
        Safety and immunogenicity of nonadjuvanted and MF59-adjuvanted influenza A/H9N2 vaccine preparations.
        Clin Infect Dis. 2006; 43: 1135-1142
        • Leroux-Roels I.
        • Borkowski A.
        • Vanwolleghem T.
        • Drame M.
        • Clement F.
        • Hons E.
        • et al.
        Antigen sparing and cross-reactive immunity with an adjuvanted rH5N1 prototype pandemic influenza vaccine: a randomised controlled trial.
        Lancet. 2007; 370: 580-589
        • Galli G.
        • Hancock K.
        • Hoschler K.
        • DeVos J.
        • Praus M.
        • Bardelli M.
        • et al.
        Fast rise of broadly cross-reactive antibodies after boosting long-lived human memory B cells primed by an MF59 adjuvanted prepandemic vaccine.
        Proc Nat Acad Sci U S A. 2009; 106: 7962-7967
        • Khurana S.
        • Verma N.
        • Yewdell J.W.
        • Hilbert A.K.
        • Castellino F.
        • Lattanzi M.
        • et al.
        MF59 adjuvant enhances diversity and affinity of antibody-mediated immune response to pandemic influenza vaccines.
        Sci Transl Med. 2011; 3: 85ra48
        • Nohynek H.
        • Jokinen J.
        • Partinen M.
        • Vaarala O.
        • Kirjavainen T.
        • Sundman J.
        • et al.
        AS03 adjuvanted AH1N1 vaccine associated with an abrupt increase in the incidence of childhood narcolepsy in Finland.
        PLoS ONE. 2012; 7: e33536
        • Heinen P.P.
        • Rijsewijk F.A.
        • de Boer-Luijtze E.A.
        • Bianchi A.T.
        Vaccination of pigs with a DNA construct expressing an influenza virus M2-nucleoprotein fusion protein exacerbates disease after challenge with influenza a virus.
        J Gen Virol. 2002; 83: 1851-1859
        • Khurana S.
        • Loving C.L.
        • Manischewitz J.
        • King L.R.
        • Gauger P.C.
        • Henningson J.
        • et al.
        Vaccine-induced anti-HA2 antibodies promote virus fusion and enhance influenza virus respiratory disease.
        Sci Transl Med. 2013; 5: 200ra114