1887

Abstract

Antibodies directed against the conserved regions within the influenza A haemagglutinin (HA) protein are detected at low frequency in humans. These antibodies display a broad reactivity against divergent influenza virus strains and could potentially offer broad protection. The in vivo protective effect of these antibodies is mainly mediated through Fc receptor effector functions. While antibody-dependent phagocytosis (ADP) of anti-HA antibodies has been demonstrated in human sera and sera from influenza virus-infected macaques, it is not known whether ADP can also be induced by vaccination and what the relative strength of ADP responses is in comparison to other antibody functions. Using a cohort of influenza virus-infected and immunized macaques, we demonstrate that infection as well as immunization with DNA-encoding HA induces high-titre ADP responses against HA, which are of potency 100–1000 times higher than virus inhibitory functions including antibody-dependent cell-mediated cytotoxicity (ADCC), virus neutralization (VN) and haemagglutinin inhibition (HAI). ADP activity was equally high against HA of heterologous influenza strains of the same subtype, in contrast to virus inhibitory functions, which were all greatly diminished. ADP titres against H5, representing a hetero-subtypic virus, were much lower. ADP was measured in THP-1 cells but was also observed in primary peripheral blood monocytes and neutrophils. Furthermore, at high serum dilution enhanced infection of both monocytes and myeloid dendritic cells (mDC) was observed. Hence, influenza virus infection as well as DNA-immunization against HA can induce high-titre ADP responses that can potentially enhance influenza virus infection of primary phagocytic and dendritic cells.

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/content/journal/jgv/10.1099/jgv.0.001251
2019-03-28
2019-12-15
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References

  1. Osterholm MT, Kelley NS, Sommer A, Belongia EA. Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis. Lancet Infect Dis 2012;12:36–44 [CrossRef][PubMed]
    [Google Scholar]
  2. Syrjänen RK, Jokinen J, Ziegler T, Sundman J, Lahdenkari M et al. Effectiveness of pandemic and seasonal influenza vaccines in preventing laboratory-confirmed influenza in adults: a clinical cohort study during epidemic seasons 2009-2010 and 2010-2011 in Finland. PLoS One 2014;9:e108538 [CrossRef][PubMed]
    [Google Scholar]
  3. Young B, Sadarangani S, Jiang L, Wilder-Smith A, Chen MI. Duration of influenza vaccine effectiveness: a systematic review, meta-analysis, and meta-regression of test-negative design case-control studies. J Infect Dis 2018;217:731–741 [CrossRef][PubMed]
    [Google Scholar]
  4. Park SJ, Kim EH, Pascua PN, Kwon HI, Lim GJ et al. Evaluation of heterosubtypic cross-protection against highly pathogenic H5N1 by active infection with human seasonal influenza A virus or trivalent inactivated vaccine immunization in ferret models. J Gen Virol 2014;95:793–798 [CrossRef][PubMed]
    [Google Scholar]
  5. Sridhar S, Begom S, Bermingham A, Hoschler K, Adamson W et al. Cellular immune correlates of protection against symptomatic pandemic influenza. Nat Med 2013;19:1305–1312 [CrossRef][PubMed]
    [Google Scholar]
  6. Wilkinson TM, Li CK, Chui CS, Huang AK, Perkins M et al. Preexisting influenza-specific CD4+ T cells correlate with disease protection against influenza challenge in humans. Nat Med 2012;18:274–280 [CrossRef][PubMed]
    [Google Scholar]
  7. de Vries RD, Altenburg AF, Rimmelzwaan GF. Universal influenza vaccines, science fiction or soon reality?. Expert Rev Vaccines 2015;14:1299–1301 [CrossRef][PubMed]
    [Google Scholar]
  8. Krammer F. Strategies to induce broadly protective antibody responses to viral glycoproteins. Expert Rev Vaccines 2017;16:503–513 [CrossRef][PubMed]
    [Google Scholar]
  9. Osterhaus A, Fouchier R, Rimmelzwaan G. Towards universal influenza vaccines?. Philos Trans R Soc Lond B Biol Sci 2011;366:2766–2773 [CrossRef][PubMed]
    [Google Scholar]
  10. Brandenburg B, Koudstaal W, Goudsmit J, Klaren V, Tang C et al. Mechanisms of hemagglutinin targeted influenza virus neutralization. PLoS One 2013;8:e80034 [CrossRef][PubMed]
    [Google Scholar]
  11. Ekiert DC, Bhabha G, Elsliger MA, Friesen RH, Jongeneelen M et al. Antibody recognition of a highly conserved influenza virus epitope. Science 2009;324:246–251 [CrossRef][PubMed]
    [Google Scholar]
  12. Dilillo DJ, Palese P, Wilson PC, Ravetch JV. Broadly neutralizing anti-influenza antibodies require Fc receptor engagement for in vivo protection. J Clin Invest 2016;126:605–610 [CrossRef][PubMed]
    [Google Scholar]
  13. Ana-Sosa-Batiz F, Johnston APR, Hogarth PM, Wines BD, Barr I et al. Antibody-dependent phagocytosis (ADP) responses following trivalent inactivated influenza vaccination of younger and older adults. Vaccine 2017;35:6451–6458 [CrossRef][PubMed]
    [Google Scholar]
  14. Ana-Sosa-Batiz F, Vanderven H, Jegaskanda S, Johnston A, Rockman S et al. Influenza-specific antibody-dependent phagocytosis. PLoS One 2016;11:e0154461 [CrossRef][PubMed]
    [Google Scholar]
  15. Jegaskanda S, Amarasena TH, Laurie KL, Tan HX, Butler J et al. Standard trivalent influenza virus protein vaccination does not prime antibody-dependent cellular cytotoxicity in macaques. J Virol 2013;87:13706–13718 [CrossRef][PubMed]
    [Google Scholar]
  16. Jegaskanda S, Luke C, Hickman HD, Sangster MY, Wieland-Alter WF et al. Generation and protective ability of influenza virus-specific antibody-dependent cellular cytotoxicity in humans elicited by vaccination, natural infection, and experimental challenge. J Infect Dis 2016;214:945–952 [CrossRef][PubMed]
    [Google Scholar]
  17. Kristensen AB, Lay WN, Ana-Sosa-Batiz F, Vanderven HA, Madhavi V et al. Antibody responses with Fc-mediated functions after vaccination of HIV-infected subjects with Trivalent Influenza Vaccine. J Virol 2016;90:5724–5734 [CrossRef][PubMed]
    [Google Scholar]
  18. Terajima M, Cruz J, Co MD, Lee JH, Kaur K et al. Complement-dependent lysis of influenza a virus-infected cells by broadly cross-reactive human monoclonal antibodies. J Virol 2011;85:13463–13467 [CrossRef][PubMed]
    [Google Scholar]
  19. Valkenburg SA, Zhang Y, Chan KY, Leung K, Wu JT et al. Preexisting antibody-dependent cellular cytotoxicity-activating antibody responses are stable longitudinally and cross-reactive responses are not boosted by recent influenza exposure. J Infect Dis 2016;214:1159–1163 [CrossRef][PubMed]
    [Google Scholar]
  20. Zhong W, Liu F, Wilson JR, Holiday C, Li ZN et al. Antibody-dependent cell-mediated cytotoxicity to hemagglutinin of influenza A viruses after influenza vaccination in humans. Open Forum Infect Dis 2016;3:ofw102 [CrossRef][PubMed]
    [Google Scholar]
  21. Koopman G, Mooij P, Dekking L, Mortier D, Nieuwenhuis IG et al. Correlation between virus replication and antibody responses in macaques following infection with pandemic influenza A virus. J Virol 2016;90:1023–1033 [CrossRef][PubMed]
    [Google Scholar]
  22. Jegaskanda S, Weinfurter JT, Friedrich TC, Kent SJ. Antibody-dependent cellular cytotoxicity is associated with control of pandemic H1N1 influenza virus infection of macaques. J Virol 2013;87:5512–5522 [CrossRef][PubMed]
    [Google Scholar]
  23. Hoeve MA, Nash AA, Jackson D, Randall RE, Dransfield I. Influenza virus A infection of human monocyte and macrophage subpopulations reveals increased susceptibility associated with cell differentiation. PLoS One 2012;7:e29443 [CrossRef][PubMed]
    [Google Scholar]
  24. Dong W, Bhide Y, Sicca F, Meijerhof T, Guilfoyle K et al. Cross-protective immune responses induced by sequential influenza virus infection and by sequential vaccination with inactivated influenza vaccines. Front Immunol 2018;9:2312 [CrossRef][PubMed]
    [Google Scholar]
  25. Jegaskanda S, Reading PC, Kent SJ. Influenza-specific antibody-dependent cellular cytotoxicity: toward a universal influenza vaccine. J Immunol 2014;193:469–475 [CrossRef][PubMed]
    [Google Scholar]
  26. Krammer F, Palese P. Advances in the development of influenza virus vaccines. Nat Rev Drug Discov 2015;14:167–182 [CrossRef][PubMed]
    [Google Scholar]
  27. He W, Chen CJ, Mullarkey CE, Hamilton JR, Wong CK et al. Alveolar macrophages are critical for broadly-reactive antibody-mediated protection against influenza A virus in mice. Nat Commun 2017;8:846 [CrossRef][PubMed]
    [Google Scholar]
  28. Mullarkey CE, Bailey MJ, Golubeva DA, Tan GS, Nachbagauer R et al. Broadly neutralizing hemagglutinin stalk-specific antibodies induce potent phagocytosis of immune complexes by neutrophils in an Fc-dependent manner. mBio 2016;7: [CrossRef]
    [Google Scholar]
  29. Colamussi ML, White MR, Crouch E, Hartshorn KL. Influenza A virus accelerates neutrophil apoptosis and markedly potentiates apoptotic effects of bacteria. Blood 1999;93:2395–2403[PubMed]
    [Google Scholar]
  30. Ettensohn DB, Frampton MW, Nichols JE, Roberts NJ. Human alveolar macrophages may not be susceptible to direct infection by a Human Influenza Virus. J Infect Dis 2016;214:1658–1665 [CrossRef][PubMed]
    [Google Scholar]
  31. Baharom F, Thomas S, Bieder A, Hellmér M, Volz J et al. Protection of human myeloid dendritic cell subsets against influenza A virus infection is differentially regulated upon TLR stimulation. J Immunol 2015;194:4422–4430 [CrossRef][PubMed]
    [Google Scholar]
  32. Smed-Sörensen A, Chalouni C, Chatterjee B, Cohn L, Blattmann P et al. Influenza A virus infection of human primary dendritic cells impairs their ability to cross-present antigen to CD8 T cells. PLoS Pathog 2012;8:e1002572 [CrossRef][PubMed]
    [Google Scholar]
  33. Taubenberger JK, Morens DM. The pathology of influenza virus infections. Annu Rev Pathol 2008;3:499–522 [CrossRef][PubMed]
    [Google Scholar]
  34. Tate MD, Ioannidis LJ, Croker B, Brown LE, Brooks AG et al. The role of neutrophils during mild and severe influenza virus infections of mice. PLoS One 2011;6:e17618 [CrossRef][PubMed]
    [Google Scholar]
  35. Durani U, Dioverti Prono MV, Tosh PK, Patnaik M, Barreto JN et al. Influenza infection in neutropenic adults. Infect Dis 2017;49:141–146 [CrossRef][PubMed]
    [Google Scholar]
  36. Raymond DD, Bajic G, Ferdman J, Suphaphiphat P, Settembre EC et al. Conserved epitope on influenza-virus hemagglutinin head defined by a vaccine-induced antibody. Proc Natl Acad Sci USA 2018;115:168–173 [CrossRef][PubMed]
    [Google Scholar]
  37. Khurana S, Loving CL, Manischewitz J, King LR, Gauger PC et al. Vaccine-induced anti-HA2 antibodies promote virus fusion and enhance influenza virus respiratory disease. Sci Transl Med 2013;5:200:200ra114 [CrossRef][PubMed]
    [Google Scholar]
  38. Rajão DS, Chen H, Perez DR, Sandbulte MR, Gauger PC et al. Vaccine-associated enhanced respiratory disease is influenced by haemagglutinin and neuraminidase in whole inactivated influenza virus vaccines. J Gen Virol 2016;97:1489–1499 [CrossRef][PubMed]
    [Google Scholar]
  39. Souza CK, Rajão DS, Sandbulte MR, Lopes S, Lewis NS et al. The type of adjuvant in whole inactivated influenza a virus vaccines impacts vaccine-associated enhanced respiratory disease. Vaccine 2018;36:6103–6110 [CrossRef][PubMed]
    [Google Scholar]
  40. Mooij P, Grødeland G, Koopman G, Andersen TK, Mortier D et al. Needle-free delivery of DNA: Targeting of hemagglutinin to MHC class II molecules protects rhesus macaques against H1N1 influenza. Vaccine 2019;37:817–826 [CrossRef][PubMed]
    [Google Scholar]
  41. Safronetz D, Rockx B, Feldmann F, Belisle SE, Palermo RE et al. Pandemic swine-origin H1N1 influenza A virus isolates show heterogeneous virulence in macaques. J Virol 2011;85:1214–JVI.01848-10–1223 [CrossRef][PubMed]
    [Google Scholar]
  42. van Wesenbeeck L, Meeuws H, van Immerseel A, Ispas G, Schmidt K et al. Comparison of the FilmArray RP, Verigene RV+, and Prodesse ProFLU+/FAST+ multiplex platforms for detection of influenza viruses in clinical samples from the 2011-2012 influenza season in Belgium. J Clin Microbiol 2013;51:2977–2985 [CrossRef][PubMed]
    [Google Scholar]
  43. Grodeland G, Mjaaland S, Roux KH, Fredriksen AB, Bogen B. DNA vaccine that targets hemagglutinin to MHC class II molecules rapidly induces antibody-mediated protection against influenza. J Immunol 2013;191:3221–3231 [CrossRef][PubMed]
    [Google Scholar]
  44. Jegaskanda S, Job ER, Kramski M, Laurie K, Isitman G et al. Cross-reactive influenza-specific antibody-dependent cellular cytotoxicity antibodies in the absence of neutralizing antibodies. J Immunol 2013;190:1837–1848 [CrossRef][PubMed]
    [Google Scholar]
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