1,081
Views
15
CrossRef citations to date
0
Altmetric
Reviews

Current challenges: from the path of “original antigenic sin” towards the development of universal flu vaccines

Flu vaccine efficacy encounters significant hurdles from pre-existing immunity of the host suggesting assessment of host immunity before vaccination

, &
Pages 21-36 | Received 14 Jun 2019, Accepted 23 Oct 2019, Published online: 09 Nov 2019

References

  • Paules C, Subbarao K. Influenza. Lancet 2017;390(10095):697–708. doi:10.1016/S0140-6736(17)30129-0.
  • Chu CM, Dawson IM, Elford WJ. Filamentous forms associated with newly isolated influenza virus. Lancet 1949;253(6554):602. doi:10.1016/S0140-6736(49)91699-2.
  • Ducatez MF, Pelletier C, Meyer G. Influenza D virus in cattle, France, 2011-2014. Emerg Infect Dis 2015;21(2):368–371. doi:10.3201/eid2102.141449.
  • Odagiri T, Matsuzaki Y, Okamoto M, et al. Isolation and characterization of influenza C viruses in the Philippines and Japan. J Clin Microbiol 2015;53(3):847–858. doi:10.1128/JCM.02628-14.
  • Zhai SL, Zhang H, Chen SN, et al. Influenza D virus in animal species in Guangdong Province, Southern China. Emerg Infect Dis 2017;23(8):1392–1396. doi:10.3201/eid2308.170059.
  • Nair H, Brooks WA, Katz M, et al. Global burden of respiratory infections due to seasonal influenza in young children: a systematic review and meta-analysis. Lancet 2011;378(9807):1917–1930. doi:10.1016/S0140-6736(11)61051-9.
  • Kim H, Webster RG, Webby RJ. Influenza virus: dealing with a drifting and shifting pathogen. Viral immunol. 2018;31(2):174–183. doi:10.1089/vim.2017.0141.
  • van de Sandt CE, Kreijtz JH, Rimmelzwaan GF. Evasion of influenza A viruses from innate and adaptive immune responses. Viruses 2012;4(9):1438–1476. doi:10.3390/v4091438.
  • Doherty PC, Turner SJ, Webby RG, et al. Influenza and the challenge for immunology. Nat Immunol 2006;7(5):449–455. doi:10.1038/ni1343.
  • Gaglani M, Pruszynski J, Murthy K, et al. Influenza vaccine effectiveness against 2009 pandemic influenza A(H1N1) virus differed by vaccine type during 2013-2014 in the United States. J Infect Dis 2016;213(10):1546–1556. doi:10.1093/infdis/jiv577.
  • Zimmerman RK, Nowalk MP, Chung J, et al. 2014-2015 Influenza vaccine effectiveness in the United States by vaccine type. Clin Infect Dis 2016;63(12):1564–1573., doi:10.1093/cid/ciw635.
  • Thompson CP, Lourenco J, Walters AA, et al. A naturally protective epitope of limited variability as an influenza vaccine target. Nat Commun 2018;9(1):3859. doi:10.1038/s41467-018-06228-8.
  • Murti KG, Webster RG. Distribution of hemagglutinin and neuraminidase on influenza virions as revealed by immunoelectron microscopy. Virology 1986;149(1):36–43. doi:10.1016/0042-6822(86)90084-X.
  • Harris A, Cardone G, Winkler DC, et al. Influenza virus pleiomorphy characterized by cryoelectron tomography. Proc Natl Acad Sci U S A 2006;103(50):19123–19127. doi:10.1073/pnas.0607614103.
  • Rogers GN, Paulson JC. Receptor determinants of human and animal influenza virus isolates: differences in receptor specificity of the H3 hemagglutinin based on species of origin. Virology 1983;127(2):361–373. doi:10.1016/0042-6822(83)90150-2.
  • Shinya K, Ebina M, Yamada S, et al. Avian flu: influenza virus receptors in the human airway. Nature 2006;440(7083):435–436. doi:10.1038/440435a.
  • Sutton TC, Chakraborty S, Mallajosyula VVA, et al. Protective efficacy of influenza group 2 hemagglutinin stem-fragment immunogen vaccines. NPJ vaccines 2017;2(1):35. doi:10.1038/s41541-017-0036-2.
  • Tong S, Zhu X, Li Y, et al. New world bats harbor diverse influenza A viruses. PLoS Pathog 2013;9(10):e1003657. doi:10.1371/journal.ppat.1003657.
  • Gamblin SJ, Skehel JJ. Influenza hemagglutinin and neuraminidase membrane glycoproteins. J Biol Chem 2010;285(37):28403–28409. doi:10.1074/jbc.R110.129809.
  • Zhang Y, Lin X, Zhang F, et al. Hemagglutinin and neuraminidase matching patterns of two influenza A virus strains related to the 1918 and 2009 global pandemics. Biochem Biophys Res Commun 2009;387(2):405–408. doi:10.1016/j.bbrc.2009.07.040.
  • Baumgarth N, Herman OC, Jager GC, et al. Innate and acquired humoral immunities to influenza virus are mediated by distinct arms of the immune system. Proc Natl Acad Sci U S A 1999;96(5):2250–2255. doi:10.1073/pnas.96.5.2250.
  • Qiu C, Tian D, Wan Y, et al. Early adaptive humoral immune responses and virus clearance in humans recently infected with pandemic 2009 H1N1 influenza virus. PloS One 2011;6(8):e22603. doi:10.1371/journal.pone.0022603.
  • Mendez-Legaza JM, Ortiz de Lejarazu R, Sanz I. Heterotypic neuraminidase antibodies against different A(H1N1) strains are elicited after seasonal influenza vaccination. Vaccines 2019;7(1):30.
  • Krammer F. The human antibody response to influenza A virus infection and vaccination. Nat Rev Immunol 2019;19(6):383–397. doi:10.1038/s41577-019-0143-6.
  • Lee LY, Ha do LA, Simmons C, et al. Memory T cells established by seasonal human influenza A infection cross-react with avian influenza A (H5N1) in healthy individuals. J Clin Invest 2008;118(10):3478–3490.
  • Rimmelzwaan GF, Fouchier RA, Osterhaus AD. Influenza virus-specific cytotoxic T lymphocytes: a correlate of protection and a basis for vaccine development. Curr Opin Biotechnol 2007;18(6):529–536. doi:10.1016/j.copbio.2007.11.002.
  • Francis T. Jr. On the doctrine of Original Antigenic Sin. Proc Am Philos Soc 1960;104(6):572–578.
  • Lessler J, Riley S, Read JM, et al. Evidence for antigenic seniority in influenza A (H3N2) antibody responses in southern China. PLoS Pathog 2012;8(7):e1002802. doi:10.1371/journal.ppat.1002802.
  • Uddback IE, Steffensen MA, Pedersen SR, et al. PB1 as a potential target for increasing the breadth of T-cell mediated immunity to Influenza A. Sci Rep 2016;6:35033. doi:10.1038/srep35033.
  • Wang W, Li R, Deng Y, et al. Protective efficacy of the conserved NP, PB1, and M1 proteins as immunogens in DNA- and vaccinia virus-based universal influenza A virus vaccines in mice. Clin Vaccine Immunol 2015;22(6):618–630. doi:10.1128/CVI.00091-15.
  • Gerhard W. The role of the antibody response in influenza virus infection. Curr Top Microbiol Immunol 2001;260:171–190.
  • Couch RB. An overview of serum antibody responses to influenza virus antigens. Dev Biol 2003;115:25–30.
  • Treanor J, Wright PF. Immune correlates of protection against influenza in the human challenge model. Dev Biol 2003;115:97–104.
  • Trombetta CM, Montomoli E. Influenza immunology evaluation and correlates of protection: a focus on vaccines. Expert Rev Vaccines 2016;15(8):967–976. doi:10.1586/14760584.2016.1164046.
  • Sant AJ, DiPiazza AT, Nayak JL, et al. CD4 T cells in protection from influenza virus: viral antigen specificity and functional potential. Immunol Rev 2018;284(1):91–105. doi:10.1111/imr.12662.
  • Parker DC. T cell-dependent B cell activation. Ann Rev Immunol 1993;11(1):331–360. doi:10.1146/annurev.immunol.11.1.331.
  • Jelley-Gibbs D, Haynes L, Swain S. Antigen presentation and the regulation of CD4 memory generation to influenza. Expert Rev Clin Immunol 2006;2(4):601–611. doi:10.1586/1744666X.2.4.601.
  • Richards KA, Treanor JJ, Nayak JL, et al. Overarching immunodominance patterns and substantial diversity in specificity and functionality in the circulating human influenza A and B virus-specific CD4+ T-cell repertoire. J Infect Dis 2018;218(7):1169–1174. doi:10.1093/infdis/jiy288.
  • Sant AJ. The way forward: potentiating protective immunity to novel and pandemic influenza through engagement of memory CD4 T cells. J Infect Dis 2019;219(Supplement_1):S30–S37. doi:10.1093/infdis/jiy666.
  • Wilkinson TM, Li CK, Chui CS, et al. Preexisting influenza-specific CD4+ T cells correlate with disease protection against influenza challenge in humans. Nat Med 2012;18(2):274–280. doi:10.1038/nm.2612.
  • Takeuchi A, Saito T. CD4 CTL, a cytotoxic subset of CD4(+) T cells, their differentiation and function. Front Immunol 2017;8:194. doi:10.3389/fimmu.2017.00194.
  • Richards KA, Nayak J, Chaves FA, et al. Seasonal Influenza can poise hosts for CD4 T-cell immunity to H7N9 Avian influenza. J Infect Dis 2015;212(1):86–94. doi:10.1093/infdis/jiu662.
  • Knowlden ZA, Sant AJ. CD4 T cell epitope specificity determines follicular versus non-follicular helper differentiation in the polyclonal response to influenza infection or vaccination. Sci Rep 2016;6(1):28287. doi:10.1038/srep28287.
  • Alam S, Knowlden ZA, Sangster MY, et al. CD4 T cell help is limiting and selective during the primary B cell response to influenza virus infection. J Virol 2014;88(1):314–324. doi:10.1128/JVI.02077-13.
  • Leon B, Bradley JE, Lund FE, et al. FoxP3+ regulatory T cells promote influenza-specific Tfh responses by controlling IL-2 availability. Nat Commun 2014;5:3495. doi:10.1038/ncomms4495.
  • Nayak JL, Fitzgerald TF, Richards KA, et al. CD4+ T-cell expansion predicts neutralizing antibody responses to monovalent, inactivated 2009 pandemic influenza A(H1N1) virus subtype H1N1 vaccine. J Infect Dis 2013;207(2):297–305. doi:10.1093/infdis/jis684.
  • Valkenburg SA, Li OTW, Li A, et al. Protection by universal influenza vaccine is mediated by memory CD4 T cells. Vaccine 2018;36(29):4198–4206. doi:10.1016/j.vaccine.2018.06.007.
  • Hannoun C. The evolving history of influenza viruses and influenza vaccines. Expert Rev Vaccines 2013;12(9):1085–1094. doi:10.1586/14760584.2013.824709.
  • Sedova ES, Shcherbinin DN, Migunov AI, et al. Recombinant influenza vaccines. Acta Naturae 2012;4(4):17–27. doi:10.32607/20758251-2012-4-4-17-27.
  • Skowronski DM, Janjua NZ, De Serres G, et al. Low 2012-13 influenza vaccine effectiveness associated with mutation in the egg-adapted H3N2 vaccine strain not antigenic drift in circulating viruses. PloS one. 2014;9(3):e92153. doi:10.1371/journal.pone.0092153.
  • Widjaja L, Ilyushina N, Webster RG, et al. Molecular changes associated with adaptation of human influenza A virus in embryonated chicken eggs. Virology 2006;350(1):137–145. doi:10.1016/j.virol.2006.02.020.
  • Zost SJ, Parkhouse K, Gumina ME, 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 U S A 2017;114(47):12578–12583. doi:10.1073/pnas.1712377114.
  • Lin Y, Wharton SA, Whittaker L, et al. The characteristics and antigenic properties of recently emerged subclade 3C.3a and 3C.2a human influenza A(H3N2) viruses passaged in MDCK cells. Influenza Other Respi Viruses 2017;11(3):263–274. doi:10.1111/irv.12447.
  • Harding AT, Heaton NS. Efforts to improve the seasonal influenza vaccine. Vaccines 2018;6(2):19.
  • Trombetta CM, Marchi S, Manini I, et al. Challenges in the development of egg-independent vaccines for influenza. Expert Rev Vaccines 2019;18(7):737–750. doi:10.1080/14760584.2019.1639503.
  • Buckland B, Boulanger R, Fino M, et al. Technology transfer and scale-up of the Flublok recombinant hemagglutinin (HA) influenza vaccine manufacturing process. Vaccine 2014;32(42):5496–5502. doi:10.1016/j.vaccine.2014.07.074.
  • Webster RG, Bean WJ, Gorman OT, et al. Evolution and ecology of influenza A viruses. Microbiol Rev 1992;56(1):152–179.
  • Taubenberger JK, Kash JC. Influenza virus evolution, host adaptation, and pandemic formation. Cell Host Microbe 2010;7(6):440–451. doi:10.1016/j.chom.2010.05.009.
  • Yoshikura H. Spanish flu, Asian flu, Hong Kong flu, and seasonal influenza in Japan under social and demographic influence: review and analysis using the two-population model. Jpn J Infect Dis 2014;67(4):245–257. doi:10.7883/yoken.67.245.
  • Cox NJ, Subbarao K. Global epidemiology of influenza: past and present. Annu Rev Med 2000;51(1):407–421. doi:10.1146/annurev.med.51.1.407.
  • Webby RJ, Webster RG. Are we ready for pandemic influenza? Science 2003;302(5650):1519–1522. doi:10.1126/science.1090350.
  • Centers for Disease, C., and Prevention. Update: novel influenza A (H1N1) virus infection - Mexico, March-May, 2009. MMWR 2009;58:585–589.
  • Neumann G, Chen H, Gao GF, et al. H5N1 influenza viruses: outbreaks and biological properties. Cell Res 2010;20(1):51–61. doi:10.1038/cr.2009.124.
  • Li FC, Choi BC, Sly T, et al. Finding the real case-fatality rate of H5N1 avian influenza. J Epidemiol Community Health 2008;62(6):555–559. doi:10.1136/jech.2007.064030.
  • Yang Y, Halloran ME, Sugimoto JD, Jr. et al. Detecting human-to-human transmission of avian influenza A (H5N1). Emerg Infect Dis 2007;13(9):1348–1353. doi:10.3201/eid1309.070111.
  • Lai S, Qin Y, Cowling BJ, et al. Global epidemiology of avian influenza A H5N1 virus infection in humans, 1997-2015: a systematic review of individual case data. Lancet 2016;16(7):e108–e118. doi:10.1016/S1473-3099(16)00153-5.
  • Virlogeux V, Feng L, Tsang TK, et al. Evaluation of animal-to-human and human-to-human transmission of influenza A (H7N9) virus in China, 2013-15. Sci Rep 2018;8(1):552. doi:10.1038/s41598-017-17335-9.
  • Cohen M, Zhang XQ, Senaati HP, et al. Influenza A penetrates host mucus by cleaving sialic acids with neuraminidase. Virol J 2013;10(1):321. doi:10.1186/1743-422X-10-321.
  • Guo H, Rabouw H, Slomp A, et al. Kinetic analysis of the influenza A virus HA/NA balance reveals contribution of NA to virus-receptor binding and NA-dependent rolling on receptor-containing surfaces. PLoS Pathog 2018;14(8):e1007233. doi:10.1371/journal.ppat.1007233.
  • Doud MB, Bloom JD. Accurate measurement of the effects of all amino-acid mutations on influenza hemagglutinin. Viruses 2016;8(6):155.
  • Doud MB, Lee JM, Bloom JD. How single mutations affect viral escape from broad and narrow antibodies to H1 influenza hemagglutinin. Nat Commun 2018;9(1):1386.
  • Tan HX, Jegaskanda S, Juno JA, et al. Subdominance and poor intrinsic immunogenicity limit humoral immunity targeting influenza HA stem. J Clin Invest 2019;129(2):850–862. doi:10.1172/JCI123366.
  • Angeletti D, Yewdell JW. Is it possible to develop a “universal” influenza virus vaccine? Outflanking antibody immunodominance on the road to universal influenza vaccination. Cold Spring Harb Perspect Biol 2018;10(7):a028852.
  • Angeletti D, Kosik I, Santos JJS, et al. Outflanking immunodominance to target subdominant broadly neutralizing epitopes. Proc Natl Acad Sci U S A 2019;116(27):13474–13479. doi:10.1073/pnas.1816300116.
  • Zost SJ, Wu NC, Hensley SE, et al. Immunodominance and antigenic variation of influenza virus hemagglutinin: implications for design of universal vaccine immunogens. J Infect Dis. 2019;219(Supplement_1):S38–S45. doi:10.1093/infdis/jiy696.
  • Pica N, Hai R, Krammer F, 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 U S A 2012;109(7):2573–2578. doi:10.1073/pnas.1200039109.
  • Palese P, Wang TT. Why do influenza virus subtypes die out? A hypothesis. mBio. 2011;2(5).
  • Ndifon W. A simple mechanistic explanation for original antigenic sin and its alleviation by adjuvants. J R Soc Interface 2015;12(112):20150627.
  • Gostic KM, Ambrose M, Worobey M, et al. Potent protection against H5N1 and H7N9 influenza via childhood hemagglutinin imprinting. Science 2016;354(6313):722–726. doi:10.1126/science.aag1322.
  • Fonville JM, Wilks SH, James SL, et al. Antibody landscapes after influenza virus infection or vaccination. Science 2014;346:996–1000.
  • Tesini BL, Kanagaiah P, Wang J, et al. Broad hemagglutinin-specific memory B cell expansion by seasonal influenza virus infection reflects early-life imprinting and adaptation to the infecting virus. J Virol 2019;93(8):e00169–19.
  • Andrews SF, Huang Y, Kaur K, et al. Immune history profoundly affects broadly protective B cell responses to influenza. Sci Transl Med 2015;7(316):316ra192.
  • Zarnitsyna VI, Ellebedy AH, Davis C, et al. Masking of antigenic epitopes by antibodies shapes the humoral immune response to influenza. Phil Trans Royal Soc London. Ser B Biol Sci 2015;370(1676):20140248.
  • Nimmerjahn F, Ravetch JV. Antibody-mediated modulation of immune responses. Immun Rev 2010;236(1):265–275. doi:10.1111/j.1600-065X.2010.00910.x.
  • Zarnitsyna VI, Lavine J, Ellebedy A, et al. Multi-epitope models explain how pre-existing antibodies affect the generation of broadly protective responses to influenza. PLoS Pathog 2016;12(6):e1005692. doi:10.1371/journal.ppat.1005692.
  • Ellebedy AH. Immunizing the immune: can we overcome influenza's most formidable challenge? Vaccines 2018;6(4):68.
  • Nunez IA, Carlock MA, Allen JD, et al. Impact of age and pre-existing influenza immune responses in humans receiving split inactivated influenza vaccine on the induction of the breadth of antibodies to influenza A strains. PloS One 2017;12:e0185666. doi:10.1371/journal.pone.0185666.
  • Huang KA, Chang SC, Huang YC, et al. Antibody responses to trivalent inactivated influenza vaccine in health care personnel previously vaccinated and vaccinated for the first time. Sci Rep 2017;7(1):40027. doi:10.1038/srep40027.
  • Hai R, Krammer F, Tan GS, et al. Influenza viruses expressing chimeric hemagglutinins: globular head and stalk domains derived from different subtypes. J Virol 2012;86(10):5774–5781. doi:10.1128/JVI.00137-12.
  • Nachbagauer R, Liu WC, Choi A, et al. A universal influenza virus vaccine candidate confers protection against pandemic H1N1 infection in preclinical ferret studies. NPJ vaccines 2017;2(1):26. doi:10.1038/s41541-017-0026-4.
  • Ermler ME, Kirkpatrick E, Sun W, et al. Chimeric hemagglutinin constructs induce broad protection against Influenza B virus challenge in the mouse model. J Virol 2017;91(12):e00286-17.
  • Stevens NE, Hatjopolous A, Fraser CK, et al. Preserved antiviral adaptive immunity following polyclonal antibody immunotherapy for severe murine influenza infection. Sci Rep 2016;6(1):29154.
  • Wolf AI, Mozdzanowska K, Quinn WJ, 3rd, et al. Protective antiviral antibody responses in a mouse model of influenza virus infection require TACI. J Clin Invest 2011;121(10):3954–3964. doi:10.1172/JCI57362.
  • Tangye SG, Tarlinton DM. Memory B cells: effectors of long-lived immune responses. Eur J Immunol 2009;39(8):2065–2075. doi:10.1002/eji.200939531.
  • Andrews SF, Kaur K, Pauli NT, et al. High preexisting serological antibody levels correlate with diversification of the influenza vaccine response. J Virol 2015;89(6):3308–3317. doi:10.1128/JVI.02871-14.
  • Muramatsu M, Yoshida R, Miyamoto H, et al. Heterosubtypic antiviral activity of hemagglutinin-specific antibodies induced by intranasal immunization with inactivated influenza viruses in mice. PloS One 2013;8(8):e71534. doi:10.1371/journal.pone.0071534.
  • Impagliazzo A, Milder F, Kuipers H, et al. A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen. Science 2015;349(6254):1301–1306. doi:10.1126/science.aac7263.
  • Silva M, Nguyen TH, Philbrook P, et al. Targeted elimination of immunodominant B cells drives the germinal center reaction toward subdominant epitopes. Cell Rep 2017;21(13):3672–3680. doi:10.1016/j.celrep.2017.12.014.
  • Koopman G, Mortier D, Michels S, et al. Influenza virus infection as well as immunization with DNA encoding haemagglutinin protein induces potent antibody-dependent phagocytosis (ADP) and monocyte infection-enhancing responses in macaques. J Gen Virol 2019;100(5):738–751. doi:10.1099/jgv.0.001251.
  • Khurana S, Loving CL, Manischewitz J, et al. Vaccine-induced anti-HA2 antibodies promote virus fusion and enhance influenza virus respiratory disease. Sci Transl Med 2013;5(200):200ra114.
  • Valkenburg SA, Mallajosyula VV, Li OT, et al. Stalking influenza by vaccination with pre-fusion headless HA mini-stem. Sci Rep 2016;6(1):22666. doi:10.1038/srep22666.
  • Avnir Y, Tallarico AS, Zhu Q, et al. Molecular signatures of hemagglutinin stem-directed heterosubtypic human neutralizing antibodies against influenza A viruses. PLoS Pathog 2014;10(5):e1004103. doi:10.1371/journal.ppat.1004103.
  • Cappelletti F, Clementi N, Mancini N, et al. Virus-induced preferential antibody gene-usage and its importance in humoral autoimmunity. Semin Immunol 2015;27(2):138–143. doi:10.1016/j.smim.2015.03.008.
  • Toplak N, Kveder T, Trampus-Bakija A, et al. Autoimmune response following annual influenza vaccination in 92 apparently healthy adults. Autoimmunity Rev 2008;8(2):134–138. doi:10.1016/j.autrev.2008.07.008.
  • Bajic G, van der Poel CE, Kuraoka M, et al. Autoreactivity profiles of influenza hemagglutinin broadly neutralizing antibodies. Sci Rep 2019;9(1):3492. doi:10.1038/s41598-019-40175-8.
  • Lopez-Macias C. Virus-like particle (VLP)-based vaccines for pandemic influenza: performance of a VLP vaccine during the 2009 influenza pandemic. Human Vaccines Immunotherapeutics 2012;8:411–414.
  • Chroboczek J, Szurgot I, Szolajska E. Virus-like particles as vaccine. Acta Biochim Polonica 2014;61(3):531–539.
  • Moon EK, Kang HJ, Chu KB, et al. Immune correlates of protection induced by virus-like particles containing 2009 H1N1 pandemic influenza HA, NA or M1 proteins. Immunol Invest 2019;48(4):355–366. doi:10.1080/08820139.2018.1544640.
  • Schwartzman LM, Cathcart AL, Pujanauski LM, et al. An intranasal virus-like particle vaccine broadly protects mice from multiple subtypes of influenza A virus. mBio 2015;6(4):e01044.
  • Wu CY, Yeh YC, Chan JT, et al. A VLP vaccine induces broad-spectrum cross-protective antibody immunity against H5N1 and H1N1 subtypes of influenza A virus. PloS One 2012;7(8):e42363. doi:10.1371/journal.pone.0042363.
  • Yang JR, Cheng CY, Chen CY, et al. A virus-like particle vaccination strategy expands its tolerance to H3N2 antigenic drift by enhancing neutralizing antibodies against hemagglutinin stalk. Antiviral Res 2017;140:62–75. doi:10.1016/j.antiviral.2017.01.010.
  • Anderson CS, Ortega S, Chaves FA, et al. Natural and directed antigenic drift of the H1 influenza virus hemagglutinin stalk domain. Sci Rep 2017;7(1):14614.
  • Machkovech HM, Bedford T, Suchard MA, et al. Positive selection in CD8+ T-cell epitopes of influenza virus nucleoprotein revealed by a comparative analysis of human and swine viral lineages. J Virol 2015;89(22):11275–11283. doi:10.1128/JVI.01571-15.
  • Rudenko L, Yeolekar L, Kiseleva I, et al. Development and approval of live attenuated influenza vaccines based on Russian master donor viruses: process challenges and success stories. Vaccine 2016;34(45):5436–5441. doi:10.1016/j.vaccine.2016.08.018.
  • Hoft DF, Lottenbach KR, Blazevic A, et al. Comparisons of the humoral and cellular immune responses induced by live attenuated influenza vaccine and inactivated influenza vaccine in adults. Clin Vaccine Immunol 2017;24(1):e00414-16.
  • Korenkov D, Isakova-Sivak I, Rudenko L. Basics of CD8 T-cell immune responses after influenza infection and vaccination with inactivated or live attenuated influenza vaccine. Expert Rev Vaccines 2018;17(11):977–987. doi:10.1080/14760584.2018.1541407.
  • Koutsakos M, Illing PT, Nguyen THO, et al. Human CD8(+) T cell cross-reactivity across influenza A, B and C viruses. Nat Immunol 2019;20(5):613–625. doi:10.1038/s41590-019-0320-6.
  • Grant EJ, Josephs TM, Loh L, et al. Broad CD8(+) T cell cross-recognition of distinct influenza A strains in humans. Nat Commun 2018;9(1):5427. doi:10.1038/s41467-018-07815-5.
  • Altenburg AF, Rimmelzwaan GF, de Vries RD. Virus-specific T cells as correlate of (cross-)protective immunity against influenza. Vaccine 2015;33(4):500–506. doi:10.1016/j.vaccine.2014.11.054.
  • Wang Z, Wan Y, Qiu C, et al. Recovery from severe H7N9 disease is associated with diverse response mechanisms dominated by CD8(+) T cells. Nat Commun 2015;6(1):6833. doi:10.1038/ncomms7833.
  • Cullen JG, McQuilten HA, Quinn KM, et al. CD4(+) T help promotes influenza virus-specific CD8(+) T cell memory by limiting metabolic dysfunction. Proc Natl Acad Sci USA 2019;116(10):4481.
  • Laidlaw BJ, Zhang N, Marshall HD, et al. CD4+ T cell help guides formation of CD103+ lung-resident memory CD8+ T cells during influenza viral infection. Immunity 2014;41(4):633–645. doi:10.1016/j.immuni.2014.09.007.
  • Ambrose CS, Levin MJ, Belshe RB. The relative efficacy of trivalent live attenuated and inactivated influenza vaccines in children and adults. Influenza Other Respir Viruses 2011;5(2):67–75. doi:10.1111/j.1750-2659.2010.00183.x.
  • Belshe RB, Edwards KM, Vesikari T, et al. Live attenuated versus inactivated influenza vaccine in infants and young children. N Engl J Med 2007;356(7):685–696. doi:10.1056/NEJMoa065368.
  • Wang Z, Tobler S, Roayaei J, et al. Live attenuated or inactivated influenza vaccines and medical encounters for respiratory illnesses among US military personnel. Jama 2009;301(9):945–953. doi:10.1001/jama.2009.265.
  • Eick AA, Wang Z, Hughes H, et al. Comparison of the trivalent live attenuated vs. inactivated influenza vaccines among U.S. military service members. Vaccine 2009;27(27):3568–3575. doi:10.1016/j.vaccine.2009.03.088.
  • Phillips CJ, Woolpert T, Sevick C, et al. Comparison of the effectiveness of trivalent inactivated influenza vaccine and live, attenuated influenza vaccine in preventing influenza-like illness among US military service members, 2006-2009. Clin Infect Dis 2013;56(1):11–19. doi:10.1093/cid/cis860.
  • Block SL, Yogev R, Hayden FG, et al. Shedding and immunogenicity of live attenuated influenza vaccine virus in subjects 5-49 years of age. Vaccine 2008;26(38):4940–4946. doi:10.1016/j.vaccine.2008.07.013.
  • Brickley EB, Wright PF, Khalenkov A, et al. The effect of pre-existing immunity on virus detection and immune responses in a phase II randomized trial of a Russian-backbone live attenuated influenza vaccine in Bangladeshi children. Clin Infect Dis 2018;69(5):786–794.
  • Hoschler K, Southern J, Thompson C, et al. Responses to live attenuated influenza vaccine in children vaccinated previously with Pandemrix (ASO3B adjuvanted pandemic A/H1N1pdm09). Vaccine 2018;36:3034–3040. doi:10.1016/j.vaccine.2018.04.017.
  • Coelingh KL, Luke CJ, Jin H, et al. Development of live attenuated influenza vaccines against pandemic influenza strains. Expert Rev Vaccines 2014;13(7):855–871. doi:10.1586/14760584.2014.922417.
  • Karron RA, Talaat K, Luke C, et al. Evaluation of two live attenuated cold-adapted H5N1 influenza virus vaccines in healthy adults. Vaccine 2009;27(36):4953–4960. doi:10.1016/j.vaccine.2009.05.099.
  • Wohlgemuth N, Ye Y, Fenstermacher KJ, et al. The M2 protein of live, attenuated influenza vaccine encodes a mutation that reduces replication in human nasal epithelial cells. Vaccine 2017;35(48):6691–6699. doi:10.1016/j.vaccine.2017.10.018.
  • Isakova-Sivak I, Korenkov D, Smolonogina T, et al. Broadly protective anti-hemagglutinin stalk antibodies induced by live attenuated influenza vaccine expressing chimeric hemagglutinin. Virology 2018;518:313–323. doi:10.1016/j.virol.2018.03.013.
  • Nachbagauer R, Krammer F, Albrecht RA. A live-attenuated prime, inactivated boost vaccination strategy with chimeric hemagglutinin-based universal influenza virus vaccines provides protection in ferrets: a confirmatory study. Vaccines 2018;6(3):47.
  • Isakova-Sivak I, Matyushenko V, Kotomina T, et al. Sequential immunization with universal live attenuated influenza vaccine candidates protects ferrets against a high-dose heterologous virus challenge. Vaccines 2019;7(3):61.
  • Cao RG, Suarez NM, Obermoser G, et al. 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 2014;210(2):224–233. doi:10.1093/infdis/jiu079.
  • Lartey S, Zhou F, Brokstad KA, et al. Live attenuated influenza vaccine induces tonsillar follicular T helper cell responses that correlate with antibody induction. J Infect Dis 2019.
  • Lee YT, Ko EJ, Lee Y, et al. Intranasal vaccination with M2e5x virus-like particles induces humoral and cellular immune responses conferring cross-protection against heterosubtypic influenza viruses. PloS One 2018;13(1):e0190868. doi:10.1371/journal.pone.0190868.
  • Nadmdari H, Keshavarz M, Mokhtari-Azad T, et al. Evaluation of antibody and cytokines responses in intranasally and intramuscularly administrated BALB/C mice with influenza virus-like particle. Acta Med Iranica 2017;55(10):604–611.
  • Karunarathna H, Perera R, Fang VJ, et al. Serum anti-neuraminidase antibody responses in human influenza A(H1N1)pdm09 virus infections. Emerging Microbes Infect 2019;8:404–412. doi:10.1080/22221751.2019.1572433.
  • Ma MJ, Liu C, Wu MN, et al. Influenza A(H7N9) virus antibody responses in survivors 1 year after infection, China, 2017. Emerg Infect Dis 2018;24(4):663–672. doi:10.3201/eid2404.171995.
  • Zhang S, Cubas R, Li M, et al. Virus-like particle vaccine activates conventional B2 cells and promotes B cell differentiation to IgG2a producing plasma cells. Mol Immunol 2009;46(10):1988–2001. doi:10.1016/j.molimm.2009.03.008.
  • Ellebedy AH, Jackson KJ, Kissick HT, et al. Defining antigen-specific plasmablast and memory B cell subsets in human blood after viral infection or vaccination. Nat Immunol 2016;17(10):1226–1234. doi:10.1038/ni.3533.
  • Hoft DF, Babusis E, Worku S, et al. Live and inactivated influenza vaccines induce similar humoral responses, but only live vaccines induce diverse T-cell responses in young children. J Infect Dis 2011;204(6):845–853. doi:10.1093/infdis/jir436.
  • Kang SM, Yoo DG, Lipatov AS, et al. Induction of long-term protective immune responses by influenza H5N1 virus-like particles. PloS One 2009;4(3):e4667. doi:10.1371/journal.pone.0004667.
  • Sasaki S, Jaimes MC, Holmes TH, et al. 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 2007;81(1):215–228. doi:10.1128/JVI.01957-06.
  • Koutsakos M, Wheatley AK, Loh L, et al. Circulating TFH cells, serological memory, and tissue compartmentalization shape human influenza-specific B cell immunity. Sci Transl Med 2018;10(428):eaan8405.
  • Gould VMW, Francis JN, Anderson KJ, et al. Nasal IgA provides protection against human influenza challenge in volunteers with low serum influenza antibody titre. Front Microbiol 2017;8:900. doi:10.3389/fmicb.2017.00900.
  • Hammitt LL, Bartlett JP, Li S, et al. Kinetics of viral shedding and immune responses in adults following administration of cold-adapted influenza vaccine. Vaccine 2009;27(52):7359–7366. doi:10.1016/j.vaccine.2009.09.041.
  • Nachbagauer R, Wohlbold TJ, Hirsh A, et al. Induction of broadly reactive anti-hemagglutinin stalk antibodies by an H5N1 vaccine in humans. J Virol 2014;88(22):13260–13268. doi:10.1128/JVI.02133-14.
  • Liu WC, Nachbagauer R, Stadlbauer D, et al. Sequential immunization with live-attenuated chimeric hemagglutinin-based vaccines confers heterosubtypic immunity against influenza A viruses in a preclinical ferret model. Front Immunol 2019;10:756. doi:10.3389/fimmu.2019.00756.
  • Skibinski DAG, Jones LA, Zhu YO, et al. Induction of human T-cell and cytokine responses following vaccination with a novel influenza vaccine. Sci Rep 2018;8(1):18007.
  • Nunes MC, Cutland CL, Dighero B, et al. Kinetics of hemagglutination-inhibiting antibodies following maternal influenza vaccination among mothers with and those without HIV infection and their infants. J Infect Dis 2015;212(12):1976–1987. doi:10.1093/infdis/jiv339.
  • Richards KA, Chaves FA, Krafcik FR, et al. Direct ex vivo analyses of HLA-DR1 transgenic mice reveal an exceptionally broad pattern of immunodominance in the primary HLA-DR1-restricted CD4 T-cell response to influenza virus hemagglutinin. J Virol 2007;81(14):7608–7619. doi:10.1128/JVI.02834-06.
  • He XS, Holmes TH, Zhang C, et al. Cellular immune responses in children and adults receiving inactivated or live attenuated influenza vaccines. J Virol 2006;80(23):11756–11766. doi:10.1128/JVI.01460-06.
  • Leddon SA, Richards KA, Treanor JJ, et al. Abundance and specificity of influenza reactive circulating memory follicular helper and non-follicular helper CD4 T cells in healthy adults. Immunology 2015;146(1):157–162. doi:10.1111/imm.12491.
  • Pilkinton MA, Nicholas KJ, Warren CM, et al. Greater activation of peripheral T follicular helper cells following high dose influenza vaccine in older adults forecasts seroconversion. Vaccine 2017;35(2):329–336. doi:10.1016/j.vaccine.2016.11.059.
  • Aljurayyan A, Puksuriwong S, Ahmed M, et al. Activation and induction of antigen-specific T follicular helper cells play a critical role in live-attenuated influenza vaccine-induced human mucosal anti-influenza antibody response. J Virol 2018;92(11):e00114-18. doi:10.1128/JVI.00114-18.
  • Hong S, Zhang Z, Liu H, et al. B cells are the dominant antigen-presenting cells that activate naive CD4(+) T cells upon immunization with a virus-derived nanoparticle antigen. Immunity 2018;49(4):695–708 e694.
  • Scheible K, Zhang G, Baer J, et al. CD8+ T cell immunity to 2009 pandemic and seasonal H1N1 influenza viruses. Vaccine 2011;29(11):2159–2168. doi:10.1016/j.vaccine.2010.12.073.
  • Clover RD, Crawford S, Glezen WP, et al. Comparison of heterotypic protection against influenza A/Taiwan/86 (H1N1) by attenuated and inactivated vaccines to A/Chile/83-like viruses. J Infect Dis 1991;163(2):300–304. doi:10.1093/infdis/163.2.300.
  • Kreijtz JH, Bodewes R, van Amerongen G, et al. Primary influenza A virus infection induces cross-protective immunity against a lethal infection with a heterosubtypic virus strain in mice. Vaccine 2007;25(4):612–620. doi:10.1016/j.vaccine.2006.08.036.
  • Nguyen HH, Moldoveanu Z, Novak MJ, et al. Heterosubtypic immunity to lethal influenza A virus infection is associated with virus-specific CD8(+) cytotoxic T lymphocyte responses induced in mucosa-associated tissues. Virology 1999;254(1):50–60. doi:10.1006/viro.1998.9521.
  • Song JM, Van Rooijen N, Bozja J, et al. Vaccination inducing broad and improved cross protection against multiple subtypes of influenza A virus. Proc Natl Acad Sci U S A 2011;108(2):757–761. doi:10.1073/pnas.1012199108.
  • Dupuis M, Murphy TJ, Higgins D, et al. Dendritic cells internalize vaccine adjuvant after intramuscular injection. Cell Immunol 1998;186(1):18–27. doi:10.1006/cimm.1998.1283.
  • Calabro S, Tortoli M, Baudner BC, et al. Vaccine adjuvants alum and MF59 induce rapid recruitment of neutrophils and monocytes that participate in antigen transport to draining lymph nodes. Vaccine 2011;29(9):1812–1823. doi:10.1016/j.vaccine.2010.12.090.
  • Goff PH, Hayashi T, Martinez-Gil L, et al. Synthetic toll-like receptor 4 (TLR4) and TLR7 ligands as influenza virus vaccine adjuvants induce rapid, sustained, and broadly protective responses. J Virol 2015;89(6):3221–3235. doi:10.1128/JVI.03337-14.
  • Wang Y, Deng L, Kang SM, et al. Universal influenza vaccines: from viruses to nanoparticles. Expert Rev Vaccines 2018;17(11):967–976. doi:10.1080/14760584.2018.1541408.
  • Del Giudice G, Rappuoli R. Inactivated and adjuvanted influenza vaccines. Curr Top Microbiol Immunol 2015;386:151–180.
  • Tregoning JS, Russell RF, Kinnear E. Adjuvanted influenza vaccines. Hum Vaccines Immunotherapeutics 2018;14:550–564. doi:10.1080/21645515.2017.1415684.
  • Khurana S, Verma N, Yewdell JW, et al. MF59 adjuvant enhances diversity and affinity of antibody-mediated immune response to pandemic influenza vaccines. Sci Transl Med 2011;3(85):85ra48.
  • Darricarrere N, Pougatcheva S, Duan X, et al. Development of a pan-H1 influenza vaccine. J Virol 2018;92(22):e01349-18.
  • Knudsen NP, Olsen A, Buonsanti C, et al. Different human vaccine adjuvants promote distinct antigen-independent immunological signatures tailored to different pathogens. Sci Rep 2016;6(1):19570.
  • Siegrist CA, Aspinall R. B-cell responses to vaccination at the extremes of age. Nat Rev Immunol 2009;9(3):185–194. doi:10.1038/nri2508.
  • Reber AJ, Kim JH, Biber R, et al. Preexisting immunity, more than aging, influences influenza vaccine responses. Open Forum Infectious Dis 2015;2(2):ofv052.
  • Domnich A, Arata L, Amicizia D, et al. Effectiveness of MF59-adjuvanted seasonal influenza vaccine in the elderly: a systematic review and meta-analysis. Vaccine 2017;35(4):513–520. doi:10.1016/j.vaccine.2016.12.011.
  • Lapi F, Marconi E, Simonetti M, et al. Adjuvanted versus nonadjuvanted influenza vaccines and risk of hospitalizations for pneumonia and cerebro/cardiovascular events in the elderly. Expert Rev Vaccines 2019;18(6):663–670. doi:10.1080/14760584.2019.1622418.
  • Galson JD, Truck J, Kelly DF, et al. Investigating the effect of AS03 adjuvant on the plasma cell repertoire following pH1N1 influenza vaccination. Sci Rep 2016;6(1):37229. doi:10.1038/srep37229.
  • van der Most RG, Clement F, Willekens J, et al. Long-term persistence of cell-mediated and humoral responses to A(H1N1)pdm09 influenza virus vaccines and the role of the AS03 adjuvant system in adults during two randomized controlled trials. Clin Vaccine Immunol 2017;24(6):e00553-16.
  • Sridhar S, Brokstad KA, Cox RJ. Influenza vaccination strategies: comparing inactivated and live attenuated influenza vaccines. Vaccines 2015;3(2):373–389. doi:10.3390/vaccines3020373.

Reprints and Corporate Permissions

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

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

Academic Permissions

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

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

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