Strategies to induce broadly protective antibody responses to viral glycoproteins

References

• Krammer F, Palese P. Advances in the development of influenza virus vaccines. Nat Rev Drug Discov. 2015;14(3):167–182. ​​​​
   PubMed Web of Science ®Google Scholar
• Tong S, Zhu X, Li Y, et al. New world bats harbor diverse influenza A viruses. Plos Pathog. 2013;9(10):e1003657.
   PubMed Web of Science ®Google Scholar
• Tong S, Li Y, Rivailler P, et al. A distinct lineage of influenza A virus from bats. Proc Natl Acad Sci U S A. 2012;109(11):4269–4274.
   PubMed Web of Science ®Google Scholar
• Runstadler J, Hill N, Hussein IT, et al. Connecting the study of wild influenza with the potential for pandemic disease. Infect Genet Evol. 2013;17:162–187.
   PubMed Web of Science ®Google Scholar
• Van De Sandt CE, Bodewes R, Rimmelzwaan GF, et al. Influenza B viruses: not to be discounted. Future Microbiol. 2015;10(9):1447–1465.
   PubMed Web of Science ®Google Scholar
• Krammer F. Emerging influenza viruses and the prospect of a universal influenza virus vaccine. Biotechnol J. 2015;10(5):690–701.
   PubMed Web of Science ®Google Scholar
• Gerdil C. The annual production cycle for influenza vaccine. Vaccine. 2003;21(16):1776–1779.
   PubMed Web of Science ®Google Scholar
• De Jong JC, Beyer WE, Palache AM, et al. 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. 2000;61(1):94–99.
   PubMed Web of Science ®Google Scholar
• Xie H, Wan XF, Ye Z, et al. H3N2 mismatch of 2014-15 northern hemisphere influenza vaccines and head-to-head comparison between human and ferret antisera derived antigenic maps. Sci Rep. 2015;5:15279.
   PubMed Web of Science ®Google Scholar
• Wrammert J, Smith K, Miller J, et al. Rapid cloning of high-affinity human monoclonal antibodies against influenza virus. Nature. 2008;453(7195):667–671.
   PubMed Web of Science ®Google Scholar
• Throsby M, Van Den Brink E, Jongeneelen M, et al. Heterosubtypic neutralizing monoclonal antibodies cross-protective against H5N1 and H1N1 recovered from human IgM+ memory B cells. Plos ONE. 2008;3(12):e3942.
   PubMed Web of Science ®Google Scholar
• Wilson PC, Andrews SF. Tools to therapeutically harness the human antibody response. Nat Rev Immunol. 2012;12(10):709–719.
   PubMed Web of Science ®Google Scholar
• Corti D, Suguitan AL, Pinna D, et al. Heterosubtypic neutralizing antibodies are produced by individuals immunized with a seasonal influenza vaccine. J Clin Invest. 2010;120(5):1663–1673.
   PubMed Web of Science ®Google Scholar
• Ferrari G, Haynes BF, Koenig S, et al. Envelope-specific antibodies and antibody-derived molecules for treating and curing HIV infection. Nat Rev Drug Discov. 2016;15(12):823–834.
   PubMed Web of Science ®Google Scholar
• West AP, Scharf L, Scheid JF, et al. Structural insights on the role of antibodies in HIV-1 vaccine and therapy. Cell. 2014;156(4):633–648.
   PubMed Web of Science ®Google Scholar
• Merk A, Subramaniam S. HIV-1 envelope glycoprotein structure. Curr Opin Struct Biol. 2013;23(2):268–276.
   PubMed Web of Science ®Google Scholar
• Wrammert J, Koutsonanos D, Li GM, et al. Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection. J Exp Med. 2011;208(1):181–193.
   PubMed Web of Science ®Google Scholar
• Henry Dunand CJ, Leon PE, Kaur K, et al. Preexisting human antibodies neutralize recently emerged H7N9 influenza strains. J Clin Invest. 2015;125(3):1255–1268.
   PubMed Web of Science ®Google Scholar
• Henry Dunand CJ, Leon PE, Huang M, et al. Both neutralizing and non-neutralizing human H7N9 influenza vaccine-induced monoclonal antibodies confer protection. Cell Host Microbe. 2016;19(6):800–813.
   PubMed Web of Science ®Google Scholar
• Ekiert DC, Wilson IA. Broadly neutralizing antibodies against influenza virus and prospects for universal therapies. Curr Opin Virol. 2012;2(2):134–141.
   PubMed Web of Science ®Google Scholar
• Ekiert DC, Bhabha G, Elsliger MA, et al. Antibody recognition of a highly conserved influenza virus epitope. Science. 2009;324(5924):246–251.
   PubMed Web of Science ®Google Scholar
• Sui J, Hwang WC, Perez S, et al. Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses. Nat Struct Mol Biol. 2009;16(3):265–273.
   PubMed Web of Science ®Google Scholar
• Corti D, Voss J, Gamblin SJ, et al. A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutinins. Science. 2011;333(6044):850–856.
   PubMed Web of Science ®Google Scholar
• Moody MA, Zhang R, Walter EB, et al. H3N2 influenza infection elicits more cross-reactive and less clonally expanded anti-hemagglutinin antibodies than influenza vaccination. Plos One. 2011;6(10):e25797.
   PubMed Web of Science ®Google Scholar
• Whittle JR, Zhang R, Khurana S, et al. Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza virus hemagglutinin. Proc Natl Acad Sci U S A. 2011;108(34):14216–14221.
   PubMed Web of Science ®Google Scholar
• Krause JC, Tsibane T, Tumpey TM, et al. Human Monoclonal antibodies to pandemic 1957 H2N2 and pandemic 1968 H3N2 influenza viruses. J Virol. 2012;86(11):6334–6340.
   PubMed Web of Science ®Google Scholar
• Krause JC, Tsibane T, Tumpey TM, et al. A broadly neutralizing human monoclonal antibody that recognizes a conserved, novel epitope on the globular head of the influenza H1N1 virus hemagglutinin. J Virol. 2011;85(20):10905–10908.
   PubMed Web of Science ®Google Scholar
• Saphire EO. An update on the use of antibodies against the filoviruses. Immunotherapy. 2013;5(11):1221–1233.
   PubMed Web of Science ®Google Scholar
• Flyak AI, Shen X, Murin CD, et al. Cross-reactive and potent neutralizing antibody responses in human survivors of natural ebolavirus infection. Cell. 2016;164(3):392–405.
   PubMed Web of Science ®Google Scholar
• Murin CD, Fusco ML, Bornholdt ZA, et al. Structures of protective antibodies reveal sites of vulnerability on ebola virus. Proc Natl Acad Sci U S A. 2014;111(48):17182–17187.
   PubMed Web of Science ®Google Scholar
• McElroy AK, Akondy RS, Davis CW, et al. Human ebola virus infection results in substantial immune activation. Proc Natl Acad Sci U S A. 2015;112(15):4719–4724.
   PubMed Web of Science ®Google Scholar
• Hashiguchi T, Fusco ML, Bornholdt ZA, et al. Structural basis for marburg virus neutralization by a cross-reactive human antibody. Cell. 2015;160(5):904–912.
   PubMed Web of Science ®Google Scholar
• Flyak AI, Ilinykh PA, Murin CD, et al. Mechanism of human antibody-mediated neutralization of marburg virus. Cell. 2015;160(5):893–903.
   PubMed Web of Science ®Google Scholar
• Corti D, Bianchi S, Vanzetta F, et al. Cross-neutralization of four paramyxoviruses by a human monoclonal antibody. Nature. 2013;501(7467):439–443.
   PubMed Web of Science ®Google Scholar
• Robinson JE, Hastie KM, Cross RW, et al. Most neutralizing human monoclonal antibodies target novel epitopes requiring both lassa virus glycoprotein subunits. Nat Commun. 2016;7:11544.
   PubMed Web of Science ®Google Scholar
• Tan GS, Leon PE, Albrecht RA, et al. Broadly-reactive neutralizing and non-neutralizing antibodies directed against the h7 influenza virus hemagglutinin reveal divergent mechanisms of protection. Plos Pathog. 2016;12(4):e1005578.
   PubMed Web of Science ®Google Scholar
• He W, Tan GS, Mullarkey CE, et al. Epitope specificity plays a critical role in regulating antibody-dependent cell-mediated cytotoxicity against influenza A virus. Proc Natl Acad Sci U S A. 2016;113(42):11931–11936.
   PubMed Web of Science ®Google Scholar
• Krammer F, Palese P, Steel J. Advances in universal influenza virus vaccine design and antibody mediated therapies based on conserved regions of the hemagglutinin. Curr Top Microbiol Immunol. 2015;386:301–321.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Avnir Y, Watson CT, Glanville J, et al. IGHV1-69 polymorphism modulates anti-influenza antibody repertoires, correlates with IGHV utilization shifts and varies by ethnicity. Sci Rep. 2016;6:20842.
   PubMed Web of Science ®Google Scholar
• He W, Mullarkey CE, Duty JA, et al. Broadly neutralizing anti-influenza virus antibodies: enhancement of neutralizing potency in polyclonal mixtures and IgA backbones. J Virol. 2015;89(7):3610–3618.
   PubMed Web of Science ®Google Scholar
• Krammer F. Novel universal influenza virus vaccine approaches. Curr Opin Virol. 2016;17:95–103.
   PubMed Web of Science ®Google Scholar
• Krammer F, Palese P. Influenza virus hemagglutinin stalk-based antibodies and vaccines. Curr Opin Virol. 2013;3(5):521–530.
   PubMed Web of Science ®Google Scholar
• Dilillo DJ, Tan GS, Palese P, et al. Broadly neutralizing hemagglutinin stalk-specific antibodies require FcγR interactions for protection against influenza virus in vivo. Nat Med. 2014;20(2):143–151.
   PubMed Web of Science ®Google Scholar
• Doud MB, Bloom JD. Accurate measurement of the effects of all amino-acid mutations on influenza hemagglutinin. Viruses. 2016;8:6.
   Web of Science ®Google Scholar
• Heaton NS, Sachs D, Chen CJ, et al. Genome-wide mutagenesis of influenza virus reveals unique plasticity of the hemagglutinin and NS1 proteins. Proc Natl Acad Sci U S A. 2013;110(50):20248–20253.
   PubMed Web of Science ®Google Scholar
• Chai N, Swem LR, Reichelt M, et al. Two escape mechanisms of influenza a virus to a broadly neutralizing stalk-binding antibody. Plos Pathog. 2016;12(6):e1005702.
   PubMed Web of Science ®Google Scholar
• Francis T. On the doctrine of original antigenic sin. Proc Am Philos Soc. 1960;104(6):572–578.
   Google Scholar
• Park MS, Kim JI, Park S, et al. Sin response to RNA viruses and antiviral immunity. Immune Netw. 2016;16(5):261–270.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Nachbagauer R, Choi A, Izikson R, et al. Age dependence and isotype specificity of influenza virus hemagglutinin stalk-reactive antibodies in humans. MBio. 2016;7:1.
   Web of Science ®Google Scholar
• Li Y, Myers JL, Bostick DL, et al. Immune history shapes specificity of pandemic H1N1 influenza antibody responses. J Exp Med. 2013;210(8):1493–1500.
   PubMed Web of Science ®Google Scholar
• Linderman SL, Hensley SE. Antibodies with ‘original antigenic sin’ properties are valuable components of secondary immune responses to influenza viruses. Plos Pathog. 2016;12(8):e1005806.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Thomson CA, Wang Y, Jackson LM, et al. Pandemic H1N1 Influenza Infection and Vaccination in Humans Induces Cross-Protective Antibodies that Target the Hemagglutinin Stem. Front Immunol. 2012;3:87.
   PubMed Web of Science ®Google Scholar
• Krammer F, Pica N, Hai R, et al. Hemagglutinin stalk-reactive antibodies are boosted following sequential infection with seasonal and pandemic h1n1 influenza virus in mice. J Virol. 2012;86(19):10302–10307.
   PubMed Web of Science ®Google Scholar
• Kirchenbaum GA, Carter DM, Ross TM. Sequential infection in ferrets with antigenically distinct seasonal h1n1 influenza viruses boosts hemagglutinin stalk-specific antibodies. J Virol. 2015;90(2):1116–1128.
   PubMed Web of Science ®Google Scholar
• Ellebedy AH, Krammer F, Li GM, et al. Induction of broadly cross-reactive antibody responses to the influenza HA stem region following H5N1 vaccination in humans. Proc Natl Acad Sci U S A. 2014;111(36):13133–13138.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Halliley JL, Khurana S, Krammer F, et al. High-affinity H7 head and stalk domain-specific antibody responses to an inactivated influenza h7n7 vaccine after priming with live attenuated influenza vaccine. J Infect Dis. 2015;212(8):1270–1278.
   PubMed Web of Science ®Google Scholar
• Krammer F, Jul-Larsen A, Margine I, et al. An H7N1 influenza virus vaccine induces broadly reactive antibody responses against H7N9 in humans. Clin Vaccine Immunol. 2014;21(8):1153–1163.
   PubMed Web of Science ®Google Scholar
• Palese P, Wang TT. Why do influenza virus subtypes die out? A hypothesis. MBio. 2011;2:5.
   Web of Science ®Google Scholar
• Tan GS, Krammer F, Eggink D, et al. A pan-h1 anti-hemagglutinin monoclonal antibody with potent broad-spectrum efficacy in vivo. J Virol. 2012;86(11):6179–6188.
   PubMed Web of Science ®Google Scholar
• Tan GS, Lee PS, Hoffman RM, et al. Characterization of a broadly neutralizing monoclonal antibody that targets the fusion domain of group 2 influenza A virus hemagglutinin. J Virol. 2014;88(23):13580–13592. doi:10.1128/JVI.02289-14. ​​​​
   Web of Science ®Google Scholar
• Wang TT, Tan GS, Hai R, et al. Broadly protective monoclonal antibodies against H3 influenza viruses following sequential immunization with different hemagglutinins. Plos Pathog. 2010;6(2):e1000796.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Chen CJ, Ermler ME, Tan GS, et al. A viruses expressing intra- or intergroup chimeric hemagglutinins. J Virol. 2016;90(7):3789–3793.
   PubMed Web of Science ®Google Scholar
• Ryder AB, Nachbagauer R, Buonocore L, et al. Vaccination with vesicular stomatitis virus-vectored chimeric hemagglutinins protects mice against divergent influenza virus challenge strains. J Virol. 2015;90(5):2544–2550.
   PubMed Web of Science ®Google Scholar
• Margine I, Krammer F, Hai R, et al. Hemagglutinin stalk-based universal vaccine constructs protect against group 2 influenza a viruses. J Virol. 2013;87(19):10435–10446.
   PubMed Web of Science ®Google Scholar
• Nachbagauer R, Miller MS, Hai R, et al. Hemagglutinin stalk immunity reduces influenza virus replication and transmission in ferrets. J Virol. 2015;90(6):3268–3273.
   PubMed Web of Science ®Google Scholar
• Krammer F, Margine I, Hai R, et al. H3 stalk-based chimeric hemagglutinin influenza virus constructs protect mice from H7N9 challenge. J Virol. 2014;88(4):2340–2343.
   PubMed Web of Science ®Google Scholar
• Krammer F, Pica N, Hai R, et al. Chimeric hemagglutinin influenza virus vaccine constructs elicit broadly protective stalk-specific antibodies. J Virol. 2013;87(12):6542–6550.
   PubMed Web of Science ®Google Scholar
• Krammer F, Hai R, Yondola M, et al. Assessment of influenza virus hemagglutinin stalk-based immunity in ferrets. J Virol. 2014;88(6):3432–3442.
   PubMed Web of Science ®Google Scholar
• Nachbagauer R, Kinzler D, Choi A, et al. A chimeric haemagglutinin-based influenza split virion vaccine adjuvanted with AS03 induces protective stalk-reactive antibodies in mice. npj Vaccines. 2016;1:16015. doi:10.1038/npjvaccines.2016.15. ​​​​
   Google Scholar
• Fehr T, Bachmann MF, Bluethmann H, et al. T-independent activation of B cells by vesicular stomatitis virus: no evidence for the need of a second signal. Cell Immunol. 1996;168(2):184–192.
   PubMed Web of Science ®Google Scholar
• Bachmann MF, Hengartner H, Zinkernagel RM. T helper cell-independent neutralizing B cell response against vesicular stomatitis virus: role of antigen patterns in B cell induction? Eur J Immunol. 1995;25(12):3445–3451.
   PubMed Web of Science ®Google Scholar
• Pushko P, Tretyakova I, Hidajat R, et al. Virus-like particles displaying H5, H7, H9 hemagglutinins and N1 neuraminidase elicit protective immunity to heterologous avian influenza viruses in chickens. Virology. 2016;501:176–182.
   PubMed Web of Science ®Google Scholar
• Tretyakova I, Pearce MB, Florese R, et al. Intranasal vaccination with H5, H7 and H9 hemagglutinins co-localized in a virus-like particle protects ferrets from multiple avian influenza viruses. Virology. 2013;442(1):67–73.
   PubMed Web of Science ®Google Scholar
• Pushko P, Pearce MB, Ahmad A, et al. Influenza virus-like particle can accommodate multiple subtypes of hemagglutinin and protect from multiple influenza types and subtypes. Vaccine. 2011;29(35):5911–5918.
   PubMed Web of Science ®Google Scholar
• Holtsberg FW, Shulenin S, Vu H, et al. Pan-ebolavirus and pan-filovirus mouse monoclonal antibodies: protection against ebola and sudan viruses. J Virol. 2015;90(1):266–278.
   PubMed Web of Science ®Google Scholar
• Keck ZY, Enterlein SG, Howell KA, et al. Macaque monoclonal antibodies targeting novel conserved epitopes within filovirus glycoprotein. J Virol. 2015;90(1):279–291.
   PubMed Web of Science ®Google Scholar
• Wang TT, Tan GS, Hai R, et al. Vaccination with a synthetic peptide from the influenza virus hemagglutinin provides protection against distinct viral subtypes. Proc Natl Acad Sci U S A. 2010;107(44):18979–18984.
   PubMed Web of Science ®Google Scholar
• Jiang Z, Gera L, Mant CT, et al. Platform technology to generate broadly cross-reactive antibodies to α-helical epitopes in hemagglutinin proteins from influenza a viruses. Biopolymers. 2016 Jan 21. doi:10.1002/bip.22808. ​​​​
   Web of Science ®Google Scholar
• Mallajosyula VV, Citron M, Lu X, et al. In vitro and in vivo characterization of designed immunogens derived from the CD-helix of the stem of influenza hemagglutinin. Proteins. 2013;81(10):1759–1775.
   PubMed Web of Science ®Google Scholar
• Janulíková J, Staneková Z, Mucha V, et al. Two distinct regions of HA2 glycopolypeptide of influenza virus hemagglutinin elicit cross-protective immunity against influenza. Acta Virol. 2012;56(3):169–176.
   PubMed Web of Science ®Google Scholar
• Staneková Z, Adkins I, Kosová M, et al. Heterosubtypic protection against influenza A induced by adenylate cyclase toxoids delivering conserved HA2 subunit of hemagglutinin. Antiviral Res. 2013;97(1):24–35.
   PubMed Web of Science ®Google Scholar
• Gocník M, Fislová T, Mucha V, et al. Antibodies induced by the HA2 glycopolypeptide of influenza virus haemagglutinin improve recovery from influenza A virus infection. J Gen Virol. 2008;89(Pt 4):958–967.
   PubMed Web of Science ®Google Scholar
• Ideno S, Sakai K, Yunoki M, et al. Immunization of rabbits with synthetic peptides derived from a highly conserved β-sheet epitope region underneath the receptor binding site of influenza A virus. Biologics. 2013;7:233–241.
   PubMedGoogle Scholar
• Doyle TM, Hashem AM, Li C, et al. Universal anti-neuraminidase antibody inhibiting all influenza A subtypes. Antiviral Res. 2013;100(2):567–574.
   PubMed Web of Science ®Google Scholar
• Schotsaert M, De Filette M, Fiers W, et al. Universal M2 ectodomain-based influenza A vaccines: preclinical and clinical developments. Expert Rev Vaccines. 2009;8(4):499–508.
   PubMed Web of Science ®Google Scholar
• Neirynck S, Deroo T, Saelens X, et al. A universal influenza A vaccine based on the extracellular domain of the M2 protein. Nat Med. 1999;5(10):1157–1163.
   PubMed Web of Science ®Google Scholar
• Schneemann A, Speir JA, Tan GS, et al. A virus-like particle that elicits cross-reactive antibodies to the conserved stem of influenza virus hemagglutinin. J Virol. 2012;86(21):11686–11697.
   PubMed Web of Science ®Google Scholar
• Chen S, Zheng D, Li C, et al. Protection against multiple subtypes of influenza viruses by virus-like particle vaccines based on a hemagglutinin conserved epitope. Biomed Res Int. 2015;901817:2015.
   Google Scholar
• Zheng D, Chen S, Qu D, et al. Influenza H7N9 LAH-HBc virus-like particle vaccine with adjuvant protects mice against homologous and heterologous influenza viruses. Vaccine. 2016;34(51):6464–6471.
   PubMed Web of Science ®Google Scholar
• Klausberger M, Tscheliessnig R, Neff S, et al. Globular head-displayed conserved influenza H1 hemagglutinin stalk epitopes confer protection against heterologous H1N1 virus. Plos One. 2016;11(4):e0153579.
   PubMed Web of Science ®Google Scholar
• Knittelfelder R, Riemer AB, Jensen-Jarolim E. Mimotope vaccination–from allergy to cancer. Expert Opin Biol Ther. 2009;9(4):493–506.
   PubMed Web of Science ®Google Scholar
• Zhong Y, Cai J, Zhang C, et al. Mimotopes selected with neutralizing antibodies against multiple subtypes of influenza A. Virol J. 2011;8:542.
   PubMed Web of Science ®Google Scholar
• Krammer F. The quest for a universal flu vaccine: headless HA 2.0. Cell Host Microbe. 2015;18(4):395–397.
   PubMed Web of Science ®Google Scholar
• Laddy DJ, Yan J, Corbitt N, et al. Immunogenicity of novel consensus-based DNA vaccines against avian influenza. Vaccine. 2007;25(16):2984–2989.
   PubMed Web of Science ®Google Scholar
• Laddy DJ, Yan J, Kutzler M, et al. Heterosubtypic protection against pathogenic human and avian influenza viruses via in vivo electroporation of synthetic consensus DNA antigens. Plos One. 2008;3(6):e2517. ​​​​
   PubMed Web of Science ®Google Scholar
• Chen MW, Cheng TJ, Huang Y, et al. A consensus-hemagglutinin-based DNA vaccine that protects mice against divergent H5N1 influenza viruses. Proc Natl Acad Sci U S A. 2008;105(36):13538–13543.
   PubMed Web of Science ®Google Scholar
• Giles BM, Crevar CJ, Carter DM, et al. A computationally-optimized hemagglutinin VLP vaccine elicits broadly-reactive antibodies that protect non-human primates from h5n1 infection. J Infect Dis. 2012 May 15;205(10):1562–1570. doi:10.1093/infdis/jis232. ​​​​ ​​​​
   PubMed Web of Science ®Google Scholar
• Giles BM, Ross TM. A computationally optimized broadly reactive antigen (COBRA) based H5N1 VLP vaccine elicits broadly reactive antibodies in mice and ferrets. Vaccine. 2011;29(16):3043–3054.
   PubMed Web of Science ®Google Scholar
• Crevar CJ, Carter DM, Lee KY, et al. Cocktail of H5N1 COBRA HA vaccines elicit protective antibodies against H5N1 viruses from multiple clades. Hum Vaccin Immunother. 2015;11(3):572–583.
   PubMed Web of Science ®Google Scholar
• Giles BM, Bissel SJ, Dealmeida DR, et al. 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(2):128–139.
   PubMed Web of Science ®Google Scholar
• Ducatez MF, Bahl J, Griffin Y, et al. Feasibility of reconstructed ancestral H5N1 influenza viruses for cross-clade protective vaccine development. Proc Natl Acad Sci U S A. 2011;108(1):349–354.
   PubMed Web of Science ®Google Scholar
• Yan J, Villarreal DO, Racine T, et al. Protective immunity to H7N9 influenza viruses elicited by synthetic DNA vaccine. Vaccine. 2014;32(24):2833–2842.
   PubMed Web of Science ®Google Scholar
• Wang B, Yu H, Yang FR, et al. Protective efficacy of a broadly cross-reactive swine influenza DNA vaccine encoding M2e, cytotoxic T lymphocyte epitope and consensus H3 hemagglutinin. Virol J. 2012;9:127.
   PubMed Web of Science ®Google Scholar
• Weaver EA, Rubrum AM, Webby RJ, et al. Protection against divergent influenza H1N1 virus by a centralized influenza hemagglutinin. Plos One. 2011;6(3):e18314.
   PubMed Web of Science ®Google Scholar
• Webby RJ, Weaver EA. Centralized consensus hemagglutinin genes induce protective immunity against H1, H3 and H5 influenza viruses. Plos One. 2015;10(10):e0140702.
   PubMed Web of Science ®Google Scholar
• Carter DM, Darby CA, Lefoley BC, et al. Design and characterization of a computationally optimized broadly reactive hemagglutinin vaccine for H1N1 influenza viruses. J Virol. 2016;90(9):4720–4734.
   PubMed Web of Science ®Google Scholar
• Zhou H, Huang Y, Yuan S, et al. Sequential immunization with consensus influenza hemagglutinins raises cross-reactive neutralizing antibodies against various heterologous HA strains. Vaccine. 2017 Jan 5;35(2):305–312. doi:10.1016/j.vaccine.2016.11.051. ​​​​
   Web of Science ®Google Scholar
• Kamlangdee A, Kingstad-Bakke B, Osorio JE. Mosaic H5 hemagglutinin provides broad humoral and cellular immune responses against influenza viruses. J Virol. 2016;90(15):6771–6783.
   PubMed Web of Science ®Google Scholar
• Kamlangdee A, Kingstad-Bakke B, Anderson TK, et al. Broad protection against avian influenza virus by using a modified vaccinia Ankara virus expressing a mosaic hemagglutinin gene. J Virol. 2014;88(22):13300–13309.
   PubMed Web of Science ®Google Scholar
• Li SQ, Schulman JL, Moran T, et al. Influenza A virus transfectants with chimeric hemagglutinins containing epitopes from different subtypes. J Virol. 1992;66(1):399–404.
   PubMed Web of Science ®Google Scholar
• Barouch DH, Stephenson KE, Borducchi EN, et al. Protective efficacy of a global HIV-1 mosaic vaccine against heterologous SHIV challenges in rhesus monkeys. Cell. 2013;155(3):531–539.
   PubMed Web of Science ®Google Scholar
• Krohn K, Stanescu I, Blazevic V, et al. A DNA HIV-1 vaccine based on a fusion gene expressing non-structural and structural genes of consensus sequence of the A-C subtypes and the ancestor sequence of the F-H subtypes. Preclinical and clinical studies. Microbes Infect. 2005;7(14):1405–1413.
   PubMed Web of Science ®Google Scholar
• Morrow MP, Tebas P, Yan J, et al. Synthetic consensus HIV-1 DNA induces potent cellular immune responses and synthesis of granzyme B, perforin in HIV infected individuals. Mol Ther. 2015;23(3):591–601.
   PubMed Web of Science ®Google Scholar
• Yan J, Corbitt N, Pankhong P, et al. Immunogenicity of a novel engineered HIV-1 clade C synthetic consensus-based envelope DNA vaccine. Vaccine. 2011;29(41):7173–7181.
   PubMed Web of Science ®Google Scholar
• Yan J, Yoon H, Kumar S, et al. Enhanced cellular immune responses elicited by an engineered HIV-1 subtype B consensus-based envelope DNA vaccine. Mol Ther. 2007;15(2):411–421.
   PubMed Web of Science ®Google Scholar
• Latimer B, Toporovski R, Yan J, et al. Strong HCV NS3/4a, NS4b, NS5a, NS5b-specific cellular immune responses induced in Rhesus macaques by a novel HCV genotype 1a/1b consensus DNA vaccine. Hum Vaccin Immunother. 2014;10(8):2357–2365.
   PubMed Web of Science ®Google Scholar
• Lennemann NJ, Rhein BA, Ndungo E, et al. Comprehensive functional analysis of N-linked glycans on Ebola virus GP1. MBio. 2014;5(1):e00862–00813.
   PubMed Web of Science ®Google Scholar
• Wang W, Nie J, Prochnow C, et al. A systematic study of the N-glycosylation sites of HIV-1 envelope protein on infectivity and antibody-mediated neutralization. Retrovirology. 2013;10:14.
   PubMed Web of Science ®Google Scholar
• Tate MD, Job ER, Deng YM, et al. Playing hide and seek: how glycosylation of the influenza virus hemagglutinin can modulate the immune response to infection. Viruses. 2014;6(3):1294–1316.
   PubMed Web of Science ®Google Scholar
• Vigerust D, Shepherd V. Virus glycosylation: role in virulence and immune interactions. Trends Microbiol. 2007;15(5):211–218.
   PubMed Web of Science ®Google Scholar
• Medina RA, Stertz S, Manicassamy B, 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. 2013;5(187):187ra170.
   Web of Science ®Google Scholar
• Chen JR, Yu YH, Tseng YC, et al. Vaccination of monoglycosylated hemagglutinin induces cross-strain protection against influenza virus infections. Proc Natl Acad Sci U S A. 2014;111(7):2476–2481.
   PubMed Web of Science ®Google Scholar
• Wang CC, Chen JR, Tseng YC, et al. Glycans on influenza hemagglutinin affect receptor binding and immune response. Proc Natl Acad Sci U S A. 2009;106(43):18137–18142.
   PubMed Web of Science ®Google Scholar
• Magadán JG, Altman MO, Ince WL, et al. Biogenesis of influenza a virus hemagglutinin cross-protective stem epitopes. Plos Pathog. 2014;10(6):e1004204.
   PubMed Web of Science ®Google Scholar
• Liu WC, Jan JT, Huang YJ, et al. Unmasking stem-specific neutralizing epitopes by abolishing n-linked glycosylation sites of influenza virus hemagglutinin proteins for vaccine design. J Virol. 2016;90(19):8496–8508.
   PubMed Web of Science ®Google Scholar
• Eggink D, Goff PH, Palese P. Guiding the immune response against influenza virus hemagglutinin toward the conserved stalk domain by hyperglycosylation of the globular head domain. J Virol. 2014;88(1):699–704.
   PubMed Web of Science ®Google Scholar
• Lin SC, Liu WC, Jan JT, et al. Glycan masking of hemagglutinin for adenovirus vector and recombinant protein immunizations elicits broadly neutralizing antibodies against H5N1 avian influenza viruses. Plos One. 2014;9(3):e92822.
   PubMed Web of Science ®Google Scholar
• Lin SC, Lin YF, Chong P, et al. Broader neutralizing antibodies against H5N1 viruses using prime-boost immunization of hyperglycosylated hemagglutinin DNA and virus-like particles. Plos One. 2012;7(6):e39075.
   PubMed Web of Science ®Google Scholar
• Dunkle LM, Izikson R. Recombinant hemagglutinin influenza vaccine provides broader spectrum protection. Expert Rev Vaccines. 2016;15(8):957–966.
   PubMed Web of Science ®Google Scholar
• Berlanda Scorza F, Tsvetnitsky V, Donnelly JJ. Universal influenza vaccines: shifting to better vaccines. Vaccine. 2016;34(26):2926–2933.
   PubMed Web of Science ®Google Scholar