Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection
Jens Wrammert, Dimitrios Koutsonanos, Gui-Mei Li, Srilatha Edupuganti, Jianhua Sui, Michael Morrissey, Megan McCausland, Ioanna Skountzou, Mady Hornig, W Ian Lipkin, Aneesh Mehta, Behzad Razavi, Carlos Del Rio, Nai-Ying Zheng, Jane-Hwei Lee, Min Huang, Zahida Ali, Kaval Kaur, Sarah Andrews, Rama Rao Amara, Youliang Wang, Suman Ranjan Das, Christopher David O'Donnell, Jon W Yewdell, Kanta Subbarao, Wayne A Marasco, Mark J Mulligan, Richard Compans, Rafi Ahmed, Patrick C Wilson, Jens Wrammert, Dimitrios Koutsonanos, Gui-Mei Li, Srilatha Edupuganti, Jianhua Sui, Michael Morrissey, Megan McCausland, Ioanna Skountzou, Mady Hornig, W Ian Lipkin, Aneesh Mehta, Behzad Razavi, Carlos Del Rio, Nai-Ying Zheng, Jane-Hwei Lee, Min Huang, Zahida Ali, Kaval Kaur, Sarah Andrews, Rama Rao Amara, Youliang Wang, Suman Ranjan Das, Christopher David O'Donnell, Jon W Yewdell, Kanta Subbarao, Wayne A Marasco, Mark J Mulligan, Richard Compans, Rafi Ahmed, Patrick C Wilson
Abstract
The 2009 pandemic H1N1 influenza pandemic demonstrated the global health threat of reassortant influenza strains. Herein, we report a detailed analysis of plasmablast and monoclonal antibody responses induced by pandemic H1N1 infection in humans. Unlike antibodies elicited by annual influenza vaccinations, most neutralizing antibodies induced by pandemic H1N1 infection were broadly cross-reactive against epitopes in the hemagglutinin (HA) stalk and head domain of multiple influenza strains. The antibodies were from cells that had undergone extensive affinity maturation. Based on these observations, we postulate that the plasmablasts producing these broadly neutralizing antibodies were predominantly derived from activated memory B cells specific for epitopes conserved in several influenza strains. Consequently, most neutralizing antibodies were broadly reactive against divergent H1N1 and H5N1 influenza strains. This suggests that a pan-influenza vaccine may be possible, given the right immunogen. Antibodies generated potently protected and rescued mice from lethal challenge with pandemic H1N1 or antigenically distinct influenza strains, making them excellent therapeutic candidates.
Figures
References
- Beigel J.H. 2008. Influenza. Crit. Care Med. 36:2660–2666 10.1097/CCM.0b013e318180b039
- Bernasconi N.L., Traggiai E., Lanzavecchia A. 2002. Maintenance of serological memory by polyclonal activation of human memory B cells. Science. 298:2199–2202 10.1126/science.1076071
- Brockwell-Staats C., Webster R.G., Webby R.J. 2009. Diversity of Influenza Viruses in Swine and the Emergence of a Novel Human Pandemic Influenza A (H1N1). Influenza Other Respir. Viruses. 3:207–213 10.1111/j.1750-2659.2009.00096.x
- Brokstad K.A., Cox R.J., Olofsson J., Jonsson R., Haaheim L.R. 1995. Parenteral influenza vaccination induces a rapid systemic and local immune response. J. Infect. Dis. 171:198–203
- Corti D., Suguitan A.L., Jr, Pinna D., Silacci C., Fernandez-Rodriguez B.M., Vanzetta F., Santos C., Luke C.J., Torres-Velez F.J., Temperton N.J., et al. 2010. Heterosubtypic neutralizing antibodies are produced by individuals immunized with a seasonal influenza vaccine. J. Clin. Invest. 120:1663–1673
- Crotty S., Felgner P., Davies H., Glidewell J., Villarreal L., Ahmed R. 2003. Cutting edge: long-term B cell memory in humans after smallpox vaccination. J. Immunol. 171:4969–4973
- Dawood F.S., Jain S., Finelli L., Shaw M.W., Lindstrom S., Garten R.J., Gubareva L.V., Xu X., Bridges C.B., Uyeki T.M.; Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team 2009. Emergence of a novel swine-origin influenza A (H1N1) virus in humans. N. Engl. J. Med. 360:2605–2615 10.1056/NEJMoa0903810
- de Wildt R.M., Tomlinson I.M., van Venrooij W.J., Winter G., Hoet R.M. 2000. Comparable heavy and light chain pairings in normal and systemic lupus erythematosus IgG(+) B cells. Eur. J. Immunol. 30:254–261 10.1002/1521-4141(200001)30:1<254::AID-IMMU254>;2-X
- Duty J.A., Szodoray P., Zheng N.Y., Koelsch K.A., Zhang Q., Swiatkowski M., Mathias M., Garman L., Helms C., Nakken B., et al. 2009. Functional anergy in a subpopulation of naive B cells from healthy humans that express autoreactive immunoglobulin receptors. J. Exp. Med. 206:139–151 10.1084/jem.20080611
- Ehrenmann F., Kaas Q., Lefranc M.P. 2010. IMGT/3Dstructure-DB and IMGT/DomainGapAlign: a database and a tool for immunoglobulins or antibodies, T cell receptors, MHC, IgSF and MhcSF. Nucleic Acids Res. 38(Database issue):D301–D307 10.1093/nar/gkp946
- Ekiert D.C., Bhabha G., Elsliger M.A., Friesen R.H., Jongeneelen M., Throsby M., Goudsmit J., Wilson I.A. 2009. Antibody recognition of a highly conserved influenza virus epitope. Science. 324:246–251 10.1126/science.1171491
- Garten R.J., Davis C.T., Russell C.A., Shu B., Lindstrom S., Balish A., Sessions W.M., Xu X., Skepner E., Deyde V., et al. 2009. Antigenic and genetic characteristics of swine-origin 2009 A(H1N1) influenza viruses circulating in humans. Science. 325:197–201 10.1126/science.1176225
- Gerhard W., Mozdzanowska K., Furchner M., Washko G., Maiese K. 1997. Role of the B-cell response in recovery of mice from primary influenza virus infection. Immunol. Rev. 159:95–103 10.1111/j.1600-065X.1997.tb01009.x
- Hancock K., Veguilla V., Lu X., Zhong W., Butler E.N., Sun H., Liu F., Dong L., DeVos J.R., Gargiullo P.M., et al. 2009. Cross-reactive antibody responses to the 2009 pandemic H1N1 influenza virus. N. Engl. J. Med. 361:1945–1952 10.1056/NEJMoa0906453
- Koelsch K., Zheng N.-Y., Zhang Q., Duty A., Helms C., Mathias M.D., Jared M., Smith K., Capra J.D., Wilson P.C. 2007. Mature B cells class switched to IgD are autoreactive in healthy individuals. J. Clin. Invest. 117:1558–1565 10.1172/JCI27628
- Krause J.C., Tumpey T.M., Huffman C.J., McGraw P.A., Pearce M.B., Tsibane T., Hai R., Basler C.F., Crowe J.E., Jr 2010. Naturally occurring human monoclonal antibodies neutralize both 1918 and 2009 pandemic influenza A (H1N1) viruses. J. Virol. 84:3127–3130 10.1128/JVI.02184-09
- Lefranc M.P., Giudicelli V., Ginestoux C., Jabado-Michaloud J., Folch G., Bellahcene F., Wu Y., Gemrot E., Brochet X., Lane J., et al. 2009. IMGT, the international ImMunoGeneTics information system. Nucleic Acids Res. 37(Database issue):D1006–D1012 10.1093/nar/gkn838
- Luke T.C., Kilbane E.M., Jackson J.L., Hoffman S.L. 2006. Meta-analysis: convalescent blood products for Spanish influenza pneumonia: a future H5N1 treatment? Ann. Intern. Med. 145:599–609
- Manicassamy B., Medina R.A., Hai R., Tsibane T., Stertz S., Nistal-Villán E., Palese P., Basler C.F., García-Sastre A. 2010. Protection of mice against lethal challenge with 2009 H1N1 influenza A virus by 1918-like and classical swine H1N1 based vaccines. PLoS Pathog. 6:e1000745 10.1371/journal.ppat.1000745
- McKean D., Huppi K., Bell M., Staudt L., Gerhard W., Weigert M. 1984. Generation of antibody diversity in the immune response of BALB/c mice to influenza virus hemagglutinin. Proc. Natl. Acad. Sci. USA. 81:3180–3184 10.1073/pnas.81.10.3180
- Okuno Y., Isegawa Y., Sasao F., Ueda S. 1993. A common neutralizing epitope conserved between the hemagglutinins of influenza A virus H1 and H2 strains. J. Virol. 67:2552–2558
- Palladino G., Mozdzanowska K., Washko G., Gerhard W. 1995. Virus-neutralizing antibodies of immunoglobulin G (IgG) but not of IgM or IgA isotypes can cure influenza virus pneumonia in SCID mice. J. Virol. 69:2075–2081
- Puck J.M., Glezen W.P., Frank A.L., Six H.R. 1980. Protection of infants from infection with influenza A virus by transplacentally acquired antibody. J. Infect. Dis. 142:844–849
- Renegar K.B., Small P.A., Jr, Boykins L.G., Wright P.F. 2004. Role of IgA versus IgG in the control of influenza viral infection in the murine respiratory tract. J. Immunol. 173:1978–1986
- Reuman P.D., Paganini C.M., Ayoub E.M., Small P.A., Jr 1983. Maternal-infant transfer of influenza-specific immunity in the mouse. J. Immunol. 130:932–936
- Sasaki S., Jaimes M.C., Holmes T.H., Dekker C.L., Mahmood K., Kemble G.W., Arvin A.M., Greenberg H.B. 2007. Comparison of the influenza virus-specific effector and memory B-cell responses to immunization of children and adults with live attenuated or inactivated influenza virus vaccines. J. Virol. 81:215–228 10.1128/JVI.01957-06
- Simmons C.P., Bernasconi N.L., Suguitan A.L., Mills K., Ward J.M., Chau N.V.V., Hien T.T., Sallusto F., Ha Q., Farrar J., et al. 2007. Prophylactic and therapeutic efficacy of human monoclonal antibodies against H5N1 influenza. PLoS Med. 4:e178 10.1371/journal.pmed.0040178
- Smith K., Garman L., Wrammert J., Zheng N.Y., Capra J.D., Ahmed R., Wilson P.C. 2009. Rapid generation of fully human monoclonal antibodies specific to a vaccinating antigen. Nat. Protoc. 4:372–384 10.1038/nprot.2009.3
- Steel J., Lowen A.C., Wang T., Yondola M., Gao Q., Haye K., Garcia-Sastre A., Palese P. 2010. Influenza virus vaccine based on the conserved hemagglutinin stalk domain. MBio. 1:e00018–10 10.1038/nmeth0410-267
- Subbarao K., Joseph T. 2007. Scientific barriers to developing vaccines against avian influenza viruses. Nat. Rev. Immunol. 7:267–278
- Sui J., Li W., Murakami A., Tamin A., Matthews L.J., Wong S.K., Moore M.J., Tallarico A.S., Olurinde M., Choe H., et al. 2004. Potent neutralization of severe acute respiratory syndrome (SARS) coronavirus by a human mAb to S1 protein that blocks receptor association. Proc. Natl. Acad. Sci. USA. 101:2536–2541 10.1073/pnas.0307140101
- Sui J., Hwang W.C., Perez S., Wei G., Aird D., Chen L.M., Santelli E., Stec B., Cadwell G., Ali M., et al. 2009. Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses. Nat. Struct. Mol. Biol. 16:265–273 10.1038/nsmb.1566
- Sweet C., Bird R.A., Jakeman K., Coates D.M., Smith H. 1987. Production of passive immunity in neonatal ferrets following maternal vaccination with killed influenza A virus vaccines. Immunology. 60:83–89
- Wang T.T., Tan G.S., Hai R., Pica N., Petersen E., Moran T.M., Palese P. 2010. Broadly protective monoclonal antibodies against H3 influenza viruses following sequential immunization with different hemagglutinins. PLoS Pathog. 6:e1000796 10.1371/journal.ppat.1000796
- Wardemann H., Yurasov S., Schaefer A., Young J.W., Meffre E., Nussenzweig M.C. 2003. Predominant autoantibody production by early human B cell precursors. Science. 301:1374–1377 10.1126/science.1086907
- Wei C.J., Boyington J.C., McTamney P.M., Kong W.P., Pearce M.B., Xu L., Andersen H., Rao S., Tumpey T.M., Yang Z.Y., Nabel G.J. 2010. Induction of broadly neutralizing H1N1 influenza antibodies by vaccination. Science. 329:1060–1064 10.1126/science.1192517
- Wrammert J., Smith K., Miller J., Langley W.A., Kokko K., Larsen C., Zheng N.Y., Mays I., Garman L., Helms C., et al. 2008. Rapid cloning of high-affinity human monoclonal antibodies against influenza virus. Nature. 453:667–671 10.1038/nature06890
- Xu R., Ekiert D.C., Krause J.C., Hai R., Crowe J.E., Jr, Wilson I.A. 2010. Structural basis of preexisting immunity to the 2009 H1N1 pandemic influenza virus. Science. 328:357–360
- Zheng N.Y., Wilson K., Wang X., Boston A., Kolar G., Jackson S.M., Liu Y.J., Pascual V., Capra J.D., Wilson P.C. 2004. Human immunoglobulin selection associated with class switch and possible tolerogenic origins for C delta class-switched B cells. J. Clin. Invest. 113:1188–1201
- Zheng N.Y., Wilson K., Jared M., Wilson P.C. 2005. Intricate targeting of immunoglobulin somatic hypermutation maximizes the efficiency of affinity maturation. J. Exp. Med. 201:1467–1478 10.1084/jem.20042483
Source: PubMed