Structural vaccinology: structure-based design of influenza A virus hemagglutinin subtype-specific subunit vaccines

Chunling Xuan1,2, Yi Shi1, Jianxun Qi1, Wei Zhang1,2, Haixia Xiao4, George F. Gao1,2,3,4()

PDF(454 KB)
PDF(454 KB)
Protein Cell ›› 2011, Vol. 2 ›› Issue (12) : 997-1005. DOI: 10.1007/s13238-011-1134-y
RESEARCH ARTICLE

Structural vaccinology: structure-based design of influenza A virus hemagglutinin subtype-specific subunit vaccines

  • Chunling Xuan1,2, Yi Shi1, Jianxun Qi1, Wei Zhang1,2, Haixia Xiao4, George F. Gao1,2,3,4()
Author information +
History +

Abstract

There is a great need for new vaccine development against influenza A viruses due to the drawbacks of traditional vaccines that are mainly prepared using embryonated eggs. The main component of the current split influenza A virus vaccine is viral hemagglutinin (HA) which induces a strong antibody-mediated immune response. To develop a modern vaccine against influenza A viruses, the current research has been focused on the universal vaccines targeting viral M2, NP and HA proteins. Crystallographic studies have shown that HA forms a trimer embedded on the viral envelope surface, and each monomer consists of a globular head (HA1) and a “rod-like” stalk region (HA2), the latter being more conserved among different HA subtypes and being the primary target for universal vaccines. In this study, we rationally designed the HA head based on the crystal structure of the 2009-pandemic influenza A (H1N1) virus HA as a model, tested its immunogenicity in mice, solved its crystal structure and further examined its immunological characteristics. The results show that the HA globular head can be easily prepared by in vitro refolding in an E. coli expression system, which maintains its intact structure and allows for the stimulation of a strong immune response. Together with recent reports on some similar HA globular head preparations we conclude that structure-based rational design of the HA globular head can be used for subtype-specific vaccines against influenza viruses.

Keywords

influenza virus / subunit vaccine / hemagglutinin / structure / design

Cite this article

Download citation ▾
Chunling Xuan, Yi Shi, Jianxun Qi, Wei Zhang, Haixia Xiao, George F. Gao. Structural vaccinology: structure-based design of influenza A virus hemagglutinin subtype-specific subunit vaccines. Prot Cell, 2011, 2(12): 997‒1005 https://doi.org/10.1007/s13238-011-1134-y

References

[1] Adams, P.D., Grosse-Kunstleve, R.W., Hung, L.W., Ioerger, T.R., McCoy, A.J., Moriarty, N.W., Read, R.J., Sacchettini, J.C., Sauter, N.K., and Terwilliger, T.C. (2002). PHENIX: building new software for automated crystallographic structure determination. Acta Crystallogr D Biol Crystallogr 58, 1948-1954 12393927.
[2] Beigel, J.H., Farrar, J., Han, A.M., Hayden, F.G., Hyer, R., de Jong, M.D., Lochindarat, S., Nguyen, T.K., Nguyen, T.H., Tran, T.H., , and the Writing Committee of the World Health Organization (WHO) Consultation on Human Influenza A/H5. (2005). Avian influenza A (H5N1) infection in humans. N Engl J Med 353, 1374-1385 16192482.
[3] Belser, J.A., Lu, X., Maines, T.R., Smith, C., Li, Y., Donis, R.O., Katz, J.M., and Tumpey, T.M. (2007). Pathogenesis of avian influenza (H7) virus infection in mice and ferrets: enhanced virulence of Eurasian H7N7 viruses isolated from humans. J Virol 81, 11139-11147 17686867.
[4] Belshe, R.B., Gruber, W.C., Mendelman, P.M., Cho, I., Reisinger, K., Block, S.L., Wittes, J., Iacuzio, D., Piedra, P., Treanor, J., (2000). Efficacy of vaccination with live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine against a variant (A/Sydney) not contained in the vaccine. J Pediatr 136, 168-175 10657821.
[5] Bommakanti, G., Citron, M.P., Hepler, R.W., Callahan, C., Heidecker, G.J., Najar, T.A., Lu, X., Joyce, J.G., Shiver, J.W., Casimiro, D.R., (2010). Design of an HA2-based Escherichia coli expressed influenza immunogen that protects mice from pathogenic challenge. Proc Natl Acad Sci U S A 107, 13701-13706 20615991.
[6] Caton, A.J., Brownlee, G.G., Yewdell, J.W., and Gerhard, W. (1982). The antigenic structure of the influenza virus A/PR/8/34 hemagglutinin (H1 subtype). Cell 31, 417-427 6186384.
[7] Claas, E.C., Osterhaus, A.D., van Beek, R., De Jong, J.C., Rimmelzwaan, G.F., Senne, D.A., Krauss, S., Shortridge, K.F., and Webster, R.G. (1998). Human influenza A H5N1 virus related to a highly pathogenic avian influenza virus. Lancet 351, 472-477 9482438.
[8] Collaborative Computational Project, Number 4. (1994). The CCP4 suite: programs for protein crystallography. Acta Crystallogr D Biol Crystallogr 50, 760-763 15299374.
[9] Corti, D., Voss, J., Gamblin, S.J., Codoni, G., Macagno, A., Jarrossay, D., Vachieri, S.G., Pinna, D., Minola, A., Vanzetta, F., (2011). A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutinins. Science 333, 850-856 21798894.
[10] Das, K., Aramini, J.M., Ma, L.C., Krug, R.M., and Arnold, E. (2010). Structures of influenza A proteins and insights into antiviral drug targets. Nat Struct Mol Biol 17, 530-538 20383144.
[11] DuBois, R.M., Aguilar-Ya?ez, J.M., Mendoza-Ochoa, G.I., Oropeza-Almazán, Y., Schultz-Cherry, S., Alvarez, M.M., White, S.W., and Russell, C.J. (2011a). The receptor-binding domain of influenza virus hemagglutinin produced in Escherichia coli folds into its native, immunogenic structure. J Virol 85, 865-872 21068239.
[12] DuBois, R.M., Aguilar-Ya?ez, J.M., Mendoza-Ochoa, G.I., Oropeza-Almazán, Y., Schultz-Cherry, S., Alvarez, M.M., White, S.W., and Russell, C.J. (2011b). The receptor-binding domain of influenza virus hemagglutinin produced in Escherichia coli folds into its native, immunogenic structure. J Virol 85, 865-872 21068239.
[13] Ekiert, D.C., Bhabha, G., Elsliger, M.A., Friesen, R.H., Jongeneelen, M., Throsby, M., Goudsmit, J., and Wilson, I.A. (2009). Antibody recognition of a highly conserved influenza virus epitope. Science 324, 246-251 19251591.
[14] Ekiert, D.C., Friesen, R.H., Bhabha, G., Kwaks, T., Jongeneelen, M., Yu, W., Ophorst, C., Cox, F., Korse, H.J., Brandenburg, B., (2011). A highly conserved neutralizing epitope on group 2 influenza A viruses. Science 333, 843-850 21737702.
[15] Emsley, P., and Cowtan, K. (2004). Coot: model-building tools for molecular graphics. Acta Crystallogr D Biol Crystallogr 60, 2126-2132 15572765.
[16] Fields, B.N., Knipe, D.M., and Howley, P.M. (2007). Fields virology, 5th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins.
[17] Furuya, Y., Regner, M., Lobigs, M., Koskinen, A., Müllbacher, A., and Alsharifi, M. (2010). Effect of inactivation method on the cross-protective immunity induced by whole ‘killed’ influenza A viruses and commercial vaccine preparations. J Gen Virol 91, 1450-1460 20147516.
[18] Gamblin, S.J., Haire, L.F., Russell, R.J., Stevens, D.J., Xiao, B., Ha, Y., Vasisht, N., Steinhauer, D.A., Daniels, R.S., Elliot, A., (2004). The structure and receptor binding properties of the 1918 influenza hemagglutinin. Science 303, 1838-1842 14764886.
[19] Guan, Y., Vijaykrishna, D., Bahl, J., Zhu, H., Wang, J., and Smith, G.J. (2010). The emergence of pandemic influenza viruses. Protein Cell 1, 9-13 21203993.
[20] Ha, Y., Stevens, D.J., Skehel, J.J., and Wiley, D.C. (2002). H5 avian and H9 swine influenza virus haemagglutinin structures: possible origin of influenza subtypes. EMBO J 21, 865-875 11867515.
[21] Igarashi, M., Ito, K., Yoshida, R., Tomabechi, D., Kida, H., and Takada, A. (2010). Predicting the antigenic structure of the pandemic (H1N1) 2009 influenza virus hemagglutinin. PLoS One 5, e855320049332.
[22] Khurana, S., Larkin, C., Verma, S., Joshi, M.B., Fontana, J., Steven, A.C., King, L.R., Manischewitz, J., McCormick, W., Gupta, R.K., (2011). Recombinant HA1 produced in E. coli forms functional oligomers and generates strain-specific SRID potency antibodies for pandemic influenza vaccines. Vaccine 29, 5657-5665 21704111.
[23] Khurana, S., Verma, S., Verma, N., Crevar, C.J., Carter, D.M., Manischewitz, J., King, L.R., Ross, T.M., and Golding, H. (2010). Properly folded bacterially expressed H1N1 hemagglutinin globular head and ectodomain vaccines protect ferrets against H1N1 pandemic influenza virus. PLoS One 5, e1154820634959.
[24] Kilbourne, E.D. (2006). Influenza pandemics of the 20th century. Emerg Infect Dis 12, 9-14 16494710.
[25] Kubo, Y., Yokoyama, M., Yoshii, H., Mitani, C., Tominaga, C., Tanaka, Y., Sato, H., and Yamamoto, N. (2007). Inhibitory role of CXCR4 glycan in CD4-independent X4-tropic human immunodeficiency virus type 1 infection and its abrogation in CD4-dependent infection. J Gen Virol 88, 3139-3144 17947541.
[26] Kurtz, J., Manvell, R.J., and Banks, J. (1996). Avian influenza virus isolated from a woman with conjunctivitis. Lancet 348, 901-902 8826845.
[27] Laskowski, R.A., MacArthur, M.W., Moss, D.S., and Thornton, J.M. (1993). PROCHECK: A program to check the stereochemical quality of protein structures. J Appl Cryst 26, 283-291 .
[28] Lin, Y.P., Shaw, M., Gregory, V., Cameron, K., Lim, W., Klimov, A., Subbarao, K., Guan, Y., Krauss, S., Shortridge, K., (2000). Avian-to-human transmission of H9N2 subtype influenza A viruses: relationship between H9N2 and H5N1 human isolates. Proc Natl Acad Sci U S A 97, 9654-9658 10920197.
[29] Lipsitch, M., Cohen, T., Murray, M., and Levin, B.R. (2007). Antiviral resistance and the control of pandemic influenza. PLoS Med 4, e1517253900.
[30] Meijer, A., Bosman, A., van de Kamp, E.E.H.M., Wilbrink, B., Du Ry van Beest Holle, M., and Koopmans, M. (2006). Measurement of antibodies to avian influenza virus A(H7N7) in humans by hemagglutination inhibition test. J Virol Methods 132, 113-120 16271401.
[31] Murshudov, G.N., Vagin, A.A., and Dodson, E.J. (1997). Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr D Biol Crystallogr 53, 240-255 15299926.
[32] Neumann, G., Noda, T., and Kawaoka, Y. (2009). Emergence and pandemic potential of swine-origin H1N1 influenza virus. Nature 459, 931-939 19525932.
[33] Otwinowski, Z., and Minor, W. (1997). Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol 276, 307-326 .
[34] Read, R.J. (2001). Pushing the boundaries of molecular replacement with maximum likelihood. Acta Crystallogr D Biol Crystallogr 57, 1373-1382 11567148.
[35] Russell, R.J., Gamblin, S.J., Haire, L.F., Stevens, D.J., Xiao, B., Ha, Y., and Skehel, J.J. (2004). H1 and H7 influenza haemagglutinin structures extend a structural classification of haemagglutinin subtypes. Virology 325, 287-296 15246268.
[36] Russell, R.J., Kerry, P.S., Stevens, D.J., Steinhauer, D.A., Martin, S.R., Gamblin, S.J., and Skehel, J.J. (2008). Structure of influenza hemagglutinin in complex with an inhibitor of membrane fusion. Proc Natl Acad Sci U S A 105, 17736-17741 19004788.
[37] Skehel, J.J., and Wiley, D.C. (2000). Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin. Annu Rev Biochem 69, 531-569 10966468.
[38] Stevens, J., Blixt, O., Tumpey, T.M., Taubenberger, J.K., Paulson, J.C., and Wilson, I.A. (2006). Structure and receptor specificity of the hemagglutinin from an H5N1 influenza virus. Science 312, 404-410 16543414.
[39] Subbarao, K., Klimov, A., Katz, J., Regnery, H., Lim, W., Hall, H., Perdue, M., Swayne, D., Bender, C., Huang, J., (1998). Characterization of an avian influenza A (H5N1) virus isolated from a child with a fatal respiratory illness. Science 279, 393-396 9430591.
[40] Sun, Y., Shi, Y., Zhang, W., Li, Q., Liu, D., Vavricka, C., Yan, J., and Gao, G.F. (2010). In silico characterization of the functional and structural modules of the hemagglutinin protein from the swine-origin influenza virus A (H1N1)-2009. Sci China Life Sci 53, 633-642 20602265.
[41] Tran, T.H., Nguyen, T.L., Nguyen, T.D., Luong, T.S., Pham, P.M., Nguyen, V.C., Pham, T.S., Vo, C.D., Le, T.Q., Ngo, T.T., , and the World Health Organization International Avian Influenza Investigative Team. (2004). Avian influenza A (H5N1) in 10 patients in Vietnam. N Engl J Med 350, 1179-1188 14985470.
[42] Vavricka, C.J., Li, Q., Wu, Y., Qi, J., Wang, M., Liu, Y., Gao, F., Liu, J., Feng, E., He, J., (2011). Structural and functional analysis of laninamivir and its octanoate prodrug reveals group specific mechanisms for influenza NA inhibition. PLoS Pathog 7, e100224922028647.
[43] Vitale, F., Russo Alesi, D., Bonura, F., Di Benedetto, M.A., Mammina, C., and Romano, N. (1991). Change in size of the envelope glycoprotein of a human immunodeficiency virus 1 (HIV 1) strain. Microbiologica 14, 15-20 2067412.
[44] Wang, T.T., Tan, G.S., Hai, R., Pica, N., Ngai, L., Ekiert, D.C., Wilson, I.A., García-Sastre, A., Moran, T.M., and Palese, P. (2010). Vaccination with a synthetic peptide from the influenza virus hemagglutinin provides protection against distinct viral subtypes. Proc Natl Acad Sci U S A 107, 18979-18984 20956293.
[45] Wilson, I.A., Skehel, J.J., and Wiley, D.C. (1981). Structure of the haemagglutinin membrane glycoprotein of influenza virus at 3 A resolution. Nature 289, 366-373 7464906.
[46] Wood, J.M., and Robertson, J.S. (2004). From lethal virus to life-saving vaccine: developing inactivated vaccines for pandemic influenza. Nat Rev Microbiol 2, 842-847 15378048.
[47] Xu, R., McBride, R., Paulson, J.C., Basler, C.F., and Wilson, I.A. (2010). Structure, receptor binding, and antigenicity of influenza virus hemagglutinins from the 1957 H2N2 pandemic. J Virol 84, 1715-1721 20007271.
[48] Yang, Y., Sugimoto, J.D., Halloran, M.E., Basta, N.E., Chao, D.L., Matrajt, L., Potter, G., Kenah, E., and Longini, I.M. Jr. (2009). The transmissibility and control of pandemic influenza A (H1N1) virus. Science 326, 729-733 19745114.
[49] Zhang, W., Qi, J., Shi, Y., Li, Q., Gao, F., Sun, Y., Lu, X., Lu, Q., Vavricka, C.J., Liu, D., (2010). Crystal structure of the swine-origin A (H1N1)-2009 influenza A virus hemagglutinin (HA) reveals similar antigenicity to that of the 1918 pandemic virus. Protein Cell 1, 459-467 21203961.
AI Summary AI Mindmap
PDF(454 KB)

Accesses

Citations

Detail

Sections
Recommended

/