tetano
Editor, Senior Moderator
JVI Accepts, published online ahead of print on 24 August 2011
J. Virol. doi:10.1128/JVI.05406-11
Copyright ? 2011,American Society for Microbiology and/or the Listed
Authors/Institutions. All Rights Reserved.
H5N1 virus-like particle vaccine elicits cross-reactive neutralizing antibodies in humans that preferentially bind to oligomeric form of influenza hemagglutinin
Surender Khurana1, Jian Wu1, Nitin Verma1, Swati Verma1, Ramadevi Raghunandan2, Jody Manischewitz1, Lisa R. King1, Eloi Kpamegan2, Steven Pincus2, Gale Smith2, Gregory Glenn2, and Hana Golding1,*
1 Division of Viral Products, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration, Bethesda, MD 20892, USA
2 Novavax Inc., Rockville, MD 20850, USA
* To whom correspondence should be addressed. E-mail: hana.golding{at}fda.hhs.gov
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ABSTRACT
Transmission of pathogenic avian influenza viruses (AIV) from wild birds to domestic poultry and humans is continuing in multiple countries around the world. In preparation for a potential AIV pandemic, multiple vaccine candidates are under development. In the case of H5N1 AIV, a clear shift in transmission from clade 1 to clade 2 viruses occurred in recent years. Virus like particle (VLP) represents an economical approach to pandemic vaccine development. In the current study, we evaluated the humoral immune response in humans vaccinated with H5N1 A/Indonesia/05/2005 (clade 2.1) VLP vaccine manufactured in Sf9 insect cells. The VLPs were comprised of the influenza hemagglutinin (HA), neuraminidase (NA) and matrix (M1) proteins. In a FDA approved Phase 1/2 human clinical study, two doses of H5N1 VLPs at 15, 45 or 90 ?g HA/dose resulted in seroconversion and production of functional antibodies. Moreover, cross-reactivity against other clade 2 subtypes was demonstrated using virus neutralization assays. H5N1 whole genome-fragment phage display libraries (GFPDL) were used to elucidate the antibody epitope repertoire in post-vaccination human sera. Diverse epitopes in HA1/HA2 and NA were recognized by post-vaccination sera from the two high-dose groups, including large segments spanning the HA1 receptor binding domain. Importantly, the vaccine elicited sera that preferentially bound to an oligomeric form of recombinant HA1 compared with monomeric HA1. The oligomeric/monomeric HA1 binding ratios of the sera correlated with the virus neutralizing titers. Additionally, the two high dose VLP vaccine groups generated NA inhibiting antibodies that were associated with binding to a C-terminal epitope close to the sialic acid binding site. These findings represent the first report describing the quality of the antibody responses in humans following AIV VLP immunization and support further development of such vaccines against emerging influenza strains.
http://jvi.asm.org/cgi/content/short/JVI.05406-11v1
J. Virol. doi:10.1128/JVI.05406-11
Copyright ? 2011,American Society for Microbiology and/or the Listed
Authors/Institutions. All Rights Reserved.
H5N1 virus-like particle vaccine elicits cross-reactive neutralizing antibodies in humans that preferentially bind to oligomeric form of influenza hemagglutinin
Surender Khurana1, Jian Wu1, Nitin Verma1, Swati Verma1, Ramadevi Raghunandan2, Jody Manischewitz1, Lisa R. King1, Eloi Kpamegan2, Steven Pincus2, Gale Smith2, Gregory Glenn2, and Hana Golding1,*
1 Division of Viral Products, Center for Biologics Evaluation and Research (CBER), Food and Drug Administration, Bethesda, MD 20892, USA
2 Novavax Inc., Rockville, MD 20850, USA
* To whom correspondence should be addressed. E-mail: hana.golding{at}fda.hhs.gov
arrow
ABSTRACT
Transmission of pathogenic avian influenza viruses (AIV) from wild birds to domestic poultry and humans is continuing in multiple countries around the world. In preparation for a potential AIV pandemic, multiple vaccine candidates are under development. In the case of H5N1 AIV, a clear shift in transmission from clade 1 to clade 2 viruses occurred in recent years. Virus like particle (VLP) represents an economical approach to pandemic vaccine development. In the current study, we evaluated the humoral immune response in humans vaccinated with H5N1 A/Indonesia/05/2005 (clade 2.1) VLP vaccine manufactured in Sf9 insect cells. The VLPs were comprised of the influenza hemagglutinin (HA), neuraminidase (NA) and matrix (M1) proteins. In a FDA approved Phase 1/2 human clinical study, two doses of H5N1 VLPs at 15, 45 or 90 ?g HA/dose resulted in seroconversion and production of functional antibodies. Moreover, cross-reactivity against other clade 2 subtypes was demonstrated using virus neutralization assays. H5N1 whole genome-fragment phage display libraries (GFPDL) were used to elucidate the antibody epitope repertoire in post-vaccination human sera. Diverse epitopes in HA1/HA2 and NA were recognized by post-vaccination sera from the two high-dose groups, including large segments spanning the HA1 receptor binding domain. Importantly, the vaccine elicited sera that preferentially bound to an oligomeric form of recombinant HA1 compared with monomeric HA1. The oligomeric/monomeric HA1 binding ratios of the sera correlated with the virus neutralizing titers. Additionally, the two high dose VLP vaccine groups generated NA inhibiting antibodies that were associated with binding to a C-terminal epitope close to the sialic acid binding site. These findings represent the first report describing the quality of the antibody responses in humans following AIV VLP immunization and support further development of such vaccines against emerging influenza strains.
http://jvi.asm.org/cgi/content/short/JVI.05406-11v1