Influenza Virus Vaccine Strategy
Inventors: Stephen Harrison, Barton Haynes, Hua-Xin Liao, James Whittle, M. Moody, Thomas Kepler
Invention Types: Therapeutics
Research Areas: Immunology
Keywords: HIV, VaccineFor More Information Contact: Caron, Connie
Seasonal antigenic drift in the influenza virus accounts for the absence of long-term immune protection in previously infected individuals. The hemagglutinin (HA), a trimeric surface glycoprotein that binds the viral receptor and promotes fusion and penetration from low-pH endosomes, is the principal surface antigen on influenza virions. HA presents conserved as well as variable epitopes, but neutralizing antibodies against the latter dominate the response to immunization and infection.
Dr. Harrison's laboratory has discovered novel antibodies having principal contacts in the receptor pocket. They derive from a B-cell lineage, found by isolating rearranged heavy- and light-chain genes from sorted single plasma cells, obtained from a subject who had received the 2007 trivalent vaccine. Two antibodies in this lineage, CH65 and CH67, neutralize a remarkably broad range of H1 seasonal isolates spanning more than three decades. There is also tentative evidence for reactivity with an H5 isolate. The 14-residue heavy-chain complementarity-determining region 3 (CDR-H3) inserts into the receptor pocket, mimicking many of the interactions made by sialic acid. Both heavy- and light-chain CDRs participate in more restricted, additional contacts with the outward-facing surface of HA1. The human B-cell repertoire thus includes the potential to generate antibodies directed primarily at the receptor-binding site. The large number of seasonal H1 viruses neutralized by antibodies CH65 and CH67 suggests that such responses are ordinarily too rare to select for resistance, or that resistance comes at too great a fitness cost - as would be the case if potential escape mutations were to compromise receptor binding. Thus, the inventors have discovered that broad neutralization of influenza virus can be achieved by antibodies with contacts that mimic those of the receptor, and their invention provides novel antibodies that indeed exhibit such mimicry. These novel antibodies might effectively treat and/or prevent infection by drifted strains of influenza.
Whittle, J.R.R., Zhang, R., Khurana, S., King, L.R., Manischewitz, J., Golding, H., Dormitzer, P.D., Haynes, B.F., Walter, E.B., Moody, M.A., Kepler, T.B., Liao, H-X., Harrison, S.C. Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza virus hemagglutinin. PNAS 108(34): 14216-21 (2011).
• Novel antibodies that broadly neutralize influenza antigenic variants.
• Compositions and kits containing the novel antibodies, as well as methods for using these novel therapeutic molecules to treat or prevent influenza viral infection.
• The invention also relates to combination therapies including the novel antibodies.
• There is a need to develop broadly neutralizing therapeutics that can effectively treat or prevent drifted strains of influenza.
• The structure and characteristics of CH65 show that it is also possible to elicit broadly neutralizing, receptor-binding site antibodies.
• They also draw a parallel with the broadly neutralizing, receptor-site antibodies against HIV-1 (e.g., antibody VRC01), which are reasonably close mimics of the functional receptor, CD4.
• An immunogen with an enhanced probability of eliciting a CH65-Iike response might protect against series of seasonal strains.
• A strategy for designing such an immunogen, based on analysis of both the structure and the lineage, could include (in addition to the native HA) a component with higher affinity for the unmutated common ancestor of CH65 and CH67 (i.e., the progenitor of the B-cell lineage), in order to induce a primary response that favors this lineage.
• On-going comparisons of structures and properties of the unmutated common ancestor and the mature CH65 and CH67 are revealing the interactions that account for their different affinities for HA. A modified HA, in which the contacts instead gain stability from mutations in the antigen, might have the desired properties.
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Related Publications: Schmidt AG, Xu H, Khan AR, O'Donnell T, Khurana S, King LR, Manischewitz J,
Golding H, Suphaphiphat P, Carfi A, Settembre EC, Dormitzer PR, Kepler TB, Zhang
R, Moody MA, Haynes BF, Liao HX, Shaw DE, Harrison SC. Preconfiguration of the
antigen-binding site during affinity maturation of a broadly neutralizing
influenza virus antibody. Proc Natl Acad Sci U S A. 2013 Jan 2;110(1):264-9. doi:
10.1073/pnas.1218256109. Epub 2012 Nov 21. PubMed PMID: 23175789.
IPStatus: Pat. Pend.