|Toward Design of a Universal Flu Vaccine|
Worldwide, influenza causes substantial deaths and yearly economic burdens, but the highly changeable nature of the flu virus complicates the production of an effective vaccine. The Centers for Disease Control and Prevention (CDC) estimates that the effectiveness of this year's flu vaccine is about 62%. For comparison, this number for childhood vaccines is routinely well over 90%. One factor in determining the vaccine's effectiveness is how closely related the viruses used in the vaccine are to the viruses circulating that year. An international team of researchers, working at synchrotron facilities including the ALS, has solved the crystal structures of antibodies that protect against broad classes of influenza strains. Greater understanding of these antibody structures may aid in the eventual development of a universal vaccine, protecting against all types of influenza viruses and thus eliminating the guesswork that currently limits vaccine effectiveness.
Influenza has two main types: influenza A and influenza B. Influenza B includes two genetically distinct forms—the Yamagata and Victoria lineages. Influenza A contains 17 subtypes of hemagglutinin (H1–H17) and 9 subtypes of neuraminidase (N1–N9). Hemagglutinin (HA) mediates the binding of the virus to target cells, and neuraminidase (NA) is involved in the release of progeny virus from infected cells. Thus, these proteins are targets for antiviral drugs, in addition to being antigens to which antibodies can be raised. Influenza A viruses are classified into subtypes, such as H1N1 or H3N2, based on antibody responses to HA and NA.
It was found that the three antibodies bind to distinct regions of the viruses. Structures of CR8033 were found to bind to HA from both types of influenza B lineages. In both cases, contacts are made through the heavy chain portion of the antibody and are cross-reactive because the HA binding pocket of influenza B is very conserved. The antibody CR9114 binds to an epitope that is similar to that of a previously characterized human antibody, FI6, which broadly neutralizes strain A viruses. However, FI6 shows large structural differences from CR9114, indicating that, while they bind to a similar region on various viruses, they employ different strategies for neutralizing those viruses.
The crystal structures showed how CR9114 likely accomplishes its cross-group neutralizing ability: the antibody recognizes residues (amino acids) that are highly conserved in the different types of influenza virus and can accommodate some of the variable residues and avoid or push away glycans (carbohydrate chains) on the periphery, which vary between subtypes and strains and normally protect the HA surface. Since antibodies similar to CR9114 are likely present in the human population, this suggests that one possible vaccination strategy against both A and B strains would be to trigger production of CR9114-type antibodies.
Research conducted by: C. Dreyfus, R. Khayat, D.C. Ekiert, J.H. Lee, Z. Metlagel, A.B. Ward, and I.A. Wilson (The Scripps Research Institute); N.S. Laursen (The Scripps Research Institute and Aarhus University, Denmark); T. Kwaks, D. Zuijdgeest, M.V. Bujny, M. Jongeneelen, R. van der Vlugt, M. Lamrani, H.J.W. M. Korse, E. Geelen, Ö. Sahin, M. Sieuwerts, J.P.J. Brakenhoff, R. Vogels, W. Koudstaal, J. Goudsmit, and R.H.E. Friesen (Crucell Vaccine Institute, Netherlands); and O.T.W. Li, L.L.M. Poon, and M. Peiris (University of Hong Kong).
Research funding: University Grants Committee, Hong Kong; Achievement Rewards for College Scientists (ARCS) Foundation; National Institutes of Health; Danish Council for Independent Research, Natural Sciences; and the Skaggs Institute. Operation of the ALS is supported by the U.S. Department of Energy, Office of Basic Energy Sciences.
Publication about this research: C. Dreyfus, N.S. Laursen, T. Kwaks, D. Zuijdgeest, R. Khayat, D.C. Ekiert, J.H. Lee, Z. Metlagel, M.V. Bujny, M. Jongeneelen, R. van der Vlugt, M. Lamrani, H.J.W. M. Korse, E. Geelen, Ö. Sahin, M. Sieuwerts, J.P. J. Brakenhoff, R. Vogels, O.T.W. Li, L.L.M. Poon, M. Peiris, W. Koudstaal, A.B. Ward, I.A. Wilson, J. Goudsmit, and R.H.E. Friesen, "Highly conserved protective epitopes on influenza B viruses," Science 337, 1343 (2012).
ALS Science Highlight #263