On Track towards a Zika Virus Vaccine
Antibody’s molecular structure reveals how it recognizes the virus.
Infection by the mosquito-borne Zika virus is usually asymptomatic or results in only mild symptoms. However, babies born to women infected during pregnancy are at risk of devastating neurodevelopmental abnormalities, including microcephaly. A team isolated and characterized antibodies from patients infected with the Zika virus with the goal of discovering new ways of fighting the virus. The team identified a class of antibodies that target a region of the antigenic Zika virus envelope protein known as the “lateral ridge.” Antibodies that attack this region of the virus are some of the most potent, indicating that the ridge is an ideal target for vaccine development.
Currently, avoiding mosquito bites is the only prevention strategy against Zika infection, as there is no vaccine or treatment. An effective vaccine against Zika infection could prevent devastating birth defects from children born to infected mothers. While efforts to develop a vaccine often use all or most of the virus to stimulate the immune system, the research team believes that focusing the immune system toward the lateral ridge portion of the Zika virus’ envelope protein domain III (EDIII) would result in a more effective vaccine.
The research team from the Rockefeller University and Caltech, along with collaborators working in Pau da Lima, Brazil and Santa Maria Mixtequilla, Mexico, and led by Dr. Davide Robbiani, screened blood samples from more than 400 people from areas in Brazil and Mexico exposed to Zika virus for antibodies capable of binding to Zika virus EDIII. The virus uses EDIII to attach to human cells and initiate infection, and therefore, it is a prime target for treatment and vaccine development. After identifying six patients with high antibody response against Zika virus EDIII, the team found that five out of the six patients had nearly identical antibodies, suggesting that these molecules were particularly good at fighting the virus. Interestingly, the antibodies are capable of not only preventing Zika infection but also infection by another flavivirus, dengue virus (DENV1). In fact, the antibodies may have been initially generated in response to an earlier infection by DENV1. Using data collected from beamline 12-2 at the Department of Energy’s Stanford Synchrotron Radiation Lightsource, the team solved crystal structures of two of these antibodies — one in complex with the Zika EDIII antigenic protein domain (Z006-ZIKV EDIII complex) and the other in complex with dengue envelope protein antigen (Z004-DENV1 EDIII) — to better understand how these antibodies work to prevent infection and how they recognize antigens from two different viruses. The two structures are themselves very similar, and when the complexes are superimposed, aligning the EDIII protein domains, the team observed that the two antibodies bind in roughly the same orientation, each recognizing the structurally similar lateral ridge on the viral protein EDIII domain. Despite the two antibodies having originated from different donors, they make interactions with the lateral ridge in a very similar way. This more detailed understanding of how this class of antibodies interacts with the Zika and dengue viral proteins could lead to a new way to fight the diseases, including a vaccine.
This work was supported by National Institutes of Health (NIH) pilot awards U19AI111825 (to D.F.R.) and UL1TR001866 (to D.F.R. and L.B.); grants R01AI037526, UM1AI100663, U19AI111825, and UL1TR001866 (to M.C.N.); grants R01AI121207, R01TW009504, R25TW009338, and U01AI088752 (to A.I.K.); grants R01AI124690 (to C.M.R.) and U19AI057229 (Cooperative Centers for Translational Research in Human Immunology Opportunity Fund Project to C.M.R. and M.R.M.); donors to the Zika Fund at Rockefeller University and anonymous donors (to C.M.R.), and the Molecular Observatory at Caltech supported by the Gordon and Betty Moore Foundation (P.J.B.). Operations at the Stanford Synchrotron Radiation Light Source (SSRL) are supported by the U.S. Department of Energy (DOE), Office of Science, Office of Basic Energy Sciences under contract DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE, Office of Science, Office of Biological and Environmental Research, and by the NIH, National Institute of General Medical Sciences (P41GM103393). Support was also provided by the Robertson Therapeutic Development Fund (to D.F.R. and M.C.N.). P.C.O. is supported by the Pew Latin American Fellows Program in the Biomedical Sciences, D.S.B. by Studienstiftung des deutschen Volkes, L.F.K.U. by the Austrian Marshall Plan Foundation, and E.E.S.R. is partly supported by Red INMUNOCANEI-Conacyt. M.C.N. is a Howard Hughes Medical Institute Investigator.
D.F. Robbiani, L. Bozzacco, J.R. Keeffe, R. Khouri, P.C. Olsen, A. Gazumyan, D. Schaefer-Babajew, S. Avila-Rios, L. Nogueira, R. Patel, S.A. Azzopardi, L.F.K. Uhl, M. Saeed, E.E. Sevilla-Reyes, M. Agudelo, K.H. Yao, J. Golijanin, H.B. Gristick, Y.E. Lee, A. Hurley, M. Caskey, J. Pai, T. Oliveira, E.A. Wunder, Jr., G. Sacramento, N. Nery, Jr., C. Orge, F. Costa, M.G. Reis, N.M. Thomas, T. Eisenreich, D.M. Weinberger, A.R.P. d. Almeida, A.P. West, Jr., C.M. Rice, P.J. Bjorkman, G. Reyes-Teran, A.I. Ko, M.R. MacDonald and M.C. Nussenzweig, “Recurrent potent human neutralizing antibodies to Zika virus in Brazil and Mexico.” Cell 169, 597 (2017). [DOI:10.1016/j.cell.2017.04.024]