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A recent study in the journal Science describes an experimental vaccine directed against respiratory syncytial virus (RSV), which is the second only to malaria in worldwide deaths of infants between one to twelve months of age. The vaccine was tested in both mice and macaques and elicited high levels of RSV-specific antibodies. The tests were so promising that early-stage human clinical trials are planned, as soon as clinical grade material can be produced.

The research, from a team in the Vaccine Research Centre (VRC) of the National Institute of Allergy and Infectious Diseases (NIAID), built on an earlier work also published in Science. In this previous work the group obtained atomic-level details of the fusion (F) glycoprotein of RSV bound to a broadly neutralising human RSV antibody. The researchers found that a region they termed antigenic site zero was exposed in RSV before it fuses with a cell and is particularly vulnerable to broadly neutralising antibodies. However, following cell fusion, the antigenic site zero effectively disappears due to F glycoprotein rearrangement. Antibodies to antigenic site zero are much more strongly neutralising than other anti-RSV antibodies, so the research team reasoned that a vaccine directed against pre-fusion F glycoprotein would be more effective than one directed against post-fusion RSV as it would elicit a more powerful antibody response. In the new study, the researchers acted on this by engineering stable variants of the F glycoprotein viral antigen which retained antigenic site zero in the absence of bound antibody. Stabilised versions of the F glycoprotein were generated that were able to withstand extremes of pH, osmolality, and temperature. Examination of X-ray crystallographic structures revealed that introduction of cysteine residues and filled hydrophobic cavities improved stability. Testing of variants on mice and macaques revealed that increased variant stability was directly related to the levels of neutralising antibody response elicited. One of the engineered antigens elicited a response ten times greater than that produced by post-fusion F protein vaccination and well in excess of threshold levels needed to protect against RSV infection.

Dr Graham, one of the lead authors of the study, points out that this is an example of a case in which “information gained from structural biology has provided the insight needed to solve an immunological puzzle and apply the findings to address a real-world public health problem”. The human clinical tests are expected to proceed in the next 18 to 24 months and will provide hope for a vaccine at last against this devastating disease.

Sources

NIH/National Institute of Allergy and Infectious Diseases. "Scientists develop candidate vaccine against respiratory syncytial virus." ScienceDaily, 31 Oct. 2013. [Accessed 20 Nov. 2013].

McLELLAN, J.S., CHEN, M., JOYCE, M. G., SASTRY, M., STEWART-JONES, G. B. E., YANG, Y., ZHANG, B., CHEN, L., SRIVATSAN, S., ZHENG, A., ZHOU, T., GRAEPEL, K. W., KUMAR, A., MOIN, S., BOYINGTON, J. C., CHUANG, G.-Y., SOTO, C., BAXA, U., BAKKER, A. Q., SPITS, H., BEAUMONT, T., ZHENG, Z., XIA, N., KO, S.-Y., TODD, J.-P., RAO, S., GRAHAM, B. S. and KWONG, P. D., 2013. Structure-Based Design of a Fusion Glycoprotein Vaccine for Respiratory Syncytial Virus. Science, 2013; 342 (6158): 592 DOI: 10.1126/science.1243283

MCLELLAN, J.S., CHEN, M., LEUNG, S., GRAEPEL, K. W., DU, X., YANG, Y., ZHOU, T., BAXA, U., YASUDA, E., BEAUMONT, T., KUMAR, A., MODJARRAD, K., ZHENG, Z., ZHAO, M., XIA, N., KWONG, P. D. and GRAHAM, B. S., 2013. Structure of RSV Fusion Glycoprotein Trimer Bound to a Prefusion-Specific Neutralizing Antibody. Science, 2013; 340 (6136): 1113 DOI: 10.1126/science.1234914