Research Article

Potent neutralization of Rift Valley fever virus by human monoclonal antibodies through fusion inhibition

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PNAS April 6, 2021 118 (14) e2025642118; https://doi.org/10.1073/pnas.2025642118

  1. Edited by Rino Rappuoli, Fondazione Toscana Life Sciences, Siena, Italy, and approved February 22, 2021 (received for review December 15, 2020)

This article has been updated

Significance

Rift Valley fever virus (RVFV)–specific monoclonal antibodies from survivors of natural infection and vaccination were isolated to understand how RVFV is targeted for neutralization by the human immune system. These antibodies bind to specific regions of the viral surface, some of which are complex quaternary epitopes, and they block RVFV infection at extremely low concentrations. A new mechanism by which these mAbs can neutralize RVFV is described whereby the antibody may prevent necessary structural rearrangements in the viral proteins for infection. The antibodies isolated here have potential use in pre-exposure prophylaxis or post-exposure therapy against RVFV infection and should be studied further in that context.

Abstract

Rift Valley fever virus (RVFV), an emerging arboviral and zoonotic bunyavirus, causes severe disease in livestock and humans. Here, we report the isolation of a panel of monoclonal antibodies (mAbs) from the B cells of immune individuals following natural infection in Kenya or immunization with MP-12 vaccine. The B cell responses of individuals who were vaccinated or naturally infected recognized similar epitopes on both Gc and Gn proteins. The Gn-specific mAbs and two mAbs that do not recognize either monomeric Gc or Gn alone but recognized the hetero-oligomer glycoprotein complex (Gc+Gn) when Gc and Gn were coexpressed exhibited potent neutralizing activities in vitro, while Gc-specific mAbs exhibited relatively lower neutralizing capacity. The two Gc+Gn–specific mAbs and the Gn domain A-specific mAbs inhibited RVFV fusion to cells, suggesting that mAbs can inhibit the exposure of the fusion loop in Gc, a class II fusion protein, and thus prevent fusion by an indirect mechanism without direct fusion loop contact. Competition-binding analysis with coexpressed Gc/Gn and mutagenesis library screening indicated that these mAbs recognize four major antigenic sites, with two sites of vulnerability for neutralization on Gn. In experimental models of infection in mice, representative mAbs recognizing three of the antigenic sites reduced morbidity and mortality when used at a low dose in both prophylactic and therapeutic settings. This study identifies multiple candidate mAbs that may be suitable for use in humans against RVFV infection and highlights fusion inhibition against bunyaviruses as a potential contributor to potent antibody-mediated neutralization.

Footnotes

  • Author contributions: N.S.C., H.Z., A.D.L., D.H.F., and J.E.C. designed research; N.S.C., H.Z., N.K., J.B.W., B.K., R.B., J.R., R.S., J.G., F.M.M., A.N.F., and B.B.G. performed research; P.R.P. contributed new reagents/analytic tools; N.S.C., H.Z., N.K., J.B.W., R.B., A.N.F., B.B.G., D.H.F., and J.E.C. analyzed data; and N.S.C. and J.E.C. wrote the paper.

  • Competing interest statement: J.E.C. has served as a consultant for Luna Biologics and Eli Lilly; is on the Scientific Advisory Boards of CompuVax and Meissa Vaccines; is a recipient of previous or active unrelated research grants from Astra Zeneca, Takeda, and IDBiologics; and is a founder of IDBiologics. Vanderbilt University has applied for patents concerning RVFV antibodies that are related to this work.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2025642118/-/DCSupplemental.

Data Availability

All study data are included in the article and/or SI Appendix.

Change History

March 31, 2021: Fig. 3 has been updated.

Published under the PNAS license.

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Proceedings of the National Academy of Sciences: 118 (14)
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