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Repeated exposure to heterologous hepatitis C viruses associates with enhanced neutralizing antibody breadth and potency

Frumento, Nicole and Figueroa, Alexis and Wang, Tingchang and Zahid, Muhammad N. and Wang, Shuyi and Massaccesi, Guido and Stavrakis, Georgia and Crowe, James E., Jr. and Flyak, Andrew I. and Ji, Hongkai and Ray, Stuart C. and Shaw, George M. and Cox, Andrea L. and Bailey, Justin R. (2022) Repeated exposure to heterologous hepatitis C viruses associates with enhanced neutralizing antibody breadth and potency. Journal of Clinical Investigation, 132 (15). ISSN 1558-8238. doi:10.1172/jci160058.

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A prophylactic hepatitis C virus (HCV) vaccine that elicits neutralizing antibodies could be key to HCV eradication. However, the genetic and antigenic properties of HCV envelope (E1E2) proteins capable of inducing anti-HCV broadly neutralizing antibodies (bNAbs) in humans have not been defined. Here, we investigated the development of bNAbs in longitudinal plasma of HCV-infected persons with persistent infection or spontaneous clearance of multiple reinfections. By measuring plasma antibody neutralization of a heterologous virus panel, we found that the breadth and potency of the antibody response increased upon exposure to multiple genetically distinct infections and with longer duration of viremia. Greater genetic divergence between infecting strains was not associated with enhanced neutralizing breadth. Rather, repeated exposure to antigenically-related, antibody sensitive E1E2s was associated with potent bNAb induction. These data reveal that a prime-boost vaccine strategy with genetically distinct, antibody sensitive viruses is a promising approach to induce potent bNAbs in humans.

Item Type:Article
Related URLs:
URLURL TypeDescription Material
Frumento, Nicole0000-0002-1697-7110
Wang, Tingchang0000-0002-2377-9606
Massaccesi, Guido0000-0002-4528-0937
Crowe, James E., Jr.0000-0002-0049-1079
Flyak, Andrew I.0000-0002-8722-479X
Ji, Hongkai0000-0002-6480-0141
Ray, Stuart C.0000-0002-1051-7260
Cox, Andrea L.0000-0002-9331-2462
Bailey, Justin R.0000-0001-5704-3130
Additional Information:© 2022, Frumento et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit Version 1 (May 19, 2022). We thank Kaitlyn Clark for technical support. This research was supported by the National Institutes of Health grant R01AI127469 (to J.R.B. and J.E.C.) and U19 AI088791 (to J.R.B., G.M.S., and A.L.C.). A.I.F. is a Cancer Research Institute Irvington Fellow supported by the Cancer Research Institute. Content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Authors contributions: J.R.B., and A.L.C conceived the study; M.N.Z., S.W., and G.M.S. performed viral sequencing and sequence analysis; S.W. and H.J. performed the statistical analysis; N.F. and A.F. performed binding, and neutralization experiments; J.E.C. and A.I.F. provided antibodies; N.F., A.L.C., G.M.S., G.S. and J.R.B. analyzed the data; N.F. and J.R.B. wrote the original draft; and all authors reviewed and edited the manuscript. Conflict of Interest: A.I.F., J.E.C., and J.R.B. are inventors of patents submitted pertaining to some of the antibodies presented in this paper. J.E.C. has served as a consultant for Luna Innovations, Merck, and GlaxoSmithKline, is a member of the Scientific Advisory Board of Meissa Vaccines and is Founder of IDBiologics. The Crowe laboratory at Vanderbilt University Medical Center has received sponsored research agreements from Takeda Pharmaceuticals, IDBiologics and AstraZeneca. The other authors declare no competing interests.
Funding AgencyGrant Number
NIHU19 AI088791
Cancer Research InstituteUNSPECIFIED
Subject Keywords:Broadly neutralizing antibodies, HCV, E1E2, antigen, vaccine
Issue or Number:15
Record Number:CaltechAUTHORS:20220718-362013200
Persistent URL:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:115671
Deposited By: Tony Diaz
Deposited On:20 Jul 2022 17:22
Last Modified:02 Sep 2022 16:51

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