Repeated exposure to heterologous hepatitis C viruses associates with enhanced neutralizing antibody breadth and potency
Abstract
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.
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 http://creativecommons.org/licenses/by/4.0/. 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.Attached Files
Accepted Version - 160058.1-20220518181406-covered-e0fd13ba177f913fd3156f593ead4cfd.pdf
Supplemental Material - 160058-JCI-RG-RV-2_sd_590949.pdf
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Additional details
- Eprint ID
- 115671
- Resolver ID
- CaltechAUTHORS:20220718-362013200
- R01AI127469
- NIH
- U19 AI088791
- NIH
- Cancer Research Institute
- Created
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2022-07-20Created from EPrint's datestamp field
- Updated
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2022-09-02Created from EPrint's last_modified field