Crimean-Congo hemorrhagic fever survivors elicit protective non-neutralizing antibodies that target 11 overlapping regions on glycoprotein GP38

Crimean-Congo hemorrhagic fever survivors elicit protective non-neutralizing antibodies that target 11 overlapping regions on glycoprotein GP38

Crimean-Congo hemorrhagic fever virus can cause lethal disease in humans yet there are no approved medical countermeasures. Viral glycoprotein GP38, exclusive to Nairoviridae, is a target of protective antibodies and is a key antigen in preclinical vaccine candidates. Here, we isolate 188 GP38-speci...

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Bibliographic Details
Published in:Cell reports (Cambridge) Vol. 43; no. 7; p. 114502
Main Authors: Shin, Olivia S., Monticelli, Stephanie R., Hjorth, Christy K., Hornet, Vladlena, Doyle, Michael, Abelson, Dafna, Kuehne, Ana I., Wang, Albert, Bakken, Russell R., Mishra, Akaash K., Middlecamp, Marissa, Champney, Elizabeth, Stuart, Lauran, Maurer, Daniel P., Li, Jiannan, Berrigan, Jacob, Barajas, Jennifer, Balinandi, Stephen, Lutwama, Julius J., Lobel, Leslie, Zeitlin, Larry, Walker, Laura M., Dye, John M., Chandran, Kartik, Herbert, Andrew S., Pauli, Noel T., McLellan, Jason S.
Format: Journal Article
Language:English
Published: United States Elsevier Inc 23-07-2024
Elsevier
Subjects:
antibody therapeutics
BASIC BIOLOGICAL SCIENCES
CCHFV
Cell Biology
CP: Immunology
Crimean-Congo hemorrhagic fever virus
GP38
human monoclonal antibody
Nairoviridae
tickborne
viral glycoprotein
antibody therapeutics
CP: Immunology
viral glycoprotein
CCHFV
tickborne
Nairoviridae
human monoclonal antibody
Crimean-Congo hemorrhagic fever virus
GP38
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Summary:Crimean-Congo hemorrhagic fever virus can cause lethal disease in humans yet there are no approved medical countermeasures. Viral glycoprotein GP38, exclusive to Nairoviridae, is a target of protective antibodies and is a key antigen in preclinical vaccine candidates. Here, we isolate 188 GP38-specific antibodies from human survivors of infection. Competition experiments show that these antibodies bind across 5 distinct antigenic sites, encompassing 11 overlapping regions. Additionally, we show structures of GP38 bound with 9 of these antibodies targeting different antigenic sites. Although these GP38-specific antibodies are non-neutralizing, several display protective efficacy equal to or better than murine antibody 13G8 in two highly stringent rodent models of infection. Together, these data expand our understanding regarding this important viral protein and may inform the development of broadly effective CCHFV antibody therapeutics. [Display omitted] •188 monoclonal antibodies against CCHFV GP38 isolated from human survivors•Isolated antibodies are non-neutralizing and target 11 overlapping sites on GP38•Structural characterization of 9 antibodies targeting diverse epitopes•Antibodies targeting specific regions afford therapeutic efficacy Crimean-Congo hemorrhagic fever virus is widespread across Africa, Asia, and Europe and causes severe disease in humans. Shin et al. report the isolation and characterization of GP38-specific antibodies from convalescent donors. Challenge experiments with authentic virus combined with structural studies provide insights into GP38 epitopes important for protection.
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content type line 23
AC02-06CH11357
USDOE
Conceptualization, O.S.S., S.R.M., C.K.H., L.Z., L.M.W., J.M.D., K.C., A.S.H., N.T.P., and J.S.M.; methodology, O.S.S., S.R.M., and C.K.H.; formal analysis, O.S.S., S.R.M., and C.K.H.; investigation, O.S.S., S.R.M., C.K.H., V.H., M.D., D.A., A.I.K., A.W., R.R.B., A.K.M., M.M., E.C., L.S., D.P.M., J.L., J. Berrigan, and J. Barajas; resources, S.R.M., S.B., J.J.L., L.L., J.M.D., and A.S.H.; writing – original draft, O.S.S., S.R.M., C.K.H., and M.D.; writing – review & editing, all authors; visualization, O.S.S., S.R.M., C.K.H., A.S.H., N.T.P., and J.S.M.; supervision, L.Z., L.M.W., J.M.D., K.C., A.S.H., N.T.P., and J.S.M.; funding acquisition, L.Z., L.M.W., J.M.D., K.C., A.S.H., and J.S.M.
AUTHOR CONTRIBUTIONS
ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2024.114502