Author: Hornet, Vladlena ; Zeitlin, Larry ; Kuehne, Ana I ; Abelson, Dafna ; Pauli, Noel T ; Herbert, Andrew S ; Lutwama, Julius J ; Barajas, Jennifer ; Maurer, Daniel P ; Stuart, Lauran ; Mishra, Akaash K ; Lobel, Leslie ; Shin, Olivia S ; Champney, Elizabeth ; Doyle, Michael ; Bakken, Russell R ; Berrigan, Jacob ; Wang, Albert ; Li, Jiannan ; McLellan, Jason S ; Walker, Laura M ; Dye, John M ; Balinandi, Stephen ; Chandran, Kartik ; Monticelli, Stephanie R ; Middlecamp, Marissa ; Hjorth, Christy K

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.

31 Mar 2020·Journal of VirologyQ2 · MEDICINE

Structure and Characterization of Crimean-Congo Hemorrhagic Fever Virus GP38

Q2 · MEDICINE

Article

Author: Moyer, Crystal L. ; Mishra, Akaash K. ; El Omari, Kamel ; Bornholdt, Zachary A. ; Abelson, Dafna M. ; Deer, Daniel J. ; McLellan, Jason S. ; Wagner, Armin ; Duman, Ramona ; Geisbert, Thomas W. ; Cross, Robert W. ; Dye, John M. ; Chandran, Kartik ; Lutwama, Julius J. ; Lobel, Leslie ; Zeitlin, Larry

Crimean-Congo hemorrhagic fever virus (CCHFV) is a priority pathogen that poses a high risk to public health. Due to the high morbidity and mortality rates associated with CCHFV infection, there is an urgent need to develop medical countermeasures for disease prevention and treatment. CCHFV GP38, a secreted glycoprotein of unknown function unique to the Nairoviridae family, was recently shown to be the target of a protective antibody against CCHFV. Here, we present the crystal structure of GP38, which revealed a novel fold with distant homology to another CCHFV glycoprotein that is suggestive of a gene duplication event. We also demonstrate that antibody 13G8 protects STAT1-knockout mice against heterologous CCHFV challenge using a clinical isolate from regions where CCHFV is endemic. Collectively, these data advance our understanding of GP38 structure and antigenicity and should facilitate future studies investigating its function.

Crimean-Congo Hemorrhagic Fever Survivors Elicit Protective Non-Neutralizing Antibodies that Target 11 Overlapping Regions on Viral Glycoprotein GP38

Author: Hornet, Vladlena ; Monticelli, Stephanie R ; Abelson, Dafna ; Middlecamp, Marissa ; Lutwama, Julius J ; Maurer, Daniel P ; Hjorth, Christy K ; Bakken, Russell R ; Dye, John M ; Kuehne, Ana I ; Lobel, Leslie ; Shin, Olivia S ; Champney, Elizabeth ; Doyle, Michael ; Herbert, Andrew S ; Stuart, Lauran ; Berrigan, Jacob ; Wang, Albert ; Li, Jiannan ; Barajas, Jennifer ; Zeitlin, Larry ; Walker, Laura M ; Pauli, Noel T ; Mishra, Akaash ; Balinandi, Stephen ; Chandran, Kartik ; McLellan, Jason S

SUMMARYCrimean-Congo hemorrhagic fever virus can cause lethal disease in humans yet there are no approved medical countermeasures. Viral glycoprotein GP38, unique toNairoviridae, is a target of protective antibodies, but extensive mapping of the human antibody response to GP38 has not been previously performed. Here, we isolated 188 GP38-specific antibodies from human survivors of infection. Competition experiments showed that these antibodies bind across five distinct antigenic sites, encompassing eleven overlapping regions. Additionally, we reveal structures of GP38 bound with nine of these antibodies targeting different antigenic sites. Although GP38-specific antibodies were non-neutralizing, several antibodies were found to have protection 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 inform the development of broadly effective CCHFV antibody therapeutics.

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Indication	Highest Phase	Country/Location	Organization	Date
Hemorrhagic Fever, Crimean	Preclinical	US	University of Georgia	26 Nov 2022
Hemorrhagic Fever, Crimean	Preclinical	US	University of Maryland Baltimore	26 Nov 2022

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