GP38-targeting monoclonal antibodies protect adult mice against lethal Crimean-Congo hemorrhagic fever virus infection

Abstract

Crimean-Congo hemorrhagic fever virus (CCHFV) is an important human pathogen. Limited evidence suggests that antibodies can protect humans against lethal CCHFV disease but the protective efficacy of antibodies has never been evaluated in adult animal models. Here, we used adult mice to investigate the protection provided against CCHFV infection by glycoprotein-targeting neutralizing and non-neutralizing monoclonal antibodies (mAbs). We identified a single non-neutralizing antibody (mAb-13G8) that protected adult type I interferon–deficient mice >90% when treatment was initiated before virus exposure and >60% when administered after virus exposure. Neutralizing antibodies known to protect neonatal mice from lethal CCHFV infection failed to confer protection regardless of immunoglobulin G subclass. The target of mAb-13G8 was identified as GP38, one of multiple proteolytically cleaved glycoproteins derived from the CCHFV glycoprotein precursor polyprotein. This study reveals GP38 as an important antibody target for limiting CCHFV pathogenesis and lays the foundation to develop immunotherapeutics against CCHFV in humans.

Structure and Characterization of Crimean-Congo Hemorrhagic Fever Virus GP38

“…To express GP38 we used a construct containing the first 515 residues of CCHFV GPC, including the native signal peptide and MLD, which ultimately were removed from mature GP38 by proteolytic processing. However, Golden et al used a tissue plasminogen activator secretion signal fused to the GP38 coding region to express and purify soluble GP38, indicating that the MLD is not required for proper maturation of GP38 (15). We also report the serum reactivity of convalescent CCHFV donors to GP38 ( GP38 is a nairovirus-specific protein with <20% sequence similarity to other viral or cellular proteins.…”

“…The studies performed here extend the protective range of mAb 13G8 beyond strain IbAr 10200 to include strain Turkey2004 (85% sequence identity to IbAr 10200). The ability of c13G8 to completely protect mice infected with strain Turkey2004 was unexpected given that m13G8 showed only limited protection in mice challenged with strain Afg09-2990 (91% sequence identity to IbAr 10200) (15). In addition, we only used a single dose of 250 µg on August 16, 2020 by guest http://jvi.asm.org/ Downloaded from antibody per mouse for protection as compared to two doses of 1 mg antibody per mouse in the previous study.…”

“…It was previously shown that the murine mAb 13G8 (m13G8) is a non-neutralizing but protective CCHFV antibody, now known to specifically target GP38 (15). m13G8 was raised against strain IbAr 10200 (clade III CCHFV) and was 90% protective against the same strain when administered before virus exposure in adult type I interferon receptor-knockout (IFNAR -/-) mice (15). However, the same study showed that m13G8 was only 20% protective against the strain on August 16, 2020 by guest http://jvi.asm.org/…”

“…Interestingly, Gc-specific neutralizing mAbs provided no such protection (15). Since no CCHFV Gn-specific mAbs have yet been reported, mAb 13G8 remains the only antibody to show protection against CCHFV in an adult mouse model.…”

“…The neutralizing mAbs were shown to target Gc, whereas the non-neutralizing mAbs were reported to target Gn (14). Golden et al recently reported that the protective non-neutralizing antibodies, initially thought to target Gn, actually bind to GP38 (15). One of these antibodies, 13G8, was shown to be protective in an adult type-I interferon-deficient mouse model for CCHFV (15).…”