Human monoclonal antibodies against chikungunya virus target multiple distinct epitopes in the E1 and E2 glycoproteins

Abstract

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes persistent arthritis in a subset of human patients. We report the isolation and functional characterization of monoclonal antibodies (mAbs) from two patients infected with CHIKV in the Dominican Republic. Single B cell sorting yielded a panel of 46 human mAbs of diverse germline lineages that targeted epitopes within the E1 or E2 glycoproteins. MAbs that recognized either E1 or E2 proteins exhibited neutralizing activity. Viral escape mutations localized the binding epitopes for two E1 mAbs to sites within domain I or the linker between domains I and III; and for two E2 mAbs between the β-connector region and the B-domain. Two of the E2-specific mAbs conferred protection in vivo in a stringent lethal challenge mouse model of CHIKV infection, whereas the E1 mAbs did not. These results provide insight into human antibody response to CHIKV and identify candidate mAbs for therapeutic intervention.

A single dose of ChAdOx1 Chik vaccine induces neutralizing antibodies against four chikungunya virus lineages in a phase 1 clinical trial

“…Animal and epidemiological studies have shown that protection from CHIKV disease is associated with the induction of neutralizing antibodies 18 , 24 – 26 , primarily directed against structural proteins 17 – 19 . A virus-like particle (VLP) vaccine has reported to induce neutralizing antibodies eight weeks following a homologous prime-boost vaccination 27 .…”

The Structural Biology of Eastern Equine Encephalitis Virus, an Emerging Viral Threat

“…The structural and functional basis of neutralization by monoclonal antibodies (mAbs) has been previously investigated for several alphaviruses such as arthritogenic CHIKV, RRV and MAYV, and encephalitic VEEV and WEEV [ 44 , 45 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 , 141 , 142 , 143 , 144 , 145 , 146 , 147 , 148 , 149 , 150 ]. In the context of EEEV, prior investigations have focused on characterization of immune response to E2 peptides and compared their cross-reactivity to VEEV [ 151 , 152 , 153 , 154 ].…”

The Structural Biology of Eastern Equine Encephalitis Virus, an Emerging Viral Threat

“…If this hypothesis is confirmed, it would suggest that EEEV has likely evolved a means for envelope protein biogenesis while avoiding a deleterious side-effect of glycosylation, i.e., immune detection. Structural basis of EEEV neutralization by monoclonal antibodies: The structural and functional basis of neutralization by monoclonal antibodies (mAbs) has been previously investigated for alphaviruses such as arthritogenic CHIKV, RRV, and, MAYV, and encephalitic VEEV and WEEV [44,45,[132][133][134][135][136][137][138][139][140][141][142][143][144][145][146][147][148][149][150]. In the context of EEEV, prior investigations have focused on characterization of immune response to E2 peptides and compared their cross-reactivity to VEEV [151][152][153][154].…”