A Neutralizing Monoclonal Antibody Targeting the Acid-Sensitive Region in Chikungunya Virus E2 Protects from Disease

Suganya Selvarajah,Trevor Barnes,Manu Mabila,Kristen M Kahle,Beatriz Salvador,Giada Rossini,Marcus O Muench,Benjamin J Doranz,Nathan M Liss,Graham Simmons,Rachel H Fong,Kimberly-Anne Mattia,Nicole R Sexton,Joy Gardner,Xiangdong Zhou,Andreas Suhrbier,Alain Michault,Vittorio Sambri,Kai Lü ,Joseph Rucker ,D.a.r Sanders ,David Tucker

doi:10.1371/journal.pntd.0002423

Abstract

The mosquito-borne alphavirus, chikungunya virus (CHIKV), has recently reemerged, producing the largest epidemic ever recorded for this virus, with up to 6.5 million cases of acute and chronic rheumatic disease. There are currently no licensed vaccines for CHIKV and current anti-inflammatory drug treatment is often inadequate. Here we describe the isolation and characterization of two human monoclonal antibodies, C9 and E8, from CHIKV infected and recovered individuals. C9 was determined to be a potent virus neutralizing antibody and a biosensor antibody binding study demonstrated it recognized residues on intact CHIKV VLPs. Shotgun mutagenesis alanine scanning of 98 percent of the residues in the E1 and E2 glycoproteins of CHIKV envelope showed that the epitope bound by C9 included amino-acid 162 in the acid-sensitive region (ASR) of the CHIKV E2 glycoprotein. The ASR is critical for the rearrangement of CHIKV E2 during fusion and viral entry into host cells, and we predict that C9 prevents these events from occurring. When used prophylactically in a CHIKV mouse model, C9 completely protected against CHIKV viremia and arthritis. We also observed that when administered therapeutically at 8 or 18 hours post-CHIKV challenge, C9 gave 100% protection in a pathogenic mouse model. Given that targeting this novel neutralizing epitope in E2 can potently protect both in vitro and in vivo, it is likely to be an important region both for future antibody and vaccine-based interventions against CHIKV.

Highlights

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus first isolated in Tanzania in 1952 [1] that has caused sporadic outbreaks of predominantly rheumatic disease every 2–50 years, primarily in Africa and Asia
We identified and characterized human monoclonal antibodies directed against CHIKV that could be utilized in prophylactic and immediate post-exposure settings
C9 potently inhibited CHIKV infection in cells and prevented viremia and arthritis in a mouse model of CHIKV disease. The epitope for this antibody includes an amino-acid residue in a key acidsensitive region of the E2 glycoprotein of CHIKV

Summary

Introduction

Chikungunya virus (CHIKV) is a mosquito-borne alphavirus first isolated in Tanzania in 1952 [1] that has caused sporadic outbreaks of predominantly rheumatic disease every 2–50 years, primarily in Africa and Asia. CHIKV disease is characterized by acute and chronic polyarthritis/polyarthralgia, which is usually symmetric and often incapacitating and occasionally protracted [4,5,6,7,8]. Other symptoms, such as fever, rash, myalgia, and/or fatigue, are often present during the acute phase. The recent epidemic was associated with atypical and severe clinical forms of CHIKV disease and some fatalities, which appeared to be restricted to the very young and elderly patients with comorbidities [8,9]

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Conclusion