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

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.

A Novel Poxvirus-Based Vaccine, MVA-CHIKV, Is Highly Immunogenic and Protects Mice against Chikungunya Infection

“…In addition, natural antibodies present in the sera of uninfected C57BL/6 mice were able to partially inhibit CHIKV (75). Furthermore, therapies based on passively transferred anti-CHIKV neutralizing antibodies conferred protection to A129 mice (42,44,45,70,71,73,(76)(77)(78) and nonhuman primates (37) against CHIKV and protection to mice against more distantly related arthrogenic alphaviruses (43,93,96), establishing the key role of humoral immunity in the control of CHIKV replication. Interestingly, complete protection from CHIKV challenge can be obtained using adoptive transfer of antibodies induced by immunization with a CHIKV/IRES vaccine candidate and occurs in the absence of CD4 ϩ /CD8 ϩ T cells (42); a titer of 35 for neutralizing antibodies was sufficient to protect mice from a challenge with 100 PFU of CHIKV (42).…”

“…Antibodies against CHIKV are crucial to control CHIKV infection (37,42,44,45,(70)(71)(72)(73)(74)(75)(76)(77)(78). Thus, to study the ability of MVA-CHIKV to elicit humoral immune responses against CHIKV, we analyzed the levels of CHIKV envelope-specific antibodies present in the sera of C57BL/6 mice immunized with one or two doses of MVA-CHIKV (see Materials and Methods).…”

Attenuated and vectored vaccines protect nonhuman primates against Chikungunya virus

“…Thus, it was of importance to assess the individual merits of new CHIKV vaccine platforms in a more stringent animal model that more closely resembles a clinical setting. Antibody responses are known to correlate with protection against CHIKV (29)(30)(31)(32)(33)(34)(35)(36), but CD4 T cell responses may also be important (37)(38)(39). Thus, it was of importance to determine the potential immunological differences that our vaccine candidate might display.…”

Chikungunya virus: epidemiology, replication, disease mechanisms, and prospective intervention strategies

“…174). Passive transfer of antisera (104,106,175) or isolated monoclonal antibodies protects against CHIKV disease in mice (160,161,176) or NHPs (177). Furthermore, in postexposure therapeutic trials, monoclonal antibodies protect against CHIKV disease in mice, even when administered at late times of infection (160,161), suggesting that immunotherapy would be effective for treatment of CHIKV infection.…”