Therapeutic administration of a recombinant human monoclonal antibody reduces the severity of chikungunya virus disease in rhesus macaques

Abstract

Chikungunya virus (CHIKV) is a mosquito-borne virus that causes a febrile syndrome in humans associated with acute and chronic debilitating joint and muscle pain. Currently no licensed vaccines or therapeutics are available to prevent or treat CHIKV infections. We recently isolated a panel of potently neutralizing human monoclonal antibodies (mAbs), one (4N12) of which exhibited prophylactic and post-exposure therapeutic activity against CHIKV in immunocompromised mice. Here, we describe the development of an engineered CHIKV mAb, designated SVIR001, that has similar antigen binding and neutralization profiles to its parent, 4N12. Because therapeutic administration of SVIR001 in immunocompetent mice significantly reduced viral load in joint tissues, we evaluated its efficacy in a rhesus macaque model of CHIKV infection. Rhesus macaques that were treated after infection with SVIR001 showed rapid elimination of viremia and less severe joint infiltration and disease compared to animals treated with SVIR002, an isotype control mAb. SVIR001 reduced viral burden at the site of infection and at distant sites and also diminished the numbers of activated innate immune cells and levels of pro-inflammatory cytokines and chemokines. SVIR001 therapy; however, did not substantively reduce the induction of CHIKV-specific B or T cell responses. Collectively, these results show promising therapeutic activity of a human anti-CHIKV mAb in rhesus macaques and provide proof-of-principle for its possible use in humans to treat active CHIKV infections.

Review: Chikungunya Arthritis: Implications of Acute and Chronic Inflammation Mechanisms on Disease Management

“…Mutation of this conserved region allowed viral clearance and enhanced neutralization, providing the structural basis for the mechanism by which chikungunya virus evades B cell–mediated clearance in chronic joint infection . Finally, rhesus macaques with chikungunya virus infection treated with SVIR001, a recombinant human IgG1 mAb that recognizes the E2 glycoprotein of chikungunya virus, showed more robust viral clearance and less severe joint inflammation compared with isotype‐treated controls . In addition, SVIR001 reduced viral burden at the site of infection, as well as at distant sites, but also diminished the number of activated innate immune cells and levels of proinflammatory cytokines and chemokines .…”

“…Neutralizing antibodies and prophylactic treatment. A number of studies have sought to characterize the neutralizing capacity of chikungunya virus–specific antibodies, the epitopes responsible for neutralization, and the mechanism of viral inhibition . Robustly neutralizing mAb to chikungunya virus bind the E2 envelope glycoprotein with conserved epitopes identified on the A and B domain.…”

“…Finally, rhesus macaques with chikungunya virus infection treated with SVIR001, a recombinant human IgG1 mAb that recognizes the E2 glycoprotein of chikungunya virus, showed more robust viral clearance and less severe joint inflammation compared with isotype‐treated controls . In addition, SVIR001 reduced viral burden at the site of infection, as well as at distant sites, but also diminished the number of activated innate immune cells and levels of proinflammatory cytokines and chemokines . Therefore, more studies are needed to examine the utility of neutralizing antibodies as a therapeutic approach to persistent chikungunya virus infection, and to confirm the efficacy of these approaches in humans.…”

Chikungunya: treatments, opportunities and possibilities

“…Neutralising antibodies have been found to be effective in animal models of CHIKV infection 14,15 . In rhesus monkeys, administration of monoclonal antibody (mAb), SVIR001 that mimics the human anti-CHIKV mAb 4N12, resulted in rapid clearance of CHIKV infec- …”

Chikungunya Virus Infection: Why Should U.S. Geriatricians Be Aware of It?

“…General Overview of Therapeutic Approach to CHIKV Infection Although promising antivirals, 35,36 immunotherapy, 37,38 and vaccines 39,40 are being developed, there is no effective prevention or curative treatment for CHIKV. 41 Current therapeutic recommendations commonly consist of supportive care, 2 with plenty of rest, ensuring adequate fluid intake, and use of acetaminophen or NSAIDs to reduce pain and fever at the acute stage.…”