Research ArticleEMERGING INFECTIONS

A lipid-encapsulated mRNA encoding a potently neutralizing human monoclonal antibody protects against chikungunya infection

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Science Immunology  17 May 2019:
Vol. 4, Issue 35, eaaw6647
DOI: 10.1126/sciimmunol.aaw6647

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mRNA-based passive immunotherapy

Passive transfer of neutralizing antibodies can protect against disease caused by chikungunya virus, an emerging mosquito-borne pathogen. However, effective treatment of chikungunya-infected patients with symptomatic disease using antibodies will require identification of high-potency immunoglobulins and an efficient platform for delivering them to patients. Kose et al. screened immortalized human B cells from a chikungunya survivor and identified a monoclonal IgG antibody with exceptional neutralizing capacity. Intravenous injection of a lipid nanoparticle–encapsulated mRNA molecule encoding this antibody protected mice against viral infection and virus-associated arthritis and also induced protective concentrations of serum antibody in macaques. The preclinical results achieved in this study paved the way for the start of translational clinical trials of mRNA-based passive immunotherapy for human chikungunya infection.

Abstract

Infection with chikungunya virus (CHIKV) causes an acute illness characterized by fever, rash, and arthralgia. However, CHIKV infection can sometimes progress to chronic arthritis or even lethal disease. CHIKV continues to cause substantial morbidity worldwide as its vector mosquitoes expand and spread. There are currently no approved vaccines or antiviral drugs available for the prevention or treatment of CHIKV. Although antibody therapy has shown promise in the prevention or treatment of CHIKV disease in preclinical models, challenges remain for implementing such therapies. Here, from the B cells of a survivor of natural CHIKV infection, we isolated ultrapotent neutralizing human monoclonal antibodies (mAbs) and encoded their sequences into mRNA molecules delivered by infusion. One human mAb, CHKV-24, was expressed to biologically significant levels in vivo after infusion of mRNAs in lipid nanoparticles in mice. We evaluated the protective capacity of CHKV-24 mAb immunoglobulin G protein or mRNA in mouse models of CHIKV infection. Treatment with CHKV-24 mRNA protected mice from arthritis, musculoskeletal tissue infection, and lethality and reduced viremia to undetectable levels at 2 days after inoculation. Infusion of macaques with CHKV-24 mRNA achieved a mean maximal mAb concentration of 10.1 to 35.9 micrograms per milliliter, with a half-life of 23 days, a level well above what is needed for protection in mice. Studies with CHKV-24 mRNA in macaques demonstrated a dose-response effect after the first dose of mRNA and maintained levels after second dose. These preclinical data with CHKV-24 mRNA suggest that it might be useful to prevent human disease.

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