A Lipid-encapsulated mRNA Encoding a Potently Neutralizing Human Monoclonal Antibody Protects Against Chikungunya Infection


Authors: N. Kose, J.M. Fox, G. Sapparapu, R. Bombardi, R.N. Tennekoon, A.D. de Silva, S.M. Elbashir, M.A. Theisen, E. Humphris-Narayanan, G. Ciaramella, S. Himansu, M.S. Diamond and J.E. Crowe Jr.

Journal: Science Immunology

DOI: 10.1126/sciimmunol.aaw6647

Publication - Summary

May 17, 2019

Summary

Scientists affiliated with Moderna, Vanderbilt, and Washington University (St. Louis) have demonstrated vaccination by lipid nanoparticle (LNP) containing mRNA encoding a human antibody against chikungunya virus. This differs from other work by Moderna where they have delivered an mRNA encoding a viral antigen as a vaccine. Chikungunya is a mosquito bourne virus that causes symptoms of arthritis, sometimes being severe.  The researchers selected the most effective antibodies against the virus from a group of people who had been exposed to the virus previously. They then encoded this antibody in mRNA, formulated it into an LNP using NanoAssemblr technology. They found the formulation was effective in preventing arthritis in healthy mice exposed to the virus and in protecting against a lethal exposure in immune-compromised mice. In non-human primate studies, they observed very high levels of mAb expression (serum concentrations as high as 28.8 µg/mL) following infusion with mRNA LNPs. This work demonstrates how therapeutic antibodies can be delivered via mRNA. This would allow different antibodies, including a variety of engineered antibodies to be encoded and delivered with minimal redevelopment of the delivery technology. 

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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