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

Nurgun Kose, Julie M. Fox, Gopal Sapparapu, Robin Bombardi, Rashika N. Tennekoon, A. Dharshan De Silva, Sayda M. Elbashir, Matthew A. Theisen, Elisabeth Humphris-Narayanan, Giuseppe Ciaramella, Sunny Himansu, Michael S. Diamond, James E. Crowe

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18 Scopus citations

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.

Original languageEnglish
Article numbereaaw6647
JournalScience immunology
Volume4
Issue number35
DOIs
StatePublished - Jan 1 2019

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    Kose, N., Fox, J. M., Sapparapu, G., Bombardi, R., Tennekoon, R. N., Dharshan De Silva, A., Elbashir, S. M., Theisen, M. A., Humphris-Narayanan, E., Ciaramella, G., Himansu, S., Diamond, M. S., & Crowe, J. E. (2019). A lipid-encapsulated mRNA encoding a potently neutralizing human monoclonal antibody protects against chikungunya infection. Science immunology, 4(35), [eaaw6647]. https://doi.org/10.1126/sciimmunol.aaw6647