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

The continued threat of emerging flaviviruses

“…Antibody discovery efforts for emerging flaviviruses will be a powerful component of preparedness efforts because they inform the development of diagnostics, allow for characterization of vaccine antigens and identify protective features of the immune response. Moreover, in vivo expression of potent flavivirus-reactive neutralizing antibodies using recently developed synthetic gene-expressing platforms, such as modified messenger RNA, provides a rapid pathway for the development of therapeutics 292 . While these gene-expression platforms also enable the rapid development of vaccine candidates, an understanding of structureimmunogen relationships and the correlates of protection may be insufficient to ensure rapid success for understudied flaviviruses in an outbreak setting.…”

In Vivo Delivery of Nucleic Acid-Encoded Monoclonal Antibodies

“…To date, mRNA-mAbs, formulated in LNP, have been evaluated targeting rabies [15], HIV [49], and CHIKV [127]. Human anti-rabies immunoglobulin and the rabies vaccine must be delivered immediately following potential rabies exposure.…”

“…Recently, Kose et al described an anti-CHIKV mRNA-mAb that was delivered by IV injection to AG129 mice that were then challenged with CHIKV. They demonstrated dose-dependent protection against the virus, with no viral load and protection against arthritis and muscoskeletal disease in competent C57BL6 mice [127]. They further evaluated expression in cynomolgus macaques, indicating rapid expression of mRNA, and repeat dosing at a 7-day interval.…”

“…Wise et al demonstrated that using an optimized delivery strategy with a 6-mg dose, divided across six injection sites, anti-HIV DMAb delivery can achieve in vivo expression levels as high as 34.4 µg/ mL [43]. These expression levels parallel mRNA expression levels, which are at > 30 μg/mL in rhesus macaques [127]. Only AAV can surpass these levels in macaques; however, virus take in animals is reported to be not consistent with AAV, and there were wide variations in delivery observed, ranging from 0 to 270 µg/mL across multiple studies.…”

The promise of mRNA vaccines: a biotech and industrial perspective

“…1 mRNA constructs can also be used to express potent monoclonal antibodies for novel immunoprophylaxis. 2 Here we review the state of the art in mRNA constructs and delivery technologies for the prevention of infectious diseases, and a review of pertinent topics to the biotechnology and pharmaceutical industries.…”