Modified mRNA Vaccines Protect against Zika Virus Infection

• Published in: Cell 2017-03, Vol.168 (6), p.1114-1125.e10
• Main Authors: Richner, Justin M., Himansu, Sunny, Dowd, Kimberly A., Butler, Scott L., Salazar, Vanessa, Fox, Julie M., Julander, Justin G., Tang, William W., Shresta, Sujan, Pierson, Theodore C., Ciaramella, Giuseppe, Diamond, Michael S.
• Format: Article
• Language: English
• Subjects: Animals; antibody neutralization; Dengue virus; Epitopes - immunology; Female; flavivirus; immunity; Lipids - chemistry; Mice; Mice, 129 Strain; Mice, Inbred BALB C; Mice, Inbred C57BL; Nanoparticles - chemistry; pathogenesis; protection; RNA vaccine; RNA, Messenger - administration & dosage; RNA, Messenger - genetics; RNA, Messenger - immunology; Viral Vaccines - administration & dosage; Viral Vaccines - immunology; Zika virus; Zika Virus - immunology; Zika Virus Infection - immunology; Zika Virus Infection - prevention & control
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2017.02.017

The emergence of ZIKV infection has prompted a global effort to develop safe and effective vaccines. We engineered a lipid nanoparticle (LNP) encapsulated modified mRNA vaccine encoding wild-type or variant ZIKV structural genes and tested immunogenicity and protection in mice. Two doses of modified mRNA LNPs encoding prM-E genes that produced virus-like particles resulted in high neutralizing antibody titers (∼1/100,000) that protected against ZIKV infection and conferred sterilizing immunity. To offset a theoretical concern of ZIKV vaccines inducing antibodies that cross-react with the related dengue virus (DENV), we designed modified prM-E RNA encoding mutations destroying the conserved fusion-loop epitope in the E protein. This variant protected against ZIKV and diminished production of antibodies enhancing DENV infection in cells or mice. A modified mRNA vaccine can prevent ZIKV disease and be adapted to reduce the risk of sensitizing individuals to subsequent exposure to DENV, should this become a clinically relevant concern. [Display omitted] •A modified mRNA vaccine encoding prM-E protects in 3 different mouse strains•Extraordinarily high titers of neutralizing antibodies (>1/100,000 EC50) are produced•Sterilizing immunity was achieved with a single prime-boost strategy•A fusion loop mutant vaccine reduced production of enhancing anti-DENV antibodies A modified mRNA vaccine induces sterilizing immunity against Zika virus while minimizing the generation of cross-reactive antibodies that may enhance dengue infection.