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Principal Investigator: Barney Graham
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2020
Award: $1,394,275
Funding agency: National Institute of Allergy and Infectious Diseases
When the MERS CoV outbreak raised global health concerns, we initiated a program to develop a candidate vaccine. Starting from Spike glycoprotein (S) sequences, we developed an immunization strategy consisting of a full-length S DNA prime and a S1 subunit protein boost that elicited high titers of neutralizing antibodies against eight different MERS-CoV strains. Based on prior studies to solve the spike structure of HKU1 (an endemic betacoronavirus) and finding stabilizing mutations that also stabilized MERS-CoV and SARS-CoV spike proteins, and prior research collaboration agreements with industry, we were able to respond quickly to the emergence SARS-CoV-2. When sequences were available we immediately ordered reagents to produce spike protein for structural studies, for the development of serological assays, and for probes to isolate B cells from survivors for antibody discovery. Cryo-electron microscopy determined 3.5-angstrom-spike trimer structure with academic collaborator. We provided protein for CDC to develop ELISA assay. We made probes to facilitate discovery of mAb555 that was first to enter clinical trials. Based on prior work, in collaboration with our industry partners, we designed a mRNA vaccine expressing the SARS-CoV-2 prefusion-stabilized spike trimer without additional experimentation and were first to start a phase 1 vaccine trial and also first to enter Phase 3. Our studies have shown that this vaccine, mRNA-1273, is immunogenic and induces a neutralizing antibody response in mice, non-human primates and humans. We showed it protects both upper and lower airway infection in mice and NHP. It was shown not to have any concerning safety signals in mice, NHP, or humans. This process validated the prototype pathogen approach to pandemic preparedness that we have advocated as a proactive method that would systematically establish the reagents and knowledge base needed to address all 25 virus families known to infect humans. We are supporting the clinical evaluation of the mRNA-1273 vaccine with serological assays developed in our laboratory, and refining our understanding of antigenic sites on the spike protein and mechanisms of neutralization. Studies are ongoing to identify additional mAbs or mAb combinations that could be second generation products if initial passive administration is successful. The steps taken to make this unprecendented response to a new viral pandemic threat will serve as a template for responses to future emerging viruses.
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