SEP 08, 2020 12:00 PM PDT

Keynote Presentation: Structure-based Vaccine Design for COVID-19 and other Respiratory Viruses

  • Barney S. Graham, MD, PhD

    Deputy Director, Vaccine Research Center, Chief, Viral Pathogenesis Laboratory, NIAID (National Institute of Allergy and Infectious Diseases)


While the frequency of pandemic threats seems to be increasing, we fortunately have new tools and technologies to make vaccines with more precision and speed and that support a more proactive approach to pandemic preparedness and response. There are ~25 virus families associated with human infection from which the next pandemic threat will likely arise. Within each relevant virus family, a database of information with accompanying reagents, assays, and animal models could be developed for prototypic viruses based on properties of tropism, transmission routes, and other distinguishing features of pathogenesis. Candidate vaccine approaches could be designed based on virus structure, transmission dynamics, entry requirements, and replication strategy. The prototype pathogen approach for pandemic preparedness has been applied to MERS CoV over the last 7 years. It was informed by structure-based immunogen-design concepts established for RSV F subunit vaccines, and focused on solving coronavirus spike structures, defining mechanisms of CoV neutralization, and evaluating MERS CoV vaccine candidates in collaboration with a commercial mRNA manufacturer. Prior spike protein engineering experience resulted in rapid sequence selection and using the mRNA manufacturing platform provided rapid GMP production a COVID-19 mRNA vaccine in record time. This candidate was tested in mice in ~25 days and humans in ~65 days from the time sequence was released. The product has been shown to be immunogenic and protective in mice, hamsters, and NHP and no safety signals have been noted. Phase 1 and 2 clinical trials demonstrated that mRNA-1273 is well tolerated and immunogenic. These data supported initiation of a 30,000 subject Phase 3 trial on July 27th, 198 days from sequence availability. The proactive preparation not only facilitated rapid vaccine development and evaluation but provided stabilized spike protein reagents that were the basis for developing serological assays and isolating potent human neutralizing mAbs being clinically evaluated for prevention and therapy.

Learning Objectives:

1. Understand the prototype pathogen approach for pandemic preparedness and role of new technologies particularly structure-based vaccine design

2. Know which types of COVID-19 vaccines have advanced into clinical vaccine trials

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