COVID-19 Structural Vaccinology

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

SARS-CoV-2 is a serious global threat that has been met with an unparalleled research response. Scientific understanding of SARS-CoV-2 is already deeper than most pathogens and it is growing rapidly. This knowledge provides an opportunity to design a vaccine that goes beyond traditional methods. For example, the spike protein is the target of leading COVID-19 vaccines, but only a fraction of antibodies that recognize the spike have been shown to neutralize the virus. Our previous work on a malaria vaccine has demonstrated that removing non-neutralizing epitopes increases neutralizing antibody titers upon vaccination. Together, this suggests that focusing the B-cell response towards broadly-neutralizing functional epitopes in SARS-CoV-2 may improve protection. The ability to precisely direct the immune response is made possible by rapid major advances in the structural definition of neutralizing epitopes in key SARS-CoV-2 antigens, and in nanoparticle technology. Guided by strong preliminary data, this proposal will pursue two independent yet complementary specific aims: 1) To immediately generate vaccine candidates that focus the immune response to neutralizing segments of the SARS-CoV-2 spike protein, and 2) Develop protein-based nanoparticles with designed immunogens that improve the immune response to SARS-CoV-2 antigens. The molecular designs proposed are driven by the hypothesis that the SARS-CoV-2 spike protein is recognized by a mixture of antibodies that differ in their neutralizing capacity. Our designs aim to increase broadly-neutralizing protective antibody titers. Published work has defined several neutralizing epitopes to target, and we will utilize unique computational design, human-guided design, and screening strategies that will generate lead candidates distinct from those created by other research groups. Our design strategies are unique in their ability to stabilize molecular structure and derive novel immunogens that would otherwise be unstable and unsuitable for vaccine development. In FY23, we published the first report in Science Advances of a novel computational design and screening platform and its application towards improving the SARS-CoV-2 spike receptor-binding domain (RBD) vaccine antigen. Our RBD immunogens elicit approximately 10-fold higher titers of neutralizing antibodies than the unmodified RBD, and they focus the antibody response towards neutralizing epitopes. These results demonstrate that our design pipeline can improve vaccine antigens. This design strategy (SPEEDesign) represents a significant methodological breakthrough because it can be applied to many vaccine antigens targeting many different pathogens. We further extended the ability of SPEEDesign to enhance immunogens by redesigning the SARS-CoV-2 RBD to enable nanoparticle display as published in Cell Reports. The RBD contains a single glycan that precludes high density display. Effective elimination of this glycan while retaining the neutralizing epitopes in the RBD and stabilizing the domain resulted in an immunogen (noNAG-RBD) that could be fused to three distinct nanoparticle platforms with no adverse effects. We established a 60-copy nonNAG-RBD nanoparticle produced similar neutralizing activity in rodents and non-human primates as full-length Spike comparator and the nanoparticle could serve as an effective booster to vaccinees immunized with full-length Spike.