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Principal Investigator: Niraj Tolia
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2024
Award: $164,252
Funding agency: National Institute of Allergy and Infectious Diseases
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 FY24, we designed amino acid modifications to the SARS-CoV-2 spike protein that increase the titers of neutralizing antibodies, and we published these results in Antiviral Research. We previously designed nine amino acid changes in the receptor-binding domain (RBD) of the spike protein and showed that they increased neutralizing antibody titers elicited by the isolated RBD. However, almost all commercial vaccines include the complete spike protein instead of the isolated RBD. We have now introduced these same amino acid changes into the complete spike protein and shown that they improve neutralizing antibody titers in rodents and non-human primates.
These same nine amino acid changes to the RBD enabled the production of a BA.5 nanoparticle vaccine that elicits high titers of broadly neutralizing antibodies. In collaboration with Peter Kwong at the Vaccine Research Center, we contributed to a study that was published in Vaccines. We previously designed the enhancing amino acid changes in the context of the parent WA1 strain and these changes also enhance the BA.5 RBD. This stabilized BA.5 RBD could then be displayed on a self-assembling nanoparticle to elicit very potent neutralizing antibody titers that neutralized diverse viral variants ranging from WA1 to BA.5.
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