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Principal Investigator: Niraj Tolia
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2021
Award: $289,320
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.
We have produced several novel improved vaccine antigens using our computational design and screening platform. These immunogens have enhanced production yields and thermostability compared to antigens in use and in clinical trials. Furthermore, several of these candidates can be manufactured by inexpensive and accessible methods using yeast, making them attractive candidates for global and/or annual distribution. Structural studies of these immunogens revealed the mechanisms driving their improved biophysical parameters and will help guide future development of vaccines for SARS-CoV-2 and related viruses.
We have completed several pre-clinical experiments in rodents demonstrating that these immunogens elicit higher levels of functional antibodies than antigens currently used in leading vaccines. Some of these immunogens are enhanced versions of the receptor binding domain (RBD), an antigen used in several late-phase clinical trials. Our RBD immunogens elicit approximately 10-fold higher titers of neutralizing antibodies than the unmodified RBD. There is a strong correlation between neutralizing antibody titer and vaccine efficacy in humans, suggesting that the duration and breadth of protection conferred by RBD-based vaccines could be improved by incorporating the amino acid changes we have identified.
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