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Principal Investigator: Niraj Tolia
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2020
Award: $100,000
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 the broadly-neutralizing functional epitopes in SARS-CoV-2 may improve protection.
The ability to precisely direct the immune response is made possible by an explosion 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 nanoparticles that improve the immune response to SARS-CoV-2 immunogens.
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 and their potential to trigger a pathogenic immune response. Our designs aim to increase broadly neutralizing protective antibody titers while decreasing non-neutralizing pathogenic titers. While published work has defined several neutralizing epitopes to target, we lack a complete structural understanding of the immune response to SARS-CoV-2. We will characterize the structure and function of human monoclonal antibodies against SARS-CoV-2 to guide immunogen design. We will then 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 validated our approach on three malaria antigens, resulting in vaccine candidates in all cases that otherwise could not be produced.
In the first months of research, we have screened dozens of computationally designed antigens and have identified lead candidates based on desirable biophysical characteristics. These lead candidates are now entering pre-clinical animal trials. Furthermore, diverse established nanoparticle platforms and novel nanoparticle designs will be evaluated for their ability to effectively present antigens, enhance the desired immune response, and increase protection. All designed immunogens and nanoparticles will be structurally characterized through x-ray crystallography and cryo-electron microscopy to ensure the correct conformational three-dimensional structure of the antigen is retained. Pre-clinical and clinical studies will be performed in collaboration with groups within LMIV and the NIH.
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