DNA Nanoparticle Vaccine for COVID-19

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PROJECT SUMMARY/ABSTRACT COVID-19 has emerged from SARS-CoV-2 within the course of several months to spread worldwide as a deadly pandemic, with the number of deaths approaching one-half million worldwide. While over one hundred vaccines are currently in development, and several already in human clinical trials, most of these early candidates consist of messenger RNA or DNA formulations used to transiently express SARS-CoV-2 subunit proteins, which may not elicit sufficiently neutralizing, long-term antibody response. Strategies to enhance antigenicity, antibody affinity maturation, and memory induction in response to subunit vaccines are of broad relevance for the design of effective vaccines against infectious diseases such as COVID-19, and may be particularly important to neutralize the SARS-CoV-2 pathogen. One approach to enhance the efficacy of subunit vaccines is to formulate antigens in a multivalent, nanoparticulate form, which promotes several aspects of humoral immunity, most notably crosslinking of B cell receptors (BCRs). This approach has been exploited both in licensed vaccines (e.g., the HPV and HBV vaccines), and in a great variety of vaccines in preclinical and clinical development. In this project, we use the unique technology of scaffolded DNA origami to engineer virus-like nanoparticles on the 10–100 nanometer scale that offer the ability to conjugate controlled copy numbers of SARS-CoV-2 antigens at controlled inter-antigen spacings. We test the relative importance of copy number, spacing, and virus-like nanoparticle size on B cell activation in vitro. Optimal constructs identified using B cell activation assays in vitro will subsequently be used to characterize T-cell and B-cell response in vivo using mouse models. Successful vaccine constructs identified from in vivo studies will be shared with commercial partners to facilitate follow-on toxicity, safety, and efficacy studies in higher animal models including non-human primates. Our results will offer a novel subunit vaccine formulation that may be generalized to other SARS-CoV variants including SARS-CoV- 1 through heterovalent protein antigen presentation, as a generalized vaccine platform to avoid future coronavirus-induced pandemics.