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The COVID-19 pandemic continues to spread throughout the world with an urgent need for a safe and protective vaccine to effectuate herd immunity to control the spread of SARS-CoV-2. Here, we report the development of a SARS-CoV-2 subunit vaccine (NVX-CoV2373) produced from the full-length spike (S) protein, stabilized in the prefusion conformation. Purified NVX-CoV2373 S form 27.2nm nanoparticles that are thermostable and bind with high affinity to the human angiotensin-converting enzyme 2 (hACE2) receptor. In mice and baboons, low-dose NVX-CoV2373 with saponin-based Matrix-M adjuvant elicits high titer anti-S IgG that is associated with blockade of hACE2 receptor binding, virus neutralization, and protection against SARS-CoV-2 challenge in mice with no evidence of vaccine-associated enhanced respiratory disease (VAERD). NVX-CoV2373 vaccine also elicits multifunctional CD4 and CD8 T cells, CD4 T follicular helper T cells (Tfh), and the generation of antigen-specific germinal center (GC) B cells in the spleen. These results support the ongoing phase 1/2 clinical evaluation of the safety and immunogenicity of NVX-CoV2327 with Matrix-M ([NCT04368988][1]). ### Competing Interest Statement GS, GG, JHT, NP, RH, HZ, MGX, ADP, MJM, MBF and LE contributed to conceptualization of experiments, generation of data and analysis, and interpretation of the results. JHT, RH, NP, SW, HH, JL, JN, BZ, KJ, SM, RK, MW, WM, SKS, BE, SB, CJW, HZ performed experiments. ADP, MGX, JP coordinated projects. MBF, ADP, MJM, LF, PAP, KLB, LS, GG, GS, LE contributed to drafting and making critical revisions with the help of others. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04368988&atom=%2Fbiorxiv%2Fearly%2F2020%2F06%2F30%2F2020.06.29.178509.atom

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