An adjuvanted SARS-CoV-2 RBD nanoparticle elicits neutralizing antibodies and fully protective immunity in aged mice

Development of affordable and effective vaccines that can also protect vulnerable populations such as the elderly from COVID-19-related morbidity and mortality is a public health priority. Here we took a systematic and iterative approach by testing several SARS-CoV-2 protein antigens and adjuvants to identify a combination that elicits neutralizing antibodies and protection in young and aged mice. In particular, SARS-CoV-2 receptorbinding domain (RBD) displayed as a protein nanoparticle (RBD-NP) was a highly effective antigen, and when formulated with an oil-in-water emulsion containing Carbohydrate fatty acid MonoSulphate derivative (CMS) induced the highest levels of cross-neutralizing antibodies compared to other oil-in-water emulsions or AS01B. Mechanistically, CMS induced antigen retention in the draining lymph node (dLN) and expression of cytokines, chemokines and type I interferon-stimulated genes at both injection site and dLN. Overall, CMS:RBD-NP is effective across multiple age groups and is an exemplar of a SARS-CoV-2 subunit vaccine tailored to the elderly. ### Competing Interest Statement FB has signed consulting agreements with Merck Sharp & Dohme Corp. (a subsidiary of Merck & Co., Inc.), Sana Biotechnology, Inc., and F. Hoffmann-La Roche Ltd. IZ reports compensation for consulting services with Implicit Biosciences. MBF is on the advisory board of Aikido Pharma. PPP and LHG are the founders and owners of LiteVax BV, the company that holds IP related to CMS. These commercial relationships are unrelated to the current study. FB, EN, TRO, YS, DJD, and OL are named inventors on several vaccine adjuvant patents. The other authors declare no commercial or financial conflict of interest.