Core 3: Non-human Primate Core

Abstract - Core 3 The current SARS-CoV-2 pandemic is the third major pathogenic outbreak caused by a betaCoV in the last two decades. Development of panbetacoronavirus (panbetaCoV) vaccines for group 2b and group 2c beta CoVs is a major priority of this P01. In addition, this P01 will evaluate alphavirus replicons, modified mRNA-lipid

nanoparticles and protein nanoparticles as panbetaCoV vaccine platforms. Nonhuman primates (NHPs) such as cynomolgus or rhesus macaques have been shown by the NHP Core 3 team to be excellent models of SARS- CoV-2 acquisition. NHPs are important components of vaccine design and testing as they have anatomical,

physiological and immunological similarities to humans. The NHP Core 3 will support the P01 by achieving the following Specific Aims: Aim 1. Test the protectivecapacityof panbetaCoVneutralizing antibodyvaccines using cynomolgus or rhesus monkeys as animal models. Down-selected B cell vaccines derived from

Projects 1, 2, 3 or 4 will be tested in NHP models. We hypothesize that macaques will be as excellent models of bat or pangolin CoV acquisition as they are for human prototype group 2b CoVs (SARS-CoV-1 and 2) and group 2c human virus, MERS. Aim 2. Test the protective capacity of panbetaCoV T cell basedvaccines

using cynomolgus or rhesus monkeys as animal models. CD8 T cell responses have been shown to be a component of immune correlates of protection from SARS-CoV-2 in rhesus macaques. The hypothesis here is that a T cell-targeted vaccine can synergize with B cell vaccines to improve protection with low neutralizing

antibody titers. Down-selected T cell vaccines derived from Project 4 will be tested in NHP models, whereT cell responses will be assessed through a step-wise epitope-based approach using assays including IFN-γ-based ELISpot, multi-parameter flow cytometry-based assays, and 10X genomics transcriptome analysis. Aim 3.

Monitor Vaccine Associated Enhancement of Disease (VAED) in macaques by panbetaCoV vaccines. We will monitor vaccinated macaques for lung pathology and enhancedBAL cytokines and lung CoV PFU. Thus, NHP Core 3 will be an integral component of this P01 and key to P01 success.