Memory-promoting Ad vaccine for long-lived protection against SARS-CoV-2

This grant will establish immunologic proof-of-concept for a second-generation SARS-CoV-2 vaccine providing extraordinarily durable T-cell and antibody responses, which together protect the respiratory mucosa and minimize the risk of antibody-dependent enhancement (ADE). The vaccine platform combines the immunostimulatory power and proven safety of adenovirus-vectored vaccines with novel in- vector adjuvants and a robust humoral component. In particular, our preliminary data show that this vaccine candidate stimulates T-cell responses in macaques that are virtually undiminished ten months after vaccination. We hypothesize that a memory-promoting adenovirus (MPAd) drives robust CD4+ T-cell responses to SARS- CoV-2 that provide both airway-resident protection and superior B-cell helper function. Aim 1: Demonstrate robust, durable CD4+ T-cell responses to MPAd/N vaccination, localized to airways and exceeding responses seen with conventional Ad vectors. Here we test if key differentiating features of Tendel's memory-promoting Ad vaccine, previously demonstrated for immunization against SIV Gag, are also seen when immunizing against SARS-CoV-2 nucleocapsid. Our hypothesis predicts balanced CD4 and CD8 responses with effector-memory character and localization to airways, which are maintained with minimal dimunition throughout the experiment. Milestone 1: Demonstrate superiority of MPAd vaccine for eliciting SARS-CoV-2-specific T cells in airways. Aim 2: Evaluate SARS-CoV-2 neutralizing antibodies and subtypes in rhesus macaques receiving Ad/RBD vs. MPAd/RBD. Tendel aims to provide a second-generation SARS-CoV-2 vaccine that evades any tendency to enhancement by combining appropriate T-cell and B-cell responses. Some previous reports have demonstrated enhanced extrinsic ADE for Th2-associated antibodies of the IgG1 class, as well as intrinsic ADE that is linked to Th2-associated effector mechanisms, especially IL-10. In this aim we test the antibody subclasses and capacity for enhancement of antibodies elicited by Ad/RBD vs. MPAd/RBD, to determine the best component for inclusion in a second-generation vaccine. Milestone 2: Choose an optimal B cell-targeted vaccine component, which does not mediate ADE, for combination with an MPAd-based T-cell component. These innovative Phase I experiments will be sufficient to establish both the technical merit and-in light of the proven commercial and government interest in Ad-vectored vaccination against SARS-CoV-2-the commercial potential of Tendel's approach.