Sunday, May 11, 2025
5/11/2025
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.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).