Immunogenicity to B and T cell vaccines in non-human primates (NHPs)

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ABSTRACT - PROJECT 3 The goal of Project 3 is to assess in nonhuman primates (NHPs), immunization strategies aimed at inducing HCV-specific bnAbs and TRMs in the liver. In particular, we will assess the magnitude and durability of bnAb responses induced by immunization with HCV E1/E2 antigens administered with adjuvants; and T cell responses induced by sequential immunization with heterologous viral vectors expressing HCV NS3-NS5b mosaic antigens. Our recent work has demonstrated the adjuvant capacity of TLR7/8 ligand 3M-052 to potently stimulate robust and durable nAb responses as well as remarkably long-lived plasma cells (LLPCs) in bone marrow, similar to responses observed with live viral vaccines. Therefore, in Aim 1 we will evaluate the capacity of 3M-052/alum to stimulate a high magnitude and durability of HCV E1/E2 specific bnAb responses. As a comparator, we will use a novel adjuvant, composed of a liposome, a TLR4 agonist (monophosphoryl lipid A, MPL) and the saponin called QS-21, (Lipo/ QS-21/ MPL), which was recently shown to induce a superior HCV glycoprotein-specific T cell response in mice. Aim 1: To determine the capacity of 3M-052/alum and Lipo/QS-21/MPL to adjuvant antigen- specific immune responses to HCV E1/E2. In this aim, we will test the hypothesis that immunization with HCV E1/E2 with adjuvant results in robust and sustained nAb responses in NHPs. In the case of T cells, our recent results demonstrate that vaccination induced CD8+ TRMs and nAb responses can synergize to provide enhanced protection against viral acquisition to mucosal infectioN. Using single cell transcriptional profiling we demonstrated that reactivation of TRMs in mucosal tissues stimulates anti-viral restriction factors in mucosal myeloid cells, thereby creating a restrictive local environment for viral entry. We hypothesize that an HCV vaccine that induces antigen-specific liver TRMs and nAbs will confer superior protection against HCV, through a similar mechanism involving local innate antiviral responses in myeloid cells and hepatocytes in the liver. Aim 2: To characterize the innate and adaptive immune responses induced by sequential immunization with heterologous viral vectors expressing HCV NS3-NS5b mosaic antigens, followed by immunization with E1/E2 and NS3-5 antigens plus adjuvant. We will immunize NHPs sequentially with Ad48 and MVA expressing Mosaic NS3-5, (to induce NS3-5 specific CD8+ T cells), followed by immunization with soluble HCV E1/E2 antigens (to induce nAbs), and soluble NS3-5 antigens (to boost the CD8+ T cell response primed by viral vectors), administered with an adjuvant. We will analyze the innate and adaptive response in three sub-aims.