Using albumin-hitchhiking intranasal vaccines to enhance immune protection against infectious disease

PROJECT SUMMARY To combat the global HIV epidemic as well as persisting threats such as SARS-CoV-2, immunization strategies are needed that elicit protection at mucosal portals of pathogen entry. However, traditional parenteral vaccines that are injected typically elicit poor mucosal immunity. While vaccination at mucosal surfaces is known to be an effective strategy to activate protective mucosal immunity, delivery of vaccine components across mucosal barriers has been a major challenge for mucosal vaccine development. Development of technologies to overcome barriers to mucosal delivery while meeting safety and efficacy requirements of prophylactic vaccines remains an urgent unmet need. While mucosal barriers are very good at keeping most vaccine components 'out', the endogenous protein albumin is known to be very good at getting 'in'. Albumin, a major blood protein also present in mucosal fluids, is constitutively transcytosed across mucosal epithelium through interactions with the neonatal Fc receptor (FcRn) while functioning in vivo as a fatty acid transporter. Exploiting this biology, we recently developed a novel immunoengineering strategy of 'albumin hitchhiking' to promote mucosal immunity using an intranasal vaccine consisting of protein immunogens conjugated to an albumin-binding polymer-lipid tail, forming 'amph-proteins'. Amph-proteins exhibit enhanced FcRn-dependent uptake into nasal mucosal tissue, leading to enhanced local immune responses in the nasal-associated lymphoid tissue (NALT) and robust long-lasting systemic and mucosal humoral responses in tandem. These results suggest that employing amph- vaccines to deliver antigen (Ag) and adjuvant across mucosal epithelium is a promising strategy to promote mucosal immunity against infectious diseases. Motivated by these findings, here we propose to further develop the amph-vaccine platform for mucosal delivery of a range of immune cargo (antigens and adjuvants) while identifying molecular and cellular mechanisms of action, immune correlates of protection, and the role of vaccine dosing and kinetics in mucosal associated lymphoid tissue (MALT) for promoting functional protective immunity in translational mouse models through the following aims. Aim 1: Identify molecular properties and kinetic mechanisms of intranasal amphiphile-antigen vaccines that drive mucosal humoral immune activation. Aim 2: Evaluate immunogenicity, adjuvanticity, and toxicity of intranasal amphiphile-antigen/adjuvant vaccines in a 'dirty' mouse model. Aim 3: Define mucosal vaccine kinetics that drive functional immune protection by evaluating efficacy of intranasal amph-vaccines in challenge models of SARS-CoV-2. Our central hypothesis is that i.n. amph-vaccines that exhibit enhanced mucosal uptake and persistence in NALT will better prime functional protective immunity against respiratory pathogens (demonstrated across multiple mouse models) by activating robust GC responses in NALT, generating a mucosal antibody response of greater magnitude, affinity, and breadth than soluble or parenteral controls.