(570a) Interbilayer-Crosslinked Multilamellar Vesicles As Synthetic Vaccines for Potent Humoral and Cellular Immune Responses

Currently licensed vaccine adjuvants promote immunity by primarily eliciting humoral immune responses without stimulating cellular immunity. As concerted humoral and cellular immune responses are thought to be required for vaccines against cancer or intracellular pathogens such as HIV and malaria, there is a great interest in new vaccine technologies that can elicit both arms of the adaptive immunity. In this work, we describe development of interbilayer-crosslinked multilamellar vesicles (ICMVs) as a potent vaccine platform and present their efficacy in a malaria model. ICMVs were formed by fusing liposomes into multilamellar vesicles and subsequent crosslinking of adjacent lipid headgroups across lipid bilayers within multilamellar vesicles. These particles exhibited substantially enhanced protein antigen loading and extended drug release kinetics compared with traditional drug delivery vehicles (e.g. liposomes and polymeric particles). Crosslinking of lipid bilayers enhanced stability of particles in serum, allowing efficient delivery of cargo antigens to antigen-presenting cells. ICMVs encapsulating model antigen ovalbumin and FDA-approved adjuvant elicited potent antibody and CD8+ T cell responses in vivo, comparable to those for strong viral vector vaccines. With the goal of translating these results to an infectious disease model, we investigated the potency of ICMVs as a malaria vaccine. ICMVs carrying a malaria antigen and adjuvant elicited robust humoral immune responses with high-avidity antibody titers lasting more than a year, whereas soluble protein immunizations produced only transient, low-avidity antibody titers. Particle immunization also led to prominent germinal center formation in lymph nodes, accompanied with increased expansion of antigen-specific CD4⁺ T cells and their differentiation into follicular helper T cells, partially explaining the long-lasting and high-avidity antibody titers elicited with ICMV immunization. These results suggest that these antigen/adjuvant-carrying ICMVs are potent particle vaccines that can elicit strong cellular and humoral immune responses, and highlight their potential as a vaccine platform against other infectious diseases.