Engineering durable immunity by optimizing HIV vaccine parameters to drive long-lived plasma cell development

PROJECT SUMMARY The HIV pandemic has been raging for nearly forty years, and despite immense effort we have yet to discover a vaccine that can induce durable, protective immunity. HIV remains an urgent global health crisis, with 38 million people living with HIV and 1.5 million people newly infected each year. For most infectious diseases but particularly HIV, vaccines are preferable to other forms of prevention or prophylaxis because of their potential durability. Ideally, a single immunization induces protective immunity that lasts for years or even decades. Antibodies are the primary mechanism of protection for nearly all available vaccines, so when considering vaccine durability, an important measure is the length of time that neutralizing antibodies can be maintained at a functional level. In this proposal, we will systematically study the effects of different vaccine parameters on antibody durability. In Aim 1, we will evaluate immunogen affinity and valency. In Aim 2, we will investigate adjuvants and vaccine platforms, including mRNA delivery. In Aim 3, we will explore dosing regimens, including promising escalating-dose strategies.