HIV mRNA vaccine strategies for efficient priming, diversity and durability of immune responses

SUMMARY Conventional vaccine strategies have not induced successful protection to diverse HIV strains. mRNA vaccine platforms enable novel modalities of antigen delivery for innovative vaccine strategies. The use of mRNA technology for HIV vaccines holds promise to conquer major barriers to induce protective responses via broadly neutralizing antibodies (bnAbs). However, mRNA vaccines to express HIV antigens capable of effectively conferring protective immunity have not been fully explored. Germinal center (GC) responses are paramount for prophylactic vaccines as they provide a highly specialized environment to affinity mature antibodies to difficult epitopes on HIV. We have demonstrated that efficient priming and longer duration of GC responses are likely favorable for broader neutralizing responses against HIV (Nature 2022). mRNA vaccines against SARS-CoV-2 have been shown to induce long-lasting GC responses after 2 doses, but the biology and effective manipulation of this process remains elusive. Particularly, a big knowledge gap is how mRNA vaccine-induced GCs differ from protein vaccines. A second knowledge gap is what mechanisms drive long- lasting GCs? A third knowledge gap is what immunological signals regulate the output of durable immune memory? HIV envelope (Env) trimer is the sole antigenic target for neutralizing antibodies. Many experimental HIV vaccines use soluble forms of Env that expose the immunodominant base of the trimer eliciting non- neutralizing antibodies. mRNA vaccines allow the realization of membrane-bound Env expression, which can present antigen in a more native form avoiding exposure of the base. Membrane-bound Env trimers can also be expressed on nanoparticles such as virus-like particles (VLPs) via mRNA delivery resembling higher density expression on native virions. Given the potential of long-lasting GC responses and the new modes of antigen delivery by membrane-bound Env or multimeric Env nanoparticles, we seek to investigate: Are HIV mRNA vaccines capable of inducing long-lasting GC responses? How can HIV mRNA vaccines optimally prime long- lasting GC responses? What sequential immunization strategies work best with HIV mRNA vaccines to induce diverse and durable memory responses? Non-human primates (NHPs) are an invaluable model for studying this biology and immunology, because of their relatedness to humans.