DNA electroporation of HIV Env elicits robust T cell responses and memory B cell responses with muted serum antibody levels that can be boosted with recombinant protein.

Broadly neutralizing antibodies against the HIV envelope protein exhibit the potential to prevent HIV-1 acquisition, a concept demonstrated both in non-human primate (NHP) challenge models and in human clinical trials. The use of DNA for vaccination, in combination with IL-12 and delivered via intradermal (ID)-adaptive electroporation (EP), has resulted in excellent cellular and humoral immunogenicity. HVTN 304 (NCT05828095) is a first-in-human, phase 1 clinical trial that evaluated the safety and immunogenicity of a novel vaccination regimen of a synthetic DNA-encoded stabilized HIV-1 Env native-like trimer (sD-NLT-AB05) adjuvanted with IL-12 DNA, either alone or in combination with a recombinant protein HIV-1 Env (Trimer 4571) adjuvanted with 3M-052-AF/Alum as a boost, in 20 participants without HIV. The DNA vectors were delivered via ID EP. The regimen did not induce autologous neutralizing antibodies in serum. Binding antibodies to Env were induced in over half of the participants receiving DNA only and in all participants who received the Trimer 4571 boost; the magnitude was increased by the second protein boost. The DNA-induced antibodies were primarily directed to the Env base; some Trimer protein-induced antibodies were directed to other regions of Env and the base. Env-specific CD4+ T cells expressing IFN-γ and/or IL-2 were detected in all participants, with CD8+ T cells detected in up to 75% of participants. The CD4+ T cell response included cells expressing IL-21. This study demonstrates that the DNA modality, in combination with a closely related heterologous boost, may be another modality to enable iterative testing of new vaccine regimens for HIV-1, as it primes a B cell response and a CD8+ T cell response without inducing high titers of serum antibody.