An enhanced synthetic multiclade DNA prime induces improved cross-clade-reactive functional antibodies when combined with an adjuvanted protein boost in nonhuman primates

The search for an efficacious human immunodeficiency virus type 1 (HIV-1) vaccine remains a pressing need. The moderate success of the RV144 Thai clinical vaccine trial suggested that vaccine-induced HIV-1-specific antibodies can reduce the risk of HIV-1 infection. Wehave made several improvements to theDNAplatform and have previously shown that improvedDNAvaccines alone are capable of inducing both binding and neutralizing antibodies in small-animal models. In this study, we explored how an improvedDNAprime and recombinant protein boost would impact HIV-specific vaccine immunogenicity in rhesus macaques (RhM). AfterDNAimmunization with either a single HIV Env consensus sequence or multiple constructs expressing HIV subtype-specific Env consensus sequences, we detected both CD4⁺ and CD8⁺ T-cell responses to all vaccine immunogens. These T-cell responses were further increased after protein boosting to levels exceeding those of DNA-only or protein-only immunization. In addition, we observed antibodies that exhibited robust cross-clade binding and neutralizing and antibody-dependent cellular cytotoxicity (ADCC) activity after immunization with theDNAprime-protein boost regimen, with the multiple-Env formulation inducing a more robust and broader response than the single-Env formulation. The magnitude and functionality of these responses emphasize the strong priming effect improved DNAimmunogens can induce, which are further expanded upon protein boost. These results support further study of an improved syntheticDNAprime together with a protein boost for enhancing anti-HIV immune responses.