Multimeric Epitope-Scaffold HIV Vaccines Target V1V2 and Differentially Tune Polyfunctional Antibody Responses

The V1V2 region of the HIV-1 Envelope is the target of several broadly neutralizing antibodies (bNAbs). RV144 vaccinees elicited binding antibodies to V1V2, which correlated with a reduced risk of HIV infection, yet these antibodies were without broad neutralizing activity. Antibodies targeting V2 also correlated with delayed infection and reduced viral load in immunized macaques challenged with SIV or SHIV. To focus immune responses on V1V2, we designed a panel of immunogens by engrafting the native, glycosylated V1V2 domain onto multimeric scaffold proteins and conducted comparative immunogenicity studies in macaques. Vaccinated macaques developed high titers of plasma and mucosal antibody responses that targeted structurally distinct V1V2 epitopes. The plasma had neutralizing activity and was functionally active for ADCC and phagocytosis that was detectable 1-2 years after immunizations ended. This study demonstrates that multivalent V1V2-scaffold protein immunogens are differentially effective at inducing V1V2-targeted antibody responses with characteristics associated with protection.