Tailoring T_fhProfiles Enhances Antibody Persistence to a Clade C HIV-1 Vaccine in Rhesus Macaques

CD4 T follicular helper cells (T_fh) are essential for establishing serological memory and have distinct helper attributes that impact both the quantity and quality of the antibody response. Insights into T_fhsubsets that promote antibody persistence and functional capacity can critically inform vaccine design. Based on the T_fhprofiles evoked by the live attenuated measles virus vaccine, renowned for its ability to establish durable humoral immunity, we investigated the potential of a T_fh1/17 recall response during the boost phase to enhance persistence of HIV-1 Envelope (Env) antibodies in rhesus macaques. Using a DNA-prime encoding gp160 antigen and T_fhpolarizing cytokines (interferon protein-10 (IP-10) and interleukin-6 (IL-6)), followed by a gp140 protein boost formulated in a cationic liposome-based adjuvant (CAF01), we successfully generated germinal center (GC) T_fh1/17 cells. In contrast, a similar DNA-prime (including IP-10) followed by gp140 formulated with monophosphoryl lipid A (MPLA)+QS-21 adjuvant predominantly induced GC T_fh1 cells. While the generation of GC T_fh1/17 cells with CAF01 and GC T_fh1 cells with MPLA+QS-21 induced comparable peak Env antibodies, the latter group demonstrated significantly greater antibody concentrations at week 8 after final immunization which persisted up to 30 weeks (gp140 IgG ng/ml-MPLA; 5500; CAF01, 2155; p <0.05). Notably, interferon γ+ Env-specific T_fhresponses were consistently higher with gp140 in MPLA+QS-21 and positively correlated with Env antibody persistence. These findings suggest that vaccine platforms maximizing GC T_fh1 induction promote persistent Env antibodies, important for protective immunity against HIV.