A combined adjuvant approach primes robust germinal center responses and humoral immunity in non-human primates

Adjuvants and antigen delivery kinetics can profoundly influence B cell responses and should be critically considered in rational vaccine design, particularly for difficult neutralizing antibody targets such as human immunodeficiency virus (HIV). Antigen kinetics can change depending on the delivery method. To promote extended immunogen bioavailability and to present antigen in a multivalent form, a native-like HIV Env trimer was modified with short phosphoserine peptide linkers to promote tight binding to aluminum hydroxide (pSer:alum). Here, we explored the use of a combined adjuvant approach that incorporates pSer:alum-mediated antigen delivery with potent adjuvants (SMNP, 3M-052) in an extensive head-to-head comparison study with conventional alum to assess germinal center (GC) and humoral immune responses. We found that priming with pSer:alum plus SMNP induced additive effects that enhanced the magnitude and persistence of GCs, which correlated with better GC-TFH cell help. Autologous HIV-neutralizing antibody titers were improved in SMNP-immunized animals after two immunizations. Over 9 months after the initial priming immunization of pSer:alum with either SMNP or 3M-052, robust Env-specific bone marrow plasma cells (BM BPC) were observed. Furthermore, pSer-modification of Env trimer reduced targeting towards immunodominant non-neutralizing epitopes. Together, the data show that a combined adjuvant approach can augment humoral immunity by modulating immunodominance and shows promise for clinical translation.