UC San Diego

Most licensed vaccines depend on the induction of neutralizing antibodies (nAb) for protection against infectious diseases. Human immunodeficiency virus (HIV) is a difficult pathogen to generate nAb responses through vaccination, due to the genetic variability and unusual structural requirements for antibodies to contact the HIV envelope spikes (Env) for neutralization. Broadly neutralizing antibody (bnAb) responses to conserved epitopes on Env are often rare and have evolved due to years of constant antigen exposure in HIV-infected individuals. Attempts to elicit bnAbs with recombinant Env trimers have been ineffective, due to the extensive somatic hypermutation and affinity maturation necessary for bnAb development. An effective HIV vaccine will require careful considerations of the route and schedule of immunization, selection of adjuvants, and design of immunogens to safely induce bnAb development in a much shorter amount of time. Here, we detail two promising strategies to circumvent HIV viral resistance and immunodominance for bnAb induction. First, we perform a comprehensive head-to-head analysis of multiple adjuvants with conventional aluminum hydroxide (alum) to assess the extent of adaptive immune responses to Env trimer. We demonstrate that a combined adjuvant approach – pairing slow delivery antigen kinetics (pSer:alum) with an ISCOMs-like saponin-based adjuvant (SMNP) – can augment germinal center (GC) responses in the lymph nodes after a priming immunization. After subsequent booster immunizations, pSer:alum + SMNP induce nAb responses in the serum and durable antigen-specific plasma cells (BPC) in the bone marrow. Second, we test rationally designed germline-targeting (GT) immunogens, as the first step of a sequential vaccination strategy, in a polyclonal system. GT immunogens, N332-GT5 (BG18-class) and 10E8-GT (10E8-class), elicited antigen-specific germinal center B cells (BGC) and memory B cells (BMem) possessing sequence characteristics and mode of binding that is similar to their respective bnAbs. Both strategies – adjuvants, as a component in vaccines, and germline-targeting, as a rationally design strategy – provide promise in the development of an HIV vaccine.