An effective human immunodeficiency virus type 1 (HIV-1)
vaccine is expected to have the greatest impact on HIV-1 spread and remains a global scientific priority. Only one candidate
vaccine has significantly reduced HIV-1 acquisition, yet at a limited efficacy of 31%, and none have delayed
disease progression in vaccinated individuals. Thus, the challenge remains to develop HIV-1 immunogens that will elicit protective immunity. A combination of two independent approaches - namely the elicitation of broadly neutralising
antibodies (
bNAb) to prevent or reduce acquisition of
infection and stimulation of effective cytotoxic T lymphocyte (CTL) responses to slow
disease progression in
breakthrough infections (recent evidence suggests that CTLs could also block HIV-1 from establishing
persistent infection) - is the current ideal. The purpose of this review is to summarise strategies and progress in the design and testing of HIV-1 immunogens to elicit
bNAb and protective CTL immune responses. Recent advances in mimicking the functional native envelope trimer structure and in designing structurally-stabilised
bNAb epitope forms to drive development of germline precursors to mature
bNAb are highlighted. Systematic or computational approaches to T cell immunogen design aimed at covering viral diversity, increasing the breadth of immune responses and/or reducing viable viral escape are discussed. We also discuss a recent novel
vaccine vector approach shown to induce extremely broad and persistent T cell responses that could clear highly pathogenic simian immunodeficiency virus (SIV) early after
infection in the monkey model. While in vitro and animal model data are promising, Phase II and III human clinical trials are ultimately needed to determine the efficacy of immunogen design approaches.