Introduction: Ending the HIV epidemic will likely require an efficacious preventative HIV vaccine. As vaccine development progresses, new challenges emerge in the context of an evolving prevention landscape.Areas covered: The progress in HIV vaccine development including trial regimens, results, and impact of pre-exposure prophylaxis (PrEP) including trial design.Expert opinion: Building upon the modest RV144 efficacy results, a follow-up study was launched in South Africa using modified vaccine constructs, ALVAC-HIV vector and gp120 protein boosts (Clade C strains). An adjuvant, MF59, was used to improve durability. Another Phase 2b regimen using an Adenovirus-26 vector with multivalent mosaic antigen inserts and a Clade C gp140 boost advanced into efficacy testing. Current vaccine efficacy studies enroll participants at risk for HIV, offer robust prevention packages, and notably do not restrict PrEP usage. With increasingly efficacious prevention options, future clinical trial designs become more complex. While formally requiring PrEP in HIV vaccine trials (e.g. PrEP ± Vaccine) may maximize protection, it raises both ethical and incremental efficacy over PrEP. Increasing vaccine complexity may lead to persistent vaccine-induced seropositivity, which presents different challenges. Discussion with the community and broader stakeholder engagement will help create solutions to these challenges.
Keywords: HIV Vaccine; challenges; clinical trials; potential candidates; regimen.