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This review describes lessons learnt from previous efficacy trials, highlights unanswered questions, and surveys new approaches in vaccine development addressing these gaps.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We conducted a targeted peer\u2010reviewed literature search of articles and conference abstracts from 1989 through 2021 for HIV vaccine studies and clinical trials. The US National Library of Medicine's Clinical Trials database was accessed to further identify clinical trials involving HIV vaccines. The content of the review was also informed by the authors\u2019 own experience and engagement with collaborators in HIV vaccine research.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>The HIV vaccine field has successfully developed multiple vaccine platforms through advanced clinical studies; however, the modest efficacy signal of the RV144 Thai trial remains the only demonstration of HIV vaccine protection in humans. Current vaccine strategies include prime\u2010boost strategies to improve elicitation of immune correlates derived from RV144, combination mosaic antigens, novel viral vectors, antigens designed to elicit broadly neutralizing antibody, new nucleic acid platforms and potent adjuvants to enhance immunogenicity across multiple classes of emerging vaccine candidates.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>HIV vaccine developers have applied lessons learnt from previous successes and failures to innovative vaccine design approaches. 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