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An effective HIV vaccine is a global health priority. We describe lessons learned from four HIV vaccine trials that failed to demonstrate efficacy and one that showed modest protection as a pathway forward.The Merck Ad5 phase IIb T-cell vaccine failed to show efficacy and might have increased the risk of HIV acquisition in men who have sex with men. Although VaxGen gp120 alone was not efficacious in groups at high risk for HIV-1 infection, the RV144 ALVAC prime and gp120 boost regimen showed 31% efficacy in low-incidence heterosexuals. All trials demonstrated the limitations of available laboratory and animal models to assess relevant vaccine-induced immune responses and predict clinical trial outcome. Analysis of innate and adaptive responses induced in RV144 will guide future trial design.Future HIV vaccine trials should define the RV144 immune responses relevant to protection, improve durability and level of protection, and assess efficacy in diverse risk groups. New strategies examining heterologous vector prime–boost, universal inserts, replicating vectors, and novel protein or adjuvant immunogens should be explored to induce T-cell and antibody responses. HIV vaccine development requires innovative ideas and a sustained long-term commitment of scientists, governments, and the community.