Although there has been extensive clinical testing of HIV-1 vaccine candidates with almost 200 phase I trials started since 1987, only four vaccine regimens have been evaluated in phase III efficacy studies. Overcoming the challenge of viral diversity would be a huge coup in HIV-1 vaccine development. Having to contend with envelope amino acid sequence diversity amongst the nine HIV subtypes and complex intersubtype recombinant viruses as well as the error-prone replication of HIV-1 enabling escape from immune control [1] may appear to make this task almost insurmountable! These complexities have driven a maturation of the global response to HIV-1 vaccine development over the past 30 years. The formations of public private partnerships that synchronize the efforts of government agencies, funders, scientists and pharmaceutical companies to address the challenges facing HIV vaccine science represent a critical evolution [2]. These partnerships focus our efforts to ensure successful product development pathways that can end in the licensure or registration and distribution of an efficacious vaccine. Being attentive to HIV vaccine clinical trial design and analysis has also optimized efficiencies in the conduct of clinical trials and has improved the understanding and interpretation of trial outcomes [3]. The use of nonhuman primate models, utilizing different viruses or host species, has contributed substantially to vaccine development through our understanding of simian immunodeficiency virus/simian human immunodeficiency virus pathogenesis and the performance of candidate vaccines in challenge studies [4]. We have developed increasingly sophisticated tools to measure and assess potential biomarkers of protection and susceptibility, with statistical and sequence analysis methods providing opportunities to exact mechanisms of vaccine efficacy [5]. This has been especially highlighted in the RV144 study, a pivotal study in Thailand showing the first evidence for acquisition efficacy in an HIV-1 vaccine study [6]. This has driven the field exponentially forward in delineating immune responses that correlate with, and may be involved in, the mechanism of observed protection, setting the scene for the next decade of HIV-1 vaccine science.

Fortunately too, the HIV vaccine field is plethoric with viral vector platforms for HIV vaccine delivery. Most advanced in development are the nonreplicating viral vectors [7] that have been studied extensively through to efficacy trials. Most notable of these is ALVAC, a canary-pox-based vaccine, studied as part of a prime–boost regimen in combination with a recombinant gp120 subunit vaccine in the RV 144 trial. ALVAC is now poised for testing further afield in high HIV incidence areas in southern Africa [1]. Further clinical research into other orthopoxvirus-based vaccines such as vaccinia (NYVAC, MVA) or fowlpox will expand our knowledge on the utility of these delivery systems. Extensive evaluation of the highly immunogenic adenovirus type 5-based vaccine platform in three proof-of-concept efficacy trials has definitively demonstrated the lack of efficacy of these candidates [8–10], making it unlikely that this vaccine delivery system will be utilized further. However, investigating other human adenovirus serotypes, such as Ad26 and Ad35, as well as nonhuman adenovirus viral vectors remain important strategies to refine our understanding of optimizing platform delivery in the nonreplicating viral vector realm. Investing in live attenuated viral vaccines, which have been shown to induce durable, multicomponent immunity thereby enabling the containment of highly contagious pathogens, make the approach of using …