Burton DR, Desrosiers RC, Doms RW, et al. a large body of work providing a more complete understanding of the development of broadly neutralizing antibodies is now becoming translated into immunogen design using several different strategies. T-cell centered vaccines, fallen out of favor after Ad5-centered trials showed improved infection rates in Ad5 seropositive vaccine recipients, are going through a comeback based in part within the encouraging results from non-human primate challenge studies using rhCMV-based immunogens. This varied array of vaccine candidates may finally allow us to identify a broadly effective HIV vaccine able to contain the epidemic. 1. Intro The last ten years have seen an extraordinary acceleration in the development of at least partially effective HIV prevention modalities. Twenty years in to the use of antiretroviral therapy, the 1st randomized trial to test treatment as prevention showed a 96% reduction of HIV acquisition in the group receiving immediate treatment1, confirming the assumption that treatment not only benefits the HIV-infected subject but also dramatically reduces the risk of SIX3 transmission. Male circumcision was demonstrated to reduce HIV-1 acquisition in three large randomized clinical tests2C4. A vaginal microbicide based on the reverse transcriptase inhibitor Tenofovir disoproxil fumarate (TDF) showed effectiveness in the CAPRISA trial5, even though VOICE trial failed to replicate CAPRISAs success, likely due to reduced adherence to study product use6. Similarly, oral Pre-Exposure Prophylaxis (PrEP) reduced HIV acquisition in males who have sex with males (MSM) in the iPrEx study7 and in serodiscordant heterosexual couples in the Partners PrEP Study8, though PrEP failed to provide safety in the FEM-PrEP9 and VOICE studies6. Despite all these advances, an effective vaccine remains the holy grail of HIV prevention due to its ease of delivery, relatively low cost, independence on adherence, and lack of associated stigma. This review will present an overview of past HIV vaccine effectiveness tests, current proof-of-concept tests as well as provide an perspective on encouraging fresh vaccine strategies about to move into phase 1 clinical tests. 2. Recent HIV vaccine effectiveness trials The 1st Bazedoxifene HIV vaccines to advance to efficacy screening were based on the notion that C similarly to other vaccines avoiding viral diseases C antibodies were most likely necessary for safety from illness. Two vaccines, each consisting of VaxGens bivalent recombinant HIV Env proteins (AIDSVAX B/B and AIDSVAX B/E), were tested concurrently in two tests in ~2500 injection drug users in Thailand (VAX003) and ~5400 MSM and high-risk women in the US and the Netherlands (VAX004). While high antibody titers were accomplished in vaccine recipients, illness rates were related between vaccine and placebo recipients in both tests; vaccine efficacy (VE) was estimated at 0.1% (95% Confidence Interval [CI], ?30.8% to 23.8%) for VAX00310 and 6% (95% CI ?17% to 24%) for VAX00411. The inability of the induced antibodies to prevent infection was attributed to their thin specificity and therefore mismatch to most circulating HIV strains; since Env is one of the most variable proteins in HIV, the focus of HIV vaccine study switched to the induction of T-cell reactions because the cellular arm of the immune system can target the more conserved, internal proteins of the computer virus. The Step Study (enrolling MSM and high-risk women in the Americas) and its sister trial Phambili (studying Bazedoxifene heterosexual men and women in South Africa) tested the concept of whether a real T-cell centered vaccine could prevent illness or, if not, at least reduce viremia in breakthrough instances. The immunogen was based on an adenoviral vector developed by Merck that encoded Bazedoxifene for HIV Gag, Nef and Pol (MRKAd5 HIV), and therefore experienced no potential for inducing Env-specific neutralizing antibodies. The vaccine.