Therapeutic Advances in Vaccines

A human immunodeficiency virus (HIV) vaccine remains a central component in the quest to control the worldwide epidemic. To examine the status of the development of HIV vaccines, we review the results of the efficacy trials carried out to date and the immunologic principles that guided them. Four vaccine concepts have been evaluated in HIV-1 vaccine efficacy trials, and the results of these trials have provided significant information for future vaccine development. While one of these trials demonstrated that a safe and effective HIV vaccine is possible, many questions remain regarding the basis for the observed protection and the most efficient way to stimulate it. Novel HIV vaccine strategies including induction of highly potent broadly neutralizing antibodies, use of novel homologous and heterologous vector systems, and vectored immunoprophylaxis seek to expand and build upon the knowledge gained from these trials. Keyword: HIV vaccine, HIV vaccine clinical trials, HIV vaccine review, AIDSVAX, Step, RV144, HVTN 505 Correspondence to: Yehuda Z. Cohen, MD Center for Virus and Vaccine Research, Beth Israel Deaconess Medical Center, E/CLS-1003, 330 Brookline Ave, Boston, 02215, USA [email protected]. edu Raphael Dolin, MD Beth Israel Deaconess Medical Center, Boston, MA, USA 494535 TAV132051013613494535Therapeutic Advances in VaccinesCohen and Dolin 2013 494535 by guest on January 24, 2014 tav.sagepub.com Downloaded from Therapeutic Advances in Vaccines 1 (3) 100 http://tav.sagepub.com Table 1. HIV vaccine efficacy trials. Efficacy trial Vaccine Population N Efficacy Other significant results Immune response Immune correlates of risk VAX004 AIDSVAX B/B (rgp120 immunogens) Primarily highrisk MSM 5403 None [Flynn et al. 2005] N/A Weak nAb response [Gilbert et al. 2010] N/A VAX003 AIDSVAX B/E (rgp120 immunogens) Injection drug users 2546 None [Pitisuttithum et al. 2006] N/A Weak nAb response [Montefiori et al. 2012] N/A Step MRKAd5 HIV1 (rAd5 vector expressing Gag, Pol, and Nef) Primarily highrisk MSM 3000 None; trial halted after meeting prespecified futility boundaries [Buchbinder et al. 2008] Significantly increased risk of HIV infection in men who were both Ad5seropositive and uncircumcised, which waned with time since vaccination [Duerr et al. 2012] CD8+ T-cell response detected in the majority of vaccinees, although weak and of narrow breadth [McElrath et al. 2008] N/A HVTN 503/ Phambili Same as Step Primarily heterosexuals 801 None; enrollment halted after lack of efficacy seen in Step [Gray et al. 2011b] N/A Similar to Step [Gray et al. 2011b] N/A RV144 ALVAC (canarypox vector expressing Env, Gag, and Pol) prime followed by AIDSVAX B/E boost Primarily low-risk heterosexuals 16,402 31.2% overall efficacy for prevention of HIV-1 infection in the modified intention-totreat analysis [Rerks-Ngarm et al. 2009]; no subsequent effect on viremia or CD4 count in vaccinees who were infected [Rerks-Ngarm et al. 2012] 68% efficacy for low or medium risk participants, no efficacy in the high-risk group; efficacy was highest over the first 12 months and then fell rapidly [Robb et al. 2012] Weak nAb response [Montefiori et al. 2012]. Moderate CD8+ and CD4+ Tcell response; the CD4+ T-cell response was directed against the V2 region of Env [de Souza et al. 2012] Binding of IgG to the V1 and V2 regions of Env correlated with protection; protection was mitigated by the presence of plasma IgA directed against Env [Haynes et al. 2012a] HVTN 505 VRC-HIVDNA01600-VP (DNA expressing Gag, Pol, Nef, and Env) prime followed by VRC-HIVADV01400-VP (rAd5 expressing Gag, Pol, and Env) boost High-risk MSM 2504 None; trial halted after meeting prespecified futility boundaries Awaiting final trial results Awaiting final trial results N/A HIV, human immunodeficiency virus; HVTN, HIV Vaccine Trials Network; IgG, immunoglobulin G; MSM, men who have sex with men; nAb, neutralizing antibody; rgp, recombinant glycoprotein; rAd5, recombinant adenovirus serotype 5. by guest on January 24, 2014 tav.sagepub.com Downloaded from