A step forward for HIV vaccines
Authors: Dan H Barouch
Journal: The Lancet HIV (2018)

Development of a safe and effective HIV vaccine will probably be essential to achieve a durable end to the HIV pandemic.1Fauci AS An HIV vaccine is essential for ending the HIV/AIDS pandemic.JAMA. 2017; 318: 1535-1536Crossref PubMed Scopus (57) Google Scholar, 2Stephenson KE D'Couto HT Barouch DH New concepts in HIV-1 vaccine development.Curr Opin Immunol. 2016; 41: 39-46Crossref PubMed Scopus (57) Google Scholar However, only four HIV vaccine regimens have been assessed for clinical efficacy in the 35-year history of the HIV epidemic.2Stephenson KE D'Couto HT Barouch DH New concepts in HIV-1 vaccine development.Curr Opin Immunol. 2016; 41: 39-46Crossref PubMed Scopus (57) Google Scholar The main challenges facing the development of an HIV vaccine are scientific and are unprecedented in the history of vaccinology, including the need to protect against globally diverse virus strains and unclear immune correlates of protection. In The Lancet HIV, Linda-Gail Bekker and colleagues report an important next chapter in the quest to develop an HIV vaccine.3Bekker L-G Moodie Z Grunenberg N et al.Subtype C ALVAC-HIV and bivalent subtype C gp120/MF59 HIV-1 vaccine in low-risk, HIV-uninfected, South African adults: a phase 1/2 trial.Lancet HIV. 2018; (published online June 10.)http://dx.doi.org/10.1016/S2352-3018(18)30071-7Summary Full Text Full Text PDF PubMed Scopus (69) Google Scholar In 2009, the RV144 trial showed the first, and to date only, positive results from an HIV vaccine efficacy trial in human beings.4Rerks-Ngarm S Pitisuttithum P Nitayaphan S et al.Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand.N Engl J Med. 2009; 361: 2209-2220Crossref PubMed Scopus (2449) Google Scholar This vaccine included priming with canarypox ALVAC vectors and boosting with alum-adjuvanted envelope (env) gp120 proteins, and it provided 31% efficacy in a low-risk population in Thailand. Although not sufficient for licensure, these data catalysed a wave of enthusiasm to understand the immune correlates of protection and to try to improve this vaccine. Findings from an immune correlates analysis indicated that antibodies against env variable loops 1 and 2 (V1V2) correlated inversely with infection risk,5Haynes BF Gilbert PB McElrath MJ et al.Immune-correlates analysis of an HIV-1 vaccine efficacy trial.N Engl J Med. 2012; 366: 1275-1286Crossref PubMed Scopus (1449) Google Scholar and a sieve analysis similarly showed vaccine-induced immune pressure on env V1V2.6Rolland M Edlefsen PT Larsen BB et al.Increased HIV-1 vaccine efficacy against viruses with genetic signatures in Env V2.Nature. 2012; 490: 417-420Crossref PubMed Scopus (348) Google Scholar These data led to a hypothesis that vaccine-elicited binding antibodies against V1V2 might have accounted for the protection observed in RV144. Additional potential correlates of protection that emerged from RV144 included IgG3 responses and CD4+ T-cell responses. A validated and predictive immune correlate of protection would be a major advance for the HIV vaccine field. Thus, a key priority has been to test this potential V1V2 immune correlate prospectively in another study. Bekker and colleagues aimed to adapt the RV144 vaccine regimen to the clade C epidemic in South Africa. New ALVAC vectors (vCP2438, expressing clade C env gp120 and clade B env gp41/gag/pro) and bivalent clade C env gp120 proteins (TV1/1086) were manufactured, and instead of the alum adjuvant used in RV144, the more potent squalene-based adjuvant MF59 was used. Bekker and colleagues assessed the safety and immunogenicity of this new vaccine in the HIV Vaccine Trials Network (HVTN) 100 trial3Bekker L-G Moodie Z Grunenberg N et al.Subtype C ALVAC-HIV and bivalent subtype C gp120/MF59 HIV-1 vaccine in low-risk, HIV-uninfected, South African adults: a phase 1/2 trial.Lancet HIV. 2018; (published online June 10.)http://dx.doi.org/10.1016/S2352-3018(18)30071-7Summary Full Text Full Text PDF PubMed Scopus (69) Google Scholar—a placebo-controlled, randomised, double-blind, phase 1/2 trial in South Africa. A late boost was added to the RV144 vaccine schedule at 12 months, with vaccine administered at months 0, 1, 3, 6, and 12. Thus, the RV144 and HVTN 100 trials differed by many variables. Binding antibody responses were of a higher magnitude and cellular immune responses were of a higher frequency in HVTN 100 compared with RV144, but V1V2-specific antibody responses were lower in HVTN 100 than in RV144. The reasons for these differences are not entirely clear but could be related to the specific env strains selected for the vaccines and the more potent adjuvant used in HVTN 100. The findings of HVTN 100 are important because prespecified immunological go/no-go criteria were achieved, including IgG antibody binding and CD4+ T-cell responses, which led to initiation of a phase 2b/3 efficacy trial (HVTN 702) to ascertain the capacity of this vaccine to protect against HIV acquisition in South Africa (NCT02968849). HVTN 702 will also test prospectively whether vaccine-elicited V1V2-binding antibodies correlate with protection. Validation of this immune correlate would be useful because it could then be used as a surrogate biomarker that would greatly accelerate HIV vaccine development moving forward. As the area of HIV vaccine research awaits efficacy results from HVTN 702, additional HIV vaccine candidates are also being pursued. These include adenovirus vectors expressing mosaic immunogens with an env gp140 protein boost, cytomegalovirus vectors that induce persistent T-cell responses, native-like env trimers, and sequential env immunisation approaches that aim to induce broadly neutralising antibodies.2Stephenson KE D'Couto HT Barouch DH New concepts in HIV-1 vaccine development.Curr Opin Immunol. 2016; 41: 39-46Crossref PubMed Scopus (57) Google Scholar One lesson from the RV144, HVTN 100, and HVTN 702 trials is that the time and resources needed to bring a vaccine candidate into efficacy trials are substantial. However, only such clinical efficacy trials can establish if a vaccine candidate protects humans. Moreover, efficacy data in humans helps to refine preclinical models and immunological assays. Therefore, we need to increase the number of efficacy trials to test a broad range of ideas for vaccines if we are to achieve the ultimate objective of developing an HIV vaccine and ending the HIV pandemic. I declare grants from the National Institutes of Health, the Gates Foundation, the Ragon Institute, the Henry Jackson Foundation, The Foundation for AIDS Research, the Defense Advanced Research Projects Agency, Janssen, and Gilead; and personal fees from IGM and AVVI Biotech; all outside the submitted work. Subtype C ALVAC-HIV and bivalent subtype C gp120/MF59 HIV-1 vaccine in low-risk, HIV-uninfected, South African adults: a phase 1/2 trialAlthough the IgG response to the HVTN 100 vaccine was lower than that reported in RV144, it exceeded the predicted 63% threshold needed for 50% vaccine efficacy using a V1V2 correlate of protection model. Thus, the subtype C HIV vaccine regimen qualified for phase 2b/3 efficacy testing, a critical next step of vaccine development. Full-Text PDF Open Access