HIV vaccine: better to start together?
Authors: Barbara K Felber, George N Pavlakis
Journal: The Lancet HIV (2019)

With 37·9 million people infected by HIV worldwide, and 1·7 million people newly infected in 2018,1UNAIDSGlobal HIV & AIDS statistics: 2019 fact sheet.https://www.unaids.org/en/resources/fact-sheetDate accessed: September 12, 2019Google Scholar development of a vaccine against HIV is of upmost importance to prevent HIV-1 infection. Findings of the HIV vaccine trial RV1442Rerks-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: 220-920Crossref Scopus (2445) Google Scholar showed modest (31·2%) vaccine efficacy with a canarypox vector (ALVAC) expressing HIV genes as a prime followed by two booster immunisations with the ALVAC vector plus recombinant HIV gp120 envelope (Env) glycoprotein (AIDSVAX B/E). Correlates of reduced risk of infection were non-neutralising antibodies against the variable V1/V2 region of Env protein and antibodies mediating antibody-dependent cellular cytotoxicity.3Haynes 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 (1444) Google Scholar, 4Rolland 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 (347) Google Scholar, 5Corey L Gilbert PB Tomaras GD et al.Immune correlates of vaccine protection against HIV-1 acquisition.Sci Transl Med. 2015; 7310rv7Crossref PubMed Scopus (135) Google Scholar Although the RV144 regimen was a promising vaccine candidate, the protective effect waned over time. HIV vaccine researchers have the daunting task of not only developing novel strategies to improve vaccine efficacy and durability but also devising vaccines that induce immune responses, recognising the enormous variability of different HIV clades worldwide. The HIV Vaccine trials Network (HVTN) has several phase 2/3 trials ongoing, which are building on the results of the RV144 trial, using ALVAC and adenovirus 26 (Ad26) vectors.6HIV Vaccine Trials NetworkOngoing HVTN trials: enrolling, in follow-up, annual health/AESI contact(s).https://www.hvtn.org/content/dam/hvtn/Science/studies/HVTN_Ongoing_Trials_06.04.19.pdfDate: June 4, 2019Date accessed: September 12, 2019Google Scholar HVTN 702 is similar to RV144 but is testing a clade C ALVAC vector and clade C gp120 Env protein; HVTN 705 is analysing a quadrivalent Ad26 vector-based mosaic vaccine and clade C gp140 Env protein; and HVTN 706 is assessing a quadrivalent Ad26 vector-based mosaic vaccine, bivalent clade C, and mosaic gp140 Env protein. Several immunogenicity trials are also ongoing,6HIV Vaccine Trials NetworkOngoing HVTN trials: enrolling, in follow-up, annual health/AESI contact(s).https://www.hvtn.org/content/dam/hvtn/Science/studies/HVTN_Ongoing_Trials_06.04.19.pdfDate: June 4, 2019Date accessed: September 12, 2019Google Scholar testing novel vaccine candidates and adjuvants, with the aim to improve immunogenicity and durability of the vaccine-induced immune responses. In The Lancet HIV, Giuseppe Pantaleo and colleagues report data from a phase 1b clinical trial (HVTN 096)7Pantaleo G Janes H Karuna S et al.Safety and immunogenicity of a multivalent HIV vaccine comprising envelope protein with either DNA or NYVAC vectors (HVTN 096): a phase 1b, double-blind, placebo-controlled trial.Lancet HIV. 2019; (published online Oct 7)https://doi.org/10.1016/S2352-3018(19)30262-0Summary Full Text Full Text PDF Scopus (27) Google Scholar in which a canarypox vector (NYVAC) or DNA vaccine vector were combined with AIDSVAX B/E gp120 Env protein. In addition to the RV144-like schedule (two NYVAC or DNA vector vaccinations at month 0 and month 1 followed by two vector plus Env protein vaccinations at month 3 and month 6), Pantaleo and colleagues also assessed a new idea in a head-to-head comparison, by including Env protein in the priming vaccination (NYVAC or DNA vector plus Env protein). Importantly, co-administration of Env protein with the NYVAC or DNA vector from month 0 was superior in inducing humoral immune responses compared with the NYVAC or DNA vector alone during priming. These co-administration regimens resulted in faster development of humoral immune responses, greater magnitude and breadth of antibody responses and improved anti-V1/V2 responses (a correlate of reduced risk of infection in the RV144 trial), and production of tier 1 neutralising antibodies. Although initial differences between the four prime and boost regimens were evened out by the fourth vaccination at month 6, robust initial responses might lead to development of protective immunity. HVTN 096 is the first clinical study to compare directly a prime and boost vaccination regimen with co-administration of the same vaccine components (vector plus Env protein) at the same time in separate anatomical sites during prime. Data from HVTN 096 support the hypothesis that simultaneous priming with both vector and protein vaccine components provides an advantage. The results build on data previously obtained in mice, rabbits, and macaques showing that priming with a combination of HIV or SIV DNA and Env protein resulted in rapid and high humoral responses,8Li J Valentin A Kulkarni V et al.HIV/SIV DNA vaccine combined with protein in a co-immunization protocol elicits highest humoral responses to envelope in mice and macaques.Vaccine. 2013; 31: 3747-3755Crossref PubMed Scopus (57) Google Scholar, 9Patel V Jalah R Kulkarni V et al.DNA and virus particle vaccination protects against acquisition and confers control of viremia upon heterologous SIV challenge.Proc Natl Acad Sci USA. 2013; 110: 2975-2980Crossref PubMed Scopus (66) Google Scholar, 10Pissani F Malherbe DC Schuman JT et al.Improvement of antibody responses by HIV envelope DNA and protein co-immunization.Vaccine. 2014; 32: 507-513Crossref PubMed Scopus (26) Google Scholar indicating translatability of this idea from animal models to human beings. One explanation for the improved early immunogenicity is that co-administration of NYVAC or DNA vectors with Env protein during the priming vaccination provides the necessary stimulus to initiate development of humoral responses. This effect could be attributable to timely interaction between follicular helper T cells, induced by NYVAC or DNA vectors, and Env-specific B lymphocytes stimulated by the protein immunogen within the lymph node. The similarity of the effects of co-administration of vector and Env protein vaccine components in human beings and animal models could provide the means to further dissect the implicated mechanisms. It remains to be established whether co-administration of the vaccine components (vector plus protein) in the same anatomical site, targeting the same draining lymph nodes from the start, would further improve antibody development. It also remains to be seen whether any of these vaccine regimens enhance vaccine efficacy. These results are important and indicate that a simple change from traditional methods of prime and boost vaccination to co-administration of Env protein during priming could improve speed and magnitude of humoral responses; further clinical development is warranted. Additional clinical trials are needed to answer whether this vaccine regimen provides the desired benefits of enhancing protection and durability, perhaps including late-booster vaccination, as implemented in the RV144 follow-up trial RV305 (NCT01435135). Persistence of effective immune responses remains an important concern for AIDS vaccines. The rapid onset of antibody development suggests the possibility to reassess vaccination schedules, perhaps prolonging time between boosts. The fact that improved humoral immunity was seen with both the NYVAC vector and the DNA vector shows that this co-delivery strategy can be implemented using different vaccine modalities and suggests applications beyond HIV vaccines. BKF and GNP are co-inventors of US Government-owned patents for DNA vaccine technology and DNA immunotherapy. Safety and immunogenicity of a multivalent HIV vaccine comprising envelope protein with either DNA or NYVAC vectors (HVTN 096): a phase 1b, double-blind, placebo-controlled trialCo-administration of gp120 Env protein components with DNA or NYVAC vectors during priming led to early and potent induction of Env V1/V2 IgG binding antibody responses. This immunisation approach should be considered for induction of preventive antibodies in future HIV vaccine efficacy trials. Full-Text PDF Open Access