Editing HIV vaccine development (section)

===Phase I===
Most initial approaches have focused on the [[HIV envelope]] protein. At least thirteen different [[gp120]] and [[gp160]] envelope candidates have been evaluated, in the US predominantly through the AIDS Vaccine Evaluation Group. Most research focused on gp120 rather than gp41/gp160, as the latter is generally more difficult to produce and did not initially offer any clear advantage over gp120 forms. Overall, they have been safe and immunogenic in diverse populations, have induced neutralizing antibody in nearly 100% recipients, but rarely induced [[Cytotoxic T cell|CD8+ cytotoxic T lymphocytes]] (CTL). Mammalian derived envelope preparations have been better inducers of neutralizing antibody than candidates produced in yeast and bacteria. Although the vaccination process involved many repeated "[[booster dose|booster]]" injections, it was challenging to induce and maintain the high anti-gp120 antibody [[titer]]s necessary to have any hope of neutralizing an HIV exposure.{{citation needed|date=January 2021}}

The availability of several recombinant [[canarypox]] [[Viral vector vaccine|vectors]] has provided interesting results that may prove to be generalizable to other [[viral vector]]s. Increasing the complexity of the canarypox vectors by including more genes/epitopes has increased the percent of volunteers that have detectable CTL to a greater extent than did increase the dose of the viral vector. CTLs from volunteers were able to kill [[PBMC|peripheral blood mononuclear cells]] infected with primary isolates of HIV, suggesting that induced CTLs could have biological significance. Besides, cells from at least some volunteers were able to kill cells infected with HIV from other clades, though the pattern of recognition was not uniform among volunteers. The canarypox vector is the first candidate HIV vaccine that has induced cross-clade functional CTL responses. The first phase I trial of the candidate vaccine in Africa was launched early in 1999 with Ugandan volunteers. The study determined the extent to which Ugandan volunteers have CTL that are active against the subtypes of HIV prevalent in Uganda, A and D. In 2015, a Phase I trial called HVTN 100 in South Africa tested the combination of a canarypox vector ALVAC and a gp120 protein adapted for the subtype C HIV common in sub-Saharan Africa, with the MF59 adjuvant. Those who received the vaccine regimen produced strong immune responses early on and the regimen was safe.<ref>{{cite journal | vauthors = Bekker LG, Moodie Z, Grunenberg N, Laher F, Tomaras GD, Cohen KW, Allen M, Malahleha M, Mngadi K, Daniels B, Innes C, Bentley C, Frahm N, Morris DE, Morris L, Mkhize NN, Montefiori DC, Sarzotti-Kelsoe M, Grant S, Yu C, Mehra VL, Pensiero MN, Phogat S, DiazGranados CA, Barnett SW, Kanesa-Thasan N, Koutsoukos M, Michael NL, Robb ML, Kublin JG, Gilbert PB, Corey L, Gray GE, McElrath MJ | display-authors = 6 | title = 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 | journal = The Lancet. HIV | volume = 5 | issue = 7 | pages = e366–e378 | date = June 2018 | pmid = 29898870 | pmc = 6028742 | doi = 10.1016/S2352-3018(18)30071-7 }}</ref>

Other strategies that have progressed to phase I trials in uninfected persons include peptides, [[lipopeptide]]s, [[DNA vaccination|DNA]], an [[attenuation (biology)|attenuated]] ''[[Salmonella]]'' vector, p24, etc. Specifically, candidate vaccines that induce one or more of the following are being sought:
* [[neutralizing antibody|neutralizing antibodies]] active against a broad range of HIV primary isolates;
* cytotoxic T cell responses in a vast majority of recipients;
* strong mucosal [[immune response]]s.<ref>{{cite journal | vauthors = Pavot V, Rochereau N, Lawrence P, Girard MP, Genin C, Verrier B, Paul S | title = Recent progress in HIV vaccines inducing mucosal immune responses | journal = AIDS | volume = 28 | issue = 12 | pages = 1701–18 | date = July 2014 | pmid = 25009956 | doi = 10.1097/qad.0000000000000308 | s2cid = 28618851 | doi-access = free }}</ref>

In 2011, researchers in National Biotech Centre in [[Madrid]] unveiled data from the Phase I clinical trial of their new vaccine, [[MVA-B]].  The vaccine induced an immunological response in 92% of the healthy subjects.<ref name="Fox News">{{cite news|url = https://www.foxnews.com/health/u-s-doctor-cautious-about-hiv-vaccine|title = New Vaccine Could Turn HIV Into Minor Infection|access-date = 29 September 2011|work = Fox News|date = 2011-09-29|archive-date = 2011-09-29|archive-url = https://web.archive.org/web/20110929194708/http://www.foxnews.com/health/2011/09/29/new-vaccine-could-turn-hiv-into-minor-infection/|url-status = live}}</ref>

In 2016, results were published of the first Phase I human clinical trial of a killed whole-HIV-1 vaccine, [[SAV001]]. HIV used in the vaccine was chemically and physically deadened through radiation. The trial, conducted in Canada in 2012, demonstrated a good safety profile and elicited antibodies to HIV-1.<ref>{{cite journal | vauthors = Choi E, Michalski CJ, Choo SH, Kim GN, Banasikowska E, Lee S, Wu K, An HY, Mills A, Schneider S, Bredeek UF, Coulston DR, Ding S, Finzi A, Tian M, Klein K, Arts EJ, Mann JF, Gao Y, Kang CY | display-authors = 6 | title = First Phase I human clinical trial of a killed whole-HIV-1 vaccine: demonstration of its safety and enhancement of anti-HIV antibody responses | journal = Retrovirology | volume = 13 | issue = 1 | page = 82 | date = November 2016 | pmid = 27894306 | pmc = 5126836 | doi = 10.1186/s12977-016-0317-2 | doi-access = free }}</ref> According to Dr. Chil-Yong Kang of [[University of Western Ontario|Western University]]'s [[Schulich School of Medicine & Dentistry]] in Canada, the developer of this vaccine, antibodies against gp120 and p24 increased to 8-fold and 64-fold, respectively after vaccination.<ref name="urlHIV vaccine produces no adverse effects in trials">{{cite news|url=http://www.medicaldaily.com/new-hiv-vaccine-proves-successful-phase-1-human-trial-255439/|title=New HIV Vaccine Proves Successful In Phase 1 Human Trial|date=2013-09-04|work=Medical Daily|access-date=2013-09-04|location=New York|archive-date=2013-09-07|archive-url=https://web.archive.org/web/20130907013033/http://www.medicaldaily.com/new-hiv-vaccine-proves-successful-phase-1-human-trial-255439|url-status=live}}</ref>

The VRC01 line of research produced an "eOD-GT8" antigen which specifically exposes the CD4 binding site for immunization, refined over time to expose less of the other sites.<ref>Duan, H. et al., Glycan Masking Focuses Immune Responses to the HIV-1 CD4-Binding Site and Enhances Elicitation of VRC01-Class Precursor Antibodies. Immunity 49, 301 (2018).</ref> As it turns out that most (but not all)<ref name=pmid34489473/> humans do have the required alleles, the problem shifted to the method of delivery. In 2021, after promising results in tests with mice and primates, scientists announced that they plan to conduct a Phase 1 trial of an [[mRNA vaccine]] against HIV if a further developed (via their 'env–gag VLP mRNA platform' which contains eOD-GT8<ref name=eOD-GT8/>) vaccine is confirmed safe and effective.<ref>{{cite news |title=Experimental MRNA HIV Vaccine Safe, Shows Promise In Animals - ScienceMag |url=https://scienmag.com/experimental-mrna-hiv-vaccine-safe-shows-promise-in-animals/ |access-date=16 January 2022 |date=9 December 2021 |archive-date=18 January 2022 |archive-url=https://web.archive.org/web/20220118182659/https://scienmag.com/experimental-mrna-hiv-vaccine-safe-shows-promise-in-animals/ |url-status=dead }}</ref><ref>{{cite journal |author=Zhang Peng |author2=Elisabeth Narayanan |display-authors= et al. |title=A multiclade env–gag VLP mRNA vaccine elicits tier-2 HIV-1-neutralizing antibodies and reduces the risk of heterologous SHIV infection in macaques |journal=Nature Medicine |date=December 2021 |volume=27 |issue=12 |pages=2234–2245 |doi=10.1038/s41591-021-01574-5 |pmid= 34887575 |s2cid= 245116317 |language=en |issn=1546-170X|doi-access=free }}</ref> On January 17, 2022 [[International AIDS Vaccine Initiative|IAVI]] and [[Moderna]] launched a phase I trial of a HIV vaccine with mRNA technology.<ref>{{Cite web|title=IAVI and Moderna launch trial of HIV vaccine antigens with mRNA te|url=https://www.iavi.org/news-resources/press-releases/2022/iavi-and-moderna-launch-trial-of-mrna-hiv-vaccine-antigens|access-date=2022-02-14|website=IAVI|language=en|archive-date=2022-02-13|archive-url=https://web.archive.org/web/20220213125552/https://www.iavi.org/news-resources/press-releases/2022/iavi-and-moderna-launch-trial-of-mrna-hiv-vaccine-antigens|url-status=dead}}</ref> On March 14, 2022 the [[National Institutes of Health]] reported that it had launched a "clinical trial of three mRNA HIV vaccines". The phase one trial is expected to conclude July 2023.{{citation needed|date=March 2023}}