Editing HIV vaccine development (section)

==Clinical trials==

Several vaccine candidates are in varying phases of [[clinical trial]]s.

===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}}

===Phase II===

''Preventive HIV vaccines''
* A recombinant Adenovirus-5 HIV vaccine (called V520) was tested in two Phase 2b studies, Phambili and STEP. On December 13, 2004, recruitment began for the [[STEP study]], a 3,000-participant [[Clinical trial#Phase II|phase II clinical trial]] of a novel HIV vaccine, at sites in North America, South America, the Caribbean and Australia.<ref>{{cite web |url=http://www.stepstudies.com/new/locations.shtml |title=STEP Study Locations |access-date=2008-11-04 |archive-url=https://web.archive.org/web/20080724081503/http://www.stepstudies.com/new/locations.shtml |archive-date=2008-07-24  }}</ref>  The trial was co-funded by the [[National Institute of Allergy and Infectious Diseases]] (NIAID), which is a division of the [[National Institutes of Health]] (NIH), and the pharmaceutical company [[Merck & Co.]] Merck developed V520 to stimulate HIV-specific cellular immunity, which prompts the body to produce T cells that kill HIV-infected cells. In previous smaller trials, this vaccine was found to be safe, because of the lack of adverse effects on the participants. The vaccine showed induced cellular immune responses against HIV in more than half of volunteers.<ref name="AIDSepidemicupdate">{{cite web|author=Joint United Nations Programme on HIV/AIDS ([[UNAIDS]])|date=December 2005|title=AIDS epidemic update|url=https://www.who.int/hiv/epi-update2005_en.pdf|access-date=2014-04-22|publisher=[[World Health Organization]]|archive-date=2014-06-29|archive-url=https://web.archive.org/web/20140629031433/http://www.who.int/hiv/epi-update2005_en.pdf|url-status=live}}</ref> V520 contains a weakened [[adenovirus]] that serves as a carrier for three subtype B HIV genes (''gag,'' ''pol'' and ''nef''). Subtype B is the most prevalent HIV subtype in the regions of the study sites. Adenoviruses are among the main causes of upper respiratory tract ailments such as the [[common cold]]. Because the vaccine contains only three HIV genes housed in a weakened adenovirus, study participants cannot become infected with HIV or get a respiratory infection from the vaccine. It was announced in September 2007 that the trial for V520 would be stopped after it determined that vaccination with V520 appeared associated with an increased risk of HIV infection in some recipients.<ref>[http://www.hvtn.org/science/step_buch.html Efficacy Results from the STEP Study (Merck V520 Protocol 023/HVTN 502): A Phase II Test-of-Concept Trial of the MRKAd5 HIV-1 Gag/Pol/Nef Trivalent Vaccine] {{webarchive|url=https://web.archive.org/web/20110726164651/http://www.hvtn.org/science/step_buch.html |date=2011-07-26 }}</ref> The foremost issue facing the recombinant adenovirus that was used is the high prevalence of the adenovirus-specific antibodies as a result of prior exposure to adenovirus. Adenovirus vectors and many other [[viral vector vaccine|viral vectors]] currently used in HIV vaccines will induce a rapid memory immune response against the vector. This results in an impediment to the development of a T cell response against the inserted antigen (HIV antigens)<ref>{{cite journal | vauthors = Sekaly RP | title = The failed HIV Merck vaccine study: a step back or a launching point for future vaccine development? | journal = The Journal of Experimental Medicine | volume = 205 | issue = 1 | pages = 7–12 | date = January 2008 | pmid = 18195078 | pmc = 2234358 | doi = 10.1084/jem.20072681 }}</ref> The results of the trial prompted the reexamination of vaccine development strategies.<ref name="pmid18597681">{{cite journal | vauthors = Iaccino E, Schiavone M, Fiume G, Quinto I, Scala G | title = The aftermath of the Merck's HIV vaccine trial | journal = Retrovirology | volume = 5 | page = 56 | date = July 2008 | pmid = 18597681 | pmc = 2483718 | doi = 10.1186/1742-4690-5-56 | doi-access = free }}</ref>
* [[HVTN 505]], a Phase IIb study, was launched in 2009 but halted in 2013 due to meeting requirements of futility.
* Potential broadly neutralizing antibodies have been cloned in the laboratory (monoclonal antibodies) and are being tested in [[passive immunity|passive vaccination]] [[clinical trial]]s.<ref name=eOD-GT8>{{Cite web|last=International AIDS Vaccine Initiative|date=2021-09-29|others=ModernaTX, Inc., The University of Texas at San Antonio, George Washington University, Fred Hutchinson Cancer Research Center, Emory University|title=A Phase 1, Randomized, First-in-human, Open-label Study to Evaluate the Safety and Immunogenicity of eOD-GT8 60mer mRNA Vaccine (mRNA-1644) and Core-g28v2 60mer mRNA Vaccine (mRNA-1644v2-Core) in HIV-1 Uninfected Adults in Good General Health|url=https://clinicaltrials.gov/ct2/show/NCT05001373|access-date=2021-11-30|archive-date=2021-11-30|archive-url=https://web.archive.org/web/20211130203340/https://clinicaltrials.gov/ct2/show/NCT05001373|url-status=live}}</ref> In May 2016, there was the launch of the Antibody Mediated Prevention (AMP) trials (HVTN 703 and HVTN 704), the first phase IIb trials of a monoclonal antibody for HIV prevention. HVTN 703 and HVTN 704 found that the VRC01 monoclonal antibody, which targets the CD4 binding site, was not able to prevent HIV acquisition.<ref>{{Cite journal|last1=Corey|first1=Lawrence|last2=Gilbert|first2=Peter B.|last3=Juraska|first3=Michal|last4=Montefiori|first4=David C.|last5=Morris|first5=Lynn|last6=Karuna|first6=Shelly T.|last7=Edupuganti|first7=Srilatha|last8=Mgodi|first8=Nyaradzo M.|last9=deCamp|first9=Allan C.|last10=Rudnicki|first10=Erika|last11=Huang|first11=Yunda|date=2021-03-18|title=Two Randomized Trials of Neutralizing Antibodies to Prevent HIV-1 Acquisition|journal=The New England Journal of Medicine|volume=384|issue=11|pages=1003–1014|doi=10.1056/NEJMoa2031738|issn=1533-4406|pmc=8189692|pmid=33730454}}</ref>
* In 2017, Janssen and the HVTN launched the phase IIb trial called HVTN 705/Imbokodo, testing the mosaic vector vaccine Ad26.Mos4.HIV and the aluminum phosphate-adjuvanted Clade C gp140 vaccines which are designed to prevent infection of all HIV subtypes around the world.<ref>{{Cite web|url=https://www.firstpost.com/tech/science/candidate-for-new-aids-vaccine-advances-to-next-phase-of-pre-approval-trials-4690471.html|title=Candidate for new AIDS vaccine advances to next phase of pre-approval trials|website=Tech2|language=en-US|access-date=2018-07-11|date=2018-07-08|archive-date=2018-07-11|archive-url=https://web.archive.org/web/20180711225342/https://www.firstpost.com/tech/science/candidate-for-new-aids-vaccine-advances-to-next-phase-of-pre-approval-trials-4690471.html|url-status=live}}</ref> In 2021 the [[NIH]] announced that the Imbokodo Phase 2b study did not provide statistically significant reduction in HIV infection.<ref name=nih2021>{{cite web |title=HIV Vaccine Candidate Does Not Sufficiently Protect Women Against HIV Infection |url=https://www.nih.gov/news-events/news-releases/hiv-vaccine-candidate-does-not-sufficiently-protect-women-against-hiv-infection |website=National Institutes of Health (NIH) |access-date=1 September 2021 |language=EN |date=31 August 2021 |archive-date=31 August 2021 |archive-url=https://web.archive.org/web/20210831235052/https://www.nih.gov/news-events/news-releases/hiv-vaccine-candidate-does-not-sufficiently-protect-women-against-hiv-infection |url-status=live }}</ref>
* In 2019, Terevac-VIH, a vaccine from Cuba, was determined to have passed the first stage of clinical trials after two years and move to the second stage of development.<ref>{{Cite web |url=https://thegeekherald.com/p/cure-for-hiv-aids-cuba-makes-a-breakthrough-nih-and-gate-foundation-will-donate-for-future-research/ |title=Cure for HIV/AIDS: Cuba makes a Breakthrough, NIH and Gate Foundation will Donate for Future Research |date=27 December 2019 |access-date=2021-12-11 |archive-date=2021-12-11 |archive-url=https://web.archive.org/web/20211211203908/https://thegeekherald.com/p/cure-for-hiv-aids-cuba-makes-a-breakthrough-nih-and-gate-foundation-will-donate-for-future-research/ |url-status=live }}</ref><ref>{{Cite web |url=https://www.cmhw.cu/en/science-and-health/5289-successful-clinical-trials-of-hiv-vaccine-in-cuba |title=Successful Clinical Trials of HIV Vaccine in Cuba |access-date=2021-12-11 |archive-date=2021-12-11 |archive-url=https://web.archive.org/web/20211211203244/https://www.cmhw.cu/en/science-and-health/5289-successful-clinical-trials-of-hiv-vaccine-in-cuba |url-status=live }}</ref>

''Therapeutic HIV vaccines''

Biosantech developed a therapeutic vaccine called Tat Oyi, which targets the tat protein of HIV. It was tested in France in a double-blind Phase I/II trial with 48 HIV-positive patients who had reached viral suppression on [[Highly active antiretroviral therapy|Highly Active Antiretroviral Therapy]] and then stopped antiretrovirals after getting the intradermal Tat Oyi vaccine.<ref>{{cite journal | vauthors = Loret EP, Darque A, Jouve E, Loret EA, Nicolino-Brunet C, Morange S, Castanier E, Casanova J, Caloustian C, Bornet C, Coussirou J, Boussetta J, Couallier V, Blin O, Dussol B, Ravaux I | display-authors = 6 | title = Intradermal injection of a Tat Oyi-based therapeutic HIV vaccine reduces of 1.5 log copies/mL the HIV RNA rebound median and no HIV DNA rebound following cART interruption in a phase I/II randomized controlled clinical trial | journal = Retrovirology | volume = 13 | page = 21 | date = April 2016 | pmid = 27036656 | pmc = 4818470 | doi = 10.1186/s12977-016-0251-3 | doi-access = free }}</ref>

===Phase III===
''Preventive HIV vaccines''

There have been no passive preventive HIV vaccines to reach Phase III yet, but some active preventive HIV vaccine candidates have entered Phase III.
* In February 2003, [[VaxGen]] announced that their [[AIDSVAX|AIDSVAX B/E]] vaccine was a failure in [[North America]] as there was not a statistically significant reduction of HIV infection within the study population.
* AIDSVAX B/E was a component, along with ALVAC, of the [[RV 144]] vaccine trial in Thailand that showed partial efficacy in preventing HIV. The AIDSVAX B/E and ALVAC vaccines targeted the [[gp120]] part of the HIV envelope. The study involved 16,395 participants who did not have HIV infection, 8197 of whom were given treatment consisting of two experimental vaccines targeting [[Subtypes of HIV|HIV types B and E]] that are prevalent in Thailand, while 8198 were given a placebo. The participants were tested for HIV every six months for three years. After three years, the vaccine group had HIV infection rates reduced by about 30% compared with those in the placebo group. However, after taking into account the seven people who already had HIV before getting vaccinated (two in the placebo group, five in the vaccine group) the difference was 26%.<ref name="Rerks-Ngarm2009">{{cite journal | vauthors = Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Chiu J, Paris R, Premsri N, Namwat C, de Souza M, Adams E, Benenson M, Gurunathan S, Tartaglia J, McNeil JG, Francis DP, Stablein D, Birx DL, Chunsuttiwat S, Khamboonruang C, Thongcharoen P, Robb ML, Michael NL, Kunasol P, Kim JH | display-authors = 6 | title = Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand | journal = The New England Journal of Medicine | volume = 361 | issue = 23 | pages = 2209–20 | date = December 2009 | pmid = 19843557 | doi = 10.1056/NEJMoa0908492 | doi-access = free }}</ref> It was discovered that participants receiving vaccines in the RV 144 trial who produced [[Immunoglobulin G|IgG]] antibodies against the [[V2 loop]] of the [[Envelope glycoprotein GP120|HIV outer envelope]] were 43% less likely to become infected than those who did not, while [[IgA]] production was associated with a 54% greater risk of infection than those who did not produce the antibodies (but not worse than placebo). Viruses collected from vaccinated participants had mutations in the V2 region. Tests of a vaccine for [[Simian immunodeficiency virus|SIV]] in monkeys found greater resistance to SIV in animals producing antibodies against this region. Therefore, further research is expected to focus on creating vaccines designed to provoke an IgG reaction against the V2 loop.<ref>{{cite journal | title = Clues emerge to explain first successful HIV vaccine trial | journal = Nature | first = Ewen | last = Callaway | name-list-style = vanc | date=16 September 2011 | doi = 10.1038/news.2011.541 }}</ref>
* In 2020, the phase IIb-III trial {{visible anchor|[[HVTN 702]]}}/"Uhambo" found that ALVAC/gp120/MF59 vaccinations were safe, and caused no harm, but had no efficacy in HIV prevention in [[South Africa]]. Vaccinations with the Uhambo vaccine regimen began late 2016 and stopped early 2020.<ref>{{cite web |url=https://www.nih.gov/news-events/news-releases/experimental-hiv-vaccine-regimen-ineffective-preventing-hiv |title=Experimental HIV vaccine regimen ineffective in preventing HIV |publisher=NIH |date=3 February 2020 |access-date=4 February 2020 |archive-date=4 February 2020 |archive-url=https://web.archive.org/web/20200204053128/https://www.nih.gov/news-events/news-releases/experimental-hiv-vaccine-regimen-ineffective-preventing-hiv |url-status=live }}</ref>
* In 2020, the Ad26.Mos4.HIV plus adjuvanted clade C gp140 vaccine regimen entered a phase III trial called HVTN 706/"Mosaico". The regimen is a combination of an adenovirus vector vaccine engineered against multiple global strains of HIV, and a protein vaccine.<ref>{{cite web|url=https://www.nih.gov/news-events/news-releases/nih-partners-launch-hiv-vaccine-efficacy-trial-americas-europe|title=NIH and partners to launch HIV vaccine efficacy trial in the Americas and Europe|date=15 July 2019|publisher=[[National Institutes of Health]]|access-date=23 July 2019|archive-date=23 July 2019|archive-url=https://web.archive.org/web/20190723131154/https://www.nih.gov/news-events/news-releases/nih-partners-launch-hiv-vaccine-efficacy-trial-americas-europe|url-status=live}}</ref> The trial was ended in January 2023 due to ineffectiveness.<ref>{{Cite web |date=2023-01-18 |title=Experimental HIV vaccine regimen safe but ineffective, study finds |url=https://www.nih.gov/news-events/news-releases/experimental-hiv-vaccine-regimen-safe-ineffective-study-finds |access-date=2023-01-26 |website=National Institutes of Health (NIH) |language=EN}}</ref>
''Therapeutic HIV vaccines''

No therapeutic HIV vaccine candidates have reached phase 3 testing yet.