Several vaccine candidates are in varying phases of clinical trials. Phase I Most initial approaches have focused on the<unk>  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 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" injections, it was challenging to induce and maintain the high anti-gp120 antibody titers necessary to have any hope of neutralizing an<unk>  exposure. The availability of several recombinant canarypox vectors has provided interesting results that may prove to be generalizable to other viral vectors. 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 peripheral blood mononuclear cells infected with primary isolates of<unk> , suggesting that induced CTLs could have biological significance. Besides, cells from at least some volunteers were able to kill cells infected with<unk>  from other clades, though the pattern of recognition was not uniform among volunteers. The canarypox vector is the first candidate<unk>  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<unk>  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<unk>  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. Other strategies that have progressed to phase I trials in uninfected persons include peptides, lipopeptides, DNA, an attenuated Salmonella vector, p24, etc. Specifically, candidate vaccines that induce one or more of the following are being sought: * neutralizing antibodies active against a broad range of<unk>  primary isolates; * cytotoxic T cell responses in a vast majority of recipients; * strong mucosal immune responses. 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. In 2016, results were published of the first Phase I human clinical trial of a killed whole-HIV-1 vaccine, SAV001.<unk>  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<unk> -1. According to Dr. Chil-Yong Kang of 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. 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<unk> , via their 'env–gag VLP mRNA platform', further developed vaccine is confirmed safe and effective. On January 17, 2022 IAVI and Moderna launched a phase I trial of a<unk>  vaccine with mRNA technology. On March 14, 2022 the National Institutes of Health (www.nih.gov) published: "NIH launches clinical trial of three mRNA<unk>  vaccines". The phase one trial is expected to conclude July of 2023. Phase II Preventive<unk>  vaccines * A recombinant Adenovirus-5<unk>  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 phase II clinical trial of a novel<unk>  vaccine, at sites in North America, South America, the Caribbean and Australia. 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<unk> -specific cellular immunity, which prompts the body to produce T cells that kill<unk> -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<unk>  in more than half of volunteers. V520 contains a weakened adenovirus that serves as a carrier for three subtype B<unk>  genes (gag, pol and nef). Subtype B is the most prevalent<unk>  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<unk>  genes housed in a weakened adenovirus, study participants cannot become infected with<unk>  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<unk>  infection in some recipients. 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 vectors currently used in<unk>  vaccines will induce a rapid memory immune response against the vector. This results in an impediment to the<unk>  of a T cell response against the inserted antigen <unk>  antigens) The results of the trial prompted the reexamination of vaccine<unk>  strategies. * HVTN 505, a Phase IIb study, was launched in 2009 but halted in 2013 due to meeting requirements of futility. * It had been observed that a few, but not all,<unk> -infected individuals naturally produce broadly neutralizing antibodies which keep the virus suppressed, and these people remain asymptomatic for decades. Potential broadly neutralizing antibodies have been cloned in the laboratory (monoclonal antibodies) and are being tested in passive vaccination clinical trials. 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<unk>  prevention. HVTN 703 and HVTN 704 found that the VRC01 monoclonal antibody, which targets the CD4 binding site, was not able to prevent<unk>  acquisition. * 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<unk>  subtypes around the world. In 2021 the NIH announced that the Imbokodo Phase 2b study did not provide statistically significant reduction in<unk>  infection. * 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<unk> . Therapeutic<unk>  vaccines Biosantech developed a therapeutic vaccine called Tat Oyi, which targets the tat protein of<unk> . It was tested in France in a double-blind Phase I/II trial with 48<unk> -positive patients who had reached viral suppression on Highly Active Antiretroviral Therapy and then stopped antiretrovirals after getting the intradermal Tat Oyi vaccine. Phase III Preventive<unk>  vaccines There have been no passive preventive<unk>  vaccines to reach Phase III yet, but some active preventive<unk>  vaccine candidates have entered Phase III. * In February 2003, VaxGen announced that their AIDSVAX B/E vaccine was a failure in North America as there was not a statistically significant reduction of<unk>  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<unk> . The AIDSVAX B/E and ALVAC vaccines targeted the gp120 part of the<unk>  envelope. The study involved 16,395 participants who did not have<unk>  infection, 8197 of whom were given treatment consisting of two experimental vaccines targeting<unk>  types B and E that are prevalent in Thailand, while 8198 were given a placebo. The participants were tested for<unk>  every six months for three years. After three years, the vaccine group had<unk>  infection rates reduced by about 30% compared with those in the placebo group. However, after taking into account the seven people who already had<unk>  before getting vaccinated (two in the placebo group, five in the vaccine group) the difference was 26%. It was discovered that participants receiving vaccines in the RV 144 trial who produced IgG antibodies against the V2 loop of the<unk>  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
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