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HIV Prevention
Overview of HIV Prevention

Released: September 17, 2020

Expiration: September 16, 2021

Joseph J. Eron
Joseph J. Eron, Jr., MD
Sharon L. Hillier
Sharon L. Hillier, PhD
Daniel R. Kuritzkes
Daniel R. Kuritzkes, 医学博士
Activity Information

Activity

Progress
1
Course Completed

Despite early hopes that a vaccine effective in blocking transmission of HIV could be developed, only 7 efficacy trials testing 4 HIV vaccine candidates have been initiated to date.128,129 Two completed trials tested vaccination with a recombinant gp120 (rgp120) for people who inject drugs,130,131 but both trials failed to provide evidence of protection.

The next generation vaccine was a recombinant vaccine based on adenovirus serotype 5 (MRKAd5). The hypothesis for the 2 MRKAd5 phase II test-of-concept trials was that a vaccine based on cellular immunity would prevent HIV infection or lower the set point for viremia after infection. The first MRKAd5 gag/pol/nef study was the Step trial, which was initiated in 2004 but closed by the trial’s data and safety monitoring board following an interim analysis in 2007 at a point when 3000 participants had been enrolled at 34 clinical trial sites.132 The analysis showed that the rate of HIV infection was similar among MRKAd5 recipients and controls (3%), and an exploratory analysis revealed that uncircumcised men and Ad5-seropositive men were more likely to acquire HIV when they had received the MRKAd5 vaccine than not at all. A companion MRKAd5 gag/pol/nef trial called the Phambili trial, which had been initiated in 2007 and had enrolled 801 participants in South Africa at the time of the Step trial suspension, was also stopped. An analysis of the Phambili trial including 3.5 years of follow-up demonstrated a higher rate of HIV infection among individuals who received the investigational vaccine (before trial closure) compared with those who received a placebo injection.133

Another HIV vaccine trial conducted in Thailand, RV144, used a prime-boost vaccine strategy composed of the “prime” vaccine—a recombinant canarypox vector vaccine that has been genetically engineered to express subtype E HIV-1 gp120—and a “booster” gp120 B/E vaccine. Given the lack of efficacy of the recombinant gp120 vaccines, the decision to move forward with this study was controversial. However, in 2009, the investigators reported that 74 out of 8198 volunteers who did not receive the vaccine became infected with HIV vs only 51 out of 8197 volunteers who did, which correlates to a 31% reduction in risk (95% CI: 1.1-52.1).6 Although the reduction in risk is modest with this vaccine and the results of this study likely only apply to those patients with subtype E virus, it may be possible to gain important insights into the correlates of protection that may assist in design of future vaccines. A modified version of RV144 is currently being evaluated in the phase IIb/III trial, HVTN 702, launched in late 2016 in adults at 15 sites in South Africa with an estimated study completion date of July 2021.

After the STEP trial results were released, the second-generation CD8+ T-cell–inducing HIV vaccine regimen developed by the National Institute of Health’s Vaccine Research Center, which also includes an Ad5 vector, moved forward with clinical testing in a scaled-back manner through the HIV Vaccine Trials Network. However, in April 2013, investigators in this trial discontinued administration of the investigational vaccine regimen based on findings from an interim review by an independent data and safety monitoring board that showed a lack of efficacy in preventing HIV infection and in reducing HIV-1 RNA levels among recipients of the vaccine who acquired HIV infection.134,135

Two open-label phase I trials—ACTG A5340 and NIH 15-1-0140—tested another vaccine discovered by the National Institutes of Health (NIH) Vaccine Research Center, VRC01, which contains broadly neutralizing antibodies targeting the HIV CD4-binding site, and evaluated this vaccine in maintaining viral suppression in patients discontinuing ARV medication.129 In 24 participants, viral suppression was more frequent than historic controls up to 4 weeks but then viral rebound occurred despite plasma VRC01 concentrations of > 50 mg/mL at a median time of 4 weeks in the A5440 study and 5.6 weeks in the NIH trial. No safety concerns were identified with this vaccine. VRC01 is currently being evaluated in several more clinical trials.

Whereas other HIV vaccine candidates are currently in development, there is an increased recognition that development of a safe and effective vaccine for prevention of HIV is an urgent priority but will also require a greater understanding of the earliest steps in HIV infection and the immune responses involved.

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