The global fight against the human immunodeficiency virus is poised to make important advances thanks to three experimental HIV vaccines that are entering the final stages of testing at sites across the globe.

While any of these three late-stage HIV vaccine trials — known as HVTN 702, Imbokodo and Mosaico — could fail, scientists say they are more hopeful than at any time since 1984, when Secretary of Health and Human Services Margaret Heckler raised hopes by predicting that there would be a test-worthy HIV vaccine within two years.

This is “perhaps one of the most optimistic moments we have been in,” said Dr. Susan Buchbinder, director of the Bridge HIV research program at the San Francisco Department of Public Health and a chair of both the Imbokodo and Mosaico trials.

“We have three vaccines currently being tested in efficacy trials,” she said, “and it takes quite a bit to actually be promising enough in the earlier stages stages of trials to move you forward into an efficacy study.”

HVTN 702

The oldest ongoing HIV vaccine trial, known as HVTN 702, is based on a prior vaccine candidate, RV144, that was effective, but not effective enough. In 2009, the RV144 clinical trial released findings showing that the vaccine lowered the rate of HIV infections by about 30 percent. To this day, RV144 remains the only HIV vaccine that have ever demonstrated any efficacy against the virus.

HVTN 702, launched in South Africa in 2016, was the first vaccine trial approved after the failure of RV144. According to the National Institute of Allergy and Infectious Diseases, the modified vaccination regime “aims to provide greater and more sustained protection than the RV144 regimen and has been adapted to the HIV subtype that predominates in southern Africa,” also known as HIV-1 clade C.

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While RV144, at 30 percent effective, did not suffice for global distribution, it pointed the way forward for vaccine researchers, who adapted RV144’s successes to create HVTN 702. Buchbinder said even a partially effective vaccine would be “a tremendous breakthrough,” and “would really have the power to change the trajectory of the epidemic.”

Dr. Anthony Fauci, director of NIAID and a longtime advocate for a vaccine that is at least 50 percent effective, said he feels “even more strongly now” that a partially effective vaccine would be worth deploying. He said that is because prevention strategies like pre-exposure prophylaxis (PrEP) and treatment as prevention (TasP) “are being so successfully used, even in the absence of a vaccine, that if one or more of these vaccines look good, have a 50-60 percent efficacy, I think that’s going to be the game changer for turning the epidemic around.”

HVTN 702 completed enrollment this summer, and clinical results are expected in late 2020 or early 2021.

Imbokodo and Mosaico

Imbokodo, the second trial, began in five southern African nations in 2017 and completed enrollment of 2,600 women this summer. In southern African nations, heterosexual women are at extremely high risk of HIV infection.

“It’s almost unbelievable, but it’s true, women between the ages of 18 and 25 — the prevalence of infection is well over 50 percent,” Fauci said. “If ever you wanted to get a population that, if the vaccine works, you’re going to know pretty quickly, then you want to go in women.”

Unlike HVTN 702, Imbokodo uses “mosaic” immunogens, which are “vaccine components designed to induce immune responses against a wide variety of global HIV strains,” according to the National Institutes of Health.

“The presumption is that a mosaic is going to give you broader coverage,” Fauci said.

In November, the third vaccine trial, Mosaico, marked its informal start after the first study participant received an injection. Mosaico is based on Imbokodo’s unique mosaic immunogen approach.

Imbokodo and Mosaico are largely identical and consist of six injections, with slightly different vaccine formulations administered during the final two clinic visits.

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In addition, while Imbokodo is only being tested in African women, Mosaico will recruit 3,800 gay men and transgender people for its clinical trials at 57 sites in the United States, Latin America and Europe. For any HIV vaccine, Fauci said there’s a need to prove it works in different at-risk populations.

Imbokodo completed enrollment of study participants this summer, marking the formal end of the recruitment process. Results from Imbokodo are expected in 2021, and results from Mosaico are expected in 2023.

Challenges ahead

Fauci noted that there has been a rapid pace of vaccine-related developments in recent years, with these three vaccine trials starting in 2016, 2017 and 2019.

“In all of these trials, intermittently the data and safety monitoring board takes a look at the data, and either says the data are so bad you have got to stop, or the data are so overwhelmingly good that you have got to stop,” Fauci said. So far, after several reviews of the data in HVTN 702 and Imbokodo, “there’s nothing there to say stop the study,” which happened in 2007 when a Merck vaccine trial was shut down after the monitoring board determined that it had no impact on prevention.

“None of these vaccines is a particularly simple regimen,” Buchbinder said, “so it’s going to require quite a bit of effort to deploy.”

“They require multiple injections, and so each one would require a minimum of four different doses in its current configuration,” Buchbinder said. But an effective vaccine could be a “stepping off point” to potentially create a simpler and more effective vaccine in the future.

And if these vaccine trials all fail, public health officials say enough tools currently exist to stop the spread of HIV — if only people would, or could, use them.

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PrEP, the daily pill that prevents HIV infection, is safe and effective, but not enough people are using it to slow HIV transmission and end the epidemic. And successful treatment of people living with HIV results in an undetectable viral load that they cannot transmit the virus via sexual activity, known as “treatment as prevention” or TasP.

“It goes exactly to what I have been saying for years and years — if you implement the tools that you have, you will definitely see an impact on the dynamics of the epidemic,” Fauci said. “I have been talking about this for well over a decade. If you implement, the incidence is going to go down. It happened dramatically in San Francisco, and it is happening right now in New York.”