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Yet another experimental HIV vaccine has failed.

The National Institute of Allergy and Infectious Diseases reported Wednesday that a Phase 3 clinical trial of a vaccine was stopped because the vaccine was ineffective at preventing HIV infection. The vaccine was being developed by Janssen, the vaccine division of Johnson & Johnson.

The Mosiaco trial, which enrolled 3,900 volunteers in multiple countries, was halted after a scheduled data review by a data and safety monitoring board found there were roughly as many new HIV infections among people in the vaccine arm as in the placebo arm. The trial was studying the vaccine in cisgender men and transgender people who have sex with cisgender men and/or transgender people.

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“We are disappointed with this outcome and stand in solidarity with the people and communities vulnerable to and affected by HIV,” Penny Heaton, Janssen’s global therapeutic area head for vaccines, said in a statement. “We remain steadfast in our commitment to advancing innovation in HIV, and we hope the data from Mosaico will provide insights for future efforts to develop a safe and effective vaccine.”

In 2021, a Phase 2b trial of a similar candidate HIV vaccine was halted when a data and safety monitoring board determined that it was not preventing infections. The Imbokodo trial was studying the vaccine in women in sub-Saharan Africa.

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“For our research partners and others who have waged a decades-long effort to develop vaccines to end the HIV/AIDS pandemic, these results are disappointing,” Susan Buchbinder, co-chair of the Mosaico trial, said in a statement.

“Although HIV continues to prove uniquely challenging for development of a vaccine, the HIV research community remains fully committed to doing just that, and each study brings us a step closer to this realization,” she said.

Buchbinder is director of Bridge HIV, a grant-funded research unit at the San Francisco Department of Public Health, and a clinical professor at the University of California, San Francisco.

The trial was conducted by the HIV Vaccine Clinical Trials Network based at the Fred Hutchinson Cancer Center in Seattle. Veteran HIV vaccine trialist Larry Corey acknowledged yet another setback in the decades-long quest to find an effective HIV vaccine.

“HIV is a constantly changing and very challenging adversary. We can become disappointed when our best efforts don’t produce the results we’re looking for,” said Corey, principal investigator of the network’s leadership and operations center. “We have, however, come a long way and made many discoveries since the time when life expectancy was very short following an HIV diagnosis.”

The vaccine was based on “mosaic” immunogens targeting HIV subtypes. The goal was to induce immune responses to a broad range of HIV strains. It was given in four injections over the course of a year.

The vaccine used the same antigen delivery system employed by J&J’s Covid-19 vaccine, a common cold virus known as adenovirus 26.

Volunteers were enrolled in the trial only after they were offered HIV pre-exposure prophylaxis, the antiretroviral drugs that can prevent infection. Those who accepted PrEP were steered towards services where they could access the drugs. People who did not want them, however, were considered for the study. Anyone in the trial who later changed their mind and wanted to use PrEP was also given access to the drugs, but remained in the trial.

At least five experimental HIV vaccines, tested over nine trials, have failed to show efficacy at the Phase 3 stage of development, said Mitchell Warren, executive director of AVAC, the AIDS Vaccine Advocacy Coalition. This latest failure hangs a big question mark over this field of research, he suggested.

“I’m not sure we know exactly where the next big investment is going to come from because there’s not an obvious vaccine candidate in HIV that is next up in our efficacy pipeline,” Warren said.

“This is another reason why this result is disappointing. This was the last true product in development. And the other activities in the field, which are very exciting … [are] quite upstream. Important upstream science, but not products that are going to be in efficacy trials anytime soon.”

Stephaun Wallace, director of external relations for the HIV Vaccine Trials Network, noted work is being done on a candidate HIV vaccine using messenger RNA, the platform successfully used by Pfizer and its partner BioNTech as well as by Moderna to create their Covid-19 vaccines. The HIV work uses the Moderna platform. Exploration of the mRNA platform as a possible basis for an HIV vaccine is still in the safety testing phase, he said.

Warren questioned, though, whether the answer is a different vaccine delivery system, suggesting the problem is probably the immune targets at which the various vaccines have aimed. He noted, for instance, that the J&J platform — adenovirus 26 — worked against Covid, but not against HIV.

“These are the harsh reminders that it’s not that we don’t have great [vaccine] platforms,” he said. “Our challenge is figuring out exactly what is the target, what is the insert? … We have the vehicles. We don’t even know what passengers to put in the vehicles.”

Wallace acknowledged the path ahead will be difficult, but said he remains optimistic that at some point, HIV vaccine efforts will meet success.

“I’m pretty certain that with continued public support and interest in this area that we will see the day that an HIV vaccine is developed,” he said.

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