Another large trial has been discontinued after Johnson & Johnson’s experimental HIV vaccine, which uses the same technology as the company’s COVID-19 vaccine, was shown to be safe but did not provide protection against HIV acquisition. Today’s announcement by the National Institutes of Health adds to a long string of disappointments in HIV vaccine research.

The Phase III Mosaico study (HVTN 706), which began in 2019, enrolled some 3,900 cisgender gay and bisexual men and transgender women in North and South America and Europe. A scheduled data review by the trial’s independent data and safety monitoring board found that the number of people who acquired HIV was statistically equivalent in the vaccine and placebo groups.

The results are not unexpected, as a parallel trial called Imbokodo (HVTN 705) was halted in 2021 after interim results showed that a similar vaccine regimen did not adequately protect young women in Africa.

Mosaico was the last large trial testing a more traditional vaccine approach for the prevention of HIV. Most experts now think more sophisticated novel approaches will be needed.

What’s more, HIV vaccine research has gotten more challenging now that candidates must measure up against pre-exposure prophylaxis (PrEP) pills or long-acting injections, which are highly effective when used consistently.

“We only enrolled participants not on PrEP after they had been given an authentic choice to go on PrEP, with barriers removed to accessing these drugs,” study cochair Susan Buchbinder, MD, of the University of California San Francisco and the San Francisco Department of Public Health, said in a statement. “One thing we’ve clearly learned from study participants is that people want a choice and that a vaccine will be an important option for those who don’t want PrEP.”

Mosaico participants will be informed of the findings, and further analyses are planned to determine why the vaccine regimen did not work and to learn more about the immunological correlates of protection against HIV.

“We are disappointed with this outcome and stand in solidarity with the people and communities vulnerable to and affected by HIV,” Penny Heaton, MD, head of global vaccine research for Janssen Research and Development (a subsidiary of J&J), said in a company press release. “Though there have been significant advances in prevention since the beginning of the global epidemic, 1.5 million people acquired HIV in 2021 alone, underscoring the high unmet need for new options and why we have long worked to tackle this global health challenge.”

A History of Disappointments 

So far, only one vaccine study—the RV144 trial in Thailand—has shown any effectiveness in preventing HIV. That trial tested a vaccine dubbed ALVAC-HIV, which used a canarypox virus vector to deliver DNA instructions for HIV proteins, plus another vaccine that contains genetically engineered HIV gp120 envelope proteins. In 2009, researchers reported that this prime-boost combination reduced new infections by 31%.

Following up on those findings, the Uhambo trial trial tested ALVAC-HIV plus a gp120 protein subunit vaccine, both adapted to target HIV clade C, the predominant subtype in southern Africa. The vaccine regimen did not prevent HIV acquisition, leading to that study’s discontinuation in 2020.

That left just two large HIV vaccine trials underway, Mosaico and Imbokodo. In both studies, participants received four doses of a vaccine dubbed Ad26.Mos4.HIV that uses an adenovirus type 26 vector (a common cold virus) to deliver a computer-designed mosaic of antigens from multiple HIV strains. Imbokodo participants also received two doses of a second vaccine containing gp140 envelope proteins from HIV clade C, while Mosaico participants got two doses of a second vaccine that also includes a mosaic of gp140 proteins from different strains.

Earlier studies showed that this vaccine approach induced potent antibody and T-cell responses and protected monkeys exposed to SIV, HIV’s simian cousin. However, the vaccine regimen did not generate broadly neutralizing antibodies that target a hidden region of HIV’s envelope protein that doesn’t change much across strains, which many researchers think will be necessary to confer broad protection.

Moving Forward
So what’s next for the HIV vaccine research field?

Scientists are now exploring novel approaches, some of which employ the messenger RNA (mRNA) technology used for the Moderna and Pfizer-BioNTech COVID-19 vaccines. 

One approach, known as germline targeting, uses a series of vaccines in a stepwise manner to encourage the development of specialized B cells and train them to produce broadly neutralizing antibodies. In a recent Phase I study, all but one of the 36 participants who received a vaccine containing an immunogen consisting of 60 engineered copies of HIV’s gp120 envelope protein developed specialized precursor B cells. After a booster, these cells produced antibodies with greater affinity for the HIV proteins. These results offer proof of concept that this approach could work, but it will be years before it can be tested in large clinical trials.

Mitchell Warren, executive director of AVAC, an organization that works to accelerate the development and global delivery of HIV prevention methods, said the news about the Mosaico findings is disappointing but not surprising.

“The hard truth is the science of HIV vaccine development is extremely challenging, but this is not the time to dial back support for ongoing research,” Warren said in a press release. “Even as researchers continue the necessary work of accelerating HIV vaccine research, the broader HIV response must act as if we may never have a vaccine and prioritize the rollout of existing prevention options and research for additional ones. Ending this pandemic requires simultaneous action on multiple fronts of research, development and delivery.”

AVAC will host a webinar at 12:00 pm on January 25 to discuss the Mosaico results and their implications for the HIV vaccine field. 
Register for the webinar here.

Click here for a POZ feature on HIV vaccine development.

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