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SEATTLE -- The abrupt and early , announced last month, was the topic of a special session at the here.

Results of the 3,800-participant trial were negative, with an identical 113 individuals in the vaccine regimen and placebo groups becoming infected with HIV in just under 2 years (incidence of 4.1 per 100 person-years), reported Susan Buchbinder, MD, of the San Francisco Department of Public Health and co-chair of the HIV Vaccine Trials Network. She noted that infection was highest among young people ages 18-20.

"No safety issues with the vaccine regimen were identified, but the regimen was not efficacious in preventing HIV acquisition," said Buchbinder.

"We learned," said Lawrence Corey, MD, of Fred Hutchinson Cancer Research Center in Seattle and principal investigator of the HIV Vaccine Trials Network. "We're not going to go down that road anymore. It's time to try another route," he told MedPage Today in an interview. "It didn't fail. We got a result that we didn't like."

Rather than working on inducing non-neutralizing antibodies, research now will focus on delivering more potent broadly neutralizing HIV-1 antibodies (bnAb), Corey said. His new mantra, inspired by Yogi Berra, he said, is to concentrate on the positive: "When there's a fork in the road, take it."

"The HIV virus has set up an amazing array of diversionary strategies," Corey said. "Making an HIV vaccine is scientifically hard -- likely the hardest antibody-mediated vaccine in the virologic world."

But there's no doubt a vaccine is needed: "The reality is we've never controlled a disease in a population without a vaccine. We're not going to give a hundred million people long-acting antiretrovirals for 10 years during their most highest-risk sexual time," he said.

Protecting against HIV will require a vaccine with sequential vaccination, Corey explained. "Unlike the COVID-19 vaccine, which has essentially the same immunogen in each shot, the HIV vaccine will be done in sequence." It will start with a germline priming shot, then "shepherding" of memory B cells, boosting and polishing them, and then a final step with plasma cells that secrete broadly neutralizing antibodies, he said.

Several phase I trials are investigating possible avenues of such research, including one that has made headway in germline priming, including , which is evaluating the safety and immunogenicity of the eOD-GT8 60mer mRNA vaccine as a "germline-targeting" immunogen.

MOSAICO involved the use of a tetravalent intramuscular vaccine candidate -- adenovirus serotype 26 Mosaic4 human immunodeficiency virus (Ad26.Mos4.HIV) -- given alone first, and then combined with a Clade C and Mosaic gp140 HIV bivalent vaccine.

"This was a valiant attempt to look at a Mosaic immunogen to try to counter the diversity of HIV, by inducing non-neutralizing antibodies," said Katharine Bar, MD, director of the Virology Core at Penn Center for AIDS Research in Philadelphia. "I think we now have another piece of evidence that non-neutralizing antibodies are not going to be broadly protective against HIV acquisition."

"Even though it's a novel approach to responding to a diverse range of viruses, it still was aiming for non-neutralizing antibodies," she told MedPage Today. "It's really challenging, but there are multiple approaches for iterative bnAb development, where we're taking focused immunogens that have just the specific epitope we're looking to generate an antibody against, and they're targeting specific B cells. The hope is that with this process, we can prime the right B cells to make very specific broadly neutralizing antibody lineages, and through these multiple attempts at the same concept, we can hopefully start inducing broadly neutralizing antibodies -- i.e., antibodies that neutralize the virus, not just bind [to it] -- and antibodies that are able to target a range of viruses across circulating variants."

"We know it's a big task, but [it's] informed by good rationale," Bar said.

Although it has taken 30 years to get to this point, the next series of phase I studies are already showing promise to stimulate the right B cells and start the process of generating these early antibody precursors, she continued. "There's promise in this field, but it is still a really daunting task. At least the end goal for these bnAb vaccines is something we believe to be effective. We just have to ... find a pathway. We have to figure out how to get through those multiple steps."

Corey predicted it will take about 5 years to determine how to construct an effective vaccine, after which trials need to be done.

"I think in a decade we can have an effective HIV vaccine," he said.

The multisite, multinational MOSAICO trial enrolled 3,800 cisgender men and transgender individuals (ages 18-60) at risk for HIV. Participants came from Argentina, Spain, Peru, Mexico, Brazil, the U.S., and other countries. They were randomized 1:1 to placebo or the vaccine regimen, with Ad26.Mos4.HIV given via intramuscular injection at day 1 and at 3 months, and then combined with the Clade C and Mosaic gp140 HIV bivalent vaccine intramuscularly at months 6 and 12.

A total of 99.6% of the participants were male at birth, 91.5% were male at screening, and the rest identified as transgender, gender queer, female, or gender variant. Most (86.6%) were Hispanic or Latino.

A unique feature of the trial, said Buchbinder, was that during recruitment all potential participants were given information about PrEP, and could opt for PrEP services instead of participating in the trial. Once in the trial, participants could switch to PrEP and remain in the trial.

"Despite ongoing risk reduction counseling and linkage to PrEP [pre-exposure prophylaxis], HIV incidence, particularly in young participants in Latin America, was very high," she said. "This is a population in great need of additional effective HIV prevention modalities."

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