Another large trial has been halted after Johnson & Johnson's experimental HIV vaccine failed to prevent infection, according to a January 18 announcement from the National Institutes of Health. The latest results add to a long string of disappointments in the HIV vaccine research field.
The news is "disappointing but not surprising," said Mitchell Warren, executive director of AVAC, an organization working to accelerate the development and global delivery of HIV prevention methods. "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. Far from it — HIV remains a global threat, and a safe, efficacious and accessible HIV vaccine is still needed to provide a durable end to the pandemic."
The phase 3 Mosaico trial, 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 review by the study's data and safety monitoring board found that although the vaccine was safe, the number of people who acquired HIV was equivalent in the vaccine and placebo groups. These participants were promptly referred for medical care and treatment.
As the study ends, trial participants — including 30 people enrolled in San Francisco through the Department of Public Health — will be informed of the findings and told whether they received the vaccine or the placebo, according to Dr. Susan Buchbinder, director of Bridge HIV, DPH's clinical trials unit, and a professor at UCSF.
"We will also be conducting study close-out procedures, including HIV testing, counseling, and linkage to HIV prevention services, as we have done throughout the course of the study," Buchbinder told the Bay Area Reporter.
What's next for HIV vaccine research?
The Mosaico results are not unexpected, as a companion trial called Imbokodo was halted in 2021 after interim results showed that a similar vaccine regimen did not provide adequate protection for young women in Africa.
Both trials tested four doses of a vaccine called Ad26.Mos4.HIV that uses an adenovirus vector — the same common cold virus used in the J&J COVID vaccine — to deliver a computer-designed mosaic of antigens from multiple strains of HIV. Participants also received two doses of a second vaccine containing either gp140 envelope proteins from the most common HIV subtype in southern Africa or a mosaic of gp140 proteins from a variety of HIV strains.
Earlier studies showed that this vaccine regimen induced potent antibody and T-cell responses and protected monkeys exposed to an HIV-like virus. But the vaccines did not generate broadly neutralizing antibodies that target a hidden portion of HIV's envelope protein, which may be necessary to confer broad protection. Mosaico was the last large trial testing a traditional vaccine approach for HIV prevention, and most experts now think more sophisticated strategies will be needed.
"We don't yet know why the vaccine didn't provide protection, but studies are underway to evaluate the immune response generated by the vaccine," Buchbinder told the B.A.R. "The results of this trial suggest that other approaches, such as those that are designed to generate broadly neutralizing antibodies, may be a more successful path forward."
Studies exploring different HIV vaccine strategies are already underway. For example, scientists with IAVI (formerly the International AIDS Vaccine Initiative) and Scripps Research in La Jolla, California are testing a series of vaccines that aim to encourage the development of specialized B-cells and train to produce broadly neutralizing antibodies. The same mRNA technology used in the Moderna and Pfizer-BioNTech COVID vaccines could help this process move faster.
In a recent early study, all but one of the 36 participants who received the initial vaccine developed specialized precursor B cells. However, it could be years before this approach is ready for large trials, and a vaccine regimen that requires multiple shots would be difficult to roll out worldwide.
What's more, HIV vaccine research has become more challenging now that experimental vaccines must measure up against 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," Buchbinder said. "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."
The latest disappointment has led some to question whether an effective and widely accessible HIV vaccine will ever be available, making other prevention tools even more crucial. Despite its effectiveness, PrEP is still not widely used outside urban gay communities in the United States and Europe.
"[W]e now have more proven HIV prevention options than ever before, but they are not reaching everyone who needs and wants them," Warren said. "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 Wednesday, January 25, at 9 a.m. Pacific time to discuss the Mosaico results and their implications for HIV vaccine research. To register, click here.
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