A Phase 3 study of an investigational HIV vaccine regimen has been discontinued following a planned, interim review by the study's independent Data and Safety Monitoring Board (DSMB) on Jan. 12, 2023.
The Mosaico study – also known as HPX3002/HVTN706 – is a Phase 3 study conducted by the HIV Vaccine Trials Network (HVTN), based at Fred Hutchinson Cancer Center in Seattle, with a consortium of global partners. The study aimed to test a "mosaic"-based HIV vaccine in multiple countries around the world among cisgender men and transgender people who have sex with cisgender men and/or transgender people.
Mosaic vaccines are intended to trigger a broader immune response than earlier vaccine models by including genetic material from a variety of HIV strains prevalent around the world. In its review, the Data and Safety Monitoring Board said the investigational vaccine was generally safe and well tolerated; however, it was not effective at preventing the acquisition of HIV-1.
"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. 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," said Dr. Susan Buchbinder, HVTN co-chair for the Mosaico Study, director of Bridge HIV at the San Francisco Department of Public Health, and a clinical professor at the University of California, San Francisco.
One of the unique features of the study was that as part of the community outreach, clinic staff members first engaged and assessed community acceptance of, and interest in, HIV pre-exposure prophylaxis (PrEP). If community members accepted PrEP, they were navigated to services to begin receiving the preventive medication. However, if community members did not accept PrEP, they were considered for the study. Participants who joined the study and later changed their mind about PrEP were also navigated to PrEP services and remained in the study.
"It was critical to us in designing the study that all potential participants were informed about and had access to PrEP. 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."
Participants in the Mosaico trial are now being informed of which study group they were in – those receiving active vaccine or those receiving placebo. Throughout the trial, study investigators ensured that anyone who acquired HIV was referred to appropriate HIV treatment and care.
"We remain committed not just to doing the research that will save lives through the creation of safe and effective vaccines, but to maintaining the highest standards of participant care and compassion as this work continues," said Dr. Jorge Sanchez, HVTN co-chair for the Mosaico study, an infectious disease specialist in Lima, Peru, and affiliate professor of the Department of Global Health at the University of Washington. He said the Mosaico study, like others, has built-in safeguards, like the interim DSMB data review, to protect study participants.
HVTN scientists, ethicists, and community advocates were integrally involved in the design and implementation of this study, and they played prominent roles in informing study leadership on how to conduct this trial ethically.
"It was important to all of us that diverse communities were engaged early on, and often, in the design phase and throughout the life of the study. From the various symposia, community and ethics consultations, and study meetings where community representatives on the study team were present, we received great feedback and perspective that informed how we collectively moved this study from concept to implementation," said Dr. Stephaun Wallace, HVTN director of External Relations, and a research epidemiologist and principal staff scientist at Fred Hutch in Seattle, who directed community engagement for the study globally.
Mitchell Warren, executive director of AVAC and a member of the Governing Council of the International AIDS Society, said engaging diverse communities worldwide, providing education, and welcoming personal choice are all critical elements of HIV vaccine studies if researchers are to discover real-world answers in real-world situations.
"There is a worldwide demand for a range of effective and acceptable HIV prevention options, including especially HIV vaccines, particularly in communities where health care delivery may be limited, at best," he said. "The study team emphasized the value of choice for participants, particularly in decisions regarding PrEP, which is becoming increasingly available globally but is not universally accepted. The Mosaico team's focus on inclusion and the design of the study to respect participants' lifestyles and choices provided an opportunity to increase representation from populations most vulnerable to HIV. The ethical and community-friendly design and conduct of this study has helped to build trust in communities that may not be inclined to trust research institutions."
The Phase 3 Mosaico study began in 2019. In September 2021, it reached full enrollment of approximately 3,900 cisgender men and transgender people who have sex with cisgender men and/or transgender people, who are at increased vulnerability to HIV acquisition. There are more than 50 trial sites in Argentina, Brazil, Italy, Mexico, Peru, Poland, Spain and the U.S.
"Our experience with the Imbokodo study in sub-Saharan Africa supports anecdotal evidence and other recent findings that many people – including many women in this study – do not choose or accept oral PrEP for their HIV prevention needs. In addition to providing insight into the decisions being made by patients and study participants, this further reinforces the critical importance of choice in HIV prevention strategies and HIV vaccine discovery," said Dr. Linda-Gail Bekker, director of the Desmond Tutu HIV Centre at the Institute of Infectious Disease and Molecular Medicine at the University of Cape Town, South Africa. Bekker was president of the International AIDS Society from 2016 to 2018.
The primary analysis of the Phase 2b Imbokodo study, which evaluated an investigational HIV vaccine regimen that was similar to Mosaico, found that the vaccine regimen did not provide sufficient protection against HIV in a population of young women in sub-Saharan Africa. The Imbokodo regimen was found to be generally well tolerated with no serious adverse events. Those findings were announced in August 2021.
"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 Dr. Larry Corey, principal investigator of HVTN's Leadership and Operations Center, headquartered at Fred Hutch in Seattle. "We have, however, come a long way and made many discoveries since the time when life expectancy was very short following an HIV diagnosis."
"Through innovative research methods, we are developing new and better treatments and making significant progress toward creating effective vaccines," said Corey. "Experimental medicine approaches starting in our labs and translating into human trials make it possible to streamline drug studies for safety and effectiveness. In one early clinical trial, for example, we're studying a potent new adjuvant compound that may make candidate vaccines more potent."
Corey said researchers are also rapidly advancing HIV prevention studies using monoclonal antibodies – particularly those that can block multiple strains of the virus.
"The Antibody Mediated Prevention Trials (AMP), launched in 2016, proved that a broadly neutralizing antibody could be safely delivered to patients intravenously and block some HIV strains. These findings led to our current and future studies, where we are investigating a variety of cocktails using newly discovered and even more potent broadly neutralizing antibodies. HIV is formidable and adaptable, but we're learning its vulnerabilities, and we're on a path to rein it in."
Mosaico was led by a global public-private partnership including Janssen Vaccines & Prevention B.V., the National Institute of Allergy and Infectious Diseases (NIAID), HVTN, and the U.S. Army Medical Research and Development Command (USAMRDC).
