MEXICO CITY – Ten years after the RV144 "Thai trial" was the first to show that an effective HIV vaccine was possible, three efficacy trials for HIV vaccines are once again underway.
The Uhambo/HVTN702, Imbokodo/HVTN705 and Mosaico/HVTN706 trials have used the results of the RV144 trial and a number of other trials to optimize their vaccines and their delivery schedules.
At a pre-conference session on "An HIV vaccine to prevent HIV acquisition" organized by the HIV Vaccine Trials Network, researchers and clinicians gave an overview of the challenges for the Imbokodo and Mosaico trials.
Dan Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center, gave an overview of the 15 years of sometimes arduous work – for one study, Barouch's team purified almost 14 grams of polyclonal antibodies from vaccinated nonhuman primates to test whether they would provide protection via passive transfer – that preceded the Imbokodo and Mosaico trials to optimize both the vaccine itself, and the vaccination regimen.
By repeatedly testing vaccine concepts in parallel clinical and preclinical trials, the team was able to improve the vaccine not just in terms of its strength, but to "expand the breadth and depth of immune responses," Barouch said. The changes led to "a phenotypic change of the immune response, not just larger magnitude."
Even so, Barouch said, those parallel trials showed that vaccines that generate a strong immune response in other primates will do so in humans. But whether that means those immune responses will protect humans from infection remains an open question.
"We don't know whether protection is translatable to humans," he said. "We will learn whether that is the case through the results of the trials."
Through 15 years of development and more than a decade of clinical work – the first patient received the first dose of the first vaccine on April 1, 2007 – the team arrived at the two closely related vaccines being tested in the Imbokodo and Mosaico trials.
In both trials, individuals will receive two doses of Ad26.Mos4.HIV vaccine, consisting of a mosaic antigen designed to protect against multiple strains of the vaccine delivered in an adenovirus vector.
In the Imbokodo trial, which is fully enrolled and testing the vaccine in 2,600 heterosexual cisgender African women, the third and fourth "boost" doses will consist of Ad26.Mos4.HIV plus Clade C gp140. Clade C is the HIV subtype that is most common in sub-Saharan Africa.
The Mosaico trial, which will be enrolling imminently and aims to vaccinate 3,800 transgender people and men who have sex with transgender people and/or men in the Americas, where clade B virus is most prevalent, the boost dose will use mosaic gp140 as well as mosaic vaccine.
Not perfect – still high impact
Even an efficacious vaccine is not expected to bring nearly the 95% risk reduction that is seen with many childhood vaccines.
"I don't think we're going to get a measles or polio vaccine," Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, told the audience during a talk on critical innovations for HIV treatment and prevention. "We're striving for a 50 to 60 percent effective vaccine."
Linda-Gail Bekker, deputy director of the Desmond Tutu HIV Centre at the University of Cape Town, agreed with that assessment. In her introduction to a symposium on "Understanding vaccine partial efficacy: not perfect – still high impact," she told the audience that "the dream is that you're going to get a vaccine that is 100 percent effective... but the first vaccines you are going to get are going to be partially effective."
Deborah Donnell, a member of the vaccine and infectious disease division and of the public health sciences division at Fred Hutchinson Cancer Research Center, explained the reasons for partial effectiveness – immunity may take a while to develop, and/or wane after a time, or the vaccine may only be effective against some strains, or in some people with specific host factors.
Whatever the reason, Donnell said, partial effectiveness is not unique to vaccines, but is "our current reality for all HIV interventions, whether it's from partial use, partial efficacy or partial coverage."
The "hard decisions" will have to be made, she added, if a vaccine shows more of a risk reduction than the RV144 trial's 31%, but less than the 50% the Imbokodo and Mosaico trials are aiming for.
Low coverage can be another reason – the Uhambo trial, which is based most closely on RV144, requires eight doses of vaccine and is expected to have a high attrition rate.
Another factor that does not make the vaccine less efficacious, but can make it harder to demonstrate efficacy, is the existence of pre-exposure prophylaxis (PrEP), which can lower the risk of contracting HIV dramatically.
Sabrina Spinosa Guzman, Janssen trials chair, described the challenges of testing a vaccine, given the existence of a highly effective prevention method, and how the trial is handling that challenge.
However, there are a number of reasons that people choose not to take PrEP. Identifying such participants is "ethical and acceptable," Guzman said, provided there is "complete transparency and ongoing participant education about effectiveness and availability of PrEP."
The Imbokodo and Mosaico trials evaluate individuals expressing interest in a trial and refer them to clinical services first to see whether such individuals are interested in PrEP rather than a vaccine. Only those who are well-informed but not interested would be eligible to participate in the trial.
However, participants who change their mind and want to start PrEP at any point after the first vaccine dose, “will be allowed to start PrEP while in the study according to the site PrEP plan,” according to the Mosaico exclusion criteria published on clinicaltrials.gov.
In general, she said, when a highly effective alternative already exists, three possible approaches are to compare, layer or combine treatments. The Imbokodo and Mosaico trials take a layering approach.
"In fact, we don't know what the efficacy of the vaccine is going to be, so we don't want to withhold treatment," by using a compare strategy. And with a combine strategy, "PrEP is so effective that one probably can't see a vaccine effect," short of trial sizes she described as "astronomical."