乌鸦传媒

There was good news and bad news in terms of HIV vaccine and therapeutics research, with several vaccine trials pushing forward even as one came to a premature halt.

The phase IIb/III HVTN 702 vaccine trial, Uhambo, was halted due to lack of efficacy. This trial examined an ALVAC gp120 vaccine, built off the work in the RV-144 trial in Thailand, but with a vaccine targeted to subtype C, the HIV strain circulating in South Africa.

The study population was comprised of 5,400 men and women ages 18-35, who received either vaccine or placebo. The group initially received the ALVAC dose at month 0 and month 1, and ALVAC plus the bivalent subtype C gp120/M159 adjuvant at months 3 and 6, plus booster doses at months 12 and 18.

However, the cumulative incidence of HIV infection from months 0 to 24 was identical in the vaccine and placebo groups, and the trial was stopped early.

"We generally feel the force of infection, the exposure rate ... is going to make it harder for us to extrapolate current animal model data and RV144 data to sub-Saharan Africa," Larry Corey, MD, principal investigator for the HIV Vaccine Trials Network, told 乌鸦传媒. "We have a whole bunch of things that need to be investigated to learn more."

Indeed, his presentation at the virtual Conference on Retroviruses and Opportunistic Infections (CROI) noted that the "exposure that women in South Africa experience may require a much greater level of immunogenicity" than the prior RV144 trial predicted.

Corey added that the next steps included sequencing the virus "to see if there's any pressure on the virus we can discern."

Mitchell Warren, executive director of AVAC: Global Advocacy for HIV Prevention, who was not involved with the research, noted a few bright spots, even in the failure of the HVTN 702 trial: "HIV programs tend to have a hard time finding people at the greatest risk, [but] HVTN recruited the right people for a clinical trial who were at risk, who need prevention options," he told 乌鸦传媒.

Warren saw this as an opportunity to expand pre-exposure prophylaxis (PrEP) access to uninfected trial participants, especially given the relationships the trial built with this population.

"As participants were getting the news, they were disappointed ... but they told trial staff 'we're here for you,' and ended up providing support to the research staff. These kinds of relationships are the bedrock of the AIDS response and they can translate into programs that can prevent HIV infections," he said.

And as Corey pointed out, there is still plenty of "skin in the game" in terms of HIV vaccine development, with the HVTN 705 and HVTN 706 trials still ongoing, as well as a broadly neutralizing antibody approach.

"We consciously had a very thought-out strategy in a parallel fashion to ... have two very distinct vaccines. The Mosaic antigen overcomes diversity issues we thought might be major weaknesses. We're not happy about the result from [HVTN] 702, but ... we need to spread the net wider," Corey said.

Phase I Antibody Trial Holds Promise

In another presentation at the virtual conference, gene transfer protocols delivering HIV-specific broadly neutralizing antibodies were safe and well-tolerated among a small group of volunteers on effective HIV antiretroviral therapy, reported Joseph Casazza, MD, of the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland.

"Monoclonal antibodies hold enormous promise for preventing and treating both established and emerging infectious diseases," said NIAID director Anthony Fauci, MD, in a statement. "Novel delivery platforms such as viral vectors could facilitate the future development and deployment of antibody-based prophylaxis and therapy, and these findings are a promising first step in that direction."

Casazza noted that adeno-associated viral (AAV) vectors have an established safety record in humans, and can be given via intramuscular injection or IV infusion.

"The simplicity of adeno-associated viruses' genetic structure make it an ideal vehicle for gene transfer," he said.

The authors also said that VRC07 is a broadly neutralizing antibody targeting the CD4 site of the HIV-1 envelope glycoprotein.

Warren, who was not involved with the research, said he was "excited by it, but we have a long way to go."

"We've long known that the role of antibodies is incredibly important, and have long been challenged how to do anything with that," he said. "It's exciting, but one of the biggest challenges is how do you deliver? If it can be made potent enough and can be manufactured as a subcutaneous injection ... how do you deliver that into the body?"

VRC 603 was an open-label phase I dose-escalation study evaluating the safety and tolerability of AAV8 VRC07 via intramuscular injection to a small group of individuals with HIV on effective antiretroviral therapy. There were three groups: a low-dose group, an intermediate-dose group, and a high-dose group.

Overall, eight volunteers with HIV were enrolled: six men, five African American. Median viral load at enrollment was under 20, median CD4 count was 528, and volunteers had a mean age of 52.

Casazza noted that three subjects in the low-dose group received two intramuscular injections, and were followed up to 2 years and 1 month, two of the three subjects in the intermediate-dose group (two injections at a slightly higher dose) were followed up to 1 year and 10 months, and three of the five in the high-dose group received seven to nine injections and were followed up to 1 year.

Researchers found measurable amounts of VRC07 in all individuals given AAV8 VRC07.

"To our knowledge, this is the first study to show the induction of an HIV-specific broadly neutralizing antibody in HIV-infected individuals," Casazza said.

An initial antibody peak was seen at 4-6 weeks, with a decrease in concentration 7-14 weeks post-product administration, and a secondary increase after 14 weeks, he said.

While Casazza noted that three of eight volunteers reported anti-drug antibody responses that appeared to blunt measured VRC07 concentrations, he said the study "establishes that AAV vectors can be used to induce the long-term production of specific human antibodies."

Warren noted the collaboration that went into this research, adding: "It's a great reminder that HIV is never going to be addressed by one product, one institution. It gives us one more example of the essential need to collaborate across institutions, across platforms, across sometimes divided landscapes of prevention and therapy."