EXPERT ANALYSIS FROM AIDS 2016

DURBAN, SOUTH AFRICA (FRONTLINE MEDICAL NEWS) – A new optimism regarding the possibility of creating a safe and effective HIV preventive vaccine was very much in evidence at the 21st International AIDS Conference.

“The HIV vaccine field is open for business,” an exuberant Larry Corey, MD, declared in a plenary address highlighting recent major progress in HIV vaccine development.

Three extremely important HIV vaccine efficacy clinical trials testing diverse promising strategies are now either in progress or soon to start, noted Dr. Corey, professor of laboratory medicine and medicine at the University of Washington and emeritus director of the Fred Hutchinson Cancer Research Center in Seattle.

“We are finally moving the needle forward with human efficacy trials that are commensurate with the need for developing an HIV vaccine,” Dr. Corey said.

He emphasized that HIV is “still the world’s most pressing global health issue,” with more than 45,000 new infections occurring annually in the United States and more than 2 million annually worldwide. And while numerous nonvaccine prevention methods have been developed, they share a major limitation: Their extended effectiveness requires continuous adherence.

“With asymptomatic acquisition, prolonged subclinical infection, and sexual transmission, getting to an AIDS-free generation will require a vaccine,” Dr. Corey predicted.

After years of discouragingly negative HIV vaccine studies, researchers finally turned a corner in 2009 with the reported results of the U.S. Military HIV Research Program–led RV144 trial, commonly known as the Thai Trial, Anthony S. Fauci, MD, recalled in an interview.

The trial, which randomized more than 16,000 young adult Thais, showed a modest 31% efficacy at 3.5 years, but a more substantial and encouraging 60% efficacy at 12 months (N Engl J Med. 2009 Dec 3;361[23]:2209-20). More importantly, the Thai trial opened up a whole new avenue to HIV vaccine development.

“We thought the Thai vaccine would induce neutralizing antibodies, but it didn’t. Instead, it induced nonneutralizing antibodies against a component of the V1V2 loop region of the HIV envelope, which was associated with protection. So the good news about that study was that even though that vaccine wasn’t efficacious enough to make it a usable vaccine, it gave us something we could improve upon by using the same platform and enhancing the response to provide greater depth, breadth, and durability,” explained Dr. Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID).

The improved vaccine consists of a canarypox-based vaccine called ALVAC-HIV and a bivalent gp120 protein subunit vaccine with MF59, a different adjuvant from that used in the Thai trial, in an effort to achieve a more robust immune response. Also, the four-injection series studied in the Thai trial is now bolstered by a booster injection at the 12-month mark. This vaccine has been altered to be specific to HIV clade C, the predominant HIV subtype in southern Africa, where the bulk of new HIV infections occur.

At the AIDS 2016 conference, Linda-Gail Bekker, MD, presented the primary immunogenicity results from the HIV Vaccine Trials Network (HVTN) 100 trial, a phase 1/2, double-blind, placebo-controlled study of the improved version of the Thai trial vaccine, known as the Clade C ALVAC-(vCP2438) and bivalent subtype C gp120/MF59 vaccine, in 252 HIV-uninfected South African adults.

The ALVAC/protein vaccine achieved cellular and humoral immune responses that exceeded all four predetermined criteria as correlates of protection. As a result, a pivotal phase III, randomized, double-blind, placebo-controlled vaccine efficacy trial known as HVTN 702 got the green light to begin in November 2016 in 5,400 HIV-negative adults in South Africa. Participants will be assessed at 24 and 36 months of follow-up, announced Dr. Bekker, cochair of HVTN 702, International AIDS Society president-elect, and deputy director of the Desmond Tutu HIV Center in Cape Town, South Africa.

As a principal investigator in the NIAID-supported HIV Vaccine Trials Network, Dr. Corey has been deeply involved in the development of this vaccine. He also is chair of the ongoing HVTN 703 and 704 phase IIb trials, testing an entirely different vaccine approach. The hypothesis being tested in HVTN 703 and 704 is that a passively infused monoclonal antibody can protect against HIV infection in 2,400 men who have sex with men and transgender men in North and South America, as well as in 1,500 women in sub-Saharan Africa. Both studies began in spring 2016.

“Every card-carrying virologist feels this should work,” according to Dr. Corey.

The rationale for having two study populations is that investigators suspect the effects of the antibody may vary depending upon whether the route of HIV acquisition is rectal or vaginal, he explained.

The monoclonal antibody contains VRC01, which effectively blocks viral binding to CD4 cells. Study participants will receive an intravenous infusion of VRC01 at 10 or 30 mg/kg or placebo every 2 months. If the results are positive and a second-generation product and delivery system can be developed, antibody-mediated prevention could also have a major potential role in interrupting maternal to child transmission of HIV resulting from intrapartum exposure or breastfeeding.

Dr. Corey also highlighted a third strategy of HIV vaccine development, one at an earlier stage. Investigators at Johnson & Johnson, in collaboration with the NIAID, HVTN, and other partners, are pursuing a multi-clade approach, one designed to protect against all clades of HIV found around the world. This strategy entails first giving an adenovirus serotype 26–vectored vaccine to prime the immune system, following up with administration of several boosters containing mosaic inserts to increase the response. This vaccine is in phase I studies with no results yet.

Dr. Fauci is not sure which if any of these three approaches will yield a safe and effective vaccine for HIV prevention.

“It’s important to realize that this is a very difficult scientific challenge,” he said. “The body does not readily make an adequate immune response against HIV, unlike virtually any other viral infection. Even the serious ones that cause a degree of morbidity and mortality – smallpox, measles, rubella, polio – ultimately the body does make a good immune response and allows us to clear the virus and leaves us with protection against subsequent exposure to the same virus. We don’t have that advantage with HIV. So it’s going to be difficult to get a safe and effective HIV vaccine, but I think the scientific challenge is worth going after and there’s a reasonable chance we might get there.”

Dr. Corey, Dr. Fauci, and Dr. Bekker reported having no financial conflicts of interest.

bjancin@frontlinemedcom.com

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