With Global Trials Expanding, More HIV Vaccines Are Put to the Test

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It's been slightly more than 35 years since the first official reports of what would later become known as the human immunodeficiency virus. These initial cases were the beginning of a global epidemic that infected an estimated 78 million people, according to the Joint United-Nations Programme on HIV/AIDS or UNAIDS. An estimated 37 million people are now living with the virus. About the same number -- approximately 35 million people -- have died from AIDS-related illnesses. The introduction of antiretroviral therapy in 1996 has saved millions of lives. Antiretrovirals have transformed a positive serostatus into a "chronic but manageable" condition similar to diabetes or asthma. But the decades-long hunt for a preventive vaccine has remained elusive.

HVTN 702

That may change soon. November will mark the beginning of the first large-scale clinical vaccine research trials in South Africa. That nation is on track to develop the world's first licensed HIV vaccine. HIV Vaccine Trials Network 702 will enroll about 5400 participants -- males and females aged 18 to 35 -- across South Africa. Participants will receive five injections over one year. The National Institute of Allergy and Infectious Diseases is sponsoring and funding HVTN 702

"After 24 months we'll look at potency and at 36 months we'll assess durability. We hope to have results in five years. We're looking for efficacy of 50 percent," said Glenda E. Gray, MBBcH, FCPaed, a physician, scientist and president of the South African Medical Research Council, speaking in July at the 21st International AIDS Conference in Durban, South Africa and reported by SciDev.net.

So far, the only HIV preventive vaccine clinical trials that have shown potential have been the United States Military HIV Research Program and Thailand Ministry of Public Health's three-year RV144 study announced in 2009. RV144 demonstrated a "modest" 31 percent efficacy using a canary pox-protein vaccine. A second vaccination shot -- known as a booster -- was given to make the regimen stronger and more durable. The vaccine's efficacy apparently peaked early at the one-year mark with 60 percent efficacy.

HVTN 702 builds on smaller Phase 1 safety and Phase II clinical trials from 2014-2015 that modified the Thai regimen to make it more "friendly" for Southern Africa. There are about 10 HIV genetic subtypes called clades, and Clade "C", which is is dominant in Southern Africa is different from Clades B and E found in Thailand.

"Vaccine developers will insert pieces of HIV in the vaccine candidate. You can't become infected from the vaccine. They insert snippets that will help the body react to the virus," explained Mitchell Warren, the executive director of AVAC, a New York City-based NGO that advocates for the accelerated ethical development of HIV vaccine and prevention options. "They had to engineer the RV144 vaccine to have the snippets from Clade C, which is the dominant strain in Southern Africa."

That region desperately needs a vaccine. Sub-Saharan Africa is home to two-thirds of all people living with HIV, according to UNAIDS. The main driver of the epidemic in this region is condomless heterosexual sex. South Africa has the unfortunate distinction of claiming the world's highest HIV prevalence -- the number of people living with the virus -- with an estimated seven million infections. About one in five South African adults are living with the virus. Some of its neighbors have even higher overall infection rates. Swaziland -- a tiny, landlocked kingdom within SA -- has the world's highest rate at 29 percent. The second-highest rate as of 2015 is in nearby Lesotho with 23 percent.

A Mosaic Vaccine?

But if HVTN 702 proves to be successful, "could it work for Kenya or Thailand, which have different HIV subtypes?" asked Warren. "We don't know," he said. "The vaccine may likely work only in one area of the world."

One strategy to address that question would be a global or so-called mosaic vaccine. The first human clinical trials of the proposed mosaic vaccine being developed by Janssen Pharmaceutical -- a division of Johnson & Johnson -- are on track to begin next year in South Africa, Rwanda, Uganda and Thailand. Smaller safety trials are currently underway. This vaccine would include inserts from many different HIV subtypes. The hope is that the vaccine would be protective against a broad range of HIV subtypes.

This research program is a partnership between the National Institutes of Health, the U.S. Military HIV Research Program, the International AIDS Vaccine Initiative, Harvard University and Boston's Beth Israel Deaconess Medical Center. The lead investigator is Harvard's Dan H. Barouch, M.D., Ph.D., who is also developing a potential Zika virus with the military. Barouch's work on the Zika vaccine was the focus of an August article in The New Yorker.

Broadly Neutralizing Antibodies, aka "The Holy Grail"

Another approach toward HIV prevention is "passive immunity." Your immune system is programmed to produce antibodies when it recognizes a foreign invader such as a bacteria or virus. Antibodies are proteins that will block or suppress the invader. Each antibody is specific to that threat. "[F]or example, an HIV antibody will not recognize or work against a flu virus. In fact, most HIV antibodies are very specific for one strain of HIV and maybe a few close relatives," notes the HIV Vaccine Trials Network.

The challenge is that HIV is constantly mutating. Researchers have discovered that a very small percentage of people living with HIV can naturally suppress their viral levels -- stop it from reproducing -- and remain healthy without taking any antiretroviral medications. The immune systems of these people -- described as "elite controllers" -- produce rare "broadly neutralizing antibodies" (bNAbs) that work against many different strains of HIV. So, instead of injecting a vaccine to trigger antibodies, scientists want to skip that step and directly inject the bNAbs. The goal is to "prime" the immune system to naturally produce more of these antibodies. These antibodies could also work as a "therapeutic vaccine" to suppress the viral levels of people living with HIV. Many researchers have described this strategy as "the holy grail" of HIV prevention.

Right now, there are two human clinical trials around this concept. HVTN 703 began in August and will enroll 1,500 adult women in the Sub-Saharan nations of Botswana, Kenya, Malawi, Mozambique, South Africa and Tanzania. Meanwhile, on this side of the Atlantic Ocean, HVTN 704 began in April and will enroll 2700 men and transgender persons who have sex with men or transgender men or women in Brazil, Peru and the United States. The study participants will be randomized with the bNAbs or a placebo by intravenous infusion every eight weeks for 72 weeks. The infusion will take about 45 minutes.

The HIV vaccine pipeline, broadly neutralizing antibodies, treatment as prevention, pre-exposure prophylaxis and other biomedical prevention strategies will be the focus of HIVR4P 2016 in Chicago, which will take place October 17-21. The biennial conference is the world's only scientific conference devoted exclusively to biomedical HIV prevention research. "I think we can safely say that this is by far the most exciting time in AIDS vaccine research and development," said AVAC's Warren. "But we still don't have a vaccine."

Rod McCullom has written and produced for ABC News and NBC, Scientific American, The Atlantic, The Nation, Ebony, Poz and many others. Rod is a Knight Science Journalism Fellow at the Massachusetts Institute of Technology.