Two of the world’s top HIV prevention clinical trial networks have joined forces to test an experimental antibody that could potentially protect people from infection by almost all strains of the rapidly mutating virus that causes AIDS.
The first of two studies, known as AMP, launched today in the United States when a clinical trial site in Nashville enrolled its first volunteer. The two parallel AMP studies, which stands for antibody mediated prevention, will eventually involve more than 4,000 participants on three continents.
Dr. Larry Corey, founder and director of the HIV Vaccine Trials Network, or HVTN, which is headquartered at Fred Hutchinson Cancer Research Center and is one of the networks conducting the trial, called AMP “a landmark study.” The HIV Prevention Trials Network (HPTN), based in Durham, North Carolina, is the other partnering organization.
Developing a vaccine that prompts the immune system to produce so-called broadly neutralizing antibodies has long been considered the holy grail of HIV researchers — urgently sought but challenging to achieve.
AMP isn’t waiting on a vaccine. What sets this study apart — besides its size, global scale, and the involvement of the two large clinical trials networks — is its unusual approach. It will deliver broadly neutralizing antibodies directly, via an intravenous infusion, or IV.
If the experimental antibodies provide protection as hoped, information gleaned from the study could help scientists figure out how to reverse-engineer a vaccine to elicit the antibodies at the concentrations needed.
“It’s not often that you know that you’re starting a landmark study. It’s not very often that you even use the word landmark,” Corey said. “If our study establishes that these antibodies are potent and will work to prevent HIV acquisition, a whole set of scientific breakthroughs will follow, some of which may take us much closer to making a potent HIV vaccine.”
Funded by the National Institute of Allergy and Infectious Diseases, a part of the National Institutes of Health, the AMP study will enroll 2,700 men and transgender people who have sex with men at 24 sites in the U.S., Brazil and Peru. A parallel study will launch later this spring and enroll 1,500 sexually active women at 15 sites in Botswana, Kenya, Malawi, Mozambique, South Africa, Tanzania and Zimbabwe.
Each volunteer — all adults at risk for HIV infection but HIV-negative when they enter the study — will receive a total of 10 infusions, once every eight weeks, and will be followed for 20 weeks after that, for a total of about 22 months per volunteer. The overall study is expected to take about five years.
To appreciate the complexity of this undertaking, let the numbers sink in for a moment: 4,200 volunteers at 39 sites in 10 countries will receive a total of 42,000 infusions and be tracked for almost two years.
“We’ve had the privilege of developing and launching the world’s most difficult trial,” said Corey’s partner in the endeavor, Dr. Myron Cohen, associate vice president for global health at the University of North Carolina at Chapel Hill and head of the HPTN. Corey and Cohen chair the AMP study.
Who better to conduct such a study than the HVTN and HPTN? Both are international collaborations of scientists, educators, and community members searching for effective ways to prevent HIV. The HVTN focuses on safe and effective HIV vaccines, while the HPTN focuses on other HIV prevention methods such as pre-exposure prophylaxis, or PrEP, and treatment as prevention. Both networks are funded by NIAID.
Antibodies are one of the natural ways that our bodies fight infection: the immune system recognizes a foreign pathogen and produces antibodies to block and fight it.
But the immune system is no match for HIV. As Cohen explained during a visit to Seattle in 2015, “When someone gets infected with HIV, there’s a race between the immune system and the virus, and the virus always wins.” The immune system makes natural antibodies to HIV, but HIV mutates so rapidly that the antibodies can’t keep up with the changes.
Because vaccines typically work by “teaching” the immune system to develop antibodies, one of the fundamental obstacles to developing an HIV vaccine has been the virus’s rapid mutation. But in recent years, scientists have discovered that in about 15 to 20 percent of people infected with HIV, the immune system eventually figures out how to produce antibodies that are effective against a broad swath of mutated HIV strains. The trouble is, these broadly neutralizing antibodies take many years to develop — too late to prevent infection in the first place.
Thus the search for the holy grail: a vaccine that could elicit such super antibodies so that they would already be present and able to fight off HIV at the time of exposure. Researchers at Fred Hutch and elsewhere have made progress in identifying the type of immune cells capable of producing such antibodies and are taking the first steps toward developing a vaccine.
The hypothesis behind the AMP study is to see whether, if they are in place from the beginning, broadly neutralizing antibodies can in fact prevent infection in humans, as they have been shown to do in cells in the laboratory and in animal studies — and if so, what concentrations are needed.
The broadly neutralizing antibody being used in the AMP trial, called VRC01, was discovered in 2010 by the NIAID Vaccine Research Center in the blood of a so-called “long-term nonprogressor” — a person who had HIV and whose body controlled the infection for more than 15 years without medicine. Laboratory tests showed that it stopped up to 90 percent of the 190 HIV strains it was tested against — representing strains from around the world — from infecting human cells. The Vaccine Research Center produced a manufactured version of the natural antibody in its biotechnology facility to use in the studies.
VRC01, trial organizers are quick to point out, is not made from live HIV, killed HIV or HIV-infected human cells. It can’t cause HIV infection or AIDS. It has been tested in humans in three smaller clinical trials for safety; none of the 140 people who received the antibody experienced serious side effects, but the AMP study will continue to carefully monitor participants as well.
The AMP study will be a randomized, double-blind, placebo-controlled clinical trial — the “gold standard” of clinical trials. Study participants will be randomly assigned to one of three groups, with one-third receiving a higher dose of antibody in their IV, one-third a lower dose and one-third the placebo — an infusion of sterile salt water with no antibodies. “Double-blinded” means that neither the trial investigators nor the participants will know which participants are assigned to which group until the end of the trial, when the coded records are “unblinded.”
All of the groups will be counseled on how to reduce the risk of contracting HIV, which raises the question of how trial researchers will know if VRC01 is protective. The answer is randomization. Risk levels across the three study groups are expected to be similar, and even with risk reduction efforts, some people will still become infected. Because all three groups will receive the same prevention counseling, any difference in infections will likely be due to the antibody, trial organizers said.
The sheer size of the trial also helps. HIV prevention trials need to enroll many more volunteers than HIV treatment trials — or for that matter, cancer or other medical treatment trials.
Even among people at risk of contracting HIV — that is, people who are sexually active and live in a community with high rates of infection — “HIV acquisition is a rare event, and our job is to make it rarer,” the HPTN’s Cohen said in a talk to HIV advocates in Seattle. “So we need lots more people and a longer time, and we counsel people to use condoms, offer PrEP, etc. But if by chance you don’t do these things, that’s how we see if things work. It’s a crazy hard way to study the problem.”
The “crazy hard” study is worth it, researchers believe, if it can hasten the end of HIV/AIDS.
When combination antiretroviral therapy, first introduced in 1996, transformed HIV from a death sentence to a chronic disease, it was hailed — prematurely, it turned out — as the end of AIDS. But as groundbreaking as the drugs were and still are, reservoirs of latent HIV-infected cells hide in the body, out of reach of the drugs. Even for those with well-suppressed HIV, who have been on antiretroviral drugs for years, the virus continues to do damage by causing low-level inflammation that increases risk of heart disease and cancer. Stop taking the medications, and the virus comes roaring back.
Then there is the expense and effort of treating people for a chronic illness for the rest of their lives. Not everyone can tolerate the drugs and not everyone has access to them or takes them as prescribed. Even in the United States, less than 40 percent of the 1.2 million people infected with HIV are on antiretroviral drugs, and just 30 percent have achieved viral suppression, leading to better health, longer lives and less likelihood of transmitting the virus, according to the Centers for Disease Control and Prevention.
For another reminder that HIV/AIDS is still very much present, look to sub-Saharan Africa. Of the 37 million people around the world with HIV, 25 million live in there. In South Africa alone, about 19 percent of the adult population is infected and 2.3 million children have been orphaned because of AIDS.
Vaccines have long been the surest path to ending or containing infectious diseases. So far, in the 30 years since the AIDS virus was identified, only one vaccine candidate has shown any protection at all, reducing the risk of contracting HIV by about 31 percent. It prompted the immune system to produce antibodies, but they were not broadly neutralizing.
Though 31 percent protection was not enough to warrant licensing, the so-called Thai Trial, named for where it was tested, was the first evidence that any vaccine regimen could protect people from HIV and was widely hailed as a breakthrough. Earlier this year in South Africa, the HVTN began testing a new version of that vaccine regimen that has been modified to boost potency and durability.
“We have two paths [toward a vaccine],” said Fred Hutch’s Corey. “One of them is non-neutralizing antibodies [as in the Thai vaccine regimen]. The other path is to develop these broadly neutralizing antibodies. In the end, I think we’ll combine those two paths, and that will get us to the promised land of a vaccine that is 80 or 90 percent effective.”
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Mary Engel is a former staff writer at Fred Hutchinson Cancer Center. Previously, she covered medicine and health policy for the Los Angeles Times, where she was part of a team that won a Pulitzer Prize for Public Service. She was also a fellow at the Knight Science Journalism Program at MIT. Follow her on Twitter @Engel140.