HIV antibody trial results offer 'proof of concept'

Outcome of AMP shows feasibility of developing potent antibody combinations to block HIV
Dr. Larry Corey speaks at a podium in front of a slide showing scientific data
Dr. Larry Corey, former president and director of Fred Hutchinson Cancer Research Center, was protocol chair of the Antibody Mediated Prevention trials and reported first results prior to the online HIV Research for Prevention scientific conference, which opened on Jan. 27. Photo by Robert Hood / Fred Hutch News Service

Editor's note: The story below was originally published on Jan. 26, 2021, upon release of the AMP results prior to an international HIV prevention conference. Details of the paired AMP trials have now been published in the March 18, 2021 edition of the New England Journal of Medicine. In it, Fred Hutch virologist Dr. Larry Corey and colleagues explained results of the trials, and Harvard HIV/AIDS researcher Dr. Bruce Walker discussed the “important implications” of these findings for future prevention efforts.

A large international study has shown that it is possible to prevent some HIV infections with infusions of a particularly potent protein known as a broadly neutralizing antibody, but it will likely take a combination of different and more potent proteins to block all strains of the shape-shifting virus.

Results of the Antibody Mediated Prevention, or AMP, trials released on Jan. 26 are an “important proof of concept” that demonstrated the feasibility of blocking HIV with bimonthly infusions of such antibodies, according to trial leader Dr. Larry Corey, the acclaimed virologist and professor at Fred Hutchinson Cancer Research Center in Seattle.

The results come from a pair of AMP trials that since 2016 have enrolled 4,623 volunteers on four continents. The study was designed to evaluate whether a single broadly neutralizing antibody, known as VRC01, could be safely delivered by intravenous drip and to provide detailed information on how well it blocked infection by multiple strains of HIV.

For years, HIV vaccine researchers have been stymied by the ability of HIV to outmaneuver a range of antibodies that our immune system normally uses to control invading viruses. AMP was set up to test whether infusions of a broadly neutralizing antibody — one that HIV could not readily evade through mutation — could block new infections.

The VRC01 antibody was originally discovered in the blood of a patient living with HIV, and mass-produced in the laboratory as a so-called monoclonal antibody. It is the same process being used to treat COVID-19 patients with manufactured antibodies that target the spike protein of the coronavirus.

The trials found that this antibody completely blocked about 30% of HIV strains circulating in the communities where the infusions were tested, but it was not potent enough to block the other 70% of strains, and therefore by itself is not an effective candidate for HIV prevention.

Opens up the field for development 

Consequently, Corey explained, this study showed that just as combinations of different antiretroviral drugs are needed to treat HIV, combinations of more potent antibodies — including some discovered since the AMP study launched — might be able to prevent it. Early trials testing such antibody cocktails in human volunteers are already underway.

“This trial was incredibly successful. It opens up the field for the development of cocktails of monoclonal antibodies,” Corey said today during a press conference in advance of the HIV Research for Prevention, an international conference on the science of HIV prevention that opens online Jan. 27.

In an interview, Corey said the study results gave him a sense of déjà vu, because decades ago he played a key role in the trials of AZT, the first antiviral found to inhibit HIV, the virus that causes AIDS. That drug, by itself, was shown to be effective at blocking HIV, but it could be overwhelmed within a few months by strains of the rapidly mutating virus that could sidestep it. 

Dr. Carl Dieffenbach speaks at a podium in a darkened room at the Seattle Public Library
Dr. Carl Dieffenbach is director of the Division of AIDS, which is responsible for HIV research with the National Institute of Allergy and Infectious Diseases. Photo by Josh Belzman / Fred Hutch News Service

To box in the rapidly changing virus, scientists realized they would need combinations of different HIV drugs — and that discovery led within a few years to triple-drug formulations in the mid-1990s that turned HIV from a death sentence to a manageable, chronic disease.

The AMP study underscores why HIV is such “a formidable virus,” Corey said, but in his view the most important discovery of the trial is that it yielded for the first time a measurable threshold that shows when monoclonal antibodies work — or when they don’t.

A test — developed by Dr. David Montefiore of the Duke Human Vaccine Institute — can measure the potency of a given antibody’s ability to block HIV. The AMP study found that if an antibody reached a certain potency threshold against an HIV strain, it would block it; if it was weaker than that level, the antibody would fail.

The study showed the antibody met the threshold against 30% of the HIV strains it encountered, but it was not potent enough to stop other strains. Importantly, the study revealed that the strength required for the antibody to work against all strains of HIV would have to be about 10 times more potent than VRC01.

Corey said that is enormously important to the design of future HIV prevention drugs.

“The test was totally predictive of what worked and what did not work,” Corey said. “Now we can use this assay for defining a more potent broadly neutralizing antibody.”

During the press conference, Corey pointed to several new studies that are testing whether more potent forms of VRC01, or combinations of even more potent broadly neutralizing antibodies identified since 2016, might be strong enough to prevent infection. They include studies of a longer-acting version of VRC01, and early trials in humans of combinations of two and three different broadly neutralizing antibodies.

“We can use this assay to develop more potent broadly neutralizing antibodies, and there’s a likelihood with this tool we can look for new ones that are better, more potent and cheaper,” Corey said.

Sponsored by NIAID, the trial spanned four continents

AMP was sponsored by the National Institute of Allergy and Infectious Diseases and enrolled volunteers into parallel trials. The trials were run collaboratively by two NIAID-supported organizations, the Hutch-based HIV Vaccine Trials Network, or HVTN; and the HIV Prevention Trials Network, or HPTN, a sister organization in North Carolina. One trial in the US, South America and Switzerland recruited men and transgender people who have sex with men. The companion trial enrolled women in seven sub-Saharan African countries.

Because VRC01 could not block all strains in the HVTN-run AMP study, the antibody was found to reduce overall HIV infections by 27%. In the study in sub-Saharan Africa — which has a different family of  HIV strains — it was 9%.

Dr. Carl Dieffenbach, who directs AIDS research at NIAID, said the AMP study solidified our understanding of antibody control of HIV and made some pathbreaking findings that will inform future prevention efforts.

“First and foremost, it showed that infusions of this broadly neutralizing antibody were safe. There were about 44,000 infusions in the course of this study on multiple continents,” he said in an interview.

“It really gives us a handle on a couple of things. It tells us what level of neutralization is required to provide protection. It also tells us the amount of antibody we would need to induce by vaccination,” he said.

Dr. Shelly Karuna (left) is a senior staff physician at Fred Hutch; Gail Broder (right) is senior community engagement project manager for AMP.
Dr. Shelly Karuna (left) is a senior staff physician at Fred Hutch; Gail Broder (right) is senior community engagement project manager for AMP.

Dr. Karuna photo by Robert Hood / Fred Hutch News Service; Broder photo courtesy of Gail Broder

Fred Hutch senior staff physician Dr. Shelly Karuna also made a comparison of the results of the AMP trials to the early studies of AZT.

“It wasn’t perfect, but let’s not make the perfect the enemy of the good,” she said. “This imperfect but good monoclonal antibody, VRC01, provides promise for the field.”

Although researchers are also finding that new oral and injectable formulations of antiviral drug combinations, or PrEP, are working to provide long-lasting protection against HIV, Karuna said that control of this pandemic is going to require a toolbox of many options.

“There are ways in which antibodies are unique,” she said. “They can also partner with our own immune system. They can complement our own immune response.”

Gail Broder, senior community engagement project manager for the AMP study, said future studies are needed to find the best combinations of antibodies that can corner HIV, similar to the way antiviral drug combinations do.

She said one of the most remarkable aspects of the study was that such large and complex trials could be carried out around the world. More than 4,500 participants agreed to regular HIV blood tests and antibody infusions every eight weeks for two years. They were divided into groups that received one of two dosages of the antibodies or a placebo. Despite all that work and uncertainty, the trials were quickly fully enrolled and had a retention rate — the percent of participants completing the expected number of visits — of better than 90%.

“We can walk away from this trial with a great deal of hope,” Broder said. “It gave us a very clear signal of where this approach to HIV prevention is going.”

Sabin Russell is a former staff writer at Fred Hutchinson Cancer Center. For two decades he covered medical science, global health and health care economics for the San Francisco Chronicle, and he wrote extensively about infectious diseases, including HIV/AIDS. He was a Knight Science Journalism Fellow at MIT and a freelance writer for the New York Times and Health Affairs. 

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