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Since it was first identified in 1983, HIV has infected more than 85 million people and caused some 40 million deaths worldwide.
While medication known as pre-exposure prophylaxis, or PrEP, can significantly reduce the risk of getting HIV, it has to be taken every day to be effective. A vaccine to provide lasting protection has eluded researchers for decades. Now, there may finally be a viable strategy for making one.
An experimental vaccine developed at Duke University triggered an elusive type of broadly neutralizing antibody in a small group of people enrolled in a 2019 clinical trial. The findings were published today in the scientific journal Cell.
“This is one of the most pivotal studies in the HIV vaccine field to date,” says Glenda Gray, an HIV expert and the president and CEO of the South African Medical Research Council, who was not involved in the study.
A few years ago, a team from Scripps Research and the International AIDS Vaccine Initiative (IAVI) showed that it was possible to stimulate the precursor cells needed to make these rare antibodies in people. The Duke study goes a step further to generate these antibodies, albeit at low levels.
“This is a scientific feat and gives the field great hope that one can construct an HIV vaccine regimen that directs the immune response along a path that is required for protection,” Gray says.
Vaccines work by training the immune system to recognize a virus or other pathogen. They introduce something that looks like the virus—a piece of it, for example, or a weakened version of it—and by doing so, spur the body’s B cells into producing protective antibodies against it. Those antibodies stick around so that when a person later encounters the real virus, the immune system remembers and is poised to attack.
While researchers were able to produce Covid-19 vaccines in a matter of months, creating a vaccine against HIV has proven much more challenging. The problem is the unique nature of the virus. HIV mutates rapidly, meaning it can quickly outmaneuver immune defenses. It also integrates into the human genome within a few days of exposure, hiding out from the immune system.
“Parts of the virus look like our own cells, and we don’t like to make antibodies against our own selves,” says Barton Haynes, director of the Duke Human Vaccine Institute and one of the authors on the paper.
The particular antibodies that researchers are interested in are known as broadly neutralizing antibodies, which can recognize and block different versions of the virus. Because of HIV’s shape-shifting nature, there are two main types of HIV and each has several strains. An effective vaccine will need to target many of them.
Some HIV-infected individuals generate broadly neutralizing antibodies, although it often takes years of living with HIV to do so, Haynes says. Even then, people don’t make enough of them to fight off the virus. These special antibodies are made by unusual B cells that are loaded with mutations they’ve acquired over time in reaction to the virus changing inside the body. “These are weird antibodies,” Haynes says. “The body doesn’t make them easily.”
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Haynes and his colleagues aimed to speed up that process in healthy, HIV-negative people. Their vaccine uses synthetic molecules that mimic a part of HIV’s outer coat, or envelope, called the membrane proximal external region. This area remains stable even as the virus mutates. Antibodies against this region can block many circulating strains of HIV.
The trial enrolled 20 healthy participants who were HIV-negative. Of those, 15 people received two of four planned doses of the investigational vaccine, and five received three doses. The trial was halted when one participant experienced an allergic reaction that was not life-threatening. The team found that the reaction was likely due to an additive in the vaccine, which they plan to remove in future testing.
Still, they found that two doses of the vaccine were enough to induce low levels of broadly neutralizing antibodies within a few weeks. Notably, B cells seemed to remain in a state of development to allow them to continue acquiring mutations, so they could evolve along with the virus. Researchers tested the antibodies on HIV samples in the lab and found that they were able to neutralize between 15 and 35 percent of them.
Jeffrey Laurence, a scientific consultant at the Foundation for AIDS Research (amfAR) and a professor of medicine at Weill Cornell Medical College, says the findings represent a step forward, but that challenges remain. “It outlines a path for vaccine development, but there’s a lot of work that needs to be done,” he says.
For one, he says, a vaccine would need to generate antibody levels that are significantly higher and able to neutralize with greater efficacy. He also says a one-dose vaccine would be ideal. “If you’re ever going to have a vaccine that’s helpful to the world, you’re going to need one dose,” he says.
Targeting more regions of the virus envelope could produce a more robust response. Haynes says the next step is designing a vaccine with at least three components, all aimed at distinct regions of the virus. The goal is to guide the B cells to become much stronger neutralizers, Haynes says. “We’re going to move forward and build on what we have learned.”
