New hope after four decades of hiv vaccine research

Several coronavirus vaccines took only a year to develop, while there is still no vaccine for the HIV virus. Despite all the difficulties, there is finally new progress after a long time.

Computer image of the immunostimulatory protein eOD-GT8.

When virologist Jose Esparza began working with the World Health Organization in the 1980s to combat the AIDS epidemic, he and many of his colleagues were convinced that a vaccine would be the solution – and that it would come quickly.

Her optimism was based on solid science: researchers knew that humans produce antibodies to the HIV virus that causes AIDS. And stimulating the body to produce antibodies was already a common and successful vaccination strategy that had dramatically reduced cases of measles, smallpox and many other diseases. Fighting AIDS seemed just as feasible.

"We thought this was going to be a no-brainer," says Esparza, a former adviser to the Bill& Melinda Gates Foundation, who is now at the University of Maryland School of Medicine. "We were not aware of the complexity of HIV." More than three decades later, there is still no viable vaccine candidate. Meanwhile, less than a year after the emergence of the SARS-CoV-2 virus, which causes COVID-19, scientists have been able to develop several effective vaccines at once.

Now, new findings are raising new hopes: at an international AIDS conference in February, researchers from Scripps Research and IAVI, a nonprofit vaccine research organization, announced promising blood test results. They come from the first phase 1 human trial of a new HIV vaccine strategy. On social networks like Twitter, the news spread like wildfire.

But the reality is far more nuanced than the hype suggests, says William Schief, an immunologist at The Scripps and senior director of vaccine development at IAVI’s Neutralizing Antibody Center. Although the immune response his team discovered is an important proof of concept, he said research is still years away from producing vaccines that reduce the likelihood of HIV infection. And even then, a potential vaccine will likely need to be administered multiple times, which could be a tough sell.

"Scientifically, it’s a beautiful concept," Esparza says. "Practically, it will not be easy to implement."

Still, after decades of setbacks, the results are welcome news. In addition, the COVID-19 vaccine effort could help accelerate work on an HIV vaccine.

"It’s a small step toward an HIV vaccine, but it’s also a giant step" that suggests a viable path forward, Schief says. "And in fact, in this particular case, it worked surprisingly well."

The three approaches to an HIV vaccine

The search for an HIV vaccine began shortly after scientists isolated the virus in 1984 and confirmed that it causes AIDS. Since then, there have been three major waves of research, says Esparza, who published a historical outline of the search for an HIV vaccine in 2013.

The first wave focused on the most established idea: trying to stimulate the human immune system to produce so-called neutralizing antibodies that inactivate certain viruses. This is the strategy used by many other vaccines, including those for COVID-19. For years, researchers worked to identify the antibodies people produced in response to HIV infection and then develop vaccines to stimulate the production of similar antibodies.

But HIV proved to be a clever enemy. Antibodies target specific proteins on the surface of the virus. However, HIV quickly mutates into variants that can’t be recognized by antibodies, so it stays one step ahead of the immune system. In one well-known study, Schief says researchers repeatedly examined the blood of HIV-infected people and found that the antibodies produced by the immune system always lagged the virus by about three to six months.

"HIV is still a much more difficult scientific target" than SARS-CoV-2, says Larry Corey. An expert in virology, immunology and vaccine development at the Fred Hutchinson Cancer Research Center in Seattle, he is also director of clinical trials at the HIV Vaccine Trials Network. "Ninety-eight percent of people are recovering from SARS-CoV-2, and we’re still at 0 for every 78 million people who have recovered from AIDS."

The early 2000s saw the beginning of the second wave of HIV vaccine strategies. They were based on the idea of targeting the body’s own "killer" T cells rather than trying to stimulate antibodies. Long-term human immunity depends on two main groups of cells: B cells and T cells. Both help produce antibodies, but T cells also seek out and destroy infected cells. The idea for T-cell vaccines was to stimulate cells that recognize internal proteins in the virus.

In a randomized phase 2 double-blind trial called STEP in 2007, the approach not only offered no protection – it also increased the risk of HIV infection. "The study failed miserably," says Esparza.

This was far from the only vaccine trial that came to nothing. After decades of human trials, only one approach has shown some degree of effectiveness in the real world. A two-vaccine combination that followed the antibody production strategy, completed in Thailand in 2009, reduced HIV infection rates by 31 percent. Only this is not enough to get an admission.

Naive B cells against the HI virus

The third and current wave of HIV vaccine research began in the late 2000s. Researchers discovered that a small minority of HIV-infected individuals produce particularly potent antibodies that can neutralize many HIV strains at once. So far, scientists have identified dozens of these special antibodies that target parts of the viral surface (similar to the spike proteins on SARS-CoV-2), which appear to be the same across strains.

People who make these proteins still can’t fight HIV on their own, because their bodies don’t make these antibodies until the viral infection is already established, and the virus continues to mutate in the meantime, Schief says. But the discovery has led to a new idea: Perhaps an effective vaccine could get a step ahead of the virus by targeting so-called naive B cells (which have not yet had contact with their antigen) circulating in our blood, Schief says. The goal would be a vaccine by which the naive B cells acquire mutations that cause them to produce broadly neutralizing antibodies even before HIV infection occurs. Here’s how the body might be able to fight off the virus when it first encounters it.

In 2010, Schief’s group began working with a class of broadly neutralizing antibodies called VRC01 – the first to be discovered by the NIH Vaccine Research Center. First, they developed an engineered protein nanoparticle that they reported could dock to naive B cells in human blood samples. In mouse studies, the nanoparticle was able to activate these cells, causing them to proliferate and mutate to produce VRC01-like antibodies. The new study aimed to find out if the same is possible with humans.

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