Another HIV vaccine fails, highlighting longstanding challenges in the field

HIV has bested another vaccine.

After promising results in earlier rounds of testing, Johnson & Johnson’s experimental HIV vaccine failed in Phase 2 trials in women in Africa. The failure is the latest in the so-far fruitless effort to create a vaccine to prevent HIV infection, the leading cause of infectious death in the world.

The results were particularly gutting, says April Randhawa, an infectious disease scientist with the HIV Vaccine Trials Network, because the J&J vaccine was the first one developed to encompass the broad variability of the virus, rather than to focus on one strain.

“It’s devastating. We had a lot of high hopes for this vaccine,” Randhawa says. “For the clinical trial sites and study participants, I think it’s probably the hardest for them.”

Developing a successful HIV vaccine will require overcoming technological and societal hurdles, Randhawa and other scientists say. Some vaccine candidates, like J&J’s, use a more traditional approach to coax a protective immune response from the body. Others—like Moderna’s mRNA-based HIV vaccine, which just began Phase 1 trials—try to convince the body to release a special kind of antibody far sooner than it normally would.

At the root of the frustration is a virus that has survived in the most head-scratching way possible—by being sloppy.

When HIV copies itself inside a human cell, it has no mechanism to proofread its genetic information, says Warner Greene, director of the Gladstone Institutes’ Michael Hulton Center for HIV Cure Research. This means that as the virus replicates, it accumulates tiny mutations that don’t necessarily affect its function but do affect the way the immune system can recognize it. One person can have several HIV variants circulating in their body all at once.

“The virus is a swarm,” Greene says. “It’s not a species, it’s a swarm of different variants.”

On top of this carelessness-as-survival-mechanism, HIV infects the very immune cells that would normally help clear a virus. The antibodies a person makes in short-term response to infection don’t block HIV infection—they aren’t neutralizing. And what are called broadly neutralizing antibodies, which can block many variants from entering cells, can take years for the body to develop, Greene says.

This is why some vaccine candidates, like Moderna’s, are trying to coax out those broadly neutralizing antibodies sooner, he says.

Randhawa has high hopes for such vaccines. She says other researchers are trying to figure out how to get human cells to display on their surfaces the right bits of viral protein in the right configuration to signal the immune system to make neutralizing antibodies fast.

“It’s a bit of an engineering problem,” she says.

Although the J&J vaccine was novel in trying to protect against multiple strains of HIV, technologically it was fairly traditional, using an non-illness-causing adenovirus to deliver four different HIV antigens. The Phase 2 trials tested it in 2,637 women in sub-Saharan Africa. Although the vaccine was safe, after 2 years of observation a nearly equal number of people in the treatment and placebo arms contracted HIV.

This disappointing result followed the failure of another more traditional vaccine. In 2020, the US National Institutes of Allergy and Infectious Diseases ended a trial of HVTN702 because it was ineffective. One shot of this two-shot vaccine contained a canarypox virus engineered to carry a piece of the HIV envelope protein; the second shot contained the HIV surface glycoprotein. The canarypox was manufactured by Sanofi Pasteur and the glycoprotein manufactured by GlaxoSmithKline.

For the most part, Greene says, the drug industry has moved toward developing HIV treatments rather than vaccines. Through an approach called preexposure prophylaxis, or PrEP, HIV antivirals are given to people at risk of infection, reducing their rate of infection and turning the treatments into de facto vaccines.

With the success of antivirals, and in the face of a disease that people can have for decades, the financial incentive is to develop stronger or more convenient treatments. Gilead Sciences makes the very popular Biktarvy, a combination pill of antivirals taken daily. Viiv Healthcare recently earned US Food and Drug Administration approval for Cabenuva, a monthly injectable mix of cabotegravir and rilpivirine.

But new HIV drugs are expensive, and where HIV is prevalent, access to even basic single antivirals can be limited. This is partly why a vaccine is needed, Randhawa says. Every person at risk of contracting HIV will have different needs if they do get infected.

“We really need to get the levels of transmission down, and a vaccine is really going to be the only thing that can do that,” she says.

In the meantime, scientists that work with her will be analyzing some of the specimens from the 25% of people who were protected by the J&J vaccine and comparing them to people who weren’t, to see if they can find immunological differences that vaccine developers can exploit. J&J will continue testing the vaccine in different trials.

Despite the years of effort, Greene says, no HIV vaccine has achieved an efficacy higher than 30%. Even a vaccine that is 50% effective would be put to great use, he says.

“The HIV vaccine story is a story of great disappointment,” he says. “I think that the vaccine is the holy grail, but we haven’t found it yet.”