It’s been a while since there was a strong milestone in the development of an effective HIV vaccine. Just last year, a large-scale trial of a promising HIV vaccine candidate was halted after the vaccine failed. But with the extraordinary success we’re seeing with COVID-19 vaccines, it’s not surprising that the positive results of a recent HIV vaccine trial have ignited wild enthusiasm. While movement by the research community in the direction of an HIV vaccine is good news, it’s important to understand exactly what the trial’s results mean, and what they do not.
Preliminary data from an early-stage phase I clinical trial do suggest that a new approach to an HIV vaccine holds promise. The data was presented at the International AIDS Society HIV Research for Prevention virtual conference in February and showed that the immune systems of 35 out of 36 healthy people who received two doses of the vaccine may be able to make broadly neutralizing antibodies (bNAbs) that could produce an immune response to the virus.
But contrary to some overly optimistic predictions circulating on social media, the trial, IAVI G001, conducted by International AIDS Vaccine Initiative (IAVI) and Scripps Research Institute, did not suggest that this approach will result in an effective vaccine—or vaccines—for HIV anytime soon. TheBody spoke with William Schief, Ph.D., a professor and immunologist at Scripps and executive director of vaccine design at IAVI’s Neutralizing Antibody Center, whose laboratory developed the vaccine, to clear up a few misconceptions.
Did the Vaccine Produce Antibodies Against HIV?
No, and it will require several complex steps to produce antibodies that prevent HIV in any or all its variations, and several more trials to get there. In the IAVI/Scripps trial, a targeted response was detected in 97% of participants who received the vaccine, which is not the same as saying those participants developed antibodies.
A targeted response, in this case, means stimulating the production of immune cells, which can start the process of generating antibodies. Those immune cells are called naive B cells, and once stimulated, they can produce precursors to a certain type of bNAb, which is the body’s immune response.
The trial achieved proof that a process called “germline targeting” triggered the activation of cells that produce bNAbs, but it did not directly produce antibodies. It’s a proof of principle, according to researchers, not proof that a specific vaccine will prevent any or all variants of HIV. It would be the first in a sequence of engineered HIV vaccine candidates that could, ultimately, protect people against HIV infection, according to Schief.
What’s a Proof of Principle?
A proof of principle is a study that tests and confirms a hypothesis. This phase I study of IAVI G001 began in 2018 to test the hypothesis that a self-assembling nanoparticle of engineered HIV envelope proteins could activate naive B cells. And it worked.
“What we did is show that the concept can work in humans,” Schief said. “We have a theory of how to design a vaccine that will elicit the response we want. We think the first shot must achieve a certain goal, to induce responses from these cells. And we showed it did. Proof of principle means you can do it again, starting from a different set of rare (B) cells.”
Schief cautioned that the study has not been peer reviewed, nor has a paper been written about the results, but he expects the review to happen sometime this summer.
How Is This Vaccine Not Like Vaccines Used for SARS-CoV-2?
All variations of HIV viruses, similar to the SARS-CoV-2 virus which can lead to COVID-19, use a structural feature called “spikes”—these allow the virus to enter human cells. The theory is, if you can develop specialized proteins to attach to these spikes and prevent them from entering human cells, you’ve found the holy grail. It worked for SARS-CoV-2, with the vaccines developed by Moderna and Pfizer—other vaccines use different mechanisms to prevent COVID-19. And in theory, for HIV, a vaccine preventing spikes from entering human cells would also be effective.
But here’s an important distinction: HIV is not one single virus. There are two types, HIV-1 and HIV-2, and many different groups and subtypes, or strains, which can mutate. That’s what makes studying HIV in all its forms so tricky, and why a single effective vaccine has been so elusive. Schief said that it is possible for an antibody to disable some HIV spikes that don’t mutate very much, although even that will take time.
“The problem with COVID is that if variants expand, it will be more difficult for one vaccine to work,” said Schief. “HIV is that same problem on steroids.” bNAbs must cover all (HIV) variants. To cover more than one variant, Schief said, researchers must induce responses from different B cells. “Our theory is, the first shot will be a mix of different vaccines to trigger different sets of cells to produce different sets of bNAb cells,” added Schief.
How Would mRNA Figure Into an HIV Vaccine?
What researchers in the IAVI/Scripps trial evaluated was not a messenger RNA (mRNA) vaccine. However, Schief said mRNA technology could be used to speed up the research process going forward. Because mRNA technology teaches the body how to make its own protein to trigger bNAbs, it can be used to deliver to spikes anchored to membranes, like in the case of the Moderna and Pfizer vaccines.
Schief said you should think of mRNA as an effective delivery system. “In the last clinical trial, we had to manufacture a protein to use in humans. That took years, starting in 2014, and was expensive, because it’s a custom process,” he said. “You want to design (the protein) to be launched by mRNA, because they have the genetic code. mRNA is easier and quicker than producing a purified protein.”
Does the Trial’s Success Mean an Effective Vaccine for HIV Will Be Available Soon?
Not anytime soon. Schief said that an effective vaccine must be based on human data demonstrating that bNAbs can be produced every time. “That’s about five to 10 years away, but hopefully sooner,” he said. “HIV doesn’t give you any freebies. Fortunately, the strategy we are pursuing is step-by-step, and that means we don’t have to hit a home run with any single trial. We can learn and modify, redesign, and go back.”
Schief’s team’s theory: Give many vaccine shots in a sequence, one by one, and test each step to determine whether it achieves its goal.
Another bright spot: Research into this technique for producing an immune response can also be used to target other difficult viruses, including Zika, malaria, hepatitis C, and influenza.
Schief and his team will be working on several trials this year. The first will be a collaboration with Moderna starting later this year, “to test a second shot and see if it can interact with cells generated by the first shot and keep them learning to produce bNAb,” said Schief. His team is also collaborating with Moderna and the National Institutes of Health to test delivery of later stages of their vaccine concept. Also with Moderna, the team will attempt to reproduce the IAVI G001 trial, this time in regions of sub-Saharan Africa, to see if the results are the same. “There is some geographical variation in the spike protein and other HIV proteins,” said Schief. “We think our vaccine concept should work for everywhere, but we want to make sure that’s true.”
William Schaffner, M.D., a professor of infectious diseases at Vanderbilt University, says the IAVI/Scripps trial is a great achievement and welcome news after a “long dry spell” in HIV vaccine research, but, like Schief, he cautions that there are many steps to go.
“It flummoxes all of us that we don’t have a vaccine yet, but remember that HIV is distinctive and it mutates rapidly,” said Schaffner. “And the virus can remain in the body, and that’s antithetical to traditional vaccines, where you give an antibody what would eliminate the virus, in the case of measles, for example.”
Schaffner, who was a clinician in the 1980s, added that people have been celebrating the premature arrival of an HIV vaccine going back to the early days of the epidemic. “Many of us thought development of a vaccine would be easier than treatment, which showed how naive we all were,” he said.