Preclinical trials point towards a future HIV vaccine

A major challenge in developing a vaccine for HIV is that the virus replicates and mutates quickly upon infection, resulting in a ‘swarm’ of viral strains existing in a single body.

Now scientists at several US institutions have conducted a series of preclinical trials indicating that they’re potentially closer to an immunisation regimen than ever before — one that could produce rare antibodies that would be effective against a wide range of HIV strains. Their findings, which build on a 2022 phase I clinical trial conducted by the non-profit scientific research organisation IAVI, thus represent a key step forward in an immunisation strategy that could protect against the virus.

The scientists’ HIV vaccine strategy involves stimulating the body to produce mature broadly neutralising antibodies (bnAbs). These are among the immune system’s key players in fighting HIV, since they can block many variants of the virus. The problem is that bnAbs produced by the human body are rare.

The original clinical trial, spearheaded in part by Professor William Schief from IAVI, Moderna and Scripps Research, focused on inducing the immune cells that could eventually evolve into the right bnAbs — ones that could protect host cells from multiple HIV strains. These precursor immune cells, known as B cells, were stimulated with the help of a priming immunogen — a customised molecule to ‘prime’ the immune system and elicit responses from the correct precursor cells.

But the primer also requires additional ‘booster’ immunogens to coax the immune system into producing not just precursor cells, but coveted VRC01-class bnAbs — a rare and specific class of antibodies known to neutralise more than 90% of diverse HIV strains. Boosters are also needed for the production of BG18 — another important bnAb class that binds to sugars on the HIV spike protein. That’s where the new studies come in: researchers developed immunisation regimens that could prime either VRC01 or BG18 precursors, and subsequently boost those precursors further down the path towards becoming bnAbs.

Priming rare antibodies

In the first study, which focused on BG18 and was published in the journal Science, Scripps Research scientists collaborated with co-senior authors Dr Shane Crotty, Chief Scientific Officer at La Jolla Institute for Immunology, and Dr Devin Sok, former vice president of discovery and innovation at IAVI. Using a priming immunogen, they consistently primed exceptionally rare BG18 precursors in a wild-type animal model.

To confirm they were able to prime the correct precursors, the researchers then teamed up with Scripps Research Professor Andrew Ward. Using cryo-EM structural analysis, they validated that the antibodies were indeed part of the BG18 class.

“The fact that priming worked well in macaques suggests that it has a good chance of succeeding in humans,” said co-first author Dr Jon Steichen, also from Scripps Research.

Steichen was also co-first author on a second study published in Science, in which mice were modified to produce a low frequency of BG18 precursors. Scripps Research and IAVI scientists, along with a team from the Ragon Institute of Mass General, MIT and Harvard, used priming methods similar to the ones used in the first paper. However, a key difference was that they also administered one of two boost immunogens using RNA technology. This resulted in boosting the primed B cells to adapt to recognise more native-like versions of HIV.

“This study showed that we can start to walk the B cells along toward bnAb development,” Steichen said.

Supercharging the immune system into action

For the third study, published in Science Translational Medicine, Schief and his team worked with IAVI scientists, wherein they primed a mouse model with the same immunogen used in the 2022 IAVI trial. This resulted in mice that produced VRC01-class precursor B cells similar to those found in people. But the researchers also designed a new booster immunogen to drive the antibody response towards becoming matured bnAbs — the next vital step in a sequential immunisation series that could effectively fight HIV. The result was a ‘prime-boost’ regimen that can drive VRC01-class B cells towards bnAb development.

“The findings demonstrate that we are able to make the antibody responses go in the right direction using this heterologous booster, which administers a different version of the vaccine than was given previously,” said Dr Christopher Cottrell, a senior staff scientist at Scripps Research who was the first co-author on this study.

Understanding the immunology

In the fourth and final study, published in Science Immunology with Cottrell again a co-first author, the researchers worked again with the Ragon Institute and used the same immunogens — but in a different mouse model where they could control the frequency of bnAb precursors that were modified to be similar to those found in humans. This allowed the researchers to take a deeper dive into the immunology associated with HIV vaccination by examining the germinal centres — specialised microstructures in the body that protect against viral reinfection. Germinal centres provide B cells with a space to rapidly increase and mutate their antibody genes, ultimately helping the immune system fight off viral strains.

In addition, the researchers examined how germinal centres accumulate HIV mutations over time. They found that a prime-boost regimen increased precursor B-cell activity in germinal centres across different lineages, which could eventually lead to an increase in matured VRC01-class bnAbs.

What’s next?

Overall, all four papers confirm that the priming step to turn on the right bnAb precursors is possible when it comes to developing an HIV vaccine. Three of those papers specifically demonstrate that it’s also possible to guide antibody precursors towards becoming bnAbs that can fight HIV. The researchers are now advancing phase I, experimental medicine trials for both the VRC01 and BG18 projects.

“Taken together, the findings give us more confidence that we’re able to prime precursors from multiple bnAb targets, and they also show that we’re starting to learn the rules for how to advance precursor maturation through heterologous boosting,” said Schief, who is a co-senior author of all four studies.

“All in all, these studies show that we have a good chance at creating an effective HIV vaccine — we just need to keep iterating and build on these findings in future clinical trials.”

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