A new type of HIV vaccine based on germline targeting—an approach that trains the immune system to produce broadly neutralizing antibodies (bnAbs)—stimulated a strong helper T-cell response in a small early clinical trial, researchers reported in Science Translational Medicine. CD4 cells—the main target of HIV—help coordinate immune system responses, including the activation of antibody-producing B-cells.

“We were quite impressed that this vaccine candidate produced such a vigorous T-cell response in almost all trial participants who received the vaccine,” Julie McElrath, MD, PhD, of Fred Hutchinson Cancer, one of the senior study authors, said in a news release.

These promising findings mean the novel approach can move into larger studies, but it will still be years before it could be tested in late-stage trials and deployed worldwide.

Researchers have spent more than three decades and billions of dollars studying HIV vaccines to prevent and treat HIV, with little success. After several traditional vaccine candidates failed in large trials, scientists at IAVI, Scripps Research and the National Institutes of Health Vaccine Research Center took a different approach, aiming to teach the immune system to generate B cells that can make bnAbs.

People with HIV normally produce antibodies against the virus, but they usually target parts that are highly variable, so they don’t recognize new viral mutations. However, a small number of people naturally produce bnAbs that target hidden conserved parts of the virus, and most people possess rare immature B cells that are potentially capable of doing so. Germline targeting uses a series of vaccines in a stepwise manner to encourage the development of these specialized precursor cells, evolve them into mature B cells and train them to produce bNAbs.

The researchers developed an immunogen, dubbed eOD-GT8 60mer, that consists of 60 engineered copies of HIV’s gp120 envelope protein fused to a lumazine synthase protein scaffold. The resulting nanoparticle is designed to spur production of bnAbs similar to VRC01, an antibody derived from a person who was able to naturally control HIV. Preclinical studies showed that eOD-GT8 60mer stimulated the desired immune responses in mice and monkeys.

“This louder HIV signal is tailored to draw out and engage those very specific B cells with the potential to produce bnAbs,” explained Lawrence Tabak, DDS, PhD, acting director of the National Institutes of Health.

The Phase I IAVI G001 trial (NCT03547245) is the first human study of this approach. The study enrolled 48 HIV-negative adult volunteers at Fred Hutch in Seattle and George Washington University in Washington, DC. They were randomly assigned to receive either two injections of different doses of eOD-GT8 60mer plus an immune-boosting adjuvant or placebo injections, spaced two months apart.

In 2021, William Schief, PhD, of Scripps, reported initial findings from IAVI?G001 at the HIV Research for Prevention Conference; detailed results were published last December in Science. Almost all participants who received the first priming vaccine dose produced precursor B cells—the first step in the pathway for generating bnAbs. After the booster shot, these B cells produced antibodies with greater affinity for the HIV envelope protein. The vaccine had a favorable safety profile with only mild to moderate temporary side effects.

Now, McElrath and her team have shown that the vaccine regimen also stimulates a strong CD4 helper T-cell response.

Robust polyfunctional CD4 cells specific for the eOD-GT8 HIV proteins and lumazine synthase were induced after two vaccines using either a 20- or 100-microgram dose. Antigen-specific helper T-cell responses were observed in 84% and 93% of vaccine recipients, respectively. Further, the researchers identified key “hotspots,” or epitopes on the HIV and lumazine synthase proteins that T cells were especially good at recognizing. What’s more, induction of vaccine-specific CD4 cells correlated with the expansion of eOD-GT8-specific memory B cells.

“These results highlight the potential of this HIV-1 nanoparticle vaccine approach to induce the critical T-cell help needed for maturing antibodies toward the pathway of broadly neutralizing against HIV,” McElrath said.

“We went beyond what is normally done by drilling down to identify the T-cell epitopes and found several broadly immunogenic epitopes that might be useful for developing boosters and for other vaccines,” Schief, another senior author, added in an IAVI news release.

Next Steps 

While these findings are promising, they are just the first step in what is expected to be a multistep vaccine regimen that elicits bnAbs with increasing affinity for HIV. So far, the researchers have not tested antibody responses against HIV, much less whether the vaccine regimen prevents HIV acquisition or leads to a functional cure in the real world.

Experts think the mRNA technology used in the Moderna and Pfizer-BioNTech COVID-19 vaccines could help speed up and lower the cost of HIV vaccine development. The mRNA vaccine technology uses lipid nanoparticles to deliver bits of genetic material that encode instructions for making proteins. Germline targeting is expected to require a series of vaccines. Because the mRNA genetic code in a vaccine can easily be swapped out, researchers will use the technology to rapidly generate and deliver successive versions of the HIV immunogen.

The IAVI G002 trial (NCT05001373) is now evaluating mRNA vaccine candidates produced by Moderna, dubbed mRNA-1644 and mRNA-1644v2-core, that deliver eOD-GT8 60mer and a related immunogen. In January 2022, the company announced that study participants had received their first doses. Another study, IAVI G003 (NCT05414786), is testing mRNA-1644 in Rwanda and South Africa.

These studies aim to produce vaccines for HIV prevention, but a therapeutic vaccine that generates nbAbs could potentially help bring about long-term remission—a functional cure—in people living with HIV. “[I]f we get it to work well enough, we could also give the vaccine to people on ART [antiretroviral therapy], which might eventually allow them to go off ART,” Schief told POZ last year.

If these studies pan out, it will be the next step in a years-long process leading up to the evaluation of the vaccines in large clinical trials. A vaccine regimen that requires multiple doses delivered over time is unlikely to be feasible in the real world, so researchers ultimately hope to develop simpler regimens that could help end the HIV epidemic worldwide.