HIV vaccine research funding faces an uncertain future

Late last week, the HIV vaccine field was dealt another major blow.

It is not a field unaccustomed to bad news. Despite nearly 40 years of effort, researchers are still actively pursuing a vaccine that can protect individuals from this highly variable virus that is one of the most vexing researchers have ever tried to combat. Not a single candidate vaccine tested thus far has proven widely effective, and, year after year, clinical trials of various vaccines have provided disappointing outcomes. Then, earlier this year, the dismantling of the U.S. Agency for International Development upended several international HIV vaccine research efforts and put some clinical trials on hold.

But the latest news may have even more substantial repercussions for the effort to develop an HIV vaccine. As reported in various news outlets, the U.S. National Institute of Allergy and Infectious Diseases (NIAID) informed both heads of the Consortia for HIV/AIDS Vaccine Research Development (CHAVD) programs — Dennis Burton of Scripps Research in La Jolla, California, and Barton Haynes of Duke University’s Human Vaccine Institute — that they would not continue funding these programs beyond the current cycle, which is set to expire at the end of 2025.

The U.S. National Institutes of Health (NIH), which oversees NIAID, is, or at least was, one of the world’s largest funders of HIV vaccine research, spending nearly $600 million on the mission in 2022, or 81% of the total global expenditure, according to data from AVAC. In 2019, the two CHAVD consortia each received $129 million in funding over seven years to advance and clinically evaluate vaccine immunogens resulting from decades of cumulative advances in deciphering what types of immune responses are most likely to ward off HIV infection. These vaccine strategies are meant to induce broad and potent antibody responses against the virus that can successfully neutralize the many variants in circulation across the globe. These broadly neutralizing antibodies (bnAbs) are considered the linchpin of a successful immune response against the virus, and in recent years, the HIV vaccine field has coalesced around the idea that bnAb-based approaches are the most promising way to make an HIV vaccine.

The 2019 CHAVD consortia were the third iteration of the program originally established in 2005 (then known as CHAVI or the Center for HIV/AIDS Vaccine Immunology) to accelerate progress in developing an HIV vaccine by addressing key immunological questions and designing and testing novel vaccine candidates. Haynes led the initial CHAVI team, which started by studying immune responses in acutely HIV-infected individuals. Then in 2012, both Haynes and Burton received grants to develop and test novel vaccine immunogens designed to induce bnAbs.

“I know it’s been frustrating, but the biology of this virus is unique,” says Haynes. The previous iterations of the consortia were essential for deducing the specific types of immune responses a vaccine should induce and figuring out how to achieve that through sequential vaccination.  “There has been steady progress,” says Haynes. “And now, lo and behold, we have three clinical trials of vaccine candidates that are working better in humans than we ever thought they would, based on studies in non-human primates and humanized mice,” he says.

In May, Burton was awaiting a request for proposals for the fourth round of CHAVD grants to begin in 2026 so his consortium could continue its ongoing work and retain qualified staff to conduct pivotal proof-of-concept studies. It is now clear this RFP will not be coming.

Even the current round of funding for ongoing long-term experiments that typically would be released in January had not materialized by mid-May, creating uncertainty among Burton’s collaborators about the viability of those ongoing studies. “We’re getting close to showing proof of concept for a broadly neutralizing antibody-based HIV vaccine, and some of the finest work is being done in non-human primates, so we’re very eager to keep those experiments going,” says Burton. “But we’ve not received the funds to do that and that’s caused us to pause a lot of experiments and could sabotage a lot of investment the NIH has already made in a proof-of-concept for this approach.”

HIV vaccine funding at the NIH will likely be affected beyond even the cuts to the CHAVD efforts. And it couldn’t have come at a worse time, according to researchers. “We’re at a point at which we’re seeing more progress than we’ve ever seen in the quest to make an HIV vaccine, and the next four to five years are going to be critical in moving toward that goal, which is still a very important one,” says Burton. But now that the CHAVD programs will not continue, there is a huge gap to fill. “This is a sad development that is really obstructing forward progress,” adds Burton.

After years of basic research and experimentation, several HIV vaccine candidates are showing promise in early-stage human clinical trials. In May, researchers from IAVI, Moderna, and multiple other partner organizations, many of which are NIH-funded, published results from two clinical trials (IAVI G002 and IAVI G003) testing the ability of an engineered immunogen (the eOD-GT8 60 mer) delivered via an mRNA lipid nanoparticle delivery system to engage and mature immune cells that could eventually give rise to HIV-specific bnAbs.

The data from early-stage clinical trials in both North American and African populations indicate that this vaccine immunogen can sufficiently prime the immune system and engage and expand the necessary immune cells — the first step in the complicated process of inducing bnAbs against the virus through a strategy known as germline targeting.  And, in the North American trial, researchers showed that a priming vaccination followed by a different booster immunogen could kick off the maturation process that guides these immune cells further down the path toward elicitation of bnAbs.

Results from a Phase 1 trial of another germline-targeting immunogen were also published in May. This immunogen (BG505 SOSIP.v4.1-GT1.1) also successfully induced important bnAb precursors in human volunteers, suggesting it is another route toward recruiting and engaging the rare human immune cells that have the potential to give rise to HIV-specific bnAbs.

Together, these studies provide a clear path for pursuing germline-targeting strategies for bnAb-based HIV vaccines that are the direct result of decades of basic and clinical research involving collaborations among dozens of institutions. “We are very optimistic about our germline-targeting HIV vaccine program,” says Mark Feinberg, president and CEO of IAVI. “The recent IAVI G002 and G003 results are very encouraging findings, and we believe that we are closer than ever before to the successful creation of an HIV vaccine.”

But as the funding landscape for HIV vaccine research shrinks, researchers are questioning how, or in some cases, if this vital work will continue. Approaches utilizing the mRNA vaccine platform may be particularly under threat despite its successful application in Moderna’s and Pfizer/BioNTech’s COVID-19 vaccines.

Last week the U.S. Department of Health and Human Services canceled hundreds of millions of dollars of contracts with Moderna to develop mRNA-based flu vaccines, including those against the H5N1 bird flu virus that were being developed for a potential pandemic. In some states, lawmakers are introducing legislation to ban mRNA-based vaccines altogether.

This response is puzzling to scientists who see vast potential for this Nobel-prize-winning technology. “The mRNA COVID vaccines probably saved millions of lives,” says Burton. “And it is increasingly understood that the mRNA platform has a lot of benefits even beyond infectious diseases and vaccines. I think it has a good future in combating cancer as well, so to downgrade or stop the whole technology would be a mistake for patients.”

Whether or not mRNA is the platform of choice for an eventual HIV vaccine, it is a valuable tool for evaluating different vaccine immunogens and moving forward quickly with proof-of-concept studies that will bring the field closer to an eventual HIV vaccine.

This effort will continue to have benefits far beyond the virus itself. “HIV vaccine development is one of the most difficult problems in biomedicine, and so what it has done is to press researchers to advance immunology at a level and pace that has been quite amazing. We’ve seen great advances because of the demands of this very difficult virus, and these advances have trickled down to many different areas of biomedicine,” says Burton. “The first example of that is the COVID vaccine — one of the major reasons that a COVID vaccine could be produced so quickly was because of the advances made in HIV vaccine research over the last decade,” he notes. This work also led to the development of vaccines for respiratory syncytial virus.

These advances don’t come cheaply or quickly, which is why long-term funding for consortia such as the CHAVD is critical. Without it, and many other U.S. government-backed research grants and programs, researchers worry that the field will become much more fragmented and lose momentum at a time when rational vaccine design efforts are beginning to bear fruit.

“We’re committed to finding ways to continue the work with the Scripps group and others around the world,” says Haynes, though he acknowledges how challenging it will be to fill the funding hole left as NIAID and NIH withdraw support for these efforts. “We will continue to collaborate to deliver a prototype sequential HIV vaccine and are looking at all possible ways to do that.”

Others, including Feinberg, remain equally committed. “This is essential work, especially now that so many HIV prevention and treatment programs are tragically suffering under U.S. government funding cuts,” he says. “IAVI is deeply committed to continuing its HIV vaccine development program, which holds so much promise, despite today’s challenging environment. We can’t give up on this effort.”