US funding cuts imperil search for HIV vaccine

A group of leading African researchers trying to develop effective vaccines against HIV is trying to figure out how to salvage their ambitious research after losing funding due to the Trump administration’s cuts to foreign aid.

The group, called the Brilliant Consortium, led by the South African Medical Research Council (SAMRC), brings together researchers from across eight African countries. Many of them have already played a key role in advancing the world’s understanding of HIV science and their research has shaped how HIV is treated and prevented around the world. These researchers have also been deeply involved in the decades-long efforts to develop an effective HIV vaccine.

While antiretroviral treatment is highly effective and keeps people who are living with HIV healthy, it is not a cure and the treatment has to be taken for life. The development of an effective HIV vaccine or cure thus remains vital to ending the epidemic — particularly as HIV programmes around the world now face extreme financial strain in light of US aid cuts.

Vaccines that induce bNAbs

While three decades of research has so far failed to deliver an effective vaccine against HIV, these efforts have built a vast body of knowledge about how the HI virus evades the immune system. The key problem, it turns out, is HIV’s broad genetic diversity and how fast it mutates. In short, the virus shape-shifts too much and comes in too many variants for traditional vaccines to target it successfully.

As a result, a consensus has emerged among researchers that to be effective, an HIV vaccine must be able to induce broadly neutralising antibodies (bNAbs). The “broadly” refers to the ability of these types of antibodies to neutralise many strains of HIV. With the right bNAbs, it is hoped that HIV won’t be able to mutate its way out of trouble.

Broadly neutralising antibodies were first discovered in the days before antiretroviral therapy was widely accessible. At the time, scientists found that a small number of people living with HIV were able to remain healthy without taking antiretrovirals. Some of these people naturally developed bNAbs that prevented the progression of HIV in their bodies and allowed them to stay healthy without treatment. Scientists are now hoping to elicit this kind of bNAb immune response using vaccines.

An abrupt halt

With an ambitious set of studies in the pipeline, the Brilliant Consortium is at the cutting edge of developing and testing these new approaches to HIV vaccine development. But abrupt funding cuts mean the future of the project is now highly uncertain.

They were instructed to suspend all work after the Trump administration froze US foreign aid on January 20 and, along with other recipients of funding from the US Agency for International Development, received official notice that their grant was terminated on February 26.

The impact has been immediate and severe.

One vaccine candidate was scheduled to enter phase 1 clinical trials at the end of January 2025, while two more were on the path to enter clinical trials by early next year. All of these trials have now been placed on hold.

“I can’t think of any other illness where in the middle of groundbreaking research, we’ve just suddenly dropped what we’re doing and abandoned the effort altogether,” Dr Nivashnee Naicker, head of HIV vaccine research at the Centre for the Aids Programme of Research in South Africa (Caprisa), tells Spotlight.

The consortium is now trying to secure alternative sources of funding to salvage its most promising and advanced research efforts. It has put out a call for support from African governments, philanthropies and private sector groups.

The harm caused by the sudden funding cuts is “unquantifiable”, says Wits University Prof Penny Moore. She says the impact extends beyond HIV vaccine development efforts and affects the indirect benefits that spending on HIV research and infrastructure has in enabling the continent to effectively respond to other infectious disease threats.

‘A trial a year’

The Brilliant Consortium aims to advance multiple vaccine candidates from preclinical studies to clinical trials, while also identifying new vaccine candidates. (Clinical research involves research that is conducted in humans, after preclinical research has been undertaken in labs and animals. Candidate vaccines typically undergo years, and sometimes even decades, of preclinical research before they are tested in humans.)

The trial that was supposed to start in January would have been the consortium’s first clinical trial. Called Brilliant 001, it was to be followed by two additional trials — Brilliant 002 and Brilliant 003 — all testing HIV vaccine candidates.

“We said we would do at least one clinical trial a year [and] people were like, ‘You’ll never do that, that’s crazy’,” says Prof Linda-Gail Bekker, director of the Desmond Tutu HIV Centre and co-principal investigator for the Brilliant Consortium. “But after our first year, our scientific advisory group, who are opinion-leading HIV vaccinologists from around the world, were like, ‘Your progress is eye-popping!’.”

The pipeline of vaccine candidates under development by the consortium largely consists of different immunogens designed to trigger a bNAb response. But it is also developing immunogens to trigger T-cell responses, with the aim to combine immunogens that can elicit both bNAb and T-cell responses into a single vaccine product.

“As a sort of second line of defence, most people acknowledge that you probably also need a vaccine that is going to induce a T-cell response,” says University of Cape Town Prof Wendy Burgess. “So we had a component [of the consortium] designing a T-cell vaccine. We have learnt from 25 years of HIV research …that this is what we need to put together,” she adds, explaining that “T-cells do a lot of things in the immune response and T-cells also help the development of antibodies”.

Combining bNAb lineages

The novel idea with Brilliant 001 was to elicit a bNAb response by combining two different immunogens into a single vaccine, together with an adjuvant to enhance the immune response.

“We were proposing a strategy that no-one had looked at before and this was to put both products together at the same time to see whether we could induce two different lineages of bNAbs,” says consortium director Prof Glenda Gray.

The immunogens in Brilliant 001’s candidate vaccine were developed in Europe and the US and donated to the consortium.

When the stop-work orders came through, the consortium had spent a year preparing for the trial and was ready to start administering the first vaccine doses to participants.

“We were working non-stop” to prepare for the trial, says Naicker, who leads the Caprisa eThekwini clinical research site, one of four trial sites. “We received our ethics approval in December … [and] we had completed all of our site activation items,” she says.

The consortium is now racing against the clock to secure funding from alternative sources to allow Brilliant 001 to progress before vaccine stock expires.

Gray says: “If our last participant doesn’t get their first vaccination by about July then we won’t be able to complete that person’s vaccination, because the vaccine has an expiry date of the following year.”

In a bid to save Brilliant 001, Bekker says the trial is being redesigned to reduce costs. This means the trial will likely have fewer participants, take place in fewer countries and investigate fewer endpoints. “We have pared it down to its absolute minimum [to answer the question] ‘Do these immunogens make neutralising antibodies?’” she says.

Other vaccine candidates at stake

The Brilliant Consortium has several other vaccine candidates in its pipeline at different stages of development. It was hoped that two other candidate products would move into early-stage clinical trials by early next year, says Bekker.

She says the consortium is in discussions with US-based Duke University and biopharmaceutical company Gennova Bio, headquartered in India, to manufacture vaccines for the Brilliant 002 and Brilliant 003 trials.

In addition, preclinical research on vaccine candidates is currently under way with messenger ribonucleic acid (mRNA) vaccines produced by the Wits/SAMRC Antiviral Gene Therapy Research Unit (Agtru). Messenger RNA technology was critical to the development of Covid vaccines made by pharmaceutical companies Moderna and Pfizer/BioNTech.

Agtru director Prof Patrick Arbuthnot says the unit is developing mRNA vaccine candidates based on the genetic sequences of the HIV that infected people who later developed bNAbs.

“The thinking was that we could use the genetic sequences of the HIV that infected these individuals … as the vaccine immunogens to induce the same bNAbs that these patients have,” he explains.

By using an mRNA vaccine platform to make the vaccines, Arbuthnot says they “can tweak the vaccine composition very quickly … change it according to what the results show and what we think might improve the efficacy”.

Multiple vaccine candidates have already been identified from people who produced bNAbs following HIV infection.

Moore says: “Over the past 20 years, we’ve identified at least 10 individuals in South Africa who developed bNAbs and we have vaccine candidates based on several of those already that are in early stages in the lab. At least two of those candidates have already moved into preclinical studies, so we have a rich pipeline of ideas that have come through, all of which are halted for now.” 

Bekker says one of the candidates, which is already in preclinical studies and was scheduled to enter human trials by early next year, is known as CAP256. This immunogen is named after a study participant identified in a Caprisa research cohort was able to naturally develop bNAbs.

Research on the CAP256 immunogen has been under way for 20 years, Moore says. “We are finally at the stage where we had an mRNA version of the vaccine, and it had gone into rabbits and looks really, really promising.” But this research has now “hit … a roadblock” due to the termination of funding.

In addition to testing promising immunogens already in the pipeline, the consortium aimed to identify new potential immunogens by strengthening surveillance of breakthrough infections that occur during clinical trials.

Burgess says: “When someone gets infected on a clinical trial of an HIV vaccine, it’s called a breakthrough infection and then those viruses get sequenced. What we wanted to do was come up with updated viral sequences for the viruses that are circulating in our region now.”

Building capacity in African countries

African researchers have long contributed to basic science research and clinical trials for HIV vaccines, but critical gaps remain in the continent’s capacity to develop a new vaccine from concept to delivery. These gaps include analysing trial results and the ability to manufacture clinical-grade mRNA vaccines. Clinical-grade products are products that can be tested and used in people. The consortium was hoping to close these gaps.

“The whole point of this grant was to set up the capacity to do everything — from the preclinical development, to small-scale manufacture of vaccines, to the clinical lots, to safety and toxicity testing, through to discovery trials, and then measuring the outputs of those discovery trials,” says Moore. This is something “we have to do as a continent [not just] for HIV, but for every other pathogen that's coming our way”.

She adds: “I don’t think it is possible to quantify the damage if we don’t manage to get this pipeline refunded somehow. It certainly goes way beyond HIV.”

This article was first published by Spotlight — health journalism in the public interest. Sign up to the Spotlight newsletter.