Hope for an HIV vaccine is renewed after decades of scientific failures

The world needs an HIV vaccine to defeat the virus that still infects more than 1 million people each year and contributes to hundreds of thousands of deaths.

Despite 20 years of failures in major HIV vaccine clinical trials—four of them in this decade alone—researchers say recent scientific advances will hopefully put them on track to develop a highly effective vaccine against the virus. .

But it probably won’t be until the 2030s.

“An effective vaccine is really the only way to provide long-term immunity against HIV, and that’s what we need,” Dr. Julie McElrath, director of the division, said Monday at the Conference on Retroviruses and Opportunistic Infections in Denver. of vaccines and infectious diseases at the Fred Hutchinson Cancer Center in Seattle.

(A California man is cured of leukemia and (almost) HIV after a revolutionary treatment)

All current HIV vaccine initiatives are carried out in laboratories, in animal studies, or in very early human trials.

At the retrovirus conference, researchers presented favorable results from two HIV vaccine studies.

One of them found that a modification of the simian version of HIV stimulated the production of what are known as broadly neutralizing antibodies against the virus in monkeys. Another study showed promise in the effort to induce immune system B cells to produce potent antibodies in humans.

HIV infects more than 1 million people each year.Photo Illustration by NBC/Getty Images

“These trials illustrate, as proof of concept, that we can train the immune system. However, we have to optimize it even further and test it in clinical trials,” Karlijn van der Straten, from the Academic Medical Center of the University of Amsterdam, who presented the study in humans, declared at a press conference on Monday.

The challenges of achieving a vaccine

However, scientists in this field face a great challenge. HIV is perhaps the most complex pathogen ever known.

“In this field we have learned from the past,” said William Schief, who leads drugmaker Moderna’s HIV vaccine efforts. “We have learned what strategies do not work.”

The cost has already been immense. Between 2000 and 2021, nearly $17 billion was spent worldwide on HIV vaccine research. According to the Joint United Nations Program on HIV/AIDS and the nonprofit group AVAC, nearly $1 billion more is spent each year.

“Maintaining funding for HIV vaccines right now is really important,” said Dr. Nina Russell, who directs HIV research at the Bill & Melinda Gates Foundation.

He also highlighted the “progress and enthusiasm” in this field and how “science and scientists in search of a vaccine against HIV continue to drive innovation and science for the benefit of other infectious diseases and global health in general.”

An example has been COVID-19. Thanks to HIV research, mRNA vaccine technology was already available in 2020 to accelerate the commercialization of a coronavirus vaccine.

The reasons behind decades of failure

In stark contrast to the coronavirus, the HIV vaccine effort has spanned four decades. Only one of nine vaccine trials against the virus has proven effective: a trial conducted in Thailand and published in 2009, which reported a modest 31% reduction in the risk of contracting HIV.

HIV vaccine researchers subsequently spent years trying to refine and improve that vaccination strategy, leading to a series of trials that began in the late 2010s but failed.

Researchers have concluded that these latest trials were doomed to failure because, apart from eliciting an immune cell-based response against HIV, they only led the immune system to produce what are known as non-neutralizing antibodies. Those weapons were not powerful enough for such a fearsome enemy.

Preventing HIV through vaccination remains a daunting challenge because the immune system does not naturally mount an effective defense against the virus, as it does with many other vaccine-preventable infections, including COVID-19.

An HIV vaccine must elicit a supercharged immune response from the body that has no natural equivalent.

That path to victory rests on a crucial caveat: A small proportion of people with HIV produce what are known as broadly neutralizing antibodies against the virus. These antibodies attack HIV in multiple ways and can neutralize a number of variants of the virus.

These antibodies are not of much use to people who develop them naturally, because they do not usually appear until several years after infection. HIV establishes a permanent reserve in the body about a week after infection, which your immune response cannot eliminate. Therefore, HIV-positive people with this type of antibodies continue to need antiretroviral treatment to stay healthy.

Researchers believe that broadly neutralizing antibodies could prevent HIV from spreading infection, as long as the defense is primed before exposure. A pair of important trials to test efficacy, published in 2021, showed that infusions of cloned versions of one of these antibodies protected people exposed to certain strains of HIV sensitive to that antibody.

However, globally, these particular strains of the virus make up only a small subset of all circulating HIV. This means that researchers can’t just make a vaccine produce that antibody and expect it to be effective. The important thing is that this study has given them an idea of ​​the level of antibodies necessary to prevent infection.

(They call it the ‘cancer-killing pill’ and it is “an immense desire” for those who face cancer)

It’s a lofty benchmark, but at least researchers now have a clearer idea of ​​the challenge ahead.

Another factor frustrating the search for an HIV vaccine is that the virus mutates dramatically. Any spot on the virus’s surface targeted by antibodies could be prone to change by mutation, allowing the virus to evade attack. Consequently, researchers are looking for targets on the surface of the virus that are not highly subject to mutations.

Experts also believe that to defend against the threat of mutations it will be necessary to attack several points of the virus. Therefore, researchers are trying to develop a portfolio of immune system stimuli that encourage the production of a series of broadly neutralizing antibodies.

Provoking the development of these antibodies requires a complex, step-by-step process to coax infection-fighting B lymphocytes, get them to multiply, and guide their maturation into powerful factories producing broadly neutralizing antibodies.

Several clinical trials underway

Dr. Carl Dieffenbach, chief of the AIDS division at the National Institute of Allergy and Infectious Diseases, said that numerous recent advances — such as mRNA, better animal models of HIV infection and high-tech imaging — have improved the accuracy of researchers in designing and accelerating the production of new proteins to stimulate immune responses against HIV.

Global collaboration between major players is also flourishing, according to researchers. Several human clinical trials of HIV vaccine components are underway.

Since 2022, three early human trials of these mRNA-based components have been launched. Among them, they have been led or funded by the global nonprofit vaccine research group IAVI, Fred Hutch, Moderna, Scripps Research, the Gates Foundation, the National Institutes of Health, the US Agency for International Development and university teams. . More trials of this type are being prepared.

On Friday, Science magazine reported recent findings that among the three mRNA trials, a substantial proportion of participants—between 7% and 18%, IAVI reported in a statement—experienced skin-related symptoms after the treatments. injections, such as hives, itching and hives.

The IAVI said in its statement that it and its partners are investigating the results of skin-related HIV trials, most of which were “mild or moderate and treated with simple anti-allergy medications.”

Researchers have demonstrated success in one such mRNA assay in carrying out a specific step in the B cell culture process.

That component of the vaccine also generated “helper” CD4 cells primed to fight HIV. Immune cells are expected to act as a conductor of the immune system, coordinating a response by sending instructions to B cells and augmenting other facets of an attack against HIV.

A complementary strategy being investigated aims to encourage the development of “killer” CD8 cells that may be poised to eliminate any immune cells that antibodies have failed to save from infection.

More importantly, researchers believe they are now much better able to distinguish between the best candidate vaccine components and those that are not. They plan to spend the next few years developing these components so that, when they put together the most promising ones in a multiple vaccine, they can be much more sure of the final success in a trial.

“An HIV vaccine could wipe out the virus,” McElrath said at the Denver conference. “So I say, ‘Let’s get to work.’”

Feinberg suggested that the first trial to test the vaccine’s effectiveness might not launch until 2030 or later. Still, he remained optimistic.

“The field of HIV vaccine development is in a better place than ever,” he said.