The long and winding road toward an HIV vaccine

The many mutations of the virus and its ability to hide from the immune system have thwarted eradication efforts

Vacuna contra el VIH
A young South African man receives an HIV vaccination as part of a scientific study in 2016. Jackie Clausen (Getty)
Jessica Mouzo

It has been 40 years since the scientific community began waging an all-out war against the Human Immunodeficiency Virus (HIV). There are no winners for now. Despite the early optimism that in 1989 predicted an HIV vaccine “in five years,” the virus proved stubborn. Thirty years later, we still don’t have an HIV vaccine. The current status is a stalemate – the virus is still alive but under siege. Science has not managed to eradicate HIV but has developed potent antiretroviral drugs to keep it at bay. HIV’s immense capacity for mutation and its extraordinary ability to hide from the immune system has frustrated the search for a vaccine. Hundreds of prototypes have been studied, but only seven have reached efficacy trials with humans (Phase IIB or Phase III). None has produced conclusive results. The latest failed HIV vaccine is the international MOSAICO study. The Phase III trial was halted a few weeks ago when the developer found that the vaccine did not protect against infection. Some scientists say the virus is winning this cat-and-mouse game for now.

The statistics look like they could describe a war. HIV has claimed 40 million lives since it was first identified in the early 1980s. It still causes 650,000 deaths and 1.5 million new cases each year worldwide. Treatments are available, and the aggressive infection has been sequenced, but there is no cure. At least $19 billion was spent from 2000-2019 on HIV research (for vaccines and other strategies), according to estimates by the Resource Tracking for HIV Prevention Research and Development. But the virus is still alive.

HIV always has the upper hand because it knows how to neutralize the immune system when it enters the body. Then it lodges in CD4 lymphocytes (a type of immune cell), which have the function of alerting the immune system to the presence of foreign agents. “HIV is a virus of absolutely amazing intelligence because it can infect and establish itself in the noble sanctuaries of our organism. CD4 lymphocytes are memory cells that remain on alert for the rest of your life [so you don’t get an infection]. They don’t die until a person dies. If I have a virus in these cells, I will never get rid of it,” said Josep Mallolas, head of the HIV-AIDS Unit at Hospital Clínic de Barcelona.

The virus inserts its genetic material into the genome of the CD4 cells and manipulates it so that, instead of performing its immune function, the CD4 cells make more copies of the virus. Thus, as it replicates and spreads, HIV destroys the CD4 cells and undermines the immune system that protects humans. Sometimes infected cells, instead of copying the virus, settle into a state of latency, as if asleep. HIV can quietly hide in these viral reservoirs for years.

In four decades of research, science has only managed to “control” the infection, says Beatriz Mothe, a researcher at Spain’s Fight Against Infections Foundation. But there are challenges ahead, such as tackling late diagnosis – a third of the cases are detected late – preventing new infections and developing vaccines. “We need to develop a functional cure – treatments that not only control the virus [as antiretrovirals do now] but also cure it. And we need a preventive vaccine. This is the only way to eradicate this pandemic,” said Mothe.

It’s not that they haven’t tried. Since the mid-1980s, researchers from all over the world have been working on it. But so far, without success. “The big problem is the very nature of the virus: it replicates very quickly, and in the process, it spontaneously changes. We have not found a sufficiently stable area of the virus for the vaccine to target,” said Vicenç Falcó, head of infectious diseases at the Vall d’Hebron Hospital in Barcelona.

A virus with many variants

The primary approach is to teach the immune system to recognize and fight this foreign invader in one way or another. This can be achieved by using an inactivated virus in a vaccine, using proteins from its envelope, or combining various strategies to train the body’s defenses to react quickly when they encounter the virus. But nothing has worked.

The first attempts at developing a vaccine applied “classical models,” said José Alcamí, a researcher at the Carlos III Health Institute and member of the Spanish Society of Infectious Diseases’ AIDS Study Group (GESIDA). For example, inactivated viruses or HIV envelope proteins were used in hopes that the immune system would learn to activate and generate antibodies when it encountered HIV. But, in practice, the immune response was very weak or nonexistent. “That strategy didn’t work because patients have very diverse HIV envelopes. The virus has an enormous capacity to evolve and mutate, much more so than influenza or SARS-CoV-2. We have many subtypes of HIV circulating, and we are not going to have a protein that covers all this diversity,” said Mothe.

The scientific community then tried to develop vaccines that would induce a response from immune system cells. Unlike the first attempts to promote HIV antibody formation, this approach tried to encourage the production of T-lymphocytes, essential types of white blood cells of the immune system that play a central role in the adaptive immune response. One potential vaccine consisted of an attenuated (non-harmful) version of an adenovirus that served as a vehicle to carry three synthetically produced HIV genes. The body was expected to recognize it and generate a potent immune response when injected. But that didn’t work either. “This failed, and the outcome was that more vaccinated people were infected than in the placebo group,” said Dr. Alcamí.

Yet another approach tried to develop a vaccine by combining the two failed strategies and inducing simultaneous cellular and antibody responses. A clinical trial using this approach in Thailand achieved 30% efficacy but also presented some limitations. “It was tested in people with a low risk of getting HIV and with a virus subtype that is only found in that area,” said Mothe. “When we tested it in a higher-risk population, and with other virus subtypes, such as the one circulating in sub-Saharan Africa, there was no sign of efficacy.” The recently terminated MOSAICO study also sought to produce a double response.

Why have all these attempts failed? First, the virus is highly mutative, much more so than other microorganisms. The virus has already mutated by the time the immune system detects the virus and reacts by creating antibodies. When the body’s defenses begin to work against the virus it encountered, HIV mutates into variants that are resistant to those antibodies. Moreover, Alcamí says the antibodies target the protein in the virus envelope that enables it to enter cells, but accessing and neutralizing this molecule is difficult. “In SARS-CoV-2, the protein is like an open hand with five fingers, and the antibodies target those fingers,” said Alcami. “In HIV, the protein is like a closed fist that only opens when interacting with the cell receptor it’s trying to penetrate. The antibodies, even if we have them, do not reach those fingers because they’re hidden in that closed fist.”

The body doesn’t know how to attack the virus effectively, says Ana Cespedes, global COO officer of the International AIDS Vaccine Initiative (IAVI), a global nonprofit research organization. “There are 60 dominant HIV strains that recombine with each other – you’re not dealing with one virus, but many different ones,” she said. In addition, Cespedes says HIV attacks the cells responsible for the immune response (the CD4 cells) and can rapidly penetrate and hide in the body. “Within four hours of sexual infection, the virus is already hidden. The body doesn’t know how to attack the virus. We have to be better than our body,” said Céspedes.

After the MOSAICO setback, the scientific community must return to the first steps in the race for the vaccine. There are no prototypes in advanced clinical trials (Phase III), although some are in earlier stages. In December 2022, Science published the positive results of a Phase I trial that used a different approach based on highly neutralizing antibodies, a rare class of antibodies capable of simultaneously neutralizing several virus strains.

It’s not the first time scientists have tried using highly neutralizing antibodies in a vaccine. Previous attempts failed because the immune cells (B cells) that produce this elite antibody army are not usually activated when they encounter the virus envelope proteins. To address this obstacle, a protein was designed to prepare the B cells to react. The vaccine was tested on 48 clinical trial participants. The results published in Science are promising because the vaccinated participants showed the presence of precursor cells of these robust antibodies. The study authors caution that this is only “a proof of concept,” a crucial first step in a strategy that aims to develop highly neutralizing antibodies against HIV. There is still some way to go: this vaccine cannot yet induce highly neutralizing antibodies mature enough to protect against infection.

These elite antibodies may hold the key to a preventive vaccine. But it won’t be easy or quick, Cespedes warns. An effective vaccine will probably need several highly neutralizing antibodies mature enough and produced in sufficient quantities to provide reasonable protection. “This makes us optimistic that there is a way forward. There is light at the end of the tunnel, but we don’t know how long the tunnel will be.”

HIV’s Achilles’ heel

The war goes on. Another strategy is underway to access that “closed fist” – the virus’s envelope protein – so antibodies can penetrate and neutralize it. Dr. Alcami says this closed structure is also the “Achilles’ heel” of the virus because it can give antibodies an advantage. “Inside the closed structure of the virus are molecular holes that antibodies can penetrate.”

The Hospital Clínic de Barcelona and the Carlos III Hospital in Madrid are working on another vaccine that blocks the transmitted founder (TF) virus, a single viral variant that establishes productive infection within a host. “If I get infected by a person with thousands of viruses circulating in his blood, I will only get one virus – the TF virus,” said Mallolas. Researchers have found that TF viruses have common characteristics and have designed molecules for vaccines that address those characteristics. But there is still a long way to go until this vaccine is ready for a large-scale clinical trial.

Eduardo Fernández Cruz, head of immunology at Gregorio Marañón Hospital in Madrid, said a vaccine “must produce a potent neutralizing response, something that works very quickly to prevent the virus from deploying its escape mechanisms.” It’s not easy, but we mustn’t give up, says Ferran Pujol, director of BCN Checkpoint, a community center in Barcelona to detect HIV and other sexually transmitted infections that recruited participants for the MOSAICO trial. “I’m worried that funding will run out and companies will abandon the search for a vaccine we need,” he said. Céspedes agrees with the urgent need to continue HIV vaccine research. “We cannot be satisfied with chronic treatment – having HIV live on in a small corner of the body. Every five minutes, a child dies of AIDS somewhere in the world. This issue must remain on the agenda.”

No vaccine is expected in the short term. Dr. Alcamí and others even doubt whether a preventive vaccine will ever be developed. “We still don’t know whether an HIV vaccine will be possible. We are at that stage of uncertainty. We will develop drugs that achieve a functional cure before we have a preventive vaccine.”

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