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[Mexico City] Despite huge advancements in the treatment and prevention of HIV/AIDS in recent decades, an effective vaccine remains elusive – and is desperately needed to end the global pandemic that kills more than 700,000 people each year.

AIDS is caused by the human immunodeficiency virus (HIV), and is one of the three big diseases affecting people in developing countries, along with tuberculosis and malaria.

According to the WHO, 37.9 million people globally are living with the disease, of which 23.3 million have access to antiretroviral therapies (ART), the best treatment currently available.

This represents an increase of 2.3 million people receiving ART since 2016, according to the UNAIDS 2018 global update. But it warns that “the scale-up of access to treatment should not be taken for granted”.

“The only way to control or eliminate a disease is with a vaccine. A vaccine will be cheaper than any other intervention and we need one because we are still no closer to controlling HIV,”

Glenda Gray, president of the South African Medical Research Council

The problem is, new infections emerge all the time: at least 1.7 million more every year, of which 160,000 are children under 15.

Glenda Gray, president of the South African Medical Research Council (SAMRC), tells SciDev.Net: “The only way to control or eliminate a disease is with a vaccine. A vaccine will be cheaper than any other intervention and we need one because we are still no closer to controlling HIV. We are missing all the milestones at a global level and at a local level.”

Larry Corey, principal investigator at the HIV Vaccine Trials Network (HVTN), highlights the magnitude of the global epidemic. “HIV is still the pandemic of our time; 5,000 people are infected every day,” he says.

Researchers such as Corey have worked on developing a vaccine against HIV since the 1980s, and although significant advancements have been made, there is still no workable protection able to be scaled up around the world.

Why is it so hard to find a vaccine that works?

Most effective vaccines use antibodies to neutralise viral infections. But scientists have seen that this doesn’t work for HIV, since the virus reproduces and mutates too fast for antibodies to be effective. Also, research has shown that there are different subtypes of HIV spread around the world: while subtype B is common in North America and Europe, subtype C prevails in southern and eastern Africa.

The virus has also evolved so that it is able to “hide” inside cells that are apparently free of infection, suppressing immune responses at an early stage of the disease. Also, Gray adds, its genetic diversity is greater than any other pathogen known to date.

“HIV has been a very difficult virus,” says Corey, a virology expert. “It masks itself in ways we have never seen a virus do so well. It is very clever, and it uses different mechanisms to evade the immune system and persist. It’s more effective than any other virus.”

Although animal models have been widely used to research vaccine efficacy, these are usually expensive and don’t guarantee that drugs will work in humans. Due to its genetic diversity, the HIV virus is able to provoke persistent infections that our immune system is not able to fight, so a vaccine has to do much better than our bodies.

Research has focused on understanding what types of immune responses have to be produced in order to win the battle against the disease.

The idea is to work with antibodies that are capable of identifying and attacking the virus before it widely infects the body. In other words, what are the weakest aspects of the virus that a vaccine can work on to be effective.

There are no human models showing a cure for HIV, which constitutes a further barrier. “One of the reasons why we haven’t got a vaccine is that no humans have ever cured themselves of HIV,” Corey explains. “Zero out of 72 million. For every infectious disease there are at least a few people who cure themselves, but that’s not the case in HIV.”

Where are we now? Trials and their promises

Large clinical trials testing vaccine efficacy against HIV started producing results back in 2003, and although a vaccine is not ready yet, significant progress has been made.

Out of more than 100 vaccines that have been tested in humans, the biggest achievement so far has been the RV144 trial, also known as the “Thai study”. The research showed the first promising results of an experimental vaccine, but the success was partial: participants were 60 per cent less likely to become infected in the few months after being vaccinated, but this  dropped to 50 per cent after three-and-a-half years.

Linda-Gail Bekker, former president of the International AIDS Society, tells SciDev.Net: “Importantly, we know [vaccination] can be achieved… the Thai vaccine taught us that. We have also now found ways to secure and create antibodies which very effectively bind and neutralise the virus.”

A modified version of the Thai vaccine is being tested in a large-scale phase 3 study in southern Africa. It is hoped it will reduce the risk of infection by at least 50 per cent and extend its protection period. The results will be public by 2021.

Another recent promising advancement was announced in July during the 10th International AIDS Conference in Mexico City: the “Mosaico” vaccine, so-called because it is composed of different strains of the virus. This vaccine has proven to be effective in tests involving women in Africa and will be further assessed in men who have sex with men (MSM) and transgender populations in the US, Argentina, Brazil, Italy, Mexico, Peru, Poland and Spain.

“Mosaico is the best vaccine we’ve seen in protecting animals. Now we actually have to see if it works in humans,” says Corey.

Bekker, who is deputy director at the Desmond Tutu HIV Centre, thinks this vaccine should have a global impact if it works. While Mosaico’s researchers are cautiously optimistic about this new “global” vaccine, others have said expectations should be tempered as the virus has proven to be highly dynamic and able to rapidly change, evading all immune responses.

An alternative path in case Mosaico doesn’t work, Corey believes, is to use identical monoclonal antibodies, to see whether this works better than the Mosaico approach. “We’re going to look at the data and see if it’s one or the other, or if it might be a bit of both. So, we do have an alternative approach,” he adds.

A recent editorial in Nature concludes: “Ultimately, only efficacy studies will determine whether any of these promising concepts are capable of reducing infection rates or the levels of pre-existing infection. But the pipeline of early phase clinical studies and accelerated pace of translation to the clinic are very encouraging developments for the field.”

HIV future

Finding at least a partially effective vaccine remains of critical importance for the HIV response.

According to global sexual health charity Avert, the biggest reduction in new infections would be achieved by a combination of oral pre-exposure prophylaxis (PrEP), universal antiretroviral treatment for people already living with HIV, and a vaccine. “An HIV vaccine is a more realistic prospect today than a decade ago and an optimistic forecast of HIV vaccine availability is that one might be available by 2030,” the organisation says on its website.

Although HIV research has historically received more financing than any other infectious disease, different experts have warned that continuous investment has come under threat. “Almost all vaccine innovations are in the public sector; pharmaceutical and biotechnology companies sit on the sidelines,” says Gray.

“It is a very high-risk business and therefore businesses have shied away from it,” adds Corey. An exception has been the Mosaico study, a public-private partnership sponsored mainly by Janssen Vaccines & Prevention, with funding from the US National Institutes of Health’s National Institute of Allergy and Infectious Diseases (NIAID) and supported by the HVTN, headquartered at the Fred Hutchinson Cancer Research Center in Seattle, which facilitates its implementation. According to Corey’s estimations, vaccine research investment in the US, the largest investor, receives $700 million annually from the government and $250 million from the Bill & Melinda Gates Foundation. “It has been really the US government and the philanthropy that have put the heavy-lifting in getting us to the point where at least there is some sense of optimism that we can develop an HIV vaccine,” he says.

UNAIDS says a scaling-up of HIV vaccine research is urgently needed. “For the past decade, investments have remained steady, at around US$900 million per year, which is less than 5 per cent of the total resources needed for the AIDS response,” it said in a statement in 2018.

“By scaling up investments in HIV vaccine research, diversifying funding and attracting the best scientists from around the world, a vaccine for HIV could become a reality.”

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