“Every vaccine I’ve done, I’ve failed. It’s like asking me how long is a piece of string. It’s like asking me, have we found the holy grail,” says Prof Glenda Gray, president of the South African Medical Research Council. 

“Every vaccine that we’ve designed has not induced neutralising antibodies, which is probably what you need to be effective against HIV.”

Adding to this, Prof Linda-Gail Bekker, deputy director of the Desmond Tutu HIV Centre, says there has not been the same unprecedented number of interested parties coming to the development table to lend their best creative ideas for HIV in the same way they have for Covid-19.

What it takes to make an HIV vaccine

To make a vaccine for HIV, Gray explains, we first have to know what kind of immune response is needed, but since few people have ever been cured of HIV, making a vaccine is challenging because it is unclear what exactly the vaccine needs to do. In other words, what kind of immune response it needs to trigger in the body.

Understanding immunity is a tricky business, and while scientists appear to have been successful in creating a vaccine for Covid-19, the SARS-CoV-2 virus is much easier to crack than HIV, says Gray.

A vaccine works by providing our bodies with what is called an immunogen, or a substance that signals to our bodies to produce a specific immune response that targets the virus. Immunogens are developed based on antigens, which are the parts of the virus that our bodies are mounting an immune response to.

Gray explains that for SARS-CoV-2, the antigen is the spike protein on the envelope of the virus, and since scientists have identified this, they can develop vaccines that would confer a certain type of immune response to target these spike proteins. 

For SARS-CoV-2, these spike proteins are the virus’ most vulnerable parts. For HIV, however, the virus’ vulnerabilities are harder to find and are constantly changing, says Gray.

Bekker says the HI virus can escape from the body’s innate immune response, meaning that as the body creates antibodies, the virus has already mutated, rendering the previously made antibodies useless yet effective at clearing a potential vaccine candidate. 

How the viruses differ

The spike proteins for SARS-CoV-2 are on the envelope of the virus. Think of a ball as the envelope, and tiny sticks as the spikes. Overall, SARS-CoV-2 has little defence.

For HIV, the viral envelope is armoured with what Gray calls glycan shields, or small parts of sugar molecules, that make the virus extremely hard to penetrate. 

Think of an armadillo, she adds, with tough protective scales. 

“HIV replicates constantly, and the conserved areas of the [viral] envelope are very hard to get to and are usually covered [by glycan shields], so to try to find a part of the envelope that’s constant, despite replication, and is easy to get to, is a huge challenge,” says Gray.

“The HI virus has developed over time a number of ways to remain in stealth mode and evade the human immune system,” adds Bekker. 

Commenting on the glycan shields which cover the antigenic parts of the viral membrane, she says the parts of the viral membrane, which would normally boost a human host’s immunity, are being camouflaged.

“There’s tremendous effort, money, science and power that has gone into unravelling the structure of HIV; trying to understand the envelope and the glycan shield and trying to find those vulnerable parts of the HIV – it’s a huge endeavour,” says Gray.

Preventing HIV infection through a vaccine

“In order for a vaccine to prevent infection, it needs to block the very earliest infection taking hold, so this requires immediate and very effective blocking of viral replication at the entry point of infection,” explains Bekker.

To prevent or get rid of disease, a vaccine needs to enhance the immune system to help the antiretrovirals (ARVs) also reduce the replication of the virus. 

“If viral load is overcome or more strongly overcome, then presumably the disease will also be reduced.”

No comparison

Though the world’s progress towards developing a vaccine for Covid-19 may inspire, it cannot be directly compared to HIV.

“For 30 years, using the same platforms [or types of vaccines], we’ve never been able to induce a neutralising antibody response the same way that you can get it with SARS-CoV-2 using the spike protein. 

“There’s no comparison,” says Gray.

“We know that first of all [SARS-CoV-2] doesn’t mutate at the same rate, and even if it mutates, the spike protein does not change every few seconds,” she says. 

“It’s like comparing a cat to a jaguar. It’s a completely different beast, even though it is a virus.”

mRNA vaccines for HIV?

Two of the first three Covid-19 vaccines showing signs of efficacy (the Moderna and Pfizer/BioNTech vaccines) make use of a newer vaccine technology using messenger RNA (these vaccines are called mRNA vaccines). This begs the question whether mRNA vaccines might be used against HIV.

“It’s an interesting question,” says Gray.

“They use the spike protein in the mRNA [vaccine] and it goes back to the issue if you can find an immunogen that is conserved across the viral replication and is easy to get to. 

“Whatever platform you use, for HIV… it’s not really the platform, it’s the immunogen that counts. The platform is what gets the immunogen into the body and helps you mount an immune response. 

“Unless you have the right immunogen, you’re not going to get the right response,” she says.

Broadly neutralising antibodies 

Gray says scientists are looking at how neutralising antibodies evolve in humans who induce broader neutralising antibodies. 

“We’ve taken the envelope of the virus at that stage, when the antibody changes, and have identified those immunogens along the pathway to broader neutralising antibodies. 

“The idea is to take those immunogens and coax the immune system to induce those broader neutralising antibodies which we think will protect people.”

She says the trick with HIV is to find the right immunogen that will train the immune system to make broader neutralising antibodies, which will then inactivate the virus on exposure.

Exciting vaccine trials under way

Gray and Bekker say that currently there are four particularly notable HIV vaccine trials under way.

The Imbokodo study, under way in South Africa and other parts of the sub-region, is a preventative vaccine that contains immunogens from around the world – in other words, it contains immunogens from different strains of HIV from around the world. 

This study, which began in November 2017, only includes women and is in the follow-up phase. 

Imbokodo’s cousin trial, MOSAICO, is an experimental vaccine regimen that will seek to prevent HIV infection in cisgender men and/or transgender persons. This study is under way in the Americas.

The third and fourth studies that Gray and Bekker highlight are both part of a larger study called AMP, or Antibody Mediated Prevention – giving people antibodies to see if it confers protection. Bekker says two AMP studies are complete, and hopefully, results will be out before the end of the year.

“There is quite a rich pipeline of ideas for HIV vaccine trials in Phase 1 and early Phase 2. So, we still have hope,” says Bekker.

As access to prevention therapies grows, like pre-exposure prophylaxis (PrEP), Bekker says designing vaccine trials becomes more complicated. 

“In other words, as populations have access to PrEP, they may happily have lower HIV incidence, which makes the studies bigger and harder to conduct. 

“This is a good problem to have, but it means we need to be creative in our designs so that the studies are not impossible to do, and we can still move the scientific research and development forward. 

“It’s an exciting time for prevention,” she emphasises.

HIV research has paved the way for other vaccines

While the search for Gray’s “holy grail” is ongoing, research for an HIV vaccine has helped in the development of vaccines for other diseases, including Covid-19.

“Covid-19, Ebola and Zika [virus] have benefited enormously from all the work that has gone into developing platforms for HIV vaccines, so if we had not invested all this money into HIV, we would not have solutions for Ebola, Zika and SARS-CoV-2. 

“It’s because of those platforms that we’ve been able to nimbly move to the next pathogen,” says Gray.

With Covid-19 taking centre stage for the past year, global resources from both the public and private sectors have been pooled in the effort to create a vaccine. Bekker says we could see significant progress should the same amount of energy and resources be redirected towards HIV.

“We haven’t seen the private industry engagement in HIV and TB that we have with Covid-19… presumably based on investment and return considerations. 

“If we did, I think the speed and progress would be logarithmically increased,” she says.

“[For the] first time now, the HIV field is finding new targets – neutralising antibody targets – which opens up new possibilities for HIV vaccine development, or even passive transfer of broadly neutralising antibodies (as was done for Covid-19, and in the AMP studies) which also offers new opportunities. 

“The question remains whether we will be able to attract the scientific and financial resources to carry this through.” DM/MC

This article was produced by Spotlight – health journalism in the public interest. Sign up for our newsletter.