by Kathryn Cleary

While progress in the race for effective COVID-19 vaccines has been rapid and impressive – with three vaccines so far appearing to be effective based on preliminary data, an effective HIV vaccine remains elusive. This is at least partly because the HI-virus is a much tougher nut to crack.

“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 Professor Glenda Gray, President of the South African Medical Research Council. “Every vaccine that we’ve designed has not induced neutralizing antibodies, which is probably what you need to be effective against HIV.”

Adding to this, Professor Linda-Gail Bekker, Deputy Director of the Desmond Tutu HIV Centre, says that there has not been the same unprecedented scientific interested parties coming to the development table to lend the greatest, and best creative ideas for HIV the same way as what has occurred [for] COVID-19.

What it takes to make an HIV vaccine

To make a vaccine for HIV, Gray explains that 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 constantly changing, says Gray.

Bekker says that the HI virus can escape from the body’s innate immune response, meaning that as the body creates antibodies, already the virus has 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 small 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 and 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 that the parts of the viral membrane, which would normally rev a human host’s immunity up, are being camouflaged.

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

The COVID-19 vaccine cannot compare to an HIV vaccine

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 neutralizing antibodies

Gray says that scientists are looking at how neutralising antibodies evolve in humans who induce broader neutralising antibodies. “We’ve taken the envelope of 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 that the trick with HIV is to the find the right immunogen that will train the immune system to make broader neutralizing antibodies, which will then inactivate the virus on exposure.

Exciting vaccine trials underway 

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

The Imbokodo study, underway in South and Southern Africa, 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 started 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 underway 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, or giving people antibodies to see if it confers protection. Bekker says that currently 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 emphasizes.

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, we’ve been able to quickly, nimbly, move to the next pathogen,” says Gray.

With COVID-19 taking centre stage for the last year, global resources from both the public and private sectors have been pulled towards creating a vaccine.

Bekker says we could see significant progress should this same amount of energy and resources be redirected towards HIV.

“We haven’t seen the private industry engagement in HIV and TB (tuberculosis) that we have seen with COVID-19. Presumably based on investment and return considerations. If we did I think the speed and the progress would be logarithmically increased,” she says.

“[For the] first time now, the HIV field is finding new targets – neutralizing antibody targets – which have opened up new possibilities for HIV vaccine development or even passive transfer of broadly neutralizing 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.”

• This story was originally published in spotlight on November 30, 2020