Covid-19 has forced the world to find ways to develop vaccines rapidly, compressing research that normally takes years into months. But for Africa’s almost four decades-long HIV pandemic, that hasn’t yet happened — and for good reasons.

The biggest challenge with HIV is that our bodies haven’t yet figured out how to produce antibodies that can completely kill the virus. In the case of SARS-CoV-2, the virus that causes Covid-19, millions of people have recovered from the virus, so researchers can use the antibodies we produce naturally to guide them as to the type of antibodies and killer cells the vaccines they develop should generate. 

But no one has ever naturally recovered from HIV.

“There is still no conclusive research on what type of immune response an HIV vaccine should be trying to trigger,” says Mitchell Warren, executive director of AVAC, a US-based HIV advocacy organisation.

“With HIV, you’re trying to do better than nature,” explains Warren. “With a Covid-19 vaccine, the jab merely has to do what nature is doing already — in the form of an immune response — just faster. But with HIV, you’re trying to do better than nature because your body isn’t able to successfully fight off the virus.”

HIV is a trickier virus than SARS-CoV-2 to develop a vaccine for. Research so far has shown us that when HIV replicates, or makes copies of itself, the new viruses contain genetic changes — or mutations — which, after many generations of copies, make them different from the virus they originated from. That is why we have two different strains of HIV — HIV-1 and HIV-2 — and it’s complicated to create a vaccine that works for both strains or even for variations, in the form of subtypes or clades, within each strain of the virus.

SARS-CoV-2, on the other hand, uses a method called proofreading when it replicates to reduce the number of errors that accumulate — and therefore the new viruses look more similar to the virus they originated from than in the case of HIV. Because there are few variations in SARS-CoV-2, it’s simpler to develop jabs that work.

Vaccine trials normally go through several stages, beginning with laboratory tests and animal studies, to ensure that they are safe and demonstrate some benefit. If positive results are obtained during this stage, by means of an immune response against the virus, the research can then progress to human trials, which happen in three phases. Each stage gets progressively bigger and fine-tunes details such as the correct dosage required. Phase three trials are the final stage of such studies before manufacturers seek regulatory approval in countries where they’d like to market their vaccine — if the jab turns out to be efficacious, of course.

A preventative vaccine — which is given to people who have not yet been infected — trains your immune system to protect itself from a particular virus. It does this by safely exposing your body to that virus, parts of the virus or a tame version of the virus in the hope of getting it to produce antibodies and killer cells which will then be able to fight off the infection.

One promising development that could help steer future HIV vaccine trials, is the results from the Antibody Mediated Prevention Trials (AMP), which are likely to be released early next year. These trials are almost the inverse of a vaccine — instead of trying to get the body to develop an immune response, people are given antibodies directly. The findings from this study could help clarify what type of immune response is needed to prevent HIV infection and in turn guide the type of jab needed.

But until then, we’ve broken down the three most promising HIV vaccine trials in the running.

1. HPX2008/HVTN 705: Imbokodo

What type of vaccine is it?

The Imbokodo trial is testing two different HIV jabs.

The first type of vaccine is known as a viral vector, or a “trojan horse”. A “trojan horse” uses a tame or inactivated virus as a carrier to help prime your immune system to respond to another virus (in this case HIV).

This shot uses a human adenovirus —  a strain of the common cold virus known as Ad26. This is the same virus that the pharmaceutical company Johnson & Johnson is currently using in its  Covid-19 vaccine trial. In the case of HIV, the Ad26 virus has been genetically altered so that it sneaks genes that make non-harmful parts of HIV into your body, but without infecting you. Because your body recognises the proteins or structure of HIV, it then starts to produce antibodies and killer T cells to fight it. This way if HIV tries to infect you, your body will already be familiar with its structure and will be able to quickly mount a defence to destroy the virus.

What makes this vaccine unique is that it uses an approach called a ‘mosaic’. Instead of just inserting the genes from one type of HIV, genetic material from several HIV variations from around the world are inserted into the Ad26 adenovirus. This increases the chances that the vaccine could work globally as it encompasses multiple variations of the virus.

The second jab that the Imbokodo trial is testing uses a lab-made protein — clade C gp140 — similar to a protein found on HIV. This works in more or less the same way as a viral vector whereby the vaccine exposes your body to the protein and elicits an immune response that can then be used to fight off the virus when it tries to infect you. In the case of this jab, the protein has been mixed with a booster substance called an adjuvant, which boosts the body’s immune response to the vaccine. This shot uses aluminium phosphate as its adjuvant, which is the same substance that is used in hepatitis A and B vaccines.

What’s being tested?

This is a proof of concept study, meaning it is designed to test if a particular idea works and is worth pursuing in further studies. In this case, the Imbokodo trial is testing whether the two vaccines in the study will work to prevent young women (between the ages of 18 and 35) in sub-Saharan Africa from getting infected with HIV.

How far along is the trial and where is it taking place?

This phase 2b study began enrolling participants in November 2017. By May 2019, they had completed enrollment with 2 637 participants across 26 research sites. The trial is taking place in Malawi, Mozambique, South Africa, Zambia and Zimbabwe. The study is expected to end in July 2022. But this date only tells us when the final data will be collected — after this date, the information will still need to be analysed before the study’s results can be published. If the vaccine is found to be harmful or not working, the trial could be stopped early.

2. HPX3002/HVTN 706: Mosaico

What type of vaccine is it?

The Mosaico study is testing the same two jabs as the Imbokodo trial. The first vaccine is a viral vector that uses the same human adenovirus — Ad26 — as the Imbokodo study. This shot uses the same mosaic vaccine design as the Imbokodo study where the same genes of different HIV subtypes are inserted into Ad26.

The second jab, like Imbokodo, is a protein vaccine. It uses a clade C gp140 protein — clade C is the subtype or variation of HIV most commonly found in southern Africa — as well as a Mosaic gp140 protein, which is designed to resemble a mix of proteins found on different subtypes of HIV around the world. This protein mix is then combined with an adjuvant or booster, aluminium phosphate, to enable the vaccine to trigger longer-lasting and stronger immunity in our bodies.

What’s being tested?

This is a large efficacy study, which means it’s trying to determine if the vaccine can produce the expected results within a controlled setting and limited variables. A controlled setting is different from our everyday living environments because researchers limit the number of variables, such as restricting who can participate in the trial, making sure people aren’t receiving several different treatments and ensuring that health workers administering the vaccine have the same skill set. The trial is looking to see whether this new vaccine approach can prevent HIV infection in cisgender men and transgender people who have sex with cisgender men and/or transgender people.

How far along is the trial and where is it taking place?

Mosaico is currently the only HIV vaccine trial to have reached phase 3, so it’s the study that’s the furthest along in this field. The first participant was enrolled in November 2019 and recruitment will continue into 2021 until there are 3 800 participants. The trial is being conducted in 39 sites in Argentina, Brazil, Mexico, Peru, Italy, Poland, Spain and the United States. The study is expected to end in March 2024 — after that date, the data will still need to be analysed before the trial’s results can be published.

3. PrEPVacc

What type of vaccine is it? 

The trial is testing two vaccine combinations — both jabs consist of a DNA-based vaccine along with a protein-based shot.

DNA vaccines work by using copies of a virus’ genes that are inserted into pieces of DNA called plasmids, which are usually from bacteria. Once in your body, these genes will produce non-harmful proteins which are similar to those on HIV. As with other jabs, these proteins will trigger an immune response that can later be used to help your body fight off HIV if you get infected. Since the genes are just lookalike synthetic copies of the virus’s genes, that don’t include any actual parts of the virus, there is no risk of someone getting infected from the vaccine itself.

The DNA jab, which is used in both jab combinations being tested in this trial, is called DNA-HIV-PT123. This DNA vaccine uses copies of the genes of HIV clade C  — the subtype of HIV most present in southern Africa and India. The DNA shot is then being tested in combination with other vaccines: one DNA jab combined with a certain type of protein vaccine, and then the same DNA shot with another type of protein shot followed by a viral vector jab and another jab of the same protein shot.

The first vaccine combination immunises participants with the DNA jab alongside a protein shot called AIDSVAX®B/E. The AIDSVAX shot contains proteins from both HIV subtypes B and E, which are most commonly found in North America and Europe and Southeast Asia. AIDSVAX, alongside a viral vector vaccine, was also used in another well known HIV vaccine trial in Thailand, called the RV144 study. This trial was the first to show that a vaccine could offer at least some protection against HIV in 2009.

The second vaccine combination is slightly more complex, as it involves three different shots given together at different intervals of the trial. First, participants are injected with the DNA vaccine in conjunction with a protein shot that closely mimics the structure of the HIV envelope (a protein membrane which surrounds the virus and has sugars attached to the outside). This protein jab is called CN54gp140+MPLA-L and is modelled on those found on the C subtype of HIV. People receive these two shots at the start of the trial and then again after four weeks.

After six months, trial volunteers get another jab called Modified Vaccinia Ankara-Chiang Mai Double Recombinant (MVA-CMDR) — along with the same protein jab that they got in the first month. Forty-eight weeks after receiving their first jab, participants then, once again, receive these two shots — MVA-CMDR and CN54gp140+MPLA-L.

Modified Vaccinia Ankara-Chiang Mai Double Recombinant (MVA-CMDR) is another form of a viral vector vaccine which uses a weakened and non-replicating poxvirus. The poxvirus is genetically altered to contain genes from the A and E subtypes of HIV. Subtype A of HIV is most commonly found in East Africa and Russia. The idea is that this will expose your body to multiple different structures and variations of HIV and in turn teach it to recognise the different proteins. Your immune system will then develop a response in the form of antibodies and killer T cells which can fight off the infection if you are exposed to the real virus.

What’s being tested?

This trial aims to assess both its vaccine candidates and pre-exposure prophylaxis (PrEP) simultaneously. PrEP is a type of HIV prevention — in this case, in the form of a daily pill containing antiretrovirals — that can prevent those at high risk from contracting HIV. This trial is testing a newer form of the HIV prevention pill, called Descovy.

The study is looking at HIV prevention in men and women between the ages of 18 and 40. It will include people from key populations who are at an increased risk of infection, such as female bar workers, people living and working around main highways, commercial sex workers, fisherfolk and men who have sex with men.

How far along is the trial?

The Phase 2b trial began in January of this year and is expected to end in March 2023. The study will include 1 688 participants, the first of which was enrolled in January 2018. It is being conducted across five sites in Uganda, Tanzania, Mozambique and South Africa. DM/MC

Want to know more about some other HIV vaccines in the pipeline? Check out this overview from AVAC. 

 This story was produced by the Bhekisisa Centre for Health Journalism, http://bhekisisa.org. Subscribe to the newsletter http://bit.ly/BhekisisaSubscribe.