On International HIV Vaccine Awareness Day (the 18^th May 2016) at the HIV Vaccine Trial Networks (HVTN) meeting, it was announced that for the first time in 7 years and the first time in Africa, a HIV phase 3 vaccine trial will be taking place. In addition to this the world’s first HIV antibody infusion trial started with its first South African participant in Soweto.

Slowly we seem to be completing a puzzle. Perhaps the most complicated one ever pieced together.

Science is a developing story. Every study, no matter how mundane, adds a puzzle piece to the picture. Sometimes it’s an edge piece, that forms the basis for studies to come and sometimes it’s a middle piece that doesn’t really help anyone at the time but will be imperative to complete the picture. In some cases though, in order to progress, scientists stop fitting in pieces to the main puzzle and start their own. This is a risk because the evidence is leading the field in a particular direction and this direction is fairly certain because multiple people have determined the same thing. Sometimes though, the risk of deviating is worth it. Risk shakes up the field; breaks down dogma and enforces flexibility. And that is what this trial could mean for HIV vaccinology.

I am beyond excited that we are having our first trial in seven years and I’m even more excited that it is happening in South Africa. Capacity building has happened over the last couple of years, allowing for South African clinicians and scientists to run these trials. This means much more opportunity for young scientists, collaborations, funding and all round focus. We are finally in the spotlight. The findings of trials always mean that interest in the field surges again. New ideas will be emerging from unexpected places.

The most recent vaccine trial regimen that showed any protection was the U.S. Military HIV Research Program-led RV144 clinical trial in Thailand completed in 2009. This regimen showed that protection was mediated by something we did not expect. All our data in the field up until that time suggested that antibodies (called broadly cross neutralizing antibodies) that could bind and coat lots of different HIV viruses (preventing entry into cells) would be our best shot at a vaccine. But protection (bear in mind it was only 31%) was achieved by antibodies that weren’t able to block infection of a cell. Instead they are able to bind to an already infected cell and call for backup. Other cells with the ability to secrete substances that pop the infected cell heed the call and come to destroy the infected. Think of the broadly cross-neutralizing antibody as Batman (pretty capable

of a fight on his own) and these other antibodies as Robin. The vaccine was tested in Thai people who have a very different epidemic to the part of the world that bears the greatest burden, Southern Africa. So the HVTN has run a series of small trials in South Africans using a vaccine that would be more appropriate for our situation. And now, we are paving the way to HVTN 702 (not to be confused with the talk radio station); the phase 3 trial guaranteed to rock the boat of science.

A phase 3 trial is a big deal. A wide range of criteria need to be fulfilled in order to proceed to one and the criteria that were set for HVTN 702 have all been met. However there is much talk in the field that we are progressing for progress’s sake. Many feel like we are creating a vaccine that has both arms tied behind its back and we are expecting it to win an arm wrestling contest. We are expecting robin to win Batman’s fight.  We are pushing a vaccine through that does not create the antibodies we know are going to protect people and are based on historically unimpressive antibodies. Should we be doing trials on things we know are not optimal or should we take the risk and acknowledge that there are clearly things we do not understand? Perhaps what now seems like an arbitrary puzzle piece will start off a new and exciting puzzle.

5400 South Africans will be enrolled from November 2016 and we will know the outcome by 2020. It’s a long time to spend on something that may not work again. What would going back to the drawing board mean for new infections? The bottom line is we have not yet managed to summon Batman to fight for our cause. We have lots of ideas on how to get him there but so far nothing has worked. Should we give up on Robin just because he is not what we expected?

Most vaccines have taken between 25-50 years to develop, so technically 30 years in, we aren’t doing too badly: we have drugs that are very effective at keeping AIDS patients well, which our government has now pledged to provide free of charge to everyone infected; we have drugs that can be used to prevent infection (pre-exposure prophylaxis) and we have lots of ideas bout what will protect people in a vaccine setting.

For me, the proof will be in the pudding. By 2020 we may have even brighter ideas about what we need and how to get there. And potentially the pessimistic view of the current phase 3 if irrelevant if it goes on to form new dogma. If all this phase 3 trial does is encourage bright and motivated young people to tackle arguably one of the most perplexing problems the world has, it will be a win. Either way, now is not a good time to be HIV.