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Exciting times for HIV vaccines, less exciting times for the virus

On International HIV Vaccine Awareness Day (the 18th 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

robin batman 1
http://www.quotesgram.com

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.

hero sidekick5400 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.

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Supervision: May the force be with you

Academia is first and foremost a teaching environment. Many people that pass through its fickle doors are earning higher degrees and those that mentor them must have a strong stomach. The supervisor-student relationship is a strange one. I, being a complete nerd, like to think of my supervisors as Yoda guiding the innocent clueless Padawan through the minefield of poorly devised experiments and failed controls. Of course, I am Luke Skywalker in this scenario.

jedi knights academics
From phdcomics.com – a must-read to retain your sanity!

I have been lucky to only experience only one bad mentor — an undergraduate advisor who made me so terrified of doing a PCR that I still suffer from post-tramatic stress disorder. In my Honours year I was supervised by a vibrant Cuban woman who truly has one of the best scientific minds I’ve ever encountered. She was always 20 steps ahead of me, which was excellent because I had no idea what I was doing. She spoke like a freight train and on that basis we did have some comical misunderstandings. Often I would just nod and then panic because I would realise that “Put those precious samples in the kitchen” couldn’t be what she meant. Then one day she told me to sit down (probably because she knew I was prone to the dramatics) – she had some bad news. She was emigrating to Aus and I needed to finish without her there. A lesser supervisor would have left and never looked back. But every week for the duration of my course, I had Skype calls with her. We spent time on Skype practicing for my presentations and copious emails back and forth as if she was in the next room. Other senior scientists in my lab also helped me  — It takes a lab to raise a scientist… This advisor was the one who taught me all the skills I needed to know in 3 months and it was glorious. I never felt orphaned and was grateful that I had her.  The best piece of advice I had from her is, “It’s ok to be slow now Simone but some of us remain slow. Don’t be one of those people, those people get eaten.” That last word may have been “beaten” (the Cuban accent still had me occasionally confused).

I have been fortunate for both my Masters and my PhD to have the same 2 supervisors who truly have my back. I have always been the one student doing things that are not the direct focus of our laboratory and my supervisors have always tried to give me the best resources and contacts. In a female-led lab, it has been a great privilege to see the success of my supervisors in a field dominated by males. With one supervisor rushing off to do the Duzi or climb another mountain and the other having the most incredible shoe collection with 3 very cute kids (she says I’m her 4th), I feel I have access to wide perspectives not only one in terms of science but in terms of  life.

I have realised that a supervisor is not just someone who is science smart but is someone who is willing to make time for you. Having an open door policy is imperative. Being hard on your student so that they don’t crumble when the science world gets tough is also important. Good supervisors never put their names on things that are sub-par and neither should you. The best line from my current supervisor? “Yes well science isn’t easy. Doing a PhD is like producing a really potent antibody. It’s how many mutations you can take in order to target lots of things.”(This is alluding to a process called somatic hypermutation, check out this video for an explanation.) She knows how to be tough on me. I hope it’s because she sees potential in me! It seems that supervision is a bit like parenting: you can mould and mould your little ball of clay but it is unclear at the start whether your masterpiece will be a wonky vase that your 5 year old made or a beautiful work of art.

Mentoring is something everyone has to do in academia and the truth of the matter is that not everyone is a good advisor. What you as a student need to remember is that you are ultimately the person that picks your supervisor. Don’t pick on fame/name alone; read the work your supervisors have been involved in and critically assess whether this person will want to see you grow or wilt in their shadow. You want to become part of a research family, not war zone. (For other good guidelines on picking a supervisor see this great article by Tara Brabazon.) So as is the case with most things in my life, I will end with another Star Wars reference; choose a Jedi, not a Sith lord to be your supervisor. The Dark Side may have more street cred, but the Light Side, well, they have publications.