Recent advances in HIV vaccine development: interview with Rogier Sanders
How did you come to be working on HIV and, in particular, vaccine development?
I first became interested in HIV during my undergraduate degree in medical biology at the University of Amsterdam. When seeking a placement, I knew I didn’t want to end up working on some vague protein or other. In this respect, HIV presented the perfect challenge because of its societal importance, and so I did a placement in Ben Berkhout’s group at the AMC. Later on, I did a second placement in New York with John Moore’s team, working on a vaccine design project at the Aaron Diamond AIDS Research Center. That work still forms the basis of what we do today.
At NCHIV 2015, you will be talking about progress made in HIV vaccine development globally. Looking back over the last 3-5 years, what would you say have been the biggest steps forwards?
I think the biggest step forwards has been neutralising antibody induction. In the past, attempts to achieve this had not been very successful. People became quite pessimistic about this approach and switched to other strategies, such as T-cell vaccines. When this failed, the focus returned to neutralising antibodies, since these are used in almost all effective vaccines.
To date, a number of major steps have been taken in this approach. First, neutralising antibodies were isolated from HIV-infected individuals, including patients from the Amsterdam Cohort Studies (ACS). As part of her pioneering work to characterise the antibodies in these patients, Hanneke Schuitemaker found that approximately 20% of HIV-infected individuals produce broadly neutralising antibodies; in other words, antibodies that are able to inhibit a wide range of virus strains. These antibodies provide a model of what we are striving to achieve in a vaccine.
In addition, precisely how these antibodies develop is now better understood. For example, we know that natural antibody production starts with naive B cells that have never been exposed to a virus or a vaccine. When stimulated, these so-called germline antibodies start to evolve and develop a higher affinity for the vaccine or the virus. This insight has led to the work on vaccines that specifically stimulate these germline antibodies.
Your group also recently made a significant breakthrough. Can you outline what this involved and what the implications of this breakthrough are?
Yes, our own work has also made an important contribution. We have succeeded in reproducing the HIV envelope glycoprotein found on the outside of the virus in a stable, true-to-nature form. Achieving stability was key; the protein was very unstable and rapidly changed shape or fell apart when used in a vaccine. As a result, the immune system was only able to produce so-called non-neutralising antibodies that, unlike neutralising antibodies, are subsequently unable to recognise the functional protein as found on the virus particle. By engineering a stable form of the envelope protein, we have managed to stimulate neutralising antibody production. The protein will now form a platform for further work on a preventive vaccine.
What are the biggest challenges that researchers still face?
We have now managed to stimulate neutralising antibodies against two strains of the virus, but the aim is to turn these into broadly neutralising antibodies that, ideally, target all or at least many different strains. In theory, our approach of targeting a shared and essential feature of all HIV strains, such as the envelope glycoprotein, should make it possible to produce antibodies that inhibit a large number of strains. Moreover, as I said, we already know from the work on patients in the Amsterdam Cohort studies that people are capable of producing these broadly neutralising antibodies themselves. Although these antibodies are not beneficial to the infected patients due to the time lag in mounting the immune response and the rapid mutation rate of the HIV virus, when such antibodies are induced by a preventive vaccine, the infecting virus would be eliminated immediately and resistance would not develop.
When can we realistically expect to see an effective HIV vaccine on the market?
That’s very hard to say. First we have to apply what we’ve now learnt to produce broadly neutralising antibodies. I think we’ll have a better idea about how easy or hard this will be in a year’s time or so.
The road to actually having a vaccine on the market, however, is a long one. Aside from the scientific challenges, the safety issues, clinical trials and production process all take time.
How does it feel to have made this breakthrough after all those years?
It feels quite overwhelming to finally have made these steps forward. Suddenly there are so many possibilities and we are trying to pursue as many of these as possible. But this overwhelming feeling is a positive one, particularly when I look back at all those years in which we struggled to move forwards. Despite the challenge, we kept to our approach because we were convinced it was the right direction.
What next?
As I mentioned, about 20% of HIV-infected people produce broadly neutralising antibodies and about 1% of these individuals produce highly potent broadly neutralising antibodies; these people are known as elite neutralisers. If we could recreate the antibodies produced by these elite neutralisers, we would be able to produce a fantastic vaccine. We are therefore now working on elucidating the configuration of the envelope proteins over time from strains isolated from two ACS elite neutralisers. This could lead to the development of sequential vaccines that mimic the natural neutralising antibody response that broadened with time in these two patients.