amfAR, The Foundation for AIDS Research

Where Are We in HIV Vaccine Research?

amfAR Krim Fellow brings us up to speed for National HIV Vaccine Awareness Day, May 18

SandersDr. Rogier Sanders is a professor of virology at the University of Amsterdam and holds a faculty position at Weill Cornell Medical College in New York City. He was one of the first recipients of an amfAR Mathilde Krim Fellowship in Basic Biomedical Research in 2008. “At a critical moment in my career,” said Dr. Sanders at the time, “the Krim Fellowship helped me move forward.” Today he is mentor to Dr. Marit van Gils of the University of Amsterdam, a 2016 Krim Fellow.

Since May 18 is HIV Vaccine Awareness Day, amfAR’s Dr. Rowena Johnston spoke to Dr. Sanders about his vaccine work and the prospects for achieving an effective vaccine in the foreseeable future.

You’ve spent your career studying the HIV envelope protein. What got you interested in it?

I started on this while doing my master’s thesis project with John Moore. The protein immediately caught my interest because it’s crucial in so many ways. In terms of molecular virology, it’s the mechanism by which the virus enters cells. It also plays a crucial role in how the virus escapes from humoral immunity. Third, it will be important to induce antibodies against the envelope protein for a vaccine, and because the envelope protein is so good at evading immunity, this will be quite a challenge. Fourth, the envelope protein can also be a target for therapeutic interventions – there are already licensed antiretroviral drugs against the envelope, and we’ve done some therapeutic work ourselves.

This variety of approaches you can take when considering the envelope protein leads to synergy. For example, by looking at the way the virus escapes from therapeutics, we were able to obtain virus mutations that helped us develop a stabilized form of the envelope protein in a conformation that resembles what you find in people living with HIV, which we have used in our vaccine projects

You and John Moore worked together to describe the SOSIP trimer in 2002. What is it, and where has that research led?

The SOSIP trimer is a soluble and stabilized version of the functional envelope spike. In a person living with HIV, the envelope protein comes in many forms, most of which are nonfunctional. The virus probably uses these as part of a decoy system – the immune system makes antibodies against the decoys. So if we want to force the immune system to make broadly neutralizing antibodies, we hypothesized it would be essential to generate a mimic of a stable, functional version of the envelope protein trimer. We were shown to be correct because SOSIP was the first protein shown to consistently induce neutralizing antibodies that were effective against viruses derived from patients. There is still difficulty in making antibodies that can neutralize different HIV strains, but various research groups are making progress in this area.

When we generated an updated version of the SOSIP trimer in 2013, we quickly realized it would make a good tool to search for broadly neutralizing antibodies in the blood of patients. We collaborated with Dennis Burton’s lab and isolated an antibody called PGDM1400, one of the most potent and broadly neutralizing antibodies we have, and this antibody is currently being tested as a therapeutic.

The SOSIP trimer was also important for enabling the definition of the structure of the envelope protein. The structure of the protein has now been solved by electron microscopy.

What are you currently working on?

Mostly we continue to work with SOSIP trimers, with a large part of our effort directed towards germline targeting. When the immune system sees a virus, for example, and starts to make antibodies against the virus, it keeps tweaking the antibodies it makes to come closer and closer to the best and most effective version of the antibody. Various research groups have discovered that this process itself, and not just the final product, is important to the effectiveness of antibodies. So we are using SOSIP trimers to get this antibody-making process started, based on the hypothesis that presenting the vulnerable antibody epitopes in their natural context (i.e., the envelope trimer) might optimize the final product.

Along these lines, we’re characterizing some very interesting patients in the Amsterdam cohort, who naturally make exceptionally potent antibodies. We are using SOSIP trimers based on the patient’s virus isolates to recapitulate the process these patients’ exceptional antibodies went through to become so potent.

Several  SOSIP proteins will be tested in clinical trials in 2018−2019. For now they will be injected as proteins, boosted by an adjuvant, and we’ll be looking to see whether it is safe and what kinds of immune responses they induce in humans.

In the longer-term future, we hope to use nanoparticle delivery of SOSIP trimers, because we’ve learned from vaccines against human papillomavirus (HPV) and hepatitis B that displaying the proteins on a nanoparticle can induce very potent antibodies.

“It’s important to keep in mind that we will probably ultimately need a combination approach for an effective vaccine.”

There is enormous variability in the HIV virus around the world, and this poses a challenge to developing a vaccine. What is the best way to overcome this challenge?

Some of the approaches we’ve discussed can help overcome the problem of viral diversity. If we can use germline targeting to select antibody precursors that have the potential to become broadly neutralizing antibodies, and use this as the prime part of a prime-boost vaccine strategy, we could follow these with a vaccine boost that consists of a cocktail of envelope trimers.

HIV vaccines tested so far have not worked as well as people would like. Are there promising candidates in clinical trials now?

When considering vaccine candidates that aim at inducing broadly neutralizing antibodies, there are at least six vaccine candidates in the testing pipeline that will enter clinical trials this year or next. Some of these include SOSIP trimers, there are germline targeting approaches from several groups, and a lineage vaccine based on patients from a group in North Carolina.

Although it’s extremely exciting that so many candidates will go into clinical testing soon, it’s important to keep in mind that we will probably ultimately need a combination approach for an effective vaccine. Some of these candidates might end up being a prime, and others a boost, and they might be put together in a prime-boost vaccine schedule.

Your work has focused on finding a way to prevent HIV transmission. Do you see any potential for your research to help efforts to treat or even cure HIV infection?

Broadly neutralizing antibodies could be used in a variety of ways, including as treatment or even as part of a combination approach to cure HIV. A lot of the effort on this front is being done by others, and they are looking to combine a latency-reversing agent with antibodies, for example, as a shock and kill strategy.

Some cure efforts are particularly focused on the effector functions of antibodies, including their ability to kill the cells infected with the virus and not just the virus particles in the blood. We and others are working on ways to modify the structure and function of antibodies to optimize their ability to kill infected cells. This could play a role in reducing or even eliminating the reservoir of HIV.