Stumbling on Greatness

By Kristen Jill Kresge, Managing Editor

When you talk with Devin Sok, the 30-year-old director of antibody discovery and development at IAVI, you get the feeling you aDevin Sok Web croppedre speaking with someone much wiser and more experienced than his age suggests. Looking at his docket of projects or lengthy list of scientific publications might lead you to the same conclusion.

Sok came to The Scripps Research Institute (TSRI) in La Jolla, California, in 2008 to pursue his PhD in organic chemistry. He landed, somewhat serendipitously, in the laboratory of Dennis Burton, co-chair of the Department of Immunology and Microbiology at TSRI and scientific director of IAVI’s Neutralizing Antibody Center.

For years, HIV researchers had only a handful of antibodies at their disposal that could neutralize a broad range of the many HIV isolates in circulation, so-called broadly neutralizing antibodies (bNAbs). Just as Sok joined Burton’s lab, things changed dramatically. Burton’s group and colleagues at IAVI had just published in Science on the isolation of a duo of much more broad and potent bNAbs that were isolated from an IAVI cohort of HIV-infected individuals. A research team at the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases (NIAID) also began identifying new bNAbs soon afterwards. The isolation of this new generation of bNAbs was followed by a feverish period of antibody discovery and characterization, setting off a new course in HIV vaccine development that continues today.

Now, with hundreds of bNAbs to work with, several of which have been shown to block infection in animal models, research in this area is booming. These bNAbs are providing vital clues that can be exploited for vaccine design. Clinical trials are also testing whether direct administration of one of these antibodies can prevent HIV infection in uninfected volunteers, what is referred to as passive administration.

For Sok, the timing was superb. He quickly immersed himself in the world of these antibodies, which became the focus of his PhD work. It turns out that HIV was a natural fit for someone whose undergraduate chemistry work focused on sugars—the outer surface of HIV is one of the most heavily sugar-coated or glycosylated viruses identified. Sok is now actively supporting efforts to develop vaccine immunogens capable of inducing bNAbs, engineering these antibodies so they are more potent and last longer in the body, and working with new animal models. His latest publication showed that cows can very quickly develop bNAbs after immunization with an engineered HIV protein, garnering headlines and inspiring many puns; I won’t milk the story for any further jokes. He is also using all of the knowledge and techniques amassed in studying HIV antibodies to see if there are other areas that can benefit from similar approaches.

In our recent interview, we talked about all of these projects and also what it is like being a young researcher in this challenging and dynamic field.

How did you come to Dennis Burton’s laboratory and become involved in HIV immunology research?

Well, I started at Scripps for my PhD. As an undergrad I studied chemistry, specifically organic chemistry, with a focus on sugars, or glycans. I chose to go to Scripps to do organic chemistry, and I chose Scripps just because it was an interdisciplinary place in case I wanted to switch more into biology.

When I first started out I was doing some glycan chemistry and jumped around to a few labs and couldn’t find something that I was really excited about. I was actually on the verge of leaving Scripps and moving to another institute because I couldn’t find something that I wanted to do. I had everything in motion to make the jump and move and this PI [principle investigator] who I was communicating with whom I was planning on moving to—he was based at Harvard in Boston—he recommended seeing one more person before I left Scripps. And so I decided to look up who else was available and found Dennis’s lab’s website primarily because of my interest in sugars and glycans. HIV envelope is a unique protein in nature in that half its molecular weight is covered in sugars, so I thought that was interesting. So I decided to meet with Dennis and talk to him a little bit about the science and see whether or not it would be a good fit. The meeting obviously went well. He had a lot of exciting projects and challenges and so I decided to try it out for a few months.

I joined Dennis’s group when Laura Walker was still in the lab and this was when the first papers on the next generation of broad neutralizing antibodies were being published. I came in right as all that was coming out and so it ended up being a really exciting place to be and all the people in the lab are super smart. It was just completely out of what I was used to and had been exposed to at that point. It was just a really difficult challenge that seemed really fun.

Sounds like luck was on your side coming into the lab at such an exciting time.

Yeah, I know. It was crazy.

Nowadays it seems you are juggling many different projects in the lab, both related to those early discoveries of broadly neutralizing antibodies and beyond that. Can you walk through what some of your work involves now?

Because of my chemistry background I think about antibodies as just protein molecules, so this was an area I quickly became interested in. It is a scale of science that I could understand. So the bulk of my PhD was focused on these new broadly neutralizing antibodies for HIV and understanding how the antibodies work and the epitopes that they target, rather than focusing more on HIV itself. There is a whole lot of work that I did related to isolating new antibodies.

That has now evolved. Now there is less interest in trying to isolate new antibodies to HIV and more work that needs to be done to evaluate antibody responses to the different immunogens that are being developed at the Neutralizing Antibody Consortium [NAC], and so that’s another big effort that I am focused on. One question I grapple with is how do we determine whether or not the immunogens that we are testing in different animal models are eliciting the right antibodies, and how do we get at those details? And through that process, I’m trying to expand more into more antibody discovery in other areas. Now that we have these tools that we developed for discovering antibodies for HIV, the question then is, how can we apply these tools to other disease areas? So that’s another area I’m interested in pursuing. We just submitted a proposal to DFID [UK Department for International Development] to identify monoclonal antibodies to treat snakebite, which affects up to 5 million people in the world. The current therapies for snakebite are from the late 19th century and haven’t really changed much. It is one of the areas where we can apply these technologies that we developed and have the potential to make a really big impact. I’m excited about that.

And then we have another project where we are trying to engineer HIV antibodies for different applications. We’re, of course, also using these antibodies to understand the virus and to develop a vaccine against it. Simultaneously we are exploring ways to use the antibodies themselves for therapy or as a prophylactic, so we’re trying to engineer and improve these antibodies, which is another area that I’m focused on.

Now that there are so many antibodies available to work with, and as they target various spots on the virus, what is the most promising avenue of research in your opinion toward designing a vaccine immunogen that could induce these?

That is a very good question. Multiple groups have taken different approaches to trying to elicit these antibodies by vaccination. The more we’re exploring, the more we learn.

From my perspective, I feel that the germline-targeting approach is a very elegant approach, and I do think it has a lot of potential. I think the great thing about the germline-targeting approach is that it is ultimately very universal. You can apply that approach and that technique to any other disease area so I think there is a lot of potential there, not only for making a significant impact against HIV, but also elsewhere. But I still think we all would be happy if there was a magical Envelope trimer that someone identified that was able to elicit all HIV antibodies.

What other areas might benefit from a germline-targeting approach? Would it only be useful for viruses for which antibodies must be heavily mutated to be capable of broad neutralization as they are for HIV?

With the majority of infectious diseases or viruses we have, if we can create an inactivated version of that virus or if it’s not very variable, that is it is relatively conserved, then we can just put it into a person and they will develop protective antibodies and we don’t have to worry about it.

But for viruses that are variable—for example influenza virus or hepatitis C or any other potential virus that might emerge that would be highly variable like HIV—these approaches can’t be used, so in those cases a germline-targeting approach might be beneficial. Because ultimately what the germline-targeting approach is trying to do is to manipulate our immune system to elicit a very specific antibody response, instead of just having a bunch of random antibody responses. I think that has important utility for a lot of pathogens that are highly variable.

For example, if we want to create a universal flu vaccine, we’ve identified conserved epitopes on influenza and if we can redirect our immune response to just hit those conserved epitopes then we wouldn’t have to take a shot every year to protect us against influenza. That’s one example.

Is this something your lab is currently exploring?

Yes, I think there is general interest in tying these approaches with influenza and malaria. The main focus is on HIV, and then we will do whatever we can elsewhere.

One topic that seems to keep coming up is this idea of the glycan holes in HIV’s surface and their role in vaccine development. As someone who specialized in glycan chemistry, how would you describe the importance of glycan holes in HIV Env and their utility in vaccine design?

I feel like it’s one of two things: it’s either going to be, to use the pun, a rabbit hole, where it would just be a distraction, or it will be useful in increasing the immunogenicity of conserved sites. So it could be, for example, like the glycan hole that was described for BG505 SOSIP, that it is in a region that isn’t present on all the other viruses. So we can develop antibodies against that hole, but whether or not that’s useful in the context of protecting against other viruses is really the question.

In other cases, if you can create a hole around these conserved epitopes defined by these broad neutralizing antibodies, the question is can you redirect immune responses against these conserved sites? I think we are still evaluating whether or not creating holes around these sites will improve antibody responses against them. They might be effective for some epitopes and not for others, so there’s still a lot of exploratory work that we could do in this area.

And then, of course, we can’t forget the cows. You recently published a study in Nature on the induction of broadly neutralizing antibodies in cows. Were you surprised by all the jokes and puns people can make about cows?

They were very funny … I loved it.

How did you first get involved with these experiments and what is their significance for HIV vaccine development?

As I mentioned before, I chose to come to Scripps to do my PhD because it is such an interdisciplinary place and there are so many different really good people working on a bunch of different areas. Cow antibodies happens to be something that a professor at Scripps was focused on. Through working with him, we knew that cows have these unique antibodies that have ultra-long loops of CDHR3. A lot of the broadly neutralizing antibodies against HIV that we’ve identified also have these long loops. After the discovery of the BG505 SOSIP trimer, it was tested as an immunogen in animal models, but it wasn’t able to elicit broadly neutralizing antibodies. So the question was, is it the immunogen that isn’t working or is it the fact that we just don’t have the right antibodies? So we decided to test the BG505 trimer in cows that have these long loops to see if we would we get broad neutralizing antibodies. And the answer is yes.

I think, in a couple ways, this finding is important for vaccine design. First, I think in all cases in science and technology, we just need to make something work first, in any system, in any case, so that we can learn how it works and then we can figure out how to apply that to make it work in humans. In this case we tried immunizing guinea pigs, rabbits, and monkeys, but we weren’t able to elicit any broadly neutralizing antibodies. For the first time we were able to do it in cows. By being able to show that we can do it by immunization in this animal model, we should be able to learn things that we can then apply to humans.

I think one of the specific things that this cow study was able to do was show us that we should focus on this concept of enriching for these long loops in humans because it should make it easier for us to elicit broad neutralizing antibodies by vaccination. So I think that becomes a specific thing that we can focus on and try to achieve.

Any ideas for how that could be accomplished?

I don’t know, but that’s something we can start really, really thinking about.

What do you think about the idea of an HIV vaccine trial in infants or adolescents because it seems they may be more likely to develop broadly neutralizing antibody responses than adults?

It is very interesting. I know that in South Africa there have been reports of children who are infected through mother-to-child transmission and in their adolescence have a higher likelihood of developing these antibodies and developing them fairly quickly. So I do think that’s a new area that definitely needs to be explored to understand why that is. I think there are probably a few hypotheses to why that could be, but I think it’s definitely going to be really exciting to look at.

Another area you mentioned working on is the use of these antibodies for prophylaxis. What are your thoughts about their role in prevention?

That’s exactly what the proposal I’m currently working on is about. I think there is a lot of potential in the use of these antibodies for prophylaxis. At the International AIDS Society’s Conference in Paris this year, Tony Fauci [head of NIAID] gave a talk on the idea of a prevention toolbox; that there’s no one drug that can take care of everything and that we should have a list of options so that people could choose what they want to do.

In the case of these antibodies, I think they potentially only need to be administered monthly or even bi-monthly, and if we can engineer them in the right way, you might be able to give them once every six months. If that’s the case then you solve a lot of issues with regards to compliance. So instead of having to take a pill every day, as you do with oral PrEP [pre-exposure prophylaxis], you just go in for one injection and it will last you for a long time. One of these antibodies, VRC01, is currently being tested for prophylaxis in the AMP trial and I think there is going to be a lot of things that we can learn from that clinical trial. I’m glad that it’s happening. VRC01 is a very broad antibody. It covers a lot of viruses. But it’s not the most potent antibody so I think there is a lot of potential for these new antibodies that are very potent to also be used for prophylaxes. The biggest hurdle with antibodies is going to be cost. But it really just comes down to the dose, which is affected by the potency. For VRC01 they are testing two different doses—30 mg/kg and 10 mg/kg. But if you have an antibody that is a hundred-fold more potent than VRC01, then you might be able to get away with only giving one mg/kg, or even less. If that’s the case then the cost for manufacturing is really, really low. The more that we can improve the potency of these antibodies, the more likely it will be that they can actually be used for prevention. The benefits are very clear—being able to give the antibody once every six months would be a huge benefit for compliance.

Is engineering these antibodies for greater potency another area that is applicable to different diseases?

Definitely. Trying to engineer these antibodies for greater potency and then also engineering the antibodies so that they stay in your body longer, a longer half life, those are things that can be directly applied to any other disease area. I think that’s the exciting part about being in HIV. You are working on things that are at the forefront of research that could be applied to some other diseases and have high potential for public health impact.

How would you describe your experiences as a young researcher in the HIV vaccine field, particularly working within the various networks that you are involved in?

It has been really exciting. I have been so lucky and so fortunate to have fallen into a good position, being in Dennis’s lab and being connected with a really good network of researchers. I’ve learned a lot and I feel like my skill sets in science have been honed and nurtured by both NAC and Scripps investigators. I have been constantly learning new things, and so, as a young investigator, it’s been the ideal experience.

It is a very fast-paced field, it takes a lot to keep up, a lot of hard work. But when you are working with people who are really good at what they do, it makes it fun.

I do wish that the opportunities that were given to me were accessible to more young investigators, and that there were more positions for young investigators to go into. I’ve been lucky to be able to continue the work that I do in different capacities through IAVI, but that’s not necessarily open to other young investigators. And I do think the fight towards an HIV vaccine is going to be a long one, unless we have some dramatic breakthrough, so the investments in these young investigators are going to be really important to keep the momentum going in the future. I try to talk to everyone—funders and policymakers—about young investigators, what we can do to keep them involved, and have positions for them to go into, especially because funding is so difficult and will potentially be even more difficult in the future.