Shane Crotty, PhD, on Engineering Vaccine Immunity

In this podcast, Shane Crotty, PhD, discusses his research in virology and how his team is working to produce better vaccines through understanding the immunology of helper T cells, germinal centers, and the human-naïve B-cell repertoire.

Additional Resources:

• Crotty S. Engineering vaccine immunity. Presented at: Conference on Retroviruses and Opportunistic Infections 2020; March 8-11, 2020; Boston, MA. https://www.croiconference.org/sessions/engineering-vaccine-immunity. 
• Moyer TJ, Kato Y, Abraham W, et al. Engineered immunogen binding to alum adjuvant enhances humoral immunity. Nat Med. 2020;26(3):430-440. https://doi.org/10.1038/s41591-020-0753-3. 
• Cirelli KM, Carnathan DG, Nogal B, et al. Slow delivery immunization enhances HIV neutralizing antibody and germinal center responses via modulation of immunodominance. Cell. 2020;180(1):206. https://doi.org/10.1016/j.cell.2019.12.027. 

Shane Crotty, PhD, is a virologist and professor in the Vaccine Discovery Division at the La Jolla Institute for Immunology on the campus of the University of California at San Diego.

TRANSCRIPT:

Amanda Balbi: Hello everyone, and welcome to another installment of Podcasts360—your go-to resource for medical news and clinical updates. I’m your moderator Amanda Balbi with Consultant360 Specialty Network.

The Conference on Retroviruses and Opportunistic Infections 2020 was a virtual meeting of the minds in infectious disease and public health. One of the many plenary sessions presented at CROI 2020 focused on engineering vaccine immunity.

Understanding the immunology of helper T cells, germinal centers, and the human naive B cell repertoire will enable better vaccine design—for HIV and beyond.

Today i’m joined by the presenter of that plenary session—Dr Shane Crotty, who is a virologist and professor in the Vaccine Discovery Division at the La Jolla Institute for Immunology on the campus of the University of California at San Diego.

Thank you for joining me today Dr Crotty. Let’s dive into your session.

To start, can you give us an overview of your session for our listeners?

Shane Crotty: Vaccines are incredibly cost-effective medical interventions. There's been intense desire to develop an HIV vaccine. But also quite a few other vaccines and so the focus of the talk, as well as my lab and the consortium we’re a part of for HIV vaccine research is really what have we been learning about the immune system specifically for vaccine development. Really classically vaccine development has been quite empirical and so we've spent intensive effort trying to better understand the fundamental immunology underlying vaccine immune responses so that we can understand why certain candidate vaccines fail and other candidate vaccines do better.

I think there were 3 major conceptual advances that I focused on today: that Tfh cells are the CD-4 T cells that you have to have to get a good antibody response.

Second, it's been recognized that the broadly neutralizing antibodies do exist against HIV, but it's been a big question as to whether since those only occur in relatively rare HIV-infected people, could those antibodies actually be developed in your average person in a vaccine?

We've demonstrated that at least for one class and brother neutralizing antibodies. Your average person does have B cells with those characteristics, indicating that those B cells normally don't get activated in or do the right thing in an HIV infection, but they do exist in your average person and can be considered targets for vaccines. That general concept we think applies to multiple broadly neutralizing antibody targets to HIV, but also other vaccine concepts in general.

And then lastly, the concept of immunodominance as an explanation for vaccine failures. So why do so many vaccines fail to generate the types of antibody responses that people are hoping that the vaccine will elicit. We think immunodominance can explain a number of those failures, including HIV vaccine failures in the past, because we've shown in multiple different experimental models now that B cells have to compete with each other.

And that you can easily have a situation where there are lots of B cells that can recognize useless epitopes on your virus or pathogen of interest, and it's only rare B cells that actually recognize neutralizing or protective epitopes. And the immune system, in many cases, just can't tell the difference until it ends up that the more common or easier response wins out, which is you get a big antibody response, but it's completely useless against nonprotected epitopes.

The rare B cells that you really care about just don't manage to compete until we showed that that definitely exists that definitely occurs, it probably explains multiple HIV vaccine failures, and we've also shown that you can modulate that you can actually change immunodominance for the better. So it's not just a fixed property. We think you can design vaccines better in the future to accommodate that.

Amanda Balbi: Great. So what would you say are the key take-home points for our audience?

Shane Crotty: I would say the take-home messages are that there is actually a lot of promise in vaccine development against HIV. And that it's generally agreed that HIV is either the most difficult neutralizing antibody target you could come up with for vaccine development or certainly it's right up there. And so the fact that we—and by we, I mean the field and many people that I collaborate with—are having real successes progressing.

Broadly neutralizing antibody vaccine development is a really good sign for the HIV vaccine field and other vaccine fields that really understanding the underlying immunology combined with the really sophisticated protein design that some labs can do now really is a promising path forward. And those things are… well ones entered clinical trials and is in the middle of its first phase one and then there's a whole host of additional ones that are now under development for advancement into clinical trial, depending on what actually happens in that first clinical trial.

In that clinical trial, it's in the… It's mostly done as I understand it, with enrollment. It's not my clinical trial, it's led by the International AIDS Vaccine Initiative and Bill Schief, but I consulted on it. And it's essentially completed enrollment, and so I think there's an expectation that they'll announce at least some results from it before the end of this year before the end of 2020.

And then if that is positive I think there'll be a lot of additional movement that that will have opened up both on from the side of really paying enough attention to the immune response, you know, to design better vaccines and then making use of really sophisticated protein engineering to try to target the desire to be cells that potentially can give you a protective antibody response.

Amanda Balbi: Absolutely. Thank you again for speaking with me today. If you’re interested in reading more about Dr Crotty’s work, please click the links below.