Interview with E. John Wherry, Ph.D.
Assistant Professor, Immunology Program
Member, Wistar Institute Vaccine Center
The Wistar Institute
Philadelphia, Pa.
www.wistar.org/vaccinecenter

Frank Hoke: Welcome to this podcast for May 31, 2007, from The Wistar Institute in Philadelphia, Pennsylvania. The Wistar Institute is an international leader in biomedical research, with special expertise in cancer research and vaccine development. My name is Frank Hoke.

We’re speaking today with Dr. John Wherry, assistant professor in the Immunology Program at The Wistar Institute and a founding member of the Wistar Institute Vaccine Center. The new Vaccine Center, launched today, will extend Wistar’s history of accomplishment in vaccine development by focusing the Institute’s scientific strengths in immunology, virology, and other research disciplines on creating new or improved vaccines against some of the most dangerous and widespread diseases in the world: HIV/AIDS, influenza, rabies, hepatitis C, malaria, and others. Dr. Wherry’s research centers on the failure of the immune system response in cases of chronic infection and in the elderly. His expertise is contributing to the development of a vaccine to treat hepatitis C and a new universal flu vaccine that would protect against all strains of the flu virus.

Dr. Wherry, many of the vaccines given to people today were developed decades ago. But there have recently been a number of new vaccines approved for use, including the rotavirus vaccine in 2006, which was based in part on research done here at The Wistar Institute. And there also seems to be a good deal of research activity right now in laboratories across the country and around the world to develop new vaccines. In terms of the science and other factors, are we entering a period in which we might expect to see significant progress in creating vaccines against some of the more important diseases threatening global health?

John Wherry:  Yes, I think so. I think over the past century we have seen development of the most vaccines in human history. But many of these in the early half of the twentieth century are really what I would consider low hanging fruit and might be considered the easier vaccines to be made. While they were no small achievement, I think we are entering into a phase now where both the development of new scientific approaches and investment of a large amount of money into HIV research, and also the recognition of the importance of global health to global economic stability are really setting the stage for a lot of new discoveries and new approaches to vaccines that should lead to a lot of new opportunities.

I think that one of the other aspects of the opportunities in vaccines that is before us right now is that we have invested a large amount of money, not only in HIV research, but also in basic science and understanding the mechanisms by which the immune system works. And a lot of the newer techniques where we can monitor global changes in gene expression in the immune system by which we can understand the genetic components of various immunological disorders and immunological functions should lead to a much greater ability to tailor vaccines and take advantage of technologies to generate a new type of vaccine in the future that incorporates both our basic understanding of how the immune system works and also the tried and true methods of trial and error for vaccines.

FH: With Dr. Hildegund Ertl and other colleagues here at Wistar, you are involved in developing a new universal flu vaccine. Can you tell me about the need for such a vaccine and the approach the Wistar team has taken to approach the team has taken to create that vaccine?

JW: Sure. Currently, the influenza vaccine is made new each year to respond to the expected emerging strain of influenza. The vaccine is then only then effective against the strain of virus that emerges that year or very closely related strains. The problem is that the virus continues to change and evolve, and especially with concerns about the H5N1 virus in Asia, and potential bio terrorism exploitation of flu, there is a need to develop a vaccine that will be universally protective. And so, the idea is a paradigm shift in how we develop a flu vaccine, to target parts of the virus that are more conserved and that will be common throughout all flu strains. And so that is really the basis of the approach being used by our group and other groups around the country.

FH: You mentioned the H5N1 virus. What is that?

JW: The H5N1 virus is the Asian flu, the pandemic strain—the strain that may become a pandemic flu that we are all hearing about on the news that is emerging in Thailand, and China and other parts of Southeast Asia.

FH: As I understand it, one of your contributions to the new flu vaccine will be a better understanding of the decline of the immune system in the elderly. Does the immune system decline significantly with age, and what does that mean in terms of vaccines and disease?

JW: Well yes, what we know is mostly based on the response to vaccines in the elderly. We know that the elderly respond more poorly to vaccines than their younger counterparts, and that has been known for quite a long time. But we don’t really understand are the mechanisms behind that, we don’t understand why it is the elderly generate poor responses to vaccines, and also to deal with infectious disease less well than do the younger populations. So what we are trying to do is understand why that might be the case and apply that knowledge to newer types of vaccines.

FH: In the research you have been doing, what have you discovered so far about the decline of the immune system with age and what strategies do you anticipate might be useful when encountering that?

JW: What we have found so far, using several different models and also looking in humans is that there are profound changes within the immune system with age; many other groups have also noticed this. But what we have found that I think is somewhat novel and perhaps most interesting to us is that there are dramatic changes in regulatory pathways in the immune system of elderly people that are not present, or at least not as profound in younger people and younger animals. So we believe, these regulatory pathways may suppress or alter the quality of the immune response to a vaccine or infection. We hope by understanding these pathways and delineating how these pathways work we may be able to design a vaccine that modifies those pathways or interrupts the negative pathways to boost immunity in the elderly.

FH: When you talk about regulatory pathways, what is meant by that?

JW: A regulatory pathway can operate a number of ways. And in many ways it may be a set of breaks or checks and balances in the immune system that limits how vigorously or how robustly the immune system responds. And these regulatory pathways are in place to prevent things like autoimmunity or to prevent tissue damage upon infection. What we think is happening in the elderly is that these negative regulatory pathways are actually preventing the normal response of the immune system to a vaccine or infection.

FH: And you can anticipate ways you might enter into that or possibly reverse it?

JW: Yes, I mean that is the goal. If we identify the pathways and understand their normal functions we clearly anticipate being able to interrupt those pathways in a targeted way during vaccination in the elderly.

FH: Might this work have implications for non-infectious diseases too, like cancer?

JW: Yes, I think a lot our work has been examining infectious disease. But from the standpoint of the immune system the problem of cancer and infectious diseases is very similar. In both cases, there is something present in the body that should not be there. Whether it is a virus, or a bacterium or a tumor, in the grandest sense doesn’t make a whole lot of a difference to the immune system. What has to be done in those situations is that the immune system has to be trained to eliminate the virus or the tumor. So fundamentally, the problems are quite similar. So we expect that some of the same pathways will be operating during cancer as we find during infectious disease.

FH: You are currently working with colleagues at Emory University on a Gates Grand Challenge Grant, sponsored by the Gates Foundation. Can you briefly describe the global heath aims of these grants and goals of the project you are working on?

JW: Sure. The Gates Grants Challenges were designed essentially to address some of the more important problems in global health that were not being addressed by government-funding agencies. And these represent basically, what Bill Gates and the Gates Foundation thought were opportunities to the developed world to intervene and prevent infectious disease, to implement better strategies, to provide vaccines and other interventions for public health throughout the world. The project that we are working on involves trying to generate more effective antiviral immunity to hepatitis C infection. Hepatitis C is a viral infection that infects between 150,000,000 and 250,000,000 people worldwide. There is no vaccine, and in a large percentage of those people infected will end up with hepatocellular carcinoma, liver cirrhosis, and ultimately need a liver transplant to survive. And certainly in the developing world that is not a very viable option. So the goals of our project are to try to understand what kinds of immunological interventions could be used to again, retrain the immune system to eliminate this chronic viral infection.

FH: When you talk about immunological interventions, in this case are you talking about vaccines, or other tactics?

JW: We’re talking about both really. And I think the type of vaccine that we would use in this case would be slightly different; it would be a type of therapeutic vaccine that would be administered to a person after they have been infected. And the goal of that vaccine would be to augment existing immune responses. We are also thinking about interventions that again, might interfere with or modify these regulatory pathways that I spoke about that appear to operating during chronic viral infections, as well as in the elderly. And so, there are several different kinds of interventions we might think about for hepatitis C.

FH: How important are vaccines to global public health? How do they compare to the other health care tools available to doctors and public health officials around the world?

JW: Well, vaccines are without question, the single most cost effective medial intervention available to mankind. Vaccines have probably saved more lives that any other type of medial intervention or anything really that’s happened to mankind. When you add up all the vaccines that are being used and if you could extrapolate the to how many people would not be here had they not been vaccinated.

And I think that, in the past perhaps century our fear of infectious disease has changed dramatically, and that is completely the result of vaccines and also antibiotics, but largely vaccines. Fifty to seventy-five years ago polio and smallpox were things that everyday people worried about and that significantly impacted the health of a large percentage of children. And so vaccines have had a major impact in the health of the developed world. What has not been realized is the potential of vaccines to change the outcomes of the developing world, and to really impact on both economic and other aspects the health of developing countries.

FH: Wistar has a strong history in terms of vaccine development, research at Wistar led to vaccines against rubella, rabies and rotavirus, for example. What role do you see Wistar playing in developing the next generation of vaccines?

JW: Well I hope we play a major role. I think between the laboratories and immunology program and other laboratories at Wistar, I think we have a lot of opportunities in front of us. Both in terms of vaccine platforms, in terms of our understanding of infectious disease and pathogenesis of infection, and also understanding different aspects of aging of the immune system and some of the regulatory pathways that I’ve discussed I think we sit with a lot of opportunities in front of us to put the pieces together to develop new kinds of vaccines that will be necessary for some of these more difficult infectious disease problems.

FH: Thank you, Dr. Wherry. Once again, Dr. John Wherry is an assistant professor in Immunology Program at The Wistar Institute and a founding member of the Wistar Institute Vaccine Center.

Thanks to all of you for listening today. I hope you’ll keep an ear out for our next podcast. Michael Paradis was our audio engineer, and I’m Frank Hoke, coming to you from The Wistar Institute. The Wistar Institute: Today’s Discoveries – Tomorrow’s Cures. On the web at www.wistar.org.