Interview with Hildegund C.J. Ertl, M.D.
Professor and Immunology Program Leader
Director, 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. Hildegund Ertl, professor and Immunology Program leader at The Wistar Institute. With more than 20 years' experience in vaccine development, Dr. Ertl is also the founding director 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. At The Wistar Institute, Dr. Ertl is overseeing major projects to develop vaccines to protect against HIV/AIDS, influenza, and rabies, as well as a therapeutic vaccine for human papillomavirus, which causes cervical cancer.

Dr. Ertl, most of the vaccines used today have been in use in the developed world for years and have reduced or even eliminated many dangerous diseases in those countries. With new actions by the Gates Foundation and a number of governments, we now see a concerted effort to get existing vaccines to the people who need them around the world. How important are these initiatives?

Hildegund C.J. Ertl, M.D.: Most of these efforts, and many, many factors actually contribute to this, are geared towards childhood vaccinations, such as vaccines against measles, mumps. These are very important vaccines for they really reduce morbidity and mortality due to these very common infections. They are utilized quite well in the U.S. and Europe, but as you said, they are underutilized especially in Africa, and due to these initiatives we are trying to get sufficient coverage to, for example, eliminate certain infections altogether such as polio virus.

FH: How do vaccines compare against other public health tools, antibiotics, drugs?

HE: Antibiotics certainly have a major impact global health. Vaccines are different from other medical interventions for they are used as preventatives. They are in general, not used after a disease has started. So in that sense, as they are given to healthy people and keep them healthy, they probably have had the most dramatic impact on global health of all known medical intervention. Just to give you an example, pox virus used to cause epidemics that would literally wipe out cities. We developed a vaccine, and now pox virus has disappeared. It no longer is there, but for some stored vials at CDC and in Russia.

FH: When you say pox, you mean smallpox?

HE: Smallpox, yes.

FH: Here at The Wistar Institute, you’re heading a $10 million federally funded project to develop a new universal flu vaccine. Why is the government investing so heavily in this vaccine? How important might it be?

HE: Well, it is actually, to be more precise, an influenza vaccine for the elderly. And there are two reasons why this is important. The elderly are more susceptible to influenza virus as compared to young people. So, influenza virus is a nasty virus that makes you really sick and you don’t want to move for a week, but if you are a young, healthy adult, you basically get up after a week and you have no after-effects. The elderly very commonly get pneumonia and they actually can die from influenza virus. So, vaccinating would be an option, but the vaccines don’t work that well in the elderly. So rather than giving us the coverage we get in young people, where the vaccination gives fairly good protection against disease, coverage in the elderly is suboptimal and many elderly in spite of having been vaccinated, still will develop an infection and the consequences. So that is why the government is investing in making more vaccines for the elderly, not to mention that all the baby boomers are getting into this age range and our elderly population is growing rapidly.

The other emphasis is on making a universal vaccine. As you know right now we have to redesign the influenza vaccine annually to take antigenic variation of the virus – changes of the virus as it evolves during the year – into effect [sic]. It’s basically hit or miss. So, we predict what are the most likely changes and then make the right vaccine, and most of the time we get it right. But once in a while the influenza virus undergoes some very dramatic changes that we didn’t predict and then all our vaccines are actually useless.

Right now everyone is very concerned about the avian influenza virus, especially the pathogenic H5N1 virus that is causing outbreaks in wildlife as well as in chickens in Asia, Africa, and Europe. Although it is still a bird virus, which means it cannot spread from human to human, it can nevertheless infect humans that have contacts with sick birds. And this virus has an extremely high fatality rate. It causes the death of more than 60% of those that become infected. Everyone is obviously very concerned that this virus will change in a way that it can sustain a pandemic in humans.  With traditional vaccines, as I said, we have to know what we are facing. As we cannot predict what changes are needed to allow for this virus to cause a pandemic, we cannot make a vaccine. We could simply circumvent this problem by making a vaccine that works against every influenza virus, and this is the other part of this government contract. 

FH: Well, that sounds like a real challenge to make a vaccine that would work against all strains of influenza, including the avian flu. What strategy are you taking to create this vaccine?

HE: Well, traditional vaccines, which is mainly the inactivated influenza virus vaccine, induce protective immunity through the induction of neutralizing antibodies that are specific for a protein that is highly variable. Basically, influenza virus, like every virus, is composed of different proteins. There are proteins on the surface that bind antibodies. Antibodies are protein molecules made in response to a virus by cells of the body, so-called B cells, that can bind to certain structural components of this virus and thus prevent the virus from infecting cells and making more virus. So it’s basically like shooting the virus. If you were in the army, you would just go and shoot it. 

So instead the body makes antibodies. The problem is these antibodies aren’t very specific for certain structural domains of the surface proteins of the virus. The virus, not being stupid, changes those structural domains constantly. So if you make an antibody, and then another virus infects that has a different kind of structure on its surface, the antibody isn’t going to do anything. So that is the concept of our current vaccines. We make vaccines that induce antibodies that hopefully will prevent the infection, for the infecting strain of virus is similar to the one we used as a vaccine.

So the virus not only has structural proteins that are on its surface, it also has internal proteins that it needs to replicate. These internal proteins are normally much more conserved than the surface proteins – meaning they do not change that much. They don’t change that much for they have really important functions for the virus that are preventing a fit virus to change those structures without losing its fitness. So, the problem is these conserved structures cannot really induce antibodies that can prevent the virus from infecting a cell, for they are not on the surface. But what they do, they can induce other immune mechanisms such a T cells that can lyse virus-infected cells before the cells have a chance to make more virus – lyse meaning kill, eliminate, bust. So our goal is to induce these T cells that don’t prevent an infection, but very rapidly eliminate infected cells.  That’s putting it simple. We probably need more than that so we are also inducing other immune responses that cross react.

FH: So you are building a vaccine that goes after elements of the virus that do not change, year to year. These are internal elements the virus needs to survive.

HE: Right.

FH: In the late 1980s and 1990s, Wistar scientists created two rabies vaccines. The first is currently the emergency treatment of choice in the U.S. for someone bitten by a rabid animal. It is also used to protect veterinarians, wildlife officers, and others who work with animals from possible infection. You’re currently working on an improved human rabies vaccine, however. How would your vaccine be an improvement on the existing vaccine? Is there a global health need for such a vaccine?

HE: Yes. Otherwise I wouldn’t be working on it. Our current vaccines, if you want to give it before an infection, as we give it to veterinarians, or wildlife officers, or people like me who work with it, you need three doses. And then the vaccine will give you protection from anywhere from one to five years. So, every year you have to be tested and once you lose antibody titers – again, these mysterious molecules that vaccines induce – you have to be revaccinated.

The vaccine is far from cheap, so that’s why it’s only used for people who really are at high risk for exposure and not generally for the population. The vaccine is normally used after someone is bitten by a rabid dog or rabid bat or rabid raccoon, and that’s obviously a notable event, so people notice something is wrong and go to a physician.  Bites are not that common in the U.S. They are very common in other countries where there are many more stray dogs than here. For example in India there are specific bite clinics, and all these clinics do is treat people who have been bitten by dogs. So in these cases, we need not only the vaccine, and we give five doses rather than three, we also need a hyperimmune serum. A hyperimmune syrum is the plasma, the non-cellular blood components, that you get from another human being who is immune to rabies virus. So it basically contains these antibodies that can prevent virus from infection. And we have to give people, together with the vaccine, these antibodies, and ideally these antibodies are from another human. They can also be from a horse for example, but then they don’t work that well, for they are eventually eliminated more rapidly. We have very little of these hyperimmune sera. There is an acute shortage, so in many countries such as India, there is no access to them.  And then we see vaccine failures.

And rabies is the most fatal virus of all viruses known to man. It causes a nearly one hundred percent fatality [rate] once you develop an infection. Right now, for example, in India, we see each year 50,000 vaccines failures, which means 50,000 people die of rabies virus. That is actually a fairly high toll for a virus infection. So for that reason, we need vaccines that either are cheap and efficacious after a single dose, to give in highly endemic areas to give to the general population, especially children that are at an increased risk for rabies, for they are more likely to play with rabid animals, or a vaccine that is less dependent on this hyperimmune serum that is in such short supply. So that’s basically our goal.

FH: With partners at other research centers, you are also taking an innovative approach to developing a vaccine against HIV/AIDS. Can you describe the strategy you’re pursuing with your HIV/AIDS vaccine? Where does that project stand right now, and what’s the next step for it?

HE: Well, to put this into historic perspective, we started about ten years ago working on an adenovirus – a virus that causes a fairly benign infection of the airways. One can modify this adenovirus genetically so that it becomes replication defective – which means it can’t grow anymore and thus harm you anymore – and we can insert genes from other viruses into this virus and basically use this adenovirus as a carrier for antigens of another virus. So we started doing this with a very common human adenovirus, which is called human serotype 5 adenovirus, and although we got some promising data, we realized fairly rapidly that a lot of humans have antibodies – again, these mysterious proteins in their body – against the adenovirus and then the vaccine doesn’t work anymore.

So, although Merck and VRC [the NIH Vaccine Research Center, under Gary Nabel] continued to pursue this effort, we decided to back away from the human serotype 5 adenovirus and instead together with collaborators from the University of Pennsylvania started developing vaccines based on adenoviruses – again, these fairly harmless viruses – that were isolated from chimpanzees. And the reasoning behind it was that humans in general don’t have close contact with chimpanzees, so they are unlikely to catch viruses from chimpanzees, so the prevalence of natural infections of humans with these chimpanzee viruses should be fairly low. On the other hand, chimpanzees are our close relatives, so the viruses that infect them are fairly close to those that infect us, and so we expected that these chimpanzee viruses would be as good as vaccine carriers as the human serotype 5 adenoviruses. And our experiments subsequently indeed showed that this was the case. So we developed these viruses, we expressed antigens of HIV in them,  we showed that they worked well in monkeys, and we are now trying to raise funding to test them in humans.

FH: So this vaccine if I understand correctly starts with an adenovirus as  kind of a backbone, and then you engineer HIV genes into it, and overall it then becomes a vaccine?

HE: Right, for if you infect a cell with it, it expresses then the antigens of HIV, and then the body will make an immune response against it.

FH: You’re currently working with colleagues at Oxford University on a Gates Grand Challenge Grant, supported by the Gates Foundation. Can you briefly describe the global health aims of these grants and the goals of the project you’re working on? 

HE: Our Gates Grant focuses on making a malaria vaccine. Malaria is, like HIV, a tremendous global health problem that is mainly affecting developing countries, and we don’t have a vaccine. We have some drugs against malaria, but malaria, the malaria-causing parasite, is changing, so it is no longer affected as well by these drugs as it used to be. So our Grand Challenge Grant from Gates Foundation, basically, focuses on making a malaria vaccine, based on these adenoviral vectors, where we also incorporate some adjuvants in order to increase the immunogenicity of the vaccine. An adjuvant is an additive to the vaccine that increases the effectiveness of the vaccine. And traditionally, right now we are using mainly alum as an adjuvant. We now know more about the immune system and can more specifically target certain pathways that have positive or negative effects on immune responses, to modulate immune responses. These are more modern types of adjuvants that very specifically target those pathways.

FH: Are there other vaccine development projects under way at Wistar?

HE: Well, there’s another project under way that deals with developing a universal influenza virus vaccine that is right now a very important and timely goal. This project is headed by Walter Gerhard, and his approach is to use a protein that’s a membrane component of the influenza virus that again due to structural constraints has parts that are very conserved. It is possible to make antibodies with a vaccine against these membrane components. The virus itself doesn’t really induce these antibodies, and these antibodies have been shown in animals to induce broad protection against different types of influenza virus. So the vaccine that he’s working on is a peptide vaccine, which is work that he’s doing in collaboration with Lazslo Otvos. And right now they’re in advanced preclinical testing with this particular vaccine.

FH: Would his vaccine, like the one you’re working on in your laboratory, also be a universal vaccine against all strains of flu, including the avian flu?

HE: His vaccine as it stands right now would not protect against all strains of the avian flu, for although these proteins are fairly conserved, they are not completely conserved, and there are a few mutations that some of the later avian influenza virus strains came up with that would circumvent protection by this vaccine. So at this stage, he’s working on proof of concept studies. One could readily add to the vaccine to ensure that it also would protect against additional strains.

FH: Wistar has a strong history in terms of vaccine development. Research at Wistar led to vaccines against rubella, rabies, and rotavirus. What role do you see Wistar playing in developing the next generation of vaccines? In particular, what role to you see the new Wistar Vaccine Center, which you now head, playing in global health in years to come? What do you hope to accomplish?

HE: Well, it’s sort of hard to predict the future. I obviously hope to accomplish with this center to follow the footsteps of those who were here before us to make vaccines that will improve global health. The vaccines we are focusing on, as you already mentioned, are rabies and HIV and influenza virus. One thing we have not worked on but that we are planning to work on is hepatitis C virus, which is another virus that has a high incidence of infections that not only cause acute infection but in many patients persist and then lead in some of those patients to liver cancer. So our goal is going to be – and we are a team of investigators with different expertise – to take a pathogen, and we’ve already started doing this with influenza virus, and then basically use our mixture of expertise to make a vaccine, test the vaccine in preclinical animals, if we have the funding conduct some limited clinical trials, and then try to partner with others, such as industry, to see if we can get this vaccine through advanced testing. I think what will really help us is our strong knowledge in immunology as a group. All of the members of the Vaccine Center are right now members of the Immunology Program. That will lead to a more sophisticated vaccine design than has been traditionally achieved by using virological approaches.

FH: Thank you, Dr. Ertl. Once again, Dr. Hildegund Ertl is a professor and Immunology Program leader at The Wistar Institute, as well as the founding director 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.

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