www.asiabiotech.com Special Feature — Bioterrorism

Bioterrorism Interview with

rofessor Donald Henderson is a Distinguished Service Professor Emeritus and Dean Emeritus of the School. He has a joint appointment in the department of . He is also Professor of Medicine and Public HealthP at the School of Medicine. He rejoined the Hopkins faculty in June 1995 after fi ve years of federal government service in which he served initially as Associate Director, Offi ce of Science and Technology Policy, executive offi ce of the President (1991- 1993). He later became the deputy assistant secretary and senior science advisor in the Department of and Human Services. From 1977 through August 1990, Dr. Henderson was dean of the Johns Hopkins School of Public Health. He came to Hopkins after directing the World Health Organization’s global eradication campaign (1966-1977). Dr. Henderson was instrumental in initiating WHO’s global program of immunization, which has vaccinated 80 percent of the world’s children against six major diseases and has as a goal the eradication of poliomyelitis. Professor Henderson is also a resident fellow of the Center for Biosecurity of the University of Pittsburgh Medical Center. He is presently a resident scholar at the Center for Biosecurity of the University of Pittsburgh Medical Center. The Center for Biosecurity was originally founded in 1998 as the Center for Civilian Biodefense Studies at the Johns Hopkins Medical Institutions. The Center was established to increase national and international awareness of the medical and public health threats posed by biological weapons. After the 9/11 attack, Dr. Henderson was appointed as the government’s fi rst Director of the Offi ce of Public Health Emergency Preparedness. He continues to serve as senior science advisor to Secretary Thompson of the Department of Health and Human Services and as Chair of the Secretary’s Council on Public Health Preparedness.

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Can you highlight the main points of the public lecture you gave in Singapore recently? The important message is that we are facing a very different set of problems in the 21st century. We are spending billions of dollars in trying to develop a vaccine that really is not in the horizon at the moment. We are also developing drugs that we have but these drugs do not cure. The number of diseases like SARs , encephalitis, monkey pox, H5N1 fl u, etc. are rising. There have been so many changes in the world that we have to recognize that we are at war with new emerging diseases. I think the world saw 30 new diseaseas in the past 35 years. These diseases are those we have never seen before. Some of them have emerged from remote areas; these are new agents that existed due to mutation and thus circulate among animals which then infect humans in contact with them. We now realize that there are a lot of diseases that can be transmitted from animals to man. Now, we have to also worry about the possiblity of some people using them as bioterrorism agents. The world is different now is due to a few reasons. Firstly, we have many developed urban areas. These places are changing very rapidly. Many of these large urban areas are in the tropical or subtropical regions. People live very closely in these places and thereby infections is easily transmitted at great speed. Many of these places do not have good sanitation. Thus, different organisms grow and have the potential of spreading as it never did before . Secondly, we are also traveling a great deal. The volume of air travel is growing immensely everyday. Now, the distance between two points on Earth is not more than 36 hours. The borders between countries are remarkably diminished now. In some poor areas, where resources are limited, many people are working very hard. These places do not have enough facilities or equipment. There is a case where hospitals in the rural part of the world have only fi ve syringes and sterilization is a problem. A number of hemorragic fever spread among the people there and, as a result, many died . This is the problem of hospitals in some areas of the world that has limited resources. Another problem we face is antibiotic resistance. The antibiotic that are effective before may not be effective when the organism mutate and develop resistance. One other problem is globalization and modernization. With modernization, we begin to process food in bulk. Producing food in huge amounts in factories has become a normal practise. In doing so, when contamination takes place, many people will be affected due to the large amount of food manufactured. This tremendous growth in food processing is a problem that we never had before. We are moving around the world at such a great pace now, it is hard to control the number of cattle or poultry we can rear. Agriculture in a large scale may cause infection of a large amount of animals. This in turn

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affects human. As we look at all these problems; overcrowding, ease of transport, large scale food processing etc, we have to also bear in mind another emerging problem—bioterrorism. In the past, people used to think that bioterrorism is bad and that no one would resolve to that because they are afraid the same terrible thing might happen to them. But now, it is different. Bioterrorism is a relatively new problem. As far as the US is concerned, there was not much concern about bioterrorism until about ten years ago. A few episodes took place. One episode is the religious cult from Japan that eleased the Sarin gas. They were also actively trying to aerolize anthrax and botulinum toxin not only in the US but also in Tokyo city. They had the intent to cause major destruction. Here is a group that does not have any connection with any state (totally independent), yet they are trying their best to use these bioterrorism agents. In another case, there was a release of anthrax in envelops. There was only 10 grams of anthrax in fi ve envelops. A small amount but it caused tremendous turmoil in the country. People all over the country were paranoid. There were buildings being evacuated. Thousands of letters were being processed not only in the US but also in other countries, in the midst of people’s fear that they might be attacked. We have not found the person who did it, but we are almost certain that this person still have more anthrax with him. There was a great deal of anxiety at that time. Now, we face another problem—H5N1 virus. The virus appeared in Hong Kong in 1997. The Hong Kong authorities killed billions of chickens due to this virus. However, recently, at the start of this year we see similar cases again. The question really is “Is it going to affect us humans”? I think from the standpoint of looking at all these, we began doing what we should have done long ago. We began to recognize we are really going to have a brand new strain of fl u virus. In 1957, a brand new strain evolved. As you know, back in history, we are looking at about two to three new strains every century. There has been a major change in the virus and we can expect a pandemic again. What happened recently in Cambodia, Thailand, Vietnam brought home the message that this is a problem that we cannot stop totally. We have to be prepared. We are going to prepare hospitals in case some people ever get infected with H5N1. Even if the virus does not spread, it could happen 10 years or 20 years later. But when we look back at what happened in 1918. That was a ferocious epidemic that killed millions. Most of the people who died were in their 20s, these people are supposed to have healthy immune systems to fi ght the infections. If we have antibiotics then, these people would not have died. However, looking at the case studies, many of them died within two or three days. This means that they died too fast and there was not even a secondary immune response that can take place. It was clearly viral pneumonia that blew out of proportion and killed many people. Now, we hope we can do much better with antibiotics. I am not sure if we can do any better then we used to be. A fl u like the one in 1918 can be as big a

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problem to us now as then. We begin to understand that notwithstanding the progress we have made in the biomedical science, we are by no means prepared to deal with this sort of problem which can result in a global catastrophe. Well, we can try coming up with a vaccine quickly. But we are using the same method of vaccine production as what we were using 50 years ago! Instead of using modern tissue cell culture, we are still using eggs. We should be using the tissue cell culture method. There has been talk about it 25 years ago but most pharmaceutical companies do not want to change due to cost problem. Also, we are not supportive of the research being done behind producing vaccine. At this point, we do not, by any means, have enough vaccines around. Many changes need to take place. We should have implemented all these changes years ago, but we are only developing them now. We cannot expect things to change overnight.

What about DNA vaccines? DNA vaccines, in theory, has a lot of problems. Many people feel that we need to keep working at it. So far, this had not been successful though. We all do recognize that vaccines can be of valuable help and we are all working at it. I think we can see a tuberculosis vaccine in about fi ve years. Malaria vaccine will take a longer time. HIV vaccine, I have to say, has always been disappointing. I do not think we are going to see an HIV vaccine soon. But a lot of work is currently being done on all three vaccines. Another area of research is to look for ways to sense or detect something very quickly. So when somebody release something into the air eg. anthrax, it will probably take two or three days before the fi rst case begins to appear. The disease moves so quickly that you will have to detect it when the agent is being released. This is so that we are able to quickly provide antibiotics or vaccines to those who might have been exposed. That is a big challenge because you are sampling a huge amount of air trying to identify very few organisms that are moving very quickly. However, there is the problem of false positives. In a big city, if there is anthrax infection, and immediately the government brings in antibiotics and vaccines but realize it is a false alarm; this may cause lose the public to lose confi dence. We cannot afford to have that. The government has got to have a high degree of specifi city and that is a tremendous challenge. We do not have anything at this point that is near to what we need. There are some people who believe that we really need smoke detector. The technique is a very simplistic analogy. We will have an anthrax detector in every home and every building. I think this idea is reaching for the moon.

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Do you see new nanotechnology as a solution to all these problems? I think nanotechnology is going to be applicable in many areas. It is really hard to defi ne where that might go. One major problem is the fact that people with inventive minds are not discussing with the people who implements things. Or do we take some other deviant route to get something less expensive and potentially applicable. No point developing an elaborate machine if no one can afford to buy it. This is where we are not getting enough communication between those who have to deal with the problems and those developing the devices.

Do you think Singapore is vulnerable to a terrorist attack? I would say yes. It certainly might. The concern is simply that terrorists are intent on disrupting the entire population and disrupting normal trade and commerce. For example, the SARS outbreak has been a lesson to everyone concerned. In Toronto, we could still feel the effect of SARS on tourism. Singapore and Hong Kong faces the same problem. A major hiccup could occur in air travel or shipping, for example, the release of an agent in an airport, could affect everyone in the world.

Do you think it is worthwhile for Singapore to prepare for an attack? If yes, how far should we go? Singapore and the US have also invested a lot in preparation for an attack. We are really going to be prepared to deal with a large number of casualties. We need to prepare for an emergent event like SARS. They are similar problems we are facing. So as we look at it, it only makes sense to be prepared for some of these things. Suppose we have 500 casualties due to whatever cause, in the next 24 hours where are these people going to go to, who is going to take care of them, what are the supplies we need, etc. Do we have enough supplies? The next issue is that there is a tendency in many parts of the world to have smaller and smaller warehouses of supplies. Consequently, there are no reserves if a major catastrophe happens. We are fi nding this to be a surprisingly diffi cult problem. Recently (another factor here), we realized that we need to have a better way to communicate among the nations and also to make decisions to develop vaccines and drugs. We recently had an exercise whereby leaders from Europe and the US sit around the table to talk about how they would react if a small outbreak is to occur. Former secretary Albright from the US was there too. In a way, this is a game, and it is called table top exercise. They got very much emotional and involved about this. The smaller countries in Europe said if a small outbreak is to occur, they would want to vaccinate all their citizens and try to protect them. The bigger countries like France and Germany object to that. There is not enough vaccines in the whole world to vaccinate everyone. We got to conserve the vaccines and you cannot take that action. We have not thought about it in that way. We usually think of “ you take care of your own problem.”

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Here certainly, they realized, “goodness if they are going to do it, we are going to take action too.” Then, they started talking about closing borders and very quickly they realized this is going to be a huge economic disaster. People cannot move across borders, and shutting down airports immediately in response to this would stop the outbreak from spreading. However, all these problems are inter-related. If you try to do that, you are going to create an enormous problem.

When did this exercise take place? It took place in January in Washington. The whole event is taped by the BBC. It received moderate amount of media coverage in Europe and the US. It led to a few countries starting to talk about this problem seriously now. If we have this problem, how can we as countries make a decision that is the best thing for all of us. Furthermore, there are only 30 countries in the world that has small pox vaccines. What happens to a country that has no vaccines? Where are they going to get vaccines because other countries would want vaccines too? How are we going to decide who is going to get the vaccines? How are we going to decide who is going to get it? Who is going to make it? When you have enough for your own country, can you afford to send some to someone else in another country? Right now, there is no organization that creates a global stockpile. This is just a realization. This is something new. We did not have to deal with this before. In the case of bird fl u, many countries are stockpiling up Tamifl u. For most countries there is no vaccine production. The amount of infl uenza vaccines that are being used is proportionate to the population For the US, we have about 90 million dose, which is about a third of our population. It is about what we use every year with a lot of pushing and encouraging for people to get vaccinated. But if we have a major fl u outbreak, eg. bird fl u, we would want to vaccinate everyone. We may be able to get away with one dose but for this vaccine, we need two doses to get enough antibodies to work. How is the manufacturer going to make such a big amount of vaccines? There have been discussions with the manufacturers all around the world about producing more vaccines but there is a limit about how much they can produce and the problem of not depending on fertile eggs have been a real limiting factor. Because the eggs have to come from fl ocks of chicken which are free of vaccines agents like viruses that infect chickens normally. They have to have a normal fl ock that is free of organisms. You can only get a number of limited eggs being produced. No one is going to produce a whole lot of chicken eggs in this special condition as it is going to cost you a lot of money. It is also not really necessary. So there is a real dilemma at this point as to what we should do to produce the fl u vaccine.

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This would be solved if we could produce tissue cell culture . Secondly, if we can stretch the amount of antigen we could only produce so much virus to produce the vaccine. If we use less virus in producing protection, that would make the vaccine go much further. It has also been demonstrated that if you put the vaccine into the skin, intracutaneously, you can use less vaccine. But it is diffi cult to do this. You have got to package this way of administration too. Packaging it is also another problem that has not been explored too.

For the past 50 years, we still use the old method of producing vaccines. How long do you see the new method being used? I would hope within a year companies would use the more modern methods. But this is going to depend on the government making the commitments with the pharmaceutical companies. Today, pharmaceutical manufacturers have been reluctant to put in a whole lot of money into producing new plants, new equipment. This is because they would not know how much of the vaccines they would be able to sell. This happened with SARS too. There was a number of companies that were very reluctant to produce any vaccines. It will be great if the government would say, “here is the contract, we will buy this amount of vaccines from you.” This way the companies can go ahead to manufacture them. But this has been very diffi cult to do. We are struggling to fi gure out how to make a commitment. What risks are we willing to take?

You said that a year from now, you hope to see some companies starting to use the new methods of manufacturing vaccinations... Yes, some of them will be but I will be very surprised if we have enough vaccines to see a change.

Are they going to use the new method of cell tissue culture? I think they will be. Some of them will, to some proportions in their production. But that is pure proposition at the moment. Some of the manufacturers said it is very diffi cult. They said they are also having diffi culty producing tissue cell culture. However, a couple of other manufacturers told us things are rather well.

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So who are the ones who have made a breakthrough in this? The biotechnology companies do not really like to talk about this. They will only talk about it very quietly. That is because they hate to say they have everything solved and the next thing they know they are disappointing everyone else.

But how is the tissue culture approach compared to the old method ? Is it faster? It should produce as good a vaccine as the old method. There is no question about it. There is supposed to be a shorter time of production. But there is a particualr problem that one should recognize. There is some very basic research we need to look at. Every year the virus is changing a little, and if you use a vaccine that is made a year or two ago, it may not provide very good protection . In the case of H5N1, we are not getting a ‘drift’, we are getting an ‘antigenic shift.’ This is an entirely different problem. So the question is what should we do now? What vaccine should we be producing? This is generally decided by the WHO. They have a group that meets different countries and they will eventually decide on what is the best strain to use. They do that around January or February. That is the production of vaccines for the next winter. When that happens, you have got a new vaccine. First, you got to get the viruses working so that it can grow well in the eggs. Then you have to begin production, you have to test it. It is very unlikely that you can deliver the vaccines in seven or eight months after you decide what strains to use. We do not have vaccines like this that we can work with. At this time, we are producing the H3N2 strain that has been going around causing major outbreaks. There is also H1N1, which is another component to it. Then you have the infl uenza virus. So you have got three different strains. It is the standard conventional vaccine for infl uenza. But right now, production is going on in the US with these three agents because this is what we need for vaccination beginning about October each year. Now, what should we do about the H5N1 strain? We only got so many eggs to produce all of the strains and thats it. The question is should we stop production and shift it to produce H5N1 or shift part of the production? Well, at this stage, there are still studies underway to fi nd out how good protection H5N1 is going to produce anyway. There is great dilemma on everybody’s part right now in terms of what is the best thing to do. Can we shift to H5N1? What if H5N1 infection does not occur, we can be assured a lot of people are going to say “ I told you so. You shouldn’t have done it.” If we do make the shift, there would not be enough vaccine to go around. Others would say, “You stupid people, why didn’t you work faster to produce the vaccine.” We cannot win on this. That we are aware of.

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The drug, Tamifl u, is produced by only one company. It has got limited production. It appears to be able to prevent infection if you are taking it. If you are treating someone with it, it seems to reduce the symptoms by 24 hours. Some believe that it will protect against any fatal outcomes too. Experience is needed here because we have not got many cases of H5N1. But the quantities is limited. Our dilemma is who do we give the drug to? Do we give it to all the patients? Or do we give them to the medical personnel who looks after the patients? If we were to give to all the patients, do we have enough doses to go around? As this medicine requires eight to ten weeks of dosage., that will take up a lot of doses. Or why don’t we ship a lot of this medicine to South Asia? So they can detect an outbreak and use the medicine to prevent it from spreading? I have seen enough fl u and we have done some calculation with the group at Imperial College and some of the people from Johns Hopkins. They fi gured that this can be effective as long as health personnel are prompt in detecting the fi rst 30 cases of infl uenza. If I am a health offi ce, I will be unlikely be fast enough to detect the fi rst 30 cases of infl uenza. If we see a few cases here and there, before we know it, there will be more than 30 cases around anyway. I will not be able to stop the spread completely. Also, countries like Vietnam has a limited number of healthcare facilitators. They would not be able to stop the spread. So that is out. The drug is in short supply. I have talked to the people in the UK four or fi ve weeks ago. They have ordered about enough drugs for 25% of their population. But it is going to take two years to be delivered. The US has about 3.5 million dose. What would happen if we have a pandemic with 25% population infected? That is 70 million people. We cannot even treat the people who have developed the fl u to start with. We really do not have enough drug for that.

You seem to have a dim view of all these. Any good news? The good news is that there is general recognition that infl uenza is a problem. Whatever happens to H5N1, we really have to discuss it seriously and there are countries which are already doing so. They are doing better research, trying to come up with better vaccines and more rapid ways of detecting the disease. There is a fl urry of activities going on. That is the good news.

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