The Fifth Haskins Lecture – November 15th, 2002

The comments below were made by Anthony Fauci at The Haskins Lectureship in Science Policy on November 15th, 2002. The title of Fauci’s lecture: BIOTERRORISM: A CLEAR AND PRESENT DANGER

“One of the first things I had to do—and I can tell you honestly I never would have imagined in my wildest dreams, through all of what we had been through with HIV/AIDS and other challenges to the public health system—the way we had to get a handle on bioterrorism was to associate ourselves, purely because of our lack of comprehension and experience, with groups of people that I never would have thought in my wildest dreams that I would be associated with. Those were people who were responsible for the offensive bioweapons program that we had in this country up to 1969, when President Nixon—essentially by executive order—discontinued that program. Not only did I have to come into contact and learn from them—as well as our allies from the bioweapon years—but I also met people who came over to our side who were on the other side in the cold war. And what I learned—and I had to learn quickly—was if you’re going to mount an appropriate biodefense effort that involves the biomedical research community, you have to know the difference between biowarfare, terrorism, warfare, and bioterrorism.

We know what warfare is; unfortunately our nation and others have been involved in some terrible wars over the past decades, all of which we in this room are familiar with. I just showed a cogent example of terrorism, but the critical issue is to understand the difference between biowarfare and bioterrorism, if you’re going to mount an appropriate biodefense for the civilian population. Now let me explain what I mean. Look at what the Army of the Department of Defense needs to deal with: They need to deal with a population that (by very definition of the fact that they’re in the service) is young and is healthy. So they have a very different population to protect than we in the civilian sector. We have to deal with infants; the elderly; pregnant women; people on immunosuppressive drugs; HIV-infected individuals; people with cancer, on or not receiving chemotherapy. So when you’re talking about vaccines and therapies, it’s an entirely different ballgame.

Second, among other points, is that biowarfare is not successful unless it is a very efficient killer in a strategic and tactical manner. In other words, you have to interrupt supply lines or kill a lot of troops. You’re not going to terrify Special Forces: You’re either going to kill them or you’re not going to kill them. Another issue is understanding the host response. You can’t possibly vaccinate everybody against every microbe, so you have to understand how to boost the immune system and how to make therapeutics.

Let’s move on rapidly now to smallpox, because that is on all the networks and in all the major newspapers.

[New slide] This is an electron micrograph of the Variola major, or smallpox, virus. I’m going to tell you a little bit about that, because you’re hearing a lot of things about it, some of which are conflicting, a lot of which are confusing. Historically, smallpox is one of the most—if not the most—important diseases known to mankind. It has actually shaped civilizations. Hundreds of millions of people have died of smallpox over the years. The earliest known case—certainly not the earliest real case—was in Pharaoh Ramses V, who died in 1157 B.C. [We know] only because we had a mummy to do DNA testing on to demonstrate smallpox. Also, smallpox is important historically because it was the prototype of what you can do with vaccines. In fact, the use of Vaccinia, which is a relative of the cowpox that was used by Edward Jenner in vaccinating James Phipps, was such an impressive feat that now we call everything a vaccine; whether it’s for Haemophilus, hepatitis, polio, we call it a vaccine. But the name “vaccine” really comes from vaccinia, which was really the first vaccination against smallpox. (Parenthetically, that is also one of the most famous unethical experiments that was ever performed—never having got an informed consent and challenging somebody with a lethal disease—but we won’t go into that right now!)

[New slide] There’s an interesting association between innate and adaptive immunity, which is shown on this slide. As we evolved as a species, the ancient predecessors of the human race had an innate immunity that was very nonspecific, which protected them against toxic affronts against them. Amoebas have it. If you look at adaptive immunity, that’s an evolution that we, and some of thehigher animals, have that can actually specifically recognize microbes. We are now beginning to understand the extraordinary interaction between innate and adaptive immunity, which can actually nonspecifically boost up the ability of the body to respond. There’s an enormous amount of work going on in that arena now. So now we’re faced with a policy decision: Do we vaccinate the 500,000 smallpox response people and the 10 million people who are health workers and firemen and police? And what about making it available to the general public? I don’t know about the editorials in Los Angeles, but the editorials in New York and Washington are saying, “In our libertarian society, we need to make vaccine available to people who want it,” which is not an unreasonable thing to say, or even to execute. But if one does that, what we need to understand are the complications of the smallpox vaccine. They’re rare, but they’re serious, and that is the reason why the administration and the Congress and others—particularly the administration, because it’s their decision—is being very deliberative about that decision, because it’s not a decision you take lightly. The best data on the complications of smallpox comes from the last big cohort in 1968.

[New slide] This is a typical primary vaccine site reaction. This is what happens if I were to vaccinate a very healthy person, day 4, then day 7. By day 14 you get a scab that falls off, and that’s it. You get a little ache, you may get some swelling of your lymph nodes, and then you’re protected. However, for every million people you vaccinate, there will be one to two deaths, and about 14 to 15 life-threatening events, and about 60 less serious events. Of the life-threatening events, there’s encephalitis, which occurs predominantly in children. If you’re going to vaccinate first responders, you’re not going to be vaccinating children, so already one of the major cohorts most susceptible to a major complication is taken out of the equation. But, if you let the vaccine be available to the general public, and a mother or a father says, “I want to vaccinate my child,” and the vaccine is made available, there may be a very rare—but nonetheless serious—complications, like encephalitis. There are also some other types of complications that I’m going to show you. I apologize for this, but I feel I’ve got to show them to you because I know there are people in the audience who are thinking, “Well, if the vaccine becomes available, maybe I will be vaccinated.” I can tell you that, at a Senate hearing, Arlen Specter pointed his finger at me and said, “I’m going to get the vaccine as soon as we get it out, because I want to get it for myself and my family.” I keep trying to show these slides, but I haven’t had the chance to show him yet.

[New slide] This is a baby who has what’s called generalized vaccinia. This is not lifethreatening. You put the vaccine on the arm and, for some reason that we don’t understand, the child can’t contain the virus that’s in the vaccine, so it just spreads. The child got well and was okay.

[New slide] This is a child who accidentally inoculated himself: The child scratched the vaccination site and then rubbed his eye, and this is what happened. Again, this is very rare. You’re talking about a couple cases out of a million vaccinations, but, when people make that decision, they better understand that.

[New slide] This is what happens when a child can’t contain the vaccine virus locally: This is called vaccinia necrosum.

[New slide] Then this is what happens when that gets bad. Again, all these adverse reactions were seen in the ‘50s and ‘60s, when we were routinely getting vaccinated against smallpox, but we didn’t have all-night CNN and we didn’t have 24-hour news. They happened, but were accepted. Why? Because there was a real threat of smallpox in the world.

[New slide] The next picture I’m going to show you—and that’s the last of the bad ones—is of a child who developed eczema vaccinatum, not because the child was vaccinated, but because of contact with a child who was vaccinated. So I vaccinate little Janey, and she goes and plays with Helen, and the child who’s unvaccinated could get it. But, again, if you’re in the middle of a smallpox problem, the complications are so rare that there’s no doubt you absolutely should get vaccinated if you have an attack. But how do you do a risk–benefit ratio analysis when you know the risk of the vaccine but you don’t really know what the risk of an attack is, except that it’s not zero? That’s a very tough calculation that we are facing now. Having said that, one of the answers is to develop a completely safe vaccine, and we can do that. There are some vaccines—particularly one called modified vaccinia Ankara, which is very safe and has been used on more than 100,000 people. We can’t prove its efficacy absent a smallpox outbreak, so we will have to go with the two-animal model, because it has never been used in the setting of a smallpox epidemic. 

Unfortunately, now we have a different kind of emerging and reemerging disease—bioterrorism—but we need to think of it in the context of the broad emergence of microbes and their interaction with mankind. So what I hope—as a biomedical researcher and a public health official—is that the amount of resources and effort and focus that we’re devoting to biological terrorism—and the defense against biological terrorism—might ultimately, if looked upon in the context of all emerging and reemerging diseases, be an important and positive boon for public health, now and in future years.” 

QUESTIONS FROM THE AUDIENCE ARE BELOW.

AUDIENCE MEMBER: My understanding was that you could still give the smallpox vaccine after infection, and, if that was the case, would a strategy be—with the proper diagnostics—to wait until infection actually occurred before people got vaccinated? 

DR. FAUCI: The answer is “yes” to your first point, and then there’s a caveat with your second point. It has been shown in some studies in Bangladesh—not overwhelmingly definitive, but strongly suggestive—that you have about three or four days to get vaccinated from the time you … come into contact and get exposed to somebody with smallpox. If I get vaccinated within those three or four days, there is a good chance that I would be protected. So you can, postexposure, vaccinate against smallpox. That’s not the usual situation with microbes, but it’s true with smallpox. That works okay for a cluster or so of smallpox cases. But it wouldn’t work that well for a massive attack. So the answer to your question is, “You’re absolutely right: You have a leeway of four or five days.” What that underscores is the point that I made, that we need a better public health delivery system, because the better the system is, the easier it’s going to be to vaccinate people who come into contact with someone, and save them from actually getting infected.

FAUCI ON ANTIBODIES

AUDIENCE MEMBER: You’ve mentioned that we might develop antibodies to some of these pathogens and store large quantities, and, of course, there have been technologies developed recently to humanize myriad antibodies, generate fully human antibodies in genetic mice, and so on. Would you elaborate a little more on that strategy, and how you see it working? 

DR. FAUCI: The strategy that’s being referred to is [this]: It is possible, with the technology we have today, to pick out a particular protein on a smallpox or on an Ebola, make an antibody against it, [and thereby] actually block the ability of that microbe to infect someone. The trouble is that the general approach is to infect people, then draw their blood and to purify it to get gamma globulin. That’s a very tedious procedure that isn’t volumefriendly. It just takes a lot of work. There’s a technology of making what are called monoclonal antibodies in the mouse, by fusing a specific cell with a tumor cell. And you can make completely unlimited quantities of antibody. You can humanize it by genetically manipulating it so that it has the appearance—to the immune system—of being a human antibody, even though it was originally derived from a mouse. Personally, I happen to think that this is an important approach: to stockpile monoclonal antibodies against botulism, against smallpox, and against other pathogens, because you can always use them like a gamma globulin shot. If there were an attack, you could get anybody who was exposed and just hit them with the appropriate, specific antibody. That’s much easier than vaccinating people a priori against 15 microbes.

FAUCI ON VACCINATING CHILDREN

AUDIENCE MEMBER: You showed Mike Lane’s data, with regard to complications, which is ’68 data. And, as you pointed out, since that time there’s been an enormous increase of immunocompromised people. Should there be a decision made to recruit, to vaccinate x hundred thousand people, do you anticipate that might be done in such an incremental way that one could look at the secondary complication rates and find out if those numbers really are relevant to the 21st century?

DR. FAUCI: Almost certainly it will be done in an incremental way—I can’t give you a 100 percent guarantee—but the complications from 1968 are a certain known number. There are those who, appropriately, argue—not argue, but put forth the fact—that, in the year 2002, there are many more immunosuppressed people. We have transplant people, we have HIV-infected people, we have people on steroids. We didn’t have that many people with these conditions back in 1968. So that tips it this way. What tips it the other way is (a) we’re going to be very exclusive in our criteria for whether or not somebody can get a vaccine, in the absence of an attack. So, if you have a history of eczema (atopic dermatitis), if you’re on steroids, if you have any suspicion that you’re HIV-infected (you should get tested) … we’re likely going to screen out a lot of the people who potentially are at increased risk today. Also, when you’re vaccinating first responders, you’re not going to be vaccinating children, and the majority of the serious problems are in the children, which I think the parents need to understand when they feel that they want to voluntarily get smallpox vaccine for their family. That doesn’t mean they shouldn’t get it, but they need to know there is a heightened risk in children.

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