Hemorrhagic Fever Viruses

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Hemorrhagic fever viruses (HFVs) are by far the most deadly of human pathogenic microbes. The CDC has designated nine HFVs as potential bioterrorism agents (Table 14.1). We will focus here on only two of these, the Ebola and Marburg viruses (Figure 14.2). Both of these viruses are fairly recent additions to the repertoire of human pathogens, and not that much is known about their interaction with their human host. There have only been a dozen or so outbreaks of these viruses since their discovery in 1967 (Marburg) and 1976 (Ebola).

We do not know what animals serve as a reservoir for these viruses—hosts that harbor them without contracting serious disease. Several nonhuman primates, such as rhesus monkeys and macaques, are fully susceptible to the ravages of Marburg and Ebola infection and would be unlikely reservoirs. Cases of human infection tend to occur in clusters, the origins of which are not always clear; in several instances human infection seems likely to have originated from contact with infected monkeys. Once one

figure 14.2

Ebola (left) and Marburg (right) virions. (Courtesy NIAID Biodefense Image Library.)

figure 14.2

Ebola (left) and Marburg (right) virions. (Courtesy NIAID Biodefense Image Library.)

person has been infected, however, transmission to others occurs through contact with fluids or tissues from previously infected individuals.

Ebola and Marburg viruses would certainly fulfill the CDC requirement that an agent have the potential to cause "public panic and social disruption." Through books and films in the past two decades, plus regular media coverage of outbreaks, these viruses may have, along with anthrax, the highest public profile of the Category A agents. Because of the high mortality rate, the fear factor may be even greater than for anthrax.

As of mid-2005, 1,848 cases of hemorrhagic fever in humans caused by Ebola had been reported to the WHO, with 1,287 fatalities (69.9%). Three hundred fifty-four cases of Marburg fever had been reported, with 288 deaths (81.3%). Almost all of these cases arose in Africa. Many have been traced to transmission through unclean clinical syringes, a common problem in rural Africa; the resulting mortality in these cases was 100%. We might hope that mortality would be somewhat lower in industrialized countries, but make no mistake: these viruses are far and away the most lethal pathogens on the CDC's A list.

Both the United States and the Soviet Union produced aerosol versions of HFVs, including Ebola and Marburg viruses, for biological warfare. These were never used, and we have no idea how effective aerosolized HFVs would be. Aerosolized HFVs are relatively stable and cause disease and death in nonhuman primates, and it is presumed they would do the same in humans. Aum Shinrikyo traveled to Zaire to obtain samples of Ebola but was unable to procure enough stock to create a weapon.

Because there have been so few cases, usually occurring in remote areas, exactly what happens in the course of a naturally acquired Ebola or Marburg infection in humans is not entirely clear. The popular depiction of humans being literally melted away from the inside out contains a good deal of dramatic license, but these are undeniably ghastly diseases. Blood vessels as well as blood cells are a frequent target of the viruses and are rapidly destroyed once the virus begins to spread in the body, causing massive internal bleeding. But organs such as the liver and kidneys are also severely damaged. Symptoms of hemorrhagic fever include the usual early signs of any microbial infection, but these are quickly followed by widespread body rashes and blood spots in the skin, blood seepage from various orifices, convulsions, delirium, and a rapid descent into shock and coma. There are no antiviral drugs effective against Marburg and Ebola. For the few people who survive, there is a long period of impairment of numerous body functions.

We know very little about the human immune response to Ebola and Marburg viruses. A 1996 study in Gabon showed that those infected with Ebola who subsequently died of circulatory collapse failed to develop a strong antibody response and had no CD8 killer cell response at all. Among close family members who did not die, about half had produced Ebola antibodies, indicating they had been exposed to the virus, and most also had activated CD8 T cells and a strong inflammatory response.

Why some people were able to mount a protective immune response to Ebola, while others weren't, is not presently known. In mice, we know that both antibodies and CD8 killer cells are induced by exposure to Ebola. Passive transfer of the antibodies to naive mice did not provide protection against subsequent exposure to Ebola, but transfer of immune CD8 T cells did. Passive transfer of HFV antibodies in nonhuman primates has not generally provided much protection, and there is little hope that this would be an effective treatment in humans.

Attempts to produce an effective vaccine against Ebola and Marburg had been generally unsuccessful until 2005, when a research group centered in Canada developed a single, DNA-based vaccine that is very potent against both Ebola and Marburg. Just one injection protected monkeys from infection by either virus. The Ebola/Marburg gene was engineered to be delivered preferentially to macrophages and dendritic cells, to optimize rapid antigen presentation of viral peptides to T cells. It is possible that with further work this vaccine could also be made effective for other A-list HFVs. More work needs to be done before human trials can begin, but this vaccine looks extremely promising.

So what do we know about the ability of this wall we hide behind— our immune system—when it comes to bioterrorism agents? Can it help us? Well, the first thing to remember is that, with the agents on the CDC's A list (not to mention lists B and C), if our immune systems could stop these agents dead in their tracks, they wouldn't be on the CDC lists. The real question is, is there anything we can do to help our immune systems do a better job?

One key to helping the immune system is to have the most thorough knowledge possible about how our immune system interacts with these pathogens once they have invaded our bodies. As we have seen, the diseases caused by A-list pathogens are so rare in the United States that we have had little opportunity to study how the immune system responds to them. And until recently we have expended little effort in developing effective clinical measures to guard against them. Most first-line health care responders have no experience with either these pathogens or their diseases, which can cost precious time in identifying the problem in a real attack.

This is quite different from the pathogen that causes AIDS—the HIV virus. We probably know more about every aspect of HIV and its interaction with human beings and their immune systems than any other pathogen on earth. If we are really concerned about bioterrorism with the agents described in this chapter, we need to know much more than we do at present about how they work, and most of all how they are handled by our immune systems. Research programs to answer these questions are currently under way.

The question is often asked, why wouldn't bioterrorists use HIV as a weapon? Why isn't it on the A list? Unquestionably, the release of HIV over a large metropolitan area could generate a maximum fear effect. And as we know all too well, all but a tiny handful of us are defenseless against HIV, with no vaccine on the immediate horizon. So the fear factor probably extends to would-be terrorists themselves. They may be extremely reluctant even to get into the same room with HIV. Another factor is that the incubation period with HIV, before frank AIDS sets in, is 6 to 10 years. Suspiciously large numbers of new cases would likely not be apparent for several years at a minimum. The immediate public relations sensation so craved by terrorists would be lost.

Still, the overall psychological impact on affected populations could be enormous. In the end, the main thing preventing use of HIV is that it is an exceptionally fragile virus. Exposure to anything other than a warm, wet human body disables it within a matter of hours. Aerosolization would almost certainly cripple it. Laboratories working with HIV must take enormous care to keep their strains viable. It is, in fact, a poor candidate for even the CDC's C list.

There are three general strategies for helping our immune systems deal with the kind of pathogens we do find on the A list. The first is to produce enough of what we might call "traditional" vaccines that are effective enough to be of help warding off a bioterrorist attack. Preferably, we would like to have vaccines that could be of help after someone has already been exposed to a particular pathogen. But traditional vaccines are designed to work prophylactically—before contact with the pathogen. They are designed to generate protective adaptive immunity in order to boost responses to subsequent exposures to the pathogen. Normally, it doesn't matter that several weeks may be required to build up that memory.

Since we don't know which populations of people might be the target of an attack, in order for this approach to be effective we would have to immunize the entire nation—against six pathogens! We do something like that now, with our children, for the most common (and potentially crippling or lethal) childhood infections. And it works. But we do not have vaccines at present for any of the A-list pathogens that are suitable for mass prophylactic immunization programs, for either children or adults.

And it is not obvious we would want to undertake such a program even if we had such vaccines. There use would likely be limited to selective immunization of "first responders"—health care personnel, police, fire, certain military units. In the case of anthrax, the causative spores of which could linger in the environment for a long time after a terrorist attack, such vaccines could be useful to immunize individuals present but not infected in an initial attack. A great deal of research is currently directed at making faster-acting vaccines for all the A-list pathogens, and almost certainly we will get some vaccines that induce adaptive immune responses more quickly. But the chances are slim they will be able to act fast enough to be of much use in treating already infected individuals once a bioterrorist attack has been unleashed.

A second approach, still in the largely theoretical stage, takes advantage of the knowledge we have gained over the past decade or so about the workings of the innate immune system. For microbial pathogens (less so for their protein toxins), we now know that the innate immune system plays a direct, cognitive role in the early stages of all infections. Dendritic cells, macrophages, neutrophils, and even B cells have receptors for the pathogen-associated molecular patterns (PAMPs) present on all microbes (chapter 5). The innate immune system, remember, is our first line of defense in any microbial infection, keeping the infection at bay long enough for the adaptive T- and B-cell response to get up and running.

So a great deal of effort is also being expended to find ways to stimulate and strengthen the innate immune response that all of us will be mounting within minutes of any pathogen invasion and lasting for as long as the pathogen remains a threat. The innate response is crucial for triggering inflammation and for processing and presenting forms of microbial antigens that will bring T and B cells into play. Instead of focusing on the antigen-specific, adaptive aspects of vaccination, more attention is being placed on "vaccines" that provide as strong a stimulus as possible to pumping up the critical innate elements of the immune system at the beginning of the response. And because they are not directed at any particular agent, we would need only one such vaccine.

An incoming pathogen will of course trigger these responses on its own, but if substances can be quickly introduced into the body to accelerate that portion of the immune response, it is reasoned, we may be able to stave off the deadliest aspects of infection long enough for the more potent adaptive immune response to get off the ground. The studies of survivors of Ebola and Marburg outbreaks referred to in the last chapter provide strong motivation for this general approach.

The third approach to helping the immune system is to build better antibodies to use for passive immunization. Ready-made antibodies provide a powerful weapon against any bacterial and many viral infections and are also useful for neutralizing micro-bial toxins. If injected during the first 24 hours or so after someone is infected with a pathogen or toxin, infection could in many instances be enormously reduced, buying precious time for the innate system to complete its job and for the adaptive system to begin functioning.

The problem, as we have seen previously, is that most of these antibodies are made in animals, usually horses, and the antibodies themselves trigger an immune response in the person into whom they are injected. A single injection of horse antibodies into a person doesn't cause a problem, because by the time that person makes antibodies against the incoming horse antibodies, the horse antibodies are gone. Those not taking part in neutralizing microbes are cleared from the blood, like any other protein. But a subsequent administration of horse antitoxin antibodies into that same person would quickly encounter large quantities of that person's antihorse antibodies and be neutralized. And it is entirely possible in a terrorist attack with large amounts of a deadly pathogen that one injection of antibody might not be enough.

Humans recovering from natural infections or planned immunizations with crippled pathogens are also a source for antibodies that could be used for passive immunization. Although a slight immune response would be triggered in the person receiving these antibodies, the response would be relatively mild compared to the reaction against horse antibodies and could be managed. But the number of persons from whom such antibodies could be harvested is vanishingly small compared to the huge numbers of people who might need treatment in the immediate aftermath of a bioterrorist attack with a particular pathogen.

Great effort is now being directed at producing "humanized" antimicrobial antibodies for use in passive immunization. This approach depends on the technique of monoclonal antibodies described in chapter 2, with a little genetic razzle-dazzle thrown in. Antibodies, say, to B. anthracis would first be produced in mice. Mouse B cells producing this antibody would then be isolated and converted to monoclonal B cells, which can be expanded enormously and used to produce theoretically unlimited amounts of monoclonal antibody specific for B. anthracis.

But these are still mouse antibodies. They will trigger the same kind of vigorous immune response in humans that horse antibodies do. This is where the razzle-dazzle comes in. It is possible to genetically engineer mouse B cells so that they produce monoclonal antibodies with most of their mouse portions replaced with a human counterpart (Figure 14.1). These humanized mouse antibodies will provoke a greatly reduced immune response in human recipients, one that will not wipe out a subsequent administration of humanized antibody. Initial trials of this concept in animal models have been highly encouraging.

So there is hope! Our immune systems clearly will need some help in building an effective immune response to pathogens used in a terrorist attack. Once our immune responses have a chance to get off the ground and make it to the adaptive response stage, they will be more than able to defend us against not only the first attack with a given pathogen, but any subsequent exposures as well.

A mouse is genetically engineered so that its antibody heavy and light chain constant region gene fragments have been exchanged with human H and L C-region gene fragments. (See also Figure 2.2.)

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