Anticipating Smallpox

 Science and Public Policy in the Face of Potential Bioterrorism

 A Symposium of the Georgetown University Health and Medicine Initiative

Edited by: Dr. Lowell T. Harmison

 

 

Organizers of the Symposium:

Cynthia Schneider
Former Ambassador to Belgium

 

Dr. Michael McDonald
Coordinator
Health and Biodefense Life Sciences and Society Initiative,
Georgetown University

Dr. Lowell T. Harmison

Table of Contents

 

 

I. Executive Summary 3

 

II. General Recommendations 8

 

II. Attendees 9

 

III. Smallpox Past and Present 10

 

IV. Individual Presentation Summaries 29

 

V. Individual Presenter Visuals 39

I. Executive Summary

Overview

On March 3, 2003, the Georgetown University Life Sciences and Society initiative convened a group of 35 top national and international experts in public health, medicine, human resources, communication, biodefense, and other aspects of the life sciences to address management of adverse effects, preparedness, and other concerns associated with smallpox vaccination in the context of an uncertain terrorist threat. The working session presentations and discussions led to a general conclusion that the smallpox campaign, at present, has multiple points of potential failure. Many of the anticipatable smallpox threats stemming from the potential actions of a flexible, intelligent enemy can and should be addressed in the shortest time possible, considering the economic impacts and other secondary effects of our responding to potential asymmetric attacks with smallpox as a weapon.

In the changing threat environment of the Iraqi war and the Severe Acute Respiratory Syndrome (SARS) epidemic, the Georgetown University Health and Biodefense panel participants (in meetings following the March 3 smallpox working session) have come to the conclusion that the National Smallpox Vaccination Program must become a subset of a larger National Biopreparedness Program. Many of the lessons learned with smallpox can be repurposed for our nation’s broader biodefense initiatives.

Ongoing solution panels are now being held to produce further specific recommendations in the following areas of biodefense:

• Social considerations and compensation
• Risk communication
• Mass psychogenic illness and psychosocial implications of quarantine/isolation
• Improvements in science
• Information technology
• Strategy, training, and implementation
• International
• Biodefense Industrial base

Threat of Smallpox

Smallpox remains one of the most dangerous potential biological weapons, because of its infectivity, severe disfiguring illness, and lethality, even in its naturally-occurring state. Historically, about one third of the population contracting naturally-occurring smallpox would die of the disease. Some forms of smallpox, such as hemorrhagic smallpox, are known to be essentially 100% lethal, even with the best medical attention.

The uniqueness of the current smallpox threat is its uncertainty, dependent upon the actions of known, and possibly unknown, terrorists willing to unleash smallpox as a weapon. Although there is no officially known naturally occurring smallpox in the world, outside of two secure repositories in the U.S. and Russia, there is intelligence that suggests that smallpox was weaponized in the U.S.S.R. prior to the collapse of the Soviet Union. Due to security lapses following the fall of the Soviet Union, it is thought that weaponized smallpox may have been introduced into the black market and may be in the hands of terrorists, and that possible stocks of weaponized smallpox may be available to terrorists through sources in North Korea, Iraq, and possibly Iran.

Current Plans to Address the Threat of Induced Smallpox

Shortfalls of the vaccinia-based smallpox vaccine were addressed in 2002. There is now enough of the vaccinia-based vaccine to inoculate ever man, woman, and child in the United States. There is, however, still a significant shortfall of smallpox vaccine to treat international cases of smallpox, if smallpox were again to become a pandemic disease. The World Health Organization destroyed its stocks of smallpox vaccine following the worldwide eradication of smallpox.

Internationally-agreed upon strategies for confronting an emerging pandemic of smallpox have yet to be codified into any meaningful kind of globally implementable plan. Some countries, such as Germany and Israel, have developed effective smallpox vaccination campaigns to address the needs of their own domestic populations. A strategic smallpox attack, which leads to a rapid global spread of smallpox is beyond the capacity of any current plans.

Several strategies for addressing the threat of induced smallpox through the National Smallpox Vaccination Program have been discussed in terms of the domestic needs of the United States. The National Smallpox Vaccination Program plan for protecting the United States citizenry from induced smallpox was completed in late 2002 and reviewed by the Institute of Medicine. However, the viability of the current U.S. smallpox strategy has increasingly been questioned as milestones are missed, actual number of vaccinees fall significantly short of projected goals of volunteer vaccinees, and patterns of potentially correlated, unanticipated adverse effects have emerged

The mandatory mass inoculation of specific populations of U.S. military personnel began in late 2002. The mass inoculation of health care workers began in early 2003 during what has been labeled the phase 1 civilian smallpox vaccination campaign. In March 2003, phase 2 of the campaign began with the initial inoculation of first responders (e.g., fire, police, EMT, and other emergency workers) that are considered most likely to come in early contact with individuals infected with the smallpox virus in the case of a biological attack.

President Bush established an objective of vaccinating 450,000 to 500,000 health care workers against smallpox by the beginning of March. The numbers of health care workers actually vaccinated has been far lower – less than ten percent of the goal by early March. Although the vaccine is now being made available to first responders, the vaccination of first responders remains low as well; while the assessment of the potential threat of an asymmetric attack with smallpox may have dramatically changed with the U.S. invasion of Iraq. In some assessments, the threat of smallpox has been reduced in comparison to the immediate threat of a SARS pandemic.

Adverse Effects Associated With the Current Smallpox Vaccine

The vaccinia-based smallpox vaccination provides relatively good immunity against smallpox infection for a period of approximately five years after vaccination and blistering of the skin around the site of the vaccination. The current smallpox vaccine uses a live vaccinia virus that commonly produces minor side effects (e.g., fever, headache, aches and pains). For about one quarter of the vaccinees, minor illness following vaccination leads to one to three days of work loss. Of greater concern, the vaccinia infection from vaccination has historically caused one death per million and potential life threatening conditions in about 17 out of one million people vaccinated. In addition, secondary infection from the vaccination site can lead to dangerous autoinoculation and infection of others upon close contact.

Known adverse effects (e.g., encephalitis, generalized vaccinia) associated with smallpox vaccination are apparent in the early stages of the vaccination campaign. More troubling, newly emerging cardiac-related cases (e.g., myocardial infarctions and myocarditis) following vaccination have led to many more hospitals pulling out of the vaccination campaign. An increasing number of states (e.g., Illinois, New York, California) have also postponed current smallpox vaccinations. By March 25, 2003, there have been 18 reported cardiac-related cases including three cardiac-related deaths under review by the CDC.

Current Concerns Regarding the Status of Vaccination

The smallpox vaccination program has stalled and may benefit from an improved strategy for pre-event and post-event vaccination. Part of the problem with the slow start of the vaccination campaign is due to the public’s perception that the risk of vaccination outweighs the uncer­tainty, and perhaps unlikely, threat of smallpox. Since smallpox has not been naturally occurring in the United States for many decades, the U.S. population has lost its perce­ption of the dangers of smallpox. Americans, with little experience of serious infectious disease and premature death, have become more risk averse in general. There also is a rising concern regarding the adverse effects of vacci­nation, in general, that has been further amplified by the negative press surrounding the perceived risks associated with the adverse effects of small­pox vaccination. Concerns about the adverse effects of smallpox have been amplified even further due to the lack of proper immunization compensation.

Recommended Interventions to Improve the Public’s Trust

Legislation proposed by the Bush administration and Judd Gregg in the Senate may lead to a reduction of the compensation concerns, if appropriately enacted. Further reduction of current adverse effects in comparison to historical trends could also improve trust in the vaccination campaign, by health care workers, first responders, and eventually the general public. Risk assessment and communication regarding smallpox vaccination adverse effects reduction could provide immediate benefits in enabling those who should be vaccinated to knowledgeably step forward on their own accord to receive vaccination, while those that are at higher risk of adverse effects are able to knowledgeably opt out of smallpox vaccination.

Several life sciences based initiatives could be developed over time to further reduce the risk of vaccination. Population data from the smallpox risk assessments could aid the program in focusing its priorities during varying pre-event and post-event scenarios. Efforts should be developed to address the psychosomatic dimensions of hoaxes, false alarms and mass psychogenic illness that could overwhelm health care infrastructure under certain conditions.

Improved vaccines, anti-viral drugs, and screening to reduce the risk of vaccination side effects with specific phenotypic and genotypic markers are likely to further reduce the danger of the smallpox vaccina­tion program, while improving herd immunity to smallpox. An enhanced strategy of establishing criteria and benchmarks for ensuring smallpox preparedness at the state and local levels is now being proposed by the Georgetown Smallpox program and could be underway within a short time. With this revised strategy, the smallpox prepared­ness program can succeed with fewer adverse effects and more confidence and support by the American public, their communities, and the professionals willingly putting themselves in harm’s way to protect them.

Conclusion

In summary, with relatively simple and cost effective extensions of the good work that has been done to date on the smallpox vaccination program, several current potential points of failure can be reduced or eliminated. Further efforts to build the National Smallpox Vaccination Program into a program addressing the broader array of preparedness considerations regarding smallpox as a first instantiation of biodefense would provide even greater benefits to the public’s health. Efforts to improve the science and technology infrastructure associated with smallpox preparedness, if properly planned and implemented, could provide cascading benefits in our preparedness for other risks of biological, chemical, and nuclear terrorism, as well as other emerging infectious diseases, such as the flu and the emerging epidemic of SARS.

General Recommendations

1: Acceleration of Modified Vaccinia Ankara vaccine clinical trials and improvement of methods of vaccine administration.

2: Implementation of a equitable compensation policy for adverse vaccination reactions.

3: Improvement of global smallpox surveillance and reporting, standardized diagnostic testing and outbreak response capabilities.

4: Formulation of guidelines for public health officials regarding containment, response and vaccination in case of a smallpox outbreak.

5: Development of adequate isolation capacity in major population centers and mobile response teams, staffed with trained and vaccinated health care practitioners, capable of isolating patients in transportable facilities.

6: Production of improved communications materials and methods to properly inform the public about smallpox issues, potential vaccinees about risks and contraindications, and health care professionals about smallpox diagnosis, containment and reporting.

III. Attendees

 

Mary Beth Albright C. Everett Koop Institute at Dartmouth

James August AFSCME

Larry Brilliant Cometa Network

Jeff Collman Georgetown University
Ed Eitson Department of Health and Human Services

Jeff Elting DC Hospital Association

Juan Enriquez Harvard University

Marty Fenstershieb Santa Clara County Health Department

Baruch Fischhoff, CMU/NATO

Larry Gostin Georgetown University

Barney Graham NIAID
Lowell Harmison

C. Everett Koop C. Everett Koop Institute at Dartmouth

Reinhard Kurth Robert Koch Institute

Steve Locke Harvard

Bob Malson DC Hospital Association
Michael McDonald Global Health Initiatives

Seong K. Mun Georgetown University

Glen Nowak Center for Disease Control and Prevention

Walter Orenstein Centers for Disease Control and Prevention

John Parker SAIC

Michael Richardson DC Hospital Association

Cynthia Schneider Georgetown University

Andy Stern SEIU

David Walker

Victor Weedn Carnegie Mellon University
Eric Weiss Stanford

Michael Zasloff Georgetown University
Howard Zucker Department of Health and Human Services

IV. Smallpox Past and Present

By David Walker

Smallpox is an ancient scourge caused by the variola virus which was eradicated in 1977. The importance of this achievement of science and public policy is difficult to overstate. Millions of lives have been saved. But eradication is not extinction. Concerns about the re-emergence of smallpox due to deliberate or accidental release have engaged the attention of policy-makers and public health officials around the world. Smallpox is transmissible from human to human and the infectious dose required to infect half of those exposed may be fewer than ten virions (2,5). It should be noted that for the United States, the potential for an outbreak of smallpox is largely a civilian issue since the military has established a policy of mandatory vaccination of personnel deployed to areas involving a significant risk of combat or bioterrorism.

Potential Sources of Smallpox

In 1978, the World Health Organization identified 76 laboratories working with smallpox isolates (3). Currently, reference stocks of variola virus are known to still exist only in secure storage at the Centers for Disease Control and Prevention in Atlanta, Georgia and the State Research Center of Virology and Biotechnology at Koltsovo in the Novosibirsk region of Russia, also known as the Vektor Institute. Smallpox virus must be handled in compliance with strict containment procedures in Biological Safety Level 4 laboratories at these two centers. However, control of viral stocks may be more uncertain than these precautions indicate.

The Vektor Institute was originally created as part of a massive bioweapons program in the former Soviet Union, which once employed up to 60,000 workers. This program produced between twenty and one hundred tons of weaponized variola virus annually for more than a decade (1,2). The whereabouts of all this material and the scientists who produced it has not been definitively ascertained. It has been reported that Libya, Iran, Syria, Iraq and North Korea have been actively recruiting experienced personnel (1). Hence, the possibility cannot be excluded that some viral stocks may have been sold on the black market.

During the eradication campaign, variolators in some of the most remote and unstable regions of the world, including Afghanistan, Paki­stan and Ethiopia, offered protection from epidemic smallpox by inocu­lating villagers with variola itself. Variolators maintained scabs obtained from smallpox victims as a source of inoculum, adding fresh material as available and passaging their stocks through susceptible individuals annually to maintain infectivity (3). There is little evidence to indicate that such material retained potency for more than one year under typical storage conditions. Nonetheless, under cool, dry conditions and protected from sunlight, viable virus can survive for years within scabs (3).

The most likely sources of seed stocks of variola virus at this time is from retained samples stored in laboratories. Despite an extensive surveillance effort by the WHO, it is possible that forgotten vials in deep-freezers may still exist outside the two known WHO collaborating centers (3). Given the passage of time, it is unlikely that material stored by variolators or weaponized smallpox produced more than a decade ago retains much potency unless it has been passaged periodically in the laboratory. Less likely sources of virus include an animal reservoir or from disinterment of smallpox victims buried in permafrost. The WHO discounts these possi­bilities (3). More speculatively, it is possible that variola virus could be reconstructed from published DNA sequences using the techniques of molecular biology.

Given a source of virus, reintroduction into the general population may be achieved by infecting individuals and allowing them to circulate during the infectious, asymptomatic phase of the disease. To produce a greater impact, the virus itself must be released. This requires large-scale production and weaponization of virus, involving substantial technical difficulties. Weaponization of smallpox at any scale requires drying, milling and sieving of the viral preparation to produce a fine, mono-dispersed pow­der that can remain suspended in the air. To retain infec­tivity during processing, storage and deployment requires the use of sophis­ticated equipment and production procedures using specialized additives. Nonethe­less, the bioweapons program in the former Soviet Union accomplished both weaponization and large-scale viral production, highlighting the importance of scientists involved with that effort and the potential for the proliferation of such knowledge.

Preparation for an Outbreak of Smallpox

The potential for the return of smallpox is a serious concern for policymakers. Many issues must be addressed to mitigate the impact of a potential release of smallpox. A policy of preemptive vaccination of military personnel and health care providers has been produced by the Bush administration. Mandatory vaccination of certain military personnel began in late 2002. Voluntary vaccination of health care workers began early in 2003, followed by voluntary inoculation of emergency responders. However, this vaccination program has been less successful than planned due to several considerations.

Improvements in vaccination programs are required to meet the goals proposed. By mid-April 2003, more than 285,000 dose of vaccine had been distributed to states and localities, but only 32,000 had been administered (6,15). Moreover, the costs of administrating vaccination have been greater than the $89 per dose budgeted. It is estimated that vaccination has cost an average of $249 from initial screening through post-vaccination follow-up. Recognizing these difficulties, the administration has recently scaled back the number of volunteers that it hopes to eventually recruit.

Preemptive vaccination

The U.S. government has obtained sufficient vaccine to immunize the entire population (4,14). However, the vaccine currently used to provide protection from smallpox is problematic and vaccination was discontinued in the United States in 1972 due to the risk of complica­tions. It is the oldest vaccine known and approval for use has been grandfathered by the FDA since it does not meet the safety criteria for new vaccines. As a live virus requiring viral replication for efficacy, the vaccine itself represents a threat to certain members of the population. Common side effects include fever, aches and pains; about one-quarter of vaccinees miss one to three days of work following vaccination. Historical data indicates that one death and seventeen life-threatening conditions per million vaccinated may be expected. Other adverse reactions include generalized or progressive vaccinia, erythema multiform, eczema vaccinatum, vaccinia necrosum and postvaccinal en­cephalitis (4). Recent experience with the voluntary vaccination campaign suggests that cardiac problems may also ensue following vaccination (17). Moreover, autoinoculation or infection with the vaccine of close contacts is possible. Particular care must be taken when changing the dressing over the inoculation site to avoid the spread of vaccinia virus.

Given the infectivity of the vaccine, patients with many conditions are contraindicated for vaccination (16), including any type of immunosuppression, such as transplant recipients, cancer patients and AIDS or ARC patients; other contraindicated individuals include sufferers of severe eczema or ectopic dermatitis and pregnant women. These groups may comprise up to twenty per cent of the population. In addition, following the recent emergence of post-vaccination cases of myocardial infarctions and myocarditis, those at risk of heart disease are advised to avoid vaccination. This significantly increases the proportion of the population for whom vaccination is contraindicated. In light of these multiple counter-indications, it is unclear whether the current vaccine can deliver the statistical level of protection within the population at large needed to provide preemptive herd immunity capable of preventing any release of smallpox from propagating beyond the index cases. A careful screening of potential vaccinees must be conducted prior to vaccination. Since the vaccine is infectious to others, not only the vaccinee, but all close contacts must meet the exclusion criteria. Again, this reduces the number of potential vaccinees.

To meet these concerns, the CDC has begun clinical trials of a new smallpox vaccine, named Modified Vaccinia Ankara. This virus is thought to offer high immunogenicity and attenuated replication, potentially alleviating many of the con­cerns with the current vaccine. However, it will be some time before the trials are com­pleted, approval for use granted, and adequate vaccine production is implemented.

Mitigating the consequences of vaccination

Several reasons are cited for the slow pace of recruitment of health care workers and first responders for the voluntary vaccination campaign. Some public health officials are uncertain regarding the immediacy of the terrorist threat of smallpox, while others have called for better communications programs to inform potential vaccinees of the importance of preemptive vaccination as well as the risks associated with the vaccine. However, the concern most frequently cited as inhibiting the recruitment of vaccination volunteers is the lack of a compensation program to reimburse volunteers for adverse reactions to the vaccine; such a program should also compensate anyone secondarily infected with the vaccine. Since vaccination volunteers are being recruited because of their job skills, unions have been vociferous in promoting the importance of a program to compensate affected individuals for associated medical expenses, death or disability, and lost work time. Congress is acting on a bill providing $40 million for compensation for adverse reactions to the smallpox vaccine.

Responding to Smallpox

The response to an outbreak of smallpox is as important as preparation for such an event. What should be done if public health officials become aware of the return of smallpox? The answer is: It depends. It depends on the number of people infected and the stage of infection when diagnosed. It depends on the number of per­sons having recent contact with an infected individual, with the traceability of con­tacts and on the size and characteristics of the locality where cases occur. It depends on whether or not index cases are initially diagnosed correctly, whether the patients have been isolated and whether the health care workers exposed were previously vaccinated. The best response must be adapted to the circumstances of an outbreak.

Nonetheless, certain objectives must be met in any outbreak. These include proper diagnosis of the condition, isolation of patients, infection control and con­tainment, and tracing and vaccination of recent contacts. If these critical objectives are not met early and completely, smallpox could begin to propagate as it once did, in a population now lacking immunity to this devastating disease. Propa­gation of smallpox beyond index cases may warrant a campaign of mass vaccination.

Diagnosis of smallpox

Smallpox is diagnosed clinically as a syndrome of symptoms (4, 11). After an incubation period of seven to seventeen days, a prodromal phase ensues lasting two or three days, characterized by severe headache, backache and fever. The rash then develops, first in the mouth and pharyngeal tissues, followed a day later on the skin. From this time, the patient is infectious, with transmissibility through direct contact and the droplet route. Developing first in the face and extremities, the rash spreads over the body in a centrifugal pattern. Beginning as small, reddish macules, the rash becomes papular over one or two days. Papules become vesicles one or two days later. Larger pustules develop from four to seven days after the onset of the rash, remaining five to eight days before crusting. The crusts will begin to separate the second week of eruption (4). On any particular body part, all the pustules will be in the same phase of development, although different parts may bear pustules in different stages (11).

Diagnosis from symptoms is important because many other syndromes can produce similar symptoms, including chicken pox, monkeypox, insect bites, acne, secondary syphilis and drug eruptions (4,11). Since a generation of physicians have been trained since the eradication of smallpox, it is possible that a diagnosing physician may never have seen an actual case of smallpox previously. Hence smallpox may be easily misdiagnosed (4,7,and 11). The CDC has issued guidance for clinicians to help diagnose smallpox and to distinguish the disease from chicken pox and ten other conditions (11).

The potential for misdiagnosis is a serious concern. If a smallpox patient is misdiagnosed, previous contacts, health care workers, other patients and visitors are all at risk of infection until isolation procedures are implemented. Once a person infected with smallpox enters a clinical setting, nosocomial infections are common (4,7). Moreover, while vaccination is thought to be effective up to three days after exposure (4), misdiagnosis may delay vaccination of recent contacts, diminishing the protective potential of the vaccine and requiring tracing the contacts of contacts, as well as expanding the number of people who must be isolated or quarantined.

The lack of a generally-accepted diagnostic assay confuses the management of the disease, as shown by recent experience with Severe Acute Respiratory Syndrome. This is true of smallpox which, like SARS, is diagnosed clinically as a syndrome of symptoms. Upon presumptive diagnosis by a clinician, samples are to be sent to the CDC for confirmatory testing. Specimens potentially containing smallpox virus must be handled by vaccinated personnel in a BL-4 laboratory.

Several methods exist for confirming a diagnosis of smallpox. The presence of characteristically-shaped orthopox virus may be visualized by electron microscopy and immunohistochemical reagents can identify viral antigens. Serological testing does not differentiate among orthopox species and previous vaccination may confuse the results. Polymerase chain reaction may be used amplify orthopox genes to allow identifica­tion. Isolation of the virus by live-cell culture followed by nucleic acid assay for orthopox genes, or growth on chorioallantois, is considered confirmatory (4). However, no standardized and easily-performed assay has been approved to assist the clinician considering an initial diagnosis of smallpox.

Treatment of smallpox

There is no treatment for smallpox approved by the FDA (4). Strict infection control procedures must be applied throughout patient care. The patient should be vaccinated immediately, especially in early-stage cases. Antibiotics may be given in the case of secondary bacterial infection of lesions. Adequate hydration and nutrition should be maintained since fluids and proteins can be lost by the lesions. Care should be taken to prevent or treat infection of the eyes.

There is no evidence that giving anti-vaccinia immunoglobulin is effective for preventing or treating clinical smallpox (4). Animal studies with cidofovir suggest that, given at the time of exposure, the drug offer protection of cowpox, monkeypox or vaccinia (4,19), suggesting that it may have value in treating adverse vaccine reactions. It is possible that cidofovir could be useful in managing smallpox, but no clinical data is currently available. Research is proceeding on anti-variola mono­clon­al antibodies and the potential for neutralizing antibody as a treatment for smallpox.

Isolation and containment

Upon an initial diagnosis of smallpox, the patient must be isolated to prevent the infection of others and must be attended by vaccinated health care workers. The patient should be isolated in a limited-access negative-pressure facility to limit the spread of the virus. All medical waste, bedding, gowning, equipment or supplies used must be autoclaved or disinfected before reuse or disposal.

The patient must be interviewed to identify recent contacts, including health care workers, admission staff and housekeeping and janitorial personnel of the diagnosing or referring facilities. An aggressive effort must be made to trace and vaccinate all contacts. Depending on time of exposure, isolation of some contacts of an index case, coupled with a second ring of tracing and vaccinating contacts of contacts may be necessary. The effectiveness of contact-tracing may be limited, depending on circumstances. For example, someone who commutes twice a day on crowded mass transit is unlikely to identify many fellow passengers. Likewise, large public venues, such as entertainment, sports events, political rallies and even church attendance may reduce the effectiveness of contact tracing and may justify mass vaccination of the public at large.

The Department of Health and Human Services has developed plans capable of vaccinating the entire population of the United States within ten days in the event of an outbreak of smallpox (6). However, it must be noted that the exclusion criteria for vaccination may depend on the nature of the threat. For example, patients with excema may be vaccinated if they have been in contact with a smallpox patient, but not vaccinated in a mass-vaccination campaign. In such a case, the protection of excluded individuals may depend on the herd immunity provided by vaccinees preventing the propagation of the disease within the community. The capacity of the current vaccine to immunize a sufficient proportion of the population to establish herd immunity is uncertain given the current exclusion criteria.

In contrast to mass vaccination, which may be supplied and coordinated on a national basis, the capacity for isolation of patients is a local resource. Isolation and containment has both a personnel and a facilities requirement. Ensuring a health-care system staffed with vaccinated personnel before the emergence of smallpox is the goal of the preemptive vaccination campaign now underway. Though costly, this effort is manageable even if smallpox remains just a memory. However, for many clinics and small hospitals, the costs associated with creating the capacity to isolate smallpox patients may be prohibitive. Still, the ability to isolate patients potentially infected with smallpox, SARS or other highly-transmissible diseases is a critical aspect of the response to potential bioterrorism.

The allocation of resources such as isolation facilities need not be uniformly distributed. Cities at high risk may need to develop clinical isolation capacity, even in the absence of a specific threat of smallpox. This is demonstrated clearly as public health officials apply infection containment and control methods to limit the spread of SARS. This effort requires the use of the same types of isolation facilities that would be needed to cope with an outbreak of smallpox. Examples of localities that might benefit from the creation or expansion of isolation facilities include major population centers, major governmental or financial centers, major ports of entry or sites at specific risk of terrorism.

As an example, Washington, DC currently has 183 negative-pressure isolation suites ready for use. Using an $8 million grant from the Department of Defense to the DC Department of Health, the DC Hos­pital Association is expanding the capacity for infection control and the ability to respond to public health challenges. Sixty-two additional isola­tion suites are now being constructed, clinical air handling is being upgraded and other improvements are also being implemented (12). As a government center and specific target of terrorism, Washington is taking preemptive action to meet the challenges of potential bioterrorism (13).

Post-outbreak vaccination

In case of an outbreak, vaccination will be the front line of defense against smallpox Since vaccination is thought to provide strong immunity against smallpox for three to five years (4), vaccination in childhood will provide little protection, requiring revaccination to renew immunity. In the event of an outbreak, what should the goals of a vaccination campaign be? Smallpox was eradicated by a strict and energetic program of tracing and vaccinating contacts (3). Sometimes a second ring of tracing and vaccination of contacts of contacts was required. In any outbreak of smallpox now, public health authorities would respond in the same way. But it is uncertain whether a strategy of targeted vaccination alone would be a sufficient response to a smallpox outbreak. It depends on circumstances.

As the eradication campaign was completing its task, many of the last refuges of the disease were isolated rural villages and communities. In such an environment, patrolled by a rigorous surveillance campaign, identification of smallpox patients and identification of recent contacts was more straightforward. In areas where smallpox was endemic, it was readily recognized and most of the contacts were known to the patient, so the tracing and vaccination of contacts was facilitated. However, among large populations, mass vaccination in childhood was routinely practiced until eradication was nearly complete (3).

But would a strategy of targeted vaccination be well adapted to the needs of an outbreak in a modern city? Misdiagnosis is frequent among populations where smallpox is rare (4,7) and a generation of physicians is now in practice for whom smallpox is only a textbook possibility. Delayed diagnosis promotes propagation. The epidemiology of the disease in a population devoid of immunity is uncertain, clouding the decision to rely on targeted vaccination or resort to mass vaccination.

The desirability of mass immunity is offset by the known risks of the vaccine. A nationwide vaccination campaign could result in hundreds of deaths and many more adverse reactions from the vaccine alone. In Britain during 1962, a smallpox outbreak of 62 cases with 24 deaths prompted the vaccination of six million people. Nearly as many died from vaccinia as from variola (7). Still, mass vaccination was a public health success since it extinguished the outbreak.

The exclusion criteria for mass vaccination after an outbreak of smallpox must be carefully defined and could cause complications in the screening procedures. There could be many unanticipated results associated with mass vaccination. Consider an urban population of several million to be vaccinated within ten days. Since HIV infection is a contraindication, would each vaccine candidate need to be tested for HIV? Could such testing be done in time? How many clinical visits would be necessary by each candidate? Particular care must be taken in changing the dressing over each inoculation site or the city may soon be swarming with vaccinia virus. It is even possible that a mass vaccination campaign could create an epidemic of vaccinia among pregnant women and immunocompromised individuals, including cancer patients and transplant recipients.

The potential for unanticipated and potentially unmanageable consequences complicates the decision to initiate any mass vaccination campaign and public expectations must be considered. How would the public react today to an outbreak of smallpox–a deadly, communicable, untreatable disease? Would there be public panic or immediate demands for protection through vaccination? Would dozens of deaths and life-threatening vaccine reactions be accepted, would vaccination itself provoke outcry, particularly in the event of significant transmission of vaccine to contraindicated individuals? Policymakers and public health officials can anticipate such concerns by the public. Effective communication methods and materials to address these issues could be created before an outbreak of smallpox, mitigating the potential for panic and facilitating a more effective response.

Mathematical models have been created to help analyze outcomes under different conditions (8, 9, and 10). These models are applied in different ways and the studies undertaken using them support different conclusions regarding mass or targeted vaccination. Nonetheless, some common features of these models emerge. The models are sensitive to various factors. These factors include the initial number of people infected, the transmissibility from person to person, the traceability of contacts, the size of the community affected and the proportion of immune individuals. The perceived quantization of such factors during a smallpox outbreak may serve as a guide to formulation of policy regarding what actions to take under which circumstances.

For example, a few cases of smallpox in a small community with good traceability might favor a strategy of targeted vaccination. A significant outbreak in a large city where some victims had used mass transit for several days might justify mass vaccination.

Historical data shows that transmissibility varies with weather and climate. Transmissibility via the droplet route is higher in winter and early spring because aerosolized virus survives longer at low temperatures and humidity (4). Transmissibility may be higher in communities with a large proportion of uninsured since individuals lacking medical insurance often delay seeking clinical care. A consensus model that could incorporate observed and historical data would be useful in formulating plans and policies before an outbreak and analyzing choices among strategies during a crisis.

Conclusions and Recommendations

Smallpox plagued humanity for more than three thousand years. The eradication of smallpox in 1977 was a singular public health triumph. But eradication has created conditions ripe for catastrophe. The world now largely lacks immunity to smallpox. Variola virus has been cited as one of the most dangerous of organisms for use in bioterrorism (1,2,5) because of its high historical mortality rate of about 30%, its high transmissibility from human to human and its low infectious dose. Policymakers and public health officials take this potential threat seriously. Planning and precautions have begun but much remains to be done and even the elucidation of the issues is incomplete. Nonetheless, some conclusions may be drawn and recommendations for future action may be proposed.

Current status

Smallpox remains a worrisome prospect, not an imminent threat. While there are concerns that illicit bioweapons programs have been attempted by governments and independent terrorist groups, there has been no public demonstration of any current active program of weaponizing smallpox. Rather, it is the desire of such agencies to possess such weapons and the potential residue of discontinued programs that is of concern. We are haunted by smallpox in our past.

Even absent specific intelligence predicting an outbreak, smallpox is a prospect worrisome enough to prompt action by public health officials and attention from policymakers. We must consider not only a response to smallpox as a specific case, but also the potential for any use of bioweapons or a sudden increase in virulence of an existing disease or an epidemic of some emerging infection, such as SARS, dengue, Ebola, Marburg or other hemorrhagic fever. Many of the same preparations pertain to infection containment and control procedures and the design and capacity of facilities in general.

Moreover, as demonstrated by the spread of SARS around the world in just a few months, the potential return of smallpox is a global problem. International cooperation is essential, not only in preventing any use of smallpox as a weapon, or in reacting to any such use, but also in worldwide surveillance, reporting and sharing of reliable public health information.

A mass vaccination campaign is not warranted at this time, given the limitations and risks of the current vaccine. If smallpox were to ever reappear, vaccinated health care workers will be needed to respond. Depending on circumstances, it may be necessary to rely on post-outbreak vaccination of clinical personnel and first-responders, since it is thought that vaccination offers protection if administered within three days of exposure. The program of preemptive vaccination may provide a core of preimmunized caregivers in case of an outbreak. Specific locales may be at particular risk of bioterrorism or international transmission of disease and could serve as a focus for such efforts.

In the event of an outbreak of smallpox, the case for emphasizing a strategy of target vaccination or mass vaccination is not clear and most likely depends on the circumstances of the outbreak. It is likely that any use of mass vaccination would be limited to specific regions affected by the outbreak, although it is reassuring that sufficient vaccine is available to vaccinate the entire population of the United States. There is a need for further study of the relative merits of mass or targeted vaccination and better understanding as to which is appropriate under different circumstances. The development of a consensus mathematical model would facilitate analysis of this and other issues.

The need for a better vaccine

Jenner was the first to demonstrate the concept of immunity and vaccination was first used to protect against smallpox. The remarkable results of this bold experiment has given us the luxury of making few improvements on his discovery, although Jenner’s vaccine is not related to our current vaccine, the origins of which are lost in the mists of the nineteenth century. But smallpox was eradicated at the dawn of the modern era of molecular biology and research on new smallpox vaccines has languished.

The current vaccine does not meet the standards for approval today. There is a need for a better vaccine. The CDC has begun trials on MVA, a promising alternative vaccine. Other potential vaccines already exist and, given resources, clinical trials could be accelerated. It may be possible to coordinate vaccine trials with the current voluntary vaccination program serving as a control and comparison group, potentially improving the statistical interpretation of clinical results.

If a safe vaccine was available, mass vaccination might be feasible, reducing the likelihood of the use of smallpox as a weapon and protecting contraindicated individuals by herd immunity. In a mostly-immune population, human-to-human transmission is limited and an outbreak is unlikely to spread beyond the index cases. However, preemptive mass vaccination is unfeasible with the current vaccine. In the case of mass vaccination, the need to safely and effectively vaccinate large numbers of people in a short time will strain public health resources. Improvements in the methods used for vaccination could improve the safety of the procedure and accelerate the pace of inoculation.

Recommendation

Acceleration of Modified Vaccinia Ankara vaccine clinical trials and improvement of methods of vaccine administration.

The need for an equitable compensation policy

Health care workers and first responders have been slow to volunteer for the current vaccination program. This may be because they do not properly understand the need for preparedness or the risks of vaccination. If so, better communications methods and materials may resolve matters. But volunteers are sought because of their job skills and unions representing workers point out that the risks associated with vaccination are real and without a compensation policy in place the burden falls on the vaccinee. Compensatable issues for vaccinees include lost work time due to complications, medical expenses and death or disability. Since the vaccine is communicable, persons secondarily infected with the vaccine deserve compensation as well. Moreover, vaccinees should be indemnified against liability relating to transmission of the vaccine to others.

 

Recommendation

Implementation of an equitable compensation policy for adverse vaccination reactions.

The need to know if smallpox returns

How will we know if smallpox has returned? We will know only if it is diagnosed, only if it is confirmed, only if it is reported. If the health care community is properly informed of symptoms and diagnostic methods, and properly reports an index case to the CDC, then isolation, containment, tracing and vaccination of contacts and other procedures can be implemented. But if smallpox is misdiagnosed, or not reported, spread of the disease beyond the index case is likely.

Since clinical testing for smallpox involves sending a sample to the CDC, smallpox will rarely be diagnosed before other possible diagnoses are shown to be negative. If a standardized clinical assay was approved for smallpox, it would increase the awareness of clinicians of the potential for smallpox and could become part of a routine panel of testing for certain syndromes, particularly in locales at increased risk. Given the communicability of smallpox, early diagnosis is critical.

Just as important as diagnosis, proper reporting of cases is critical to containing outbreaks of disease, as shown by the recent migration of SARS around the world. Global cooperation is necessary in ongoing surveillance for smallpox and reliable international reporting of any confirmed case anywhere in the world. The importance of such an effort highlights the importance of clinical awareness of smallpox and the ability to quickly and correctly diagnose it, even in remote regions. Smallpox anywhere is a threat everywhere. This is true not only because global travel is rapid and common, but also because any outbreak of smallpox could provide raw material to those seeking to start a program of weaponizing smallpox. For these reasons, epidemiological and surveillance efforts relating to smallpox deserve more attention and resources.

Recommendation

Improvement of global smallpox surveillance and reporting, standardized diagnostic testing and outbreak response capabilities.

The need for an effective response to smallpox

Beyond initial isolation, infection control and contact tracing and vaccination, the best strategy for responding to an outbreak of smallpox depends on the circumstances of the outbreak. Public health officials need guidance to help them manage the disease, particularly in deciding whether to expand beyond targeted vaccination to mass vaccination. Factors such as population size, density, contact traceability, climate, the proportion of uninsured individuals and transit systems as well as commercial or entertainment venues all exert an effect on the rate of human-to-human transmission, the critical parameter in containing an outbreak.

The CDC has developed a Smallpox Response Plan addressing many of these issues and has posted it on the internet (18). Coordinated methods of informing and advising local and regional public health officials on managing an outbreak of smallpox are needed before an outbreak, throughout any crisis and continuing with an extended smallpox surveillance and certification process.

Recommendation

Formulation of guidelines for public health officials regarding containment, response and vaccination in a smallpox outbreak.

The need for proper facilities

The ability to respond to an outbreak of smallpox is a local phenome­non. Major cities are now upgrading their capacity for negative-pressure isolation of patients. While improving clinical preparedness in places such as Washington, DC is important since it is a major government center and is recognized as a specific target of terrorism, an outbreak in a major center can result in cases that soon appear in distant places, as the spread of SARS demonstrates. This means that areas not at specific risk may need the ability to respond to diseases that require infection control and containment such as SARS and smallpox. But the cost of facility improvements could be prohibi­tive for many clinics. Moreover, even with the 245 suites soon to be available, in a major outbreak Washington could find itself short of capacity to isolate patients. Other cities face similar needs for clinical surge capacity.

One way to mitigate the need for surge capacity in large centers as well as providing emergency isolation capacity for other municipalities could be to establish nationally-coordinated regional response teams, capable of transporting portable isolation enclosure that could be quickly delivered to the site of any outbreak lacking adequate clinical isolation capacity.

Recommendation

Development of adequate isolation capacity in major population centers and mobile response teams, staffed with trained and vaccinated health care practitioners, capable of isolating patients in transportable facilities.

The need for a well-informed community

To properly prepare for the potential return of smallpox and gain cooperation achieving goals such as the current program of voluntary vaccination of health care workers and first-responders, better methods of communicating with professionals and the public are needed. For example, vaccine candidates need to be fully informed about risks of the vaccine, contraindications, proper care of the inoculation site, infection control precautions, what side effects are common and which symptoms require further medical attention. Since more than a quarter-century has passed since the eradication of smallpox, there is a need to properly inform health care workers about the disease, including recognition of symptoms, diagnostic and confirmation methods, isolation and infection control procedures and reporting requirements.

The CDC has developed an extensive web site to address these needs (14). In particular, a comprehensive smallpox response plan has been adopted to give guidance to public health officials in managing any outbreak of smallpox (18). Vaccination candidates and the public can also find useful information at these sites. These initiatives are the subject of ongoing review and revision. Additional materials and messages could be prepared to help inform the community through other media outlets.

Public awareness of potential threats is an important concern for policymakers at present. It is important to inform the public, but care must be taken not to incite anxiety, panic or demands for inappropriate action. Smallpox may be second only to nuclear weapons in its capacity to inspire terror in target populations. The public needs to be made aware of the potential for the return of smallpox and informed of the many actions undertaken to prevent or prepare for such an event.

The United States is always under one of five Terror Alert Levels. This is useful for alerting the public and providing guidance to public safety officials in security decisions. But not all times or locations are at equal risk of an outbreak of smallpox and it would be useful to inform the public of such differentiation. It could allow residents and visitors to higher risk areas understand the need for security procedures and provide guidance for personal precautions, especially at times of specific intelligence indications. At the same time, making distinctions could reassure others that, while a global threat may exist, some areas should be vigilant, not frightened. To avoid panic and irrational demands for mass vaccination, materials could be prepared in advance to inform the public about the risk of a return of smallpox, risks of vaccination and what to do in the event of an outbreak.

Recommendation

Production of improved communications materials and methods to properly inform the public about smallpox issues, potential vaccinees about risks and contraindications, and health care professionals about smallpox diagnosis, containment and reporting.

The need for a coherent global approach to novel or emerging infections

These recommendations are applicable specifically to smallpox, but they also illustrate the need to proactively mobilize policy and public health resources to respond to any atypical outbreak of disease--either naturally-occurring emerging infections, such as SARS or Ebola, dengue and other hemorrhagic fevers, or through bioterrorism, such as smallpox or anthrax. Local and international capabilities for surveillance, diagnosis, reporting, contain­ment and treatment of smallpox must be developed to control the potential for outbreaks of disease in a world of global mobility.

References

(1) Henderson, D.A., The looming threat of Bioterrorism. Science (1999) 283: 1279-1282

(2) Alibek, K., Biohazard: the chilling true story of the largest Covert bioweapons program in the world, told from the inside by the man who ran it. New York: Random House (1999)

(3) Fenner, F., Henderson, D.A., Arita, I., Jezek, Z. Ladnyi, I.D., Smallpox and its Eradication. Geneva: World Health Organization (1988) Accessed 1 April 2003 at www.who.int/emc/diseases/smallpox/smallpoxeradication.html

(4) Breman, J.G and Henderson, D.A., Diagnosis and Management of Smallpox. N Engl J Med (2002) 346: 1300-1308

(5) Henderson, D.A. et al,. Smallpox as a Biological Weapon: Medical and Public Health Management. JAMA (1999) 281: 2127-2137

(6) Connolly, C., U.S. Smallpox Vaccine Program Lags; Workers Decline Immunizations. The Washington Post, 13 April 2003.

7) Pennington, H., Smallpox Scares. London Review of Books, 5 September 2002.

(8) Kaplan, E.H., Craft, D.L. and Wein L.M., Emergency response to a smallpox attack: The case for mass vaccination. PNAS (2002) www.pnas.org/cgi/10.1073/pnas.162282799

(9) Bozzette, S. et al., A Model for a Smallpox Vaccination Policy. N Engl J Med (2003) 348: 416-425

(10) Halloran, M.E., et al. Containing Bioterrorist Smallpox. Science (2002) 298: 1428-1432

(11) Evaluating Patients for Smallpox; Acute, Generalized Vesicular or Pustular Rash Illness Protocol. CDC, Version 1.0, 31 January 2002.

(12) Dr. Jeffrey A. Elting, Medical Director for Bioterrorism Response Coordination, District of Columbia Hospital Association. Personal communication.

(13) Goldstein, A., Progress Cited on Health Threat. The Washington Post, 17 April 2003.

(14) www.bt.cdc.gov/agent/smallpox/index.asp

(15) www.cdc.gov/od/oc/media/spvaccin.htm

(16) www.bt.cdc.gov/agent/smallpox/vaccination/contraindications-public.asp

(17) www.bt.cdc.gov/agent/smallpox/vaccination/heartproblems.asp

(18) www.bt.cdc.gov/agent/smallpox/response-plan/index.asp

(19) Bray, M., Cidofovir protects mice against lethal aerosol or intranasal cowpox virus challenge J Infect Dis (2000) 181: 10-19

Abbreviations

WHO World Health Organization

FDA Food and Drug Administration

AIDS Acquired Immunodeficiency Syndrome

ARC AIDS-related complex

CDC Centers for Disease Control and Prevention

SARS Severe Acute Respiratory Syndrome

BL-4 Biosafety Level Four

V. Individual Presentation Summaries

I. Presentation by Walter Orenstein, MC, CDC

There are many things to consider when looking at smallpox and the efficacy of vaccination : how the smallpox will occur, the total risks of the vaccine versus responsibility and how we respond to an attack, how quickly we can respond, etc.

The eradication of smallpox ranks as one of the greatest public health achievements of our time. The last naturally occurring case of smallpox occurred in 1977 at a hospital in Somalia.

The Course of Smallpox

There is a natural course of smallpox. The incubation period for smallpox is generally 12 to 14 days with a range of 7 to 17 days. The patient, while infected, is not contagious. Symptoms include fever, backaches, headaches, frequent abdominal symptoms such as vomiting. The fever is very high, often 103 or 104 degrees Fahrenheit. They become contagious at the end when lesions develop in their mouth. Those lesions break down at the end of the period and beginning of the rash. That’s when virus gets into oral secretions and contagiousness takes effect.

The first stage is called the macule stage which lasts about a day. Small lesions appear. The capular stage is another day or two – they are contagious, but are not recognized as having smallpox. These are cases of the first few days where the person is contagious but do not show a classic diagnosable condition. Around day 4 or 5 or so, you begin to see the _____* stage which is fluid filling and then filling with pus. They are very contagious, but you can begin considering the diagnosis of smallpox. People are most contagious during the first 7 – 10 days. Most transmission outside the household occurs during the beginning period, at the hospital. The patient begins to recover about 10 – 14 days after the rash and begins a period of scabbing in which the virus is in the lesions, but they’re not contagious at this point.

What can be done to prevent infection_____.* Respirators prevent infection. However, exceptions include air-borne mists – this occurs with patients who have a cough during the most infectious part of the illness. Fortunately, the cough is an unusual manifestation of normal smallpox which is why airborne spread is unusual. It’s rare that the candidate develops one.

The strategy used to eradicate smallpox is containment. The use of the vaccine is a misnomer. The first part of the strategy is to find the cases and isolate them. The second issue has been to find the contacts of these people and to vaccinate them. Many efforts are made to get to them within the first 3 – 4 days, but that is not a requirement for the success of this program. The goal is to take steps to figure out who you need to vaccinate and not rely on mass efforts.

Classical smallpox when it gets into the sphincter is easily diagnosable. There are some studies done that look at people coughing and ways the virus comes out as large or small droplets and it was much more likely to come as large droplets. It’s not just population susceptibility that affects transmission, but also the biology of how the smallpox attacks

*This presentation was recorded. Please excuse any words that may have been omitted due to unclear recordings.

 

the body. The third issue is traceable transmission and in general, we have some cases we

can trace back. You need people who can go out and who are trained to rapidly identify people at risk and initiate vaccination. Normal take is a reaction as opposed to all other vaccines where normally people experience nothing. The take is a maximum of 8 – 12 days, and there are many nuisances, but not many serious reactions.

Another issue is the ability to spread. The risk to vaccinees and contacts is much lower, but not insignificant. What is the risk of adverse events today? On one hand, it can be substantially higher because we have a very different population today. We don’t have previously vaccinated individuals, there’s much more immune suppression around, many don’t know they’re immune suppressed, many people with HIV/AIDS and there’s a higher incidence of eczema or other topicals, 11% of the population in fact. On the other hand, it could be lower because we have some new vaccinees and we’re adopting extraordinary screenings. We go overboard in many cases to screen out those who might have complications.

One issue we deal with is female preparedness. We have to educate the doctors so they can find those cases. We need to be able to implement public health inventions and have places where these people can be put and not transmit the disease. We must establish a spot team and offer vaccines to those people so we have a category of people ready to react should there be a case. We know a lot of about natural transmission, but not much about unnatural transmission. We have to be prepared to rapidly implement total population vaccination should it become necessary. We also have communication objectives and the reason for that is helping states and communities in communication efforts, utilizing and establishing partnerships to address communication needs, etc.

In 2002, the President issued his recommendation on smallpox vaccination. This includes vaccinating the smallpox response team, the DOD, personnel, the record staff, and for us, most importantly, the President did not recommend routine vaccination of the general population feeling the threat did not merit it at the time. Although, he did ask that a method be developed to vaccinate the general public should the situation arise. The program began in earnest on January 24 th when a resolution from the Homeland Security Act was signed by the Secretary. As of February 21 st, 7354 people were vaccinated, including Chicago and Los Angeles County officials, public health workers and healthcare workers. About 10% of the acute care hospitals had at least one vaccinated worker. In terms of where orders are coming in, the part of the country that’s the slowest is the southwest.

Probably the #1 assertion is threat assessment. It is difficult to convey the importance of doing this with regards to the threat. If there was an attack, what is the duration, type, etc. will it be a genetically modified virus or the natural traditional? Vaccination effectiveness – how effective is it? Do we modify it? The third area of certainty is – what is the risk of adverse reaction to today’s population? Risk of vaccines and transmission and what types of events will we see? Of the 7300+ vaccinations we’ve had, we have 5 reports of adverse events. One suspected case was a case of angina which was probably unrelated. Other issues include what’s the public power in the case of adverse events and what type of true response is needed? How much do we need – full-action preparedness? How many people need to be vaccinated? What about other agents of bioterrorism?

Additional challenges are liability. No hospital wants to be tied to a transmission with a bone marrow transplant per se. Compensation is a big issue, and liability is a big issue for lack of hospital participation and lack of employee participation. What are the opportunity costs because of this and how do we maximize benefits? Given the voluntary nature of the program, we have said repeatedly, this is voluntary. This is a tough sell for many people. We have to minimize the threat.

II. Presentation by Major General John Parker, M.D. USA (ret)

SAIC, Formerly Commander, Ft. Detrick

At the country level, do they have a research and development program? Then, how sophisticated is that R&D program? What do we know about the whole thing? This is one factor in assessing the threat. Then if they have an R&D program, is there any evidence where they scale the R&D program to a production program that’s of particular value, anthrax, smallpox, etc. and then, there’s the question of once they know how to produce this in quantities, do they process it? What do I mean by the process? The bacteria, the fungus or lycogene – could be sized or coded and it could be hydrated at the last minute. One sizing process used for a pathogen is a screen – it’s sharp enough so it shapes it and breaks it down. I’m giving you information on a delivery device, not a weapon. It could take the form of an envelope, i.e. anthrax, there’s a check part in each of these places. Our challenge team would say there’s risk and intent.

In the leadership area, the potential for use is of concern. In the case of our present focus towards Iraq, if we look at the psychiatric propensity for using a weapon of mass destruction, we have historical precedent. Chemicals have already been used on a very susceptible population. The threat is very real. The possibility of this actually happening is another question. It’s atrocious, and it’s hard to jump over the Judeo-Christian barrier in front of us thinking it’ s way out of line.

History of Biological Warfare

In 1937, scientists in this country were very concerned about what would happen in Germany or Japan and other countries in the world. They raised the issues of biological terrorism. In 1938, almost 1939, Roosevelt decided to set up committees to study what was going on in Germany and Japan. For the next five years, the committees met and produced information for Roosevelt that Japan and Germany were on a fast track to developing sophisticated biological weapons. In 1942, Roosevelt said we have to compete with this and in 1943, we were in a full offensive mode. We produced anthrax, we produced botulinum toxin and we produced it for the UK as well. The interesting thing is Germany was well advanced in the science of distributing biologicals. Japan dropped Ricin fleas on China hoping to spread plague. Germany studied the London subway with aerosols, and everyone had production facilities. The US was moving production facilities from Fort Detrick to Indiana and the actual production place was in Indiana. We had an isolated island in the Gulf of Mexico where we’d do our testing.

The consequences took too long and the cost of nuclear bomb or weapon was much greater. They probably didn’t have impact on the battlefield. All of a sudden, the battlefield was the world, and we now have terrorism. It has opened up a new door that terrorism brings fear and fear is what people are after when they’re on the terrorist side. Now the use of biological or chemical weapons outside the field now has more uses.

III. Presentation by Barney Graham, M.D., Ph.D., NIAID/NIH

Since September 11 th, things have changed, but the primary mission is the same. People have had this fear of vaccines for a very long time because there’s a small number of significant complications associated with them. The smallpox vaccine is relatively safe. One problem that’s happened since October is the media hype about the dangers of vaccines has swung the pendulum way too far.

Vaccination can be a nuisance, but it is not a bad vaccine. A poster from Japan in the mid-1800s shows they saw the vaccine as a powerful tool. We also saw this in the last smallpox epidemic in this country in 1947 when a case of smallpox was noted and within a few days, 6.5 million workers were inoculated. Many New Yorkers lined up for the vaccine. This occurred and there was a case that came in. 6.5 million were vaccinated in days, there were 12 cases reported and then 2 smallpox related deaths reported. Then there were 3 vaccine-related deaths. There were two unvaccinated infants who died of eczema-related complications.

Some non-specific dermatological conditions include post-vaccine encephalitis. The next relates to containment – you have inoculation or transmission to others related to inadvertent spread of pus. Much of this can be better managed by better screening, education, and counseling. One example is the change in the dressing technique that was implemented in the late 80s. Using an outside transparent dressing that’s semi-permeable is permeable to water vapor. This allows the site to “breathe” and is effective. However, if you completely cover the lesion, it doesn’t heal as fast. We actually tear a hole in the middle so there’s a hole so the scar forms faster and it heals and scars within 60 days or so. The problem with this dressing is it has to be changed and it can’t be changed by the individual. Healthcare workers, someone trained has to change it.

Another adverse event deals with the ability of the virus to replicate. There’s generalized vaccinia which is for immunocompetent people. Eczema vaccinology and vaccinia are a combination of the virus ability to replicate and T-cell responses more oriented towards responses and producing cytokines that really inhibit T cell responses.

Some viruses have evolved over time. CVI was developed in the 1930s by the New York Board of Health. 16 and 8 is the strain derived from the _____* strain and it’s something the Japanese studied in 10,000 individuals. It’s replication-competent. Another virus that doesn’t grow very well grows in avian cells, but not _____ *cells. The modified vaccinia was initially passed through _____* and began attenuation in chicken embryos. It’s a stable virus, but it lacks the characteristics of the parent strains. It doesn’t replicate in the cell and 15% of the original genome of the vaccine is missing. Things that are missing are interesting because it tells you how vaccinia is virulent and how it grows. This is a gene that’s required to grow in a cell and only produces mature virulen. It can’t really spread. Vaccinia is a large virus that’s complex. All of these receptors, etc. are all lost during this process because they don’t help the virus grow.

Because of that MDA is not an agent. In some ways, it’s more immunogenic. It is safe in mammals. There was a primate study done. It’s immunogenic and in the monkey model, these bury the vaccine subcutaneously, or intradermally or given intramuscularly, you can prevent the serious consequences of smallpox. The problem is the variola is not as virulent in the monkey as it is in humans. In Germany, about 125 people received it, and articles on MDA and the modern era of immunology.

*This presentation was recorded. Please excuse any words that may have been omitted due to unclear recordings.

 

Compared to immunogenicity of MDA, evaluate the protection that MDA will give in a regular vaccine challenge.

 

That’s why there needs to be personnel so we don’t find ourselves in that situation. We have the opportunity to do this right with our healthcare workers in the public health field. Knowing they’re not being put at risk and there’s an infrastructure that can handle this, we don’t have to deal with a vaccination program.

I think there are many similarities between AIDS and the thing we’re questioning. It’s different in that AIDS asks people to stop doing something. The key to understanding the success in the AIDS education program was we tried to reduce to a reasonable likelihood the modes of transmission and the severity thereof. I would suspect that an average family doctor looking at that would be concerned when his patients said should I be vaccinated and say yes. I think the reason as that all the things we’ve seen here today in the way of adverse reactions aren’t delineated in the mind of the physician that this is high-risk and this almost never happens. What’s the most important about education in reference to AIDS was not so much how you got AIDS but how you didn’t get AIDS. There’s no evidence that I see about how small the risk is, versus how great the risk is. I think the emphasis is wrong.

Most of the people we deal with are denominator people. When you look at those materials, there’s a column about smallpox and a bunch of papers about the risks of vaccines. I think the issue is everyone is concerned that someone with a risk factor for vaccines will slip through the screening process and be vaccinated. We have examples from the trials leading to the stoppage of people who were warned to not become pregnant and had negative pregnancy tests on the day of vaccination and became pregnant. There’s been tremendous focus on the risk to society. It’s difficult to put these things into perspective. In Arlington, we ran a mock clinic and it took an hour to get through the clinic. We dealt not with waiting so much, but with careful medical screening, intensive questioning, etc. to determine if someone had a risk factor or had someone with family history for risk factors. These were challenges that were problematic in terms of the manpower and infrastructure needed. The best estimate is what is needed in a post-attack situation. The CDC delivered a template to the State that to vaccinate a million people over ten days would require staff working 16 hours/day and approximately 4700 staff members. That’s a post-attack setting which is somewhat simplified from a pre-attack setting. One issue raised is how to do we go from Phase I where we can have people being examined everyday and their site changed? Where we can have activated surveillance for all adverse events? We need to find a similar system, perhaps involving more voluntary cooperation and less pushing.

The Administration offered a proposal that would take the Public Safety Officer Benefit fund which was enacted in 1968 and has been adapted only recently. It’s $5 million nationwide and provides all available benefits for smallpox as well as incentives for police officers and firefighters who die in the line of duty or if they are permanently and totally disabled. It provides funds with a maximum cap. The Administration hasn’t provided any indication they understand needs for a fund or that it needs to be adapted to the needs of smallpox vaccination. This is all being done. The Secretary is under terrible constraints from the White House to get this discussed We’re dealing with a war on terrorism here on the US soil and are short on resources and troops. How do we pay for it? If we’re going to only focus our efforts and funds outside the territory of the US, that will not protect and deal with the war on terrorism which we know is occurring and has occurred on US soil.