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INTRODUCTION

At the World Health Assembly in May 1980, the World Health Organization (WHO) declared the world free of smallpox. Smallpox vaccination of civilians is now indicated only for laboratory workers directly involved with smallpox (variola virus) or closely related orthopox viruses (e.g., monkeypox, vaccinia, and others). Recent questions raised by the terrorist attacks in fall 2001 have renewed concerns about possible outbreaks of smallpox resulting from its use as a biological weapon. The risk of smallpox occurring as a result of a deliberate release by terrorists is not known, but is considered very low. Smallpox vaccine (vaccinia virus) is a highly effective immunizing agent against smallpox; however, its use is not without risk and reintroduction of a wide-scale vaccination program must be done judiciously, if at all.

The Advisory Committee on Immunization Practices (ACIP) provides advice and guidance to the Secretary and the Assistant Secretary for Health, Department of Health and Human Services (DHHS) and the Director, Centers for Disease Control and Prevention (CDC), regarding the most appropriate application of antigens and related agents (e.g., vaccines, antisera, immune globulins) for effective disease control in the civilian population. ACIP develops written recommendations for the routine administration of vaccines to the pediatric and adult populations, along with schedules regarding the appropriate periodicity, dosage, and contraindications applicable to the vaccines. Additionally, ACIP reviews and reports regularly on existing immunization practices and recommends improvements in national immunization efforts.

In 1980, ACIP developed guidelines recommending the use of vaccinia vaccine to protect laboratory workers from possible infection while working with nonvariola orthopoxviruses (e.g., vaccinia and monkeypox). In 1984, those recommendations were included in guidelines for biosafety in microbiological and biomedical laboratories. The guidelines expanded the recommendations to include persons working in animal care areas where studies with orthopoxviruses were being conducted. They further recommended that such workers have documented evidence of satisfactory smallpox vaccination within the preceding



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Scientific and Policy Considerations in Developing Smallpox Vaccination Options: A Workshop Report INTRODUCTION At the World Health Assembly in May 1980, the World Health Organization (WHO) declared the world free of smallpox. Smallpox vaccination of civilians is now indicated only for laboratory workers directly involved with smallpox (variola virus) or closely related orthopox viruses (e.g., monkeypox, vaccinia, and others). Recent questions raised by the terrorist attacks in fall 2001 have renewed concerns about possible outbreaks of smallpox resulting from its use as a biological weapon. The risk of smallpox occurring as a result of a deliberate release by terrorists is not known, but is considered very low. Smallpox vaccine (vaccinia virus) is a highly effective immunizing agent against smallpox; however, its use is not without risk and reintroduction of a wide-scale vaccination program must be done judiciously, if at all. The Advisory Committee on Immunization Practices (ACIP) provides advice and guidance to the Secretary and the Assistant Secretary for Health, Department of Health and Human Services (DHHS) and the Director, Centers for Disease Control and Prevention (CDC), regarding the most appropriate application of antigens and related agents (e.g., vaccines, antisera, immune globulins) for effective disease control in the civilian population. ACIP develops written recommendations for the routine administration of vaccines to the pediatric and adult populations, along with schedules regarding the appropriate periodicity, dosage, and contraindications applicable to the vaccines. Additionally, ACIP reviews and reports regularly on existing immunization practices and recommends improvements in national immunization efforts. In 1980, ACIP developed guidelines recommending the use of vaccinia vaccine to protect laboratory workers from possible infection while working with nonvariola orthopoxviruses (e.g., vaccinia and monkeypox). In 1984, those recommendations were included in guidelines for biosafety in microbiological and biomedical laboratories. The guidelines expanded the recommendations to include persons working in animal care areas where studies with orthopoxviruses were being conducted. They further recommended that such workers have documented evidence of satisfactory smallpox vaccination within the preceding

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Scientific and Policy Considerations in Developing Smallpox Vaccination Options: A Workshop Report three years. CDC has provided vaccinia vaccine for these laboratory workers since 1983.1 In 1991, ACIP further expanded smallpox vaccination recommendations to include healthcare workers involved in clinical trials using recombinant vaccinia virus vaccines and lengthened the recommendations for revaccination for persons working with vaccinia virus, recombinant vaccinia viruses, or other nonvariola orthopoxviruses to every 10 years. In June 2001, ACIP made recommendations for use of smallpox (vaccinia) vaccine to protect persons working with orthopoxviruses, and to prepare for a possible bioterrorism attack involving smallpox. Because of the fall 2001 terrorist attacks, CDC asked ACIP to again review and update its previous recommendations for smallpox (vaccinia) vaccination. As a result of this review, ACIP issued supplemental recommendations for vaccination of 1) the general population and 2) persons designated to respond or care for a suspected or confirmed case of smallpox. In addition, the proposed policy clarified and expanded the primary strategy for control and containment of smallpox in the event of an outbreak. To supplement this review process, CDC asked the Institute of Medicine (IOM) of the National Academy of Sciences (NAS) to convene a public conference to discuss the scientific, clinical, procedural, and administrative aspects of various immunization strategies. This report summarizes the discussions of that meeting. Held on June 15, 2002 in Washington, D.C., the meeting was expository, not deliberative, and its discussions and conclusions do not reflect the opinions of either IOM or the NAS. OPENING REMARKS2 The threat of smallpox has not changed appreciably since ACIP last reviewed smallpox immunization policy in June 2001. It remains difficult to obtain the virus, prepare it, and distribute it. What has changed is the availability of vaccine. Dryvax, the vaccinia (smallpox) vaccine currently licensed in the United States, is a lyophilized, live-virus preparation of infectious vaccinia virus, produced in 1975 by Wyeth Laboratories, Inc., of Marietta, Pennsylvania. Vacciniad vaccine does not contain smallpox (variola) virus. Previously, the vaccine had been prepared from calf lymph with a seed virus derived from the New York City Board of Health strain of vaccinia virus. Vaccine was administered by us 1   After the anthrax attacks of 2001, CDC formed smallpox response teams of 200 people, who were vaccinated with vaccinia. In late November 2001, a smallpox interim response plan was developed, as was a rash algorithm, followed by intensive training of 700 people. 2   The opening remarks for the meeting were presented by D.A.Henderson from Johns Hopkins University.

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Scientific and Policy Considerations in Developing Smallpox Vaccination Options: A Workshop Report ing the multiple-puncture technique with a bifurcated needle. A reformulated vaccine, produced by using cell-culture techniques, is now being developed. In fall 2001, there were 150,000 ampules of Dryvax, available at 100 doses per ampule, which would vaccinate 15 million people. However, because Dryvax is a dried product, once reconstituted it begins to deteriorate at a rapid rate, so there is a finite period of time in which it can be used, which can create substantial wastage. In September 2001, DHHS placed an order for 40 million doses of vaccine with Acambis, Inc. The 20-year contract would purchase a new vaccine produced in tissue cell culture, to be available in 2004. However, the September 11, 2001, attacks and the release of the anthrax organisms through the mail spurred the government to acquire more vaccine more quickly. Acambis and Baxter are currently producing 200 million doses of a stable tissue cell culture vaccine to be available by the end of 2002. Also in 2002, Aventis Pasteur located in a storage facility 85 million doses of vaccine prepared from calf lymph, produced in 1958. This vaccine has been tested and is available if needed; however, the newer vaccine produced in tissue cell culture is preferable. Now that sufficient vaccine will be available for the entire U.S. population should it be needed, a responsible immunization strategy must be developed. Previous experience with immunization has shown that serious complications can arise in as much as 20 percent of those who come in contact with vaccinees but are not yet vaccinated and are susceptible to complications for a variety of reasons. SCIENTIFIC BACKGROUND ON SMALLPOX AND SMALLPOX VACCINATION Smallpox Disease3 The last case of naturally occurring smallpox occurred almost 25 years ago, and 24 years ago the last episode occurred in Birmingham, England, with the laboratory escape of variola virus. As a result of its eradication, virtually all clinicians, particularly in northern countries, are unfamiliar with this disease and research on human smallpox has practically stopped. Eradication was relatively easy to achieve because humans are the only reservoirs and vectors, the disease is clinically manifest, and there is no carrier or latent state. Moreover, one episode gives lifelong protection, transmission occurs when the disease is manifest, there is a stable vaccine, and it is relatively straightforward to trace chains of transmission. 3   This section summarizes the presentation by Joel Breman, Fogarty International Center, National Institutes of Health.

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Scientific and Policy Considerations in Developing Smallpox Vaccination Options: A Workshop Report The smallpox virus replicates in the cytoplasm. The virus enters the respiratory tract and multiplies in the oropharynx. There is a brief burst of viremia that goes into cells of the reticuloendothelial system, followed by a second viremia into the skin, after which the patients then manifest the disease, which then again spreads via respiration. The incubation period for smallpox is 10 to 12 days. The prodrome, which is a mean of two to three days, is very severe, with high fever, backache, headache, and prostration. The first few days involve a macular phase—a reddish rash that is not distinctive, followed in a couple of days by papules, then vesicles, then pustules, which can become confluent over the entire body. After about two weeks there is crusting, hypopigmentation and pitting, scarring, and eventually hyperpigmentation. The infectiousness period occurs when the lesions are heaviest. There are five known classifications of smallpox. The ordinary form is the most common (~90 percent) with a 30 percent case fatality rate. The flat form accounts for about 5 percent of cases, and has a 97 percent case fatality rate. The hemorrhagic form accounts for less than 3 percent of cases but has a 100 percent fatality rate. The other classifications of smallpox are the modified form (occurring in less than 2 percent of cases and having less than a one percent fatality rate) and V. sine eruptione (occurring in less than 1 percent of cases with no known fatalities). There are no specific strains associated with hemorrhagic disease, thus it is believed to be a host response. Patients with hemorrhagic disease die despite post-exposure vaccination. The hemorrhagic cases do not look like smallpox and many of them will not resemble an infectious disease. It is likely that initially these cases will come into emergency rooms, perhaps diagnosed as acute leukemia or a variety of other things, in which case emergency room personnel are not likely to have taken the necessary precautions one would take if smallpox were suspected. Conditions that resemble the maculopapular eruptions of smallpox include drug eruptions, measles, secondary syphilis, and vaccine reactions. Chickenpox, monkeypox, and generalized vaccinia can resemble the papulovesicular eruptions of smallpox. With newer molecular approaches to diagnosis, however, more rapid and precise screening, if not confirmation, of variola and chicken pox can help in diagnosis. However, cell culture is the only reliable diagnostic tool for the orthopoxes when the clinical symptoms are indistinguishable. Smallpox is transmitted person-to-person by large airborne droplets, that is, face-to-face contact of 2 to 2.5 meters. Thus homes and hospitals are major transmission sites. However, carriers are symptomatic so investigations done with due diligence can prevent further spread. In general, it has been believed that smallpox can not be carried by the wind and travel great distances, although outbreaks in hospitals might have been due to movement of the virus through air ducts. There are certain features of smallpox making it, in temperate areas, a winter or early spring disease, and in the tropics, a hot, dry season disease, mainly because the virus persists longer on droplets in aerosols, and the nasopharynx might be more eroded and therefore more susceptible to invasion by the virus.

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Scientific and Policy Considerations in Developing Smallpox Vaccination Options: A Workshop Report The most important epidemiological index for smallpox spread or that of any infectious disease is the number of persons in an environment who, when in contact with a patient, will come down with the disease. Studies in Asia and Africa found that the attack rate in unvaccinated persons ranged from roughly 40 to 90 percent with variola major. Despite being a somewhat milder disease, the secondary attack rate for variola minor is still about 50 percent. The case fatality rate increases as years from vaccination increase, from nearly 0 percent if vaccination occurred less than 10 years prior to contact to over 10 percent when vaccination occurred more than 20 years prior to contact. Deaths from smallpox are generally due to secondary infection of lesions, pneumonia, toxemia, and hypotension. Death rates in unvaccinated patients, particularly those with the more severe form of the disease, can be as high as 50 percent. Smallpox Control Strategies and Vaccine Availability4 Although the smallpox vaccine works well in a pre-exposure and post-exposure setting, quarantine and isolation are also valuable means by which to control spread of the disease. Estimates of vaccination efficacy originally were not based on controlled clinical trials, but rather on comparisons of secondary attack rates among vaccinated and unvaccinated family contacts of cases. Vaccination status was determined by the presence of a scar and did not account for vaccine potency, scarring secondary to skin infection rather than vaccine take, or “on-time” vaccination. Estimates of pre-exposure vaccination efficacy were conservative, yet the general medical opinion is that successful vaccination or re-vaccination within three years provided 90 to 97 percent efficacy against disease. However, even with vaccination, both flat and hemorrhagic smallpox continue to have high case fatality rates—in the 90 percent range—which might reflect a host response rather than protective immunity. Effectiveness of post-exposure vaccination ranges from 20 to 90 percent. For those receiving primary post-exposure vaccination, the efficacy is around 70 percent—yielding either protection from disease or manifestation of modified smallpox, which has a much lower case fatality rate. In re-vaccinated individuals, efficacy protections are over 80 percent. Effectiveness is clearly present in those vaccinated less than seven days after exposure. Experience in developing countries, in which hospitals had very high rates in terms of smallpox transmission, demonstrated that poor infection control practices were the cause of rapid spread of the virus. Airborne precautions, including discharge of air to the outside or through a HEPA filter, closed doors, and using a N-95 or better respirator would be expected to prevent this disease. 4   This section summarizes the presentation by Harold S.Margolis, Centers for Disease Control and Prevention.

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Scientific and Policy Considerations in Developing Smallpox Vaccination Options: A Workshop Report A fitted respirator can provide 90 percent protection against any type of air leakage. Contact precautions can also help control the spread of the virus, for example, use of hand washing, masks, and eye protective gear. Several characteristics of smallpox led to its control and eventual eradication: 1) cases could be identified because smallpox is a clinically evident disease and there is no subclinical illness; 2) the disease moves relatively slowly— transmission does not occur during prodrome and maximum transmission is at the time of substantial illness; and 3) the vaccine is highly effective. Mass vaccination was the earliest strategy used. It was not until 1968 that surveillance and containment became the strategy that finally eliminated smallpox. In this approach, cases are searched for and when clinically evident disease is found a ring of immunity is created and if possible, contacts are isolated or quarantined. Determining the size of the ring is the challenge. Accumulating evidence suggests that surveillance and containment were more effective than mass vaccination in the eradication of smallpox. In West and Central Africa in 1968–1969, cases continued to occur in spite of mass vaccination, until surveillance and containment were initiated. Prolonged and intense exposure was the norm for person-to-person transmission of smallpox, suggesting that control of the movement of these contacts was central to containment. Operationally, surveillance and containment begins with case detection, followed by vaccination and quarantine of contacts of cases, and delineation of functional and geographic boundaries around cases or outbreaks (e.g., wide-area vaccination), followed by communication among areas about cases. Protocols are in place for vaccine handling, dilution, and administration in the United States. There are 162 million doses of calf-lymph-derived vaccine and there will be 362 million doses of cell-cultured-derived vaccine by January 2003. The vaccines are currently part of the national pharmaceutical stockpile, located in four regions throughout the United States. Initial shipments can be sent with a confirmed case of smallpox via Vaxicools—self-contained storage and transport units holding 300,000 doses. Any site in the United States can be reached within 12 hours. The entire stockpile could be deployed to multiple locations within a 5-day period. In summary, vaccination provides high levels of protection, both pre- and post-exposure. Current infection control practices should prevent occupational and nosocomial acquisition of smallpox. Surveillance and ring containment is the most effective means to control this disease in populations with relatively high levels of immunity from immunization, as well as in parts of the world where there are low levels of immunity, both from immunization as well as from naturally occurring disease.

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Scientific and Policy Considerations in Developing Smallpox Vaccination Options: A Workshop Report Smallpox Vaccination: Efficacy, Availability, Duration of Immunity, and Timing5 Successful primary vaccination confers full immunity to smallpox in greater than 95 percent of persons for a period of approximately 5 to 10 years. Successful re-vaccination provides protection for 10 to 20 years. The 15.4 million doses of Dryvax that had been produced in 1982 or earlier were tested in a dilutional study (dilutions were 1:5 and 1:10), the results of which were published in the April 25, 2002, issue of The New England Journal of Medicine.6 Vaccination initially was successful in a high percentage of individuals with the 1:5 dilution—a 99.1 percent take rate—compared to the 97.2 percent take rate of undiluted doses. The 1:10 dilution had a 97.1 percent take rate, not statistically different from the 1:5 dilution or the undiluted sample. Thus, the diluted vaccine can be added to the current stockpile (the 15.4 million doses can be diluted to create 77 million doses). The duration of smallpox immunity has not been satisfactorily measured. Studies of case-fatality rates in Liverpool, England, in the early 1900s showed that when decades separated vaccination from the time of a smallpox outbreak, non-vaccinated individuals had a much higher case fatality rate than vaccinated individuals. A review by Thomas Mack of the introduction of smallpox in Europe from 1950 to 1971 looked at case fatality rate vis-a-vis vaccination status.7 The case fatality rate among 680 cases of variola major was 52 percent for those never vaccinated and as high as 11 percent for those vaccinated more than 20 years before exposure. The data for those vaccinated between 1 and 20 years before exposure suggest a duration of immunity. Immunity is defined by surrogates of immunity—which can be neutralizing antibody, cellular immunity, and skin reactions. A 1990 study looked at the persistence of neutralizing antibody after re-vaccination against smallpox.8 The titer is significantly decreased after the first 3 years after re-vaccination but remains stable at a low level for at least 30 years thereafter. Whether that low level is protective is not clear but clinical observations from other studies suggest that it is. 5   This section summarizes the presentation by Anthony Fauci, National Institute of Allergy and Infectious Disease, National Institutes of Health. 6   Frey SE, Couch RB, Tacket CO, Treanor JJ, Wolff M, Newman FK, Atmar RL, Edelman R, Nolan DM, Belshe RB. 2002. Clinical responses to undiluted and diluted smallpox vaccine. New England Journal of Medicine 136(17):1265–1274. 7   Mack TM. 1972. Smallpox in Europe 1950–1971. Journal of Infectious Diseases 125(2):161–169. 8   el-Ad B, Roth Y, Winder A, Lublin-Tennenbaum T, Katz E, Schwartz T. 1990. The persistence of neutralizing antibodies after revaccination against smallpox. Journal of Infectious Diseases 161(3):446–448.

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Scientific and Policy Considerations in Developing Smallpox Vaccination Options: A Workshop Report Cellular immunity is more problematic in its measurement and relevance. A study was conducted of 26 healthy male military recruits who were vaccinated 15 to 18 years earlier.9 Blood samples collected before re-vaccination to study antigen-specific proliferative response—an indicator of cellular immunity—indicated that there was virtually no existing specificity of responses of lymphocyte proliferation prior to vaccination. However, a more recent study found that T-cell vaccinia-specific immunity can actually persist up to several decades following immunization.10 Skin reaction to vaccinia in people who previously had smallpox vaccine provides an additional source of projections about the state of immunity. In a study published in 1968, immunity to smallpox of 425 people in Afghanistan who previously not only were vaccinated but also actually had smallpox showed that 9 to 11 years after their disease more than 50 percent actually had takes, suggesting that they had lost immunity to pox viruses.11 An NIAID protocol is studying 80 individuals from 32 to 60 years old who have been previously vaccinated at least once, but not more recently than 1971. Neutralizing antibody, cell-mediated immunity will be analyzed, as well as interferon-gamma using ELISPOT assays. Baseline measurements will aim to establish the long-term persistence of immunity 30 years or longer. As for vaccination timing, if administered within four to five days following exposure it may prevent or significantly ameliorate subsequent illness. In an outbreak in Bangladesh of over 1,300 cases, including 372 deaths, few if any individuals who were vaccinated as late as 5 days into their incubation period developed clinical disease, and vaccination performed after 5 days actually reduced the clinical attack rate by 50 percent.12 In summary, primary smallpox vaccination probably provides full immunity for at least three to five years. However, beyond that, the immunity duration is still somewhat uncertain. Post-exposure vaccination within several days may prevent or ameliorate disease. However, vaccine with vaccinia, although highly effective, is one of the least safe of all licensed human vaccines. These data must be considered in deciding whether to proceed with voluntary pre-emptive mass vaccinations without credible threat of smallpox attack, voluntary pre-emptive vaccination of “first responders” only, or the use of ring versus mass vaccination in the event of a smallpox attack. 9   Moller-Larsen A, Haahr S, Heron I. 1978. Lymphocyte-mediated cytotoxicity in humans during revaccination with vaccinia virus. Infection & Immunity 21(3):687–695. 10   Demkowicz WE Jr, Littaua RA, Wang J, Ennis FA. 1996. Human cytotoxic T-cell memory: Long-lived responses to vaccinia virus. Journal of Virology 70(4):2627–2631. 11   Vichniakov VE. 1968. A study of immunity to smallpox in persons who have experienced a previous attack. Bulletin of the World Health Organization 39(3):433–437. 12   Sommer A. 1974. 1972 smallpox outbreak in Khulna municipality, Bangladesh II. Effectiveness of surveillance and containment in urban epidemic control. American Journal of Epidemiology 99:303–313.

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Scientific and Policy Considerations in Developing Smallpox Vaccination Options: A Workshop Report Smallpox Vaccination Safety13 Data on the safety of vaccinia are 35 to 40 years old. There is very little in the way of controlled data and immunological knowledge at the time was primitive. Moreover, differences in administration of vaccinia produced different reactions, depending on the number of insertions and therefore the amount of virus delivered. The first and probably most common reaction to vaccine is erythema multiforma, which occurs 7 to 14 days after vaccination. After re-vaccination, it may occur much sooner. It is sporadic and most likely an allergic or toxic reaction to components of the virus. The rash differs from a macular rash, becoming maculopapular, occasionally vesicular or even pustular, and urticarial. In rare cases, Stevens-Johnson syndrome occurs after vaccination. Diagnosis is by clinical appearance and by temporal association with the vaccine. The treatment is symptomatic, primarily benadryl. Stevens-Johnson syndrome requires more extensive measures, including systemic and topical steroids. In the past, diseases (including tetanus, syphilis, streptococcal and staphylococcal infection) may have been transmitted from patient to patient due to methods that involved dipping the needle into the bottle prior to vaccinating. Further, the use of totally occlusive dressings in the past to prevent the spread of virus created an anaerobic environment with the potential for subsequent infectious complications. In recent studies, semi-permeable occlusive dressings have been used. Accidental vaccination (by ingestion or injection) sometimes occurred with no serious adverse consequences, as compared to accidental inoculation, which could have quite serious consequences (such as keratitis, burns, eczema vaccinatum). About 20 percent of complications were, in fact, due to transmission of vaccinia from a vaccinee to some other person. Traumatic and surgical wounds predisposed individuals to accidental inoculation, as did dermal infection of any type that disrupts the skin (such as eczema, which could predispose those individuals to eczema vaccinatum). Mucosal inoculation occurred via dental extraction, tonsillar extraction, and other mucosal lesions. Young infants and children tended to have more of these complications than others, for obvious reasons. The vaccination site itches, and by scratching they would transfer the virus on to their hands. Because transfer was often by hand, inflammatory eye disease predisposed some individuals to peri-orbital and corneal lesions as a result of their rubbing their eyes. Bathing can result in autoinoculation, particularly in young infants who have lesions elsewhere on their body. 13   This section summarizes the presentation by Vincent A.Fulginiti, University of Arizona, University of Colorado.

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Scientific and Policy Considerations in Developing Smallpox Vaccination Options: A Workshop Report Antiviral agents and vaccinia immunoglobulin (VIG)14 are useful treatments for these complications, except for use in the eye, although doses are not clearly established. The recommended dosage of the currently available VIG for treatment of complications is 0.6 ml/kg of body weight. VIG must be administered intramuscularly and should be administered as early as possible after the onset of symptoms. Future reformulations of VIG might require intravenous administration. There remains a need for pharmaceutical therapy, either for the management of smallpox or for the management of smallpox side effects. The eventual development of such drugs would materially change the severity and, therefore, frequency and relevance of the side effects. The development of a drug could become an alternative to vaccination, particularly in some of the containment-oriented scenarios. Generalized vaccinia is likely to be a problem should vaccination begin. Despite its appearance, it is a benign disease with multiple lesions that heal, except in rare cases of persistent recurrent lesions. However, extensive immunological studies are needed to understand why this disease occurs. Progressive vaccinia is a greater concern. It occurs in immunologically-deficient individuals, primarily in those with cell-mediated immune deficiencies. The disease involves progressive enlargement of the primary site, with viremic spread to other parts of the body, and each lesion expands as does the primary site until the lesions overcome the individual and become fatal. Children with severe combined immunodeficiency do not survive vaccinia and children with hypogammaglobulanemia can be overwhelmed by virus and die. Other populations that are vulnerable if inoculated include those with graft-versus-host disease following solid organ transplantation, cancer survivors, and HIV-infected individuals. Thus, appropriate screening for contraindications to vaccination should be implemented and should include vaccinated persons as well as their contacts. Because there are a growing number of asymptomatic and unknown HIV-positive individuals in society, vaccination strategies must consider the implications of HIV testing. 14   During the discussion, D.A.Henderson noted that there is currently enough VIG available to treat an estimated 700 persons—based on past experience, it is estimated that 100 persons per million vaccinated would require treatment. In other words, there is enough VIG at the present time to be able to vaccinate roughly 7 million people. More will be available later in 2002.

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Scientific and Policy Considerations in Developing Smallpox Vaccination Options: A Workshop Report CDC-ACIP SMALLPOX VACCINATION POLICY REVIEW CDC’s Draft Policy Options15 In June 2001, ACIP published a statement on vaccinia vaccines in the Morbidity and Mortality Weekly Report. In February 2002, CDC asked ACIP to re-visit the issue in light of the terrorist attacks in fall 2001. In response, ACIP and the National Vaccine Advisory Committee (NVAC) formed a joint working group on smallpox to review a series of questions regarding possible immunization plans. In addition, four community forums were convened in New York, San Francisco, St. Louis, and San Antonio. Information provided to ACIP indicated that the risk for smallpox occurring as a result of a deliberate release by terrorists is considered low, and the population at risk for such an exposure cannot be determined. Therefore, pre-exposure vaccination is not recommended for any group other than laboratory or medical personnel working with non-highly attenuated orthopoxviruses. Recommendations regarding pre-exposure vaccination should be made on the basis of a calculable risk assessment that considers the risk for disease and the benefits and risks regarding vaccination. Because the current risk for exposure is considered low, benefits of vaccination do not outweigh the risk regarding vaccine complications. If the potential for an intentional release of smallpox virus increases later, pre-exposure vaccination might become indicated for selected groups (e.g., medical and public health personnel or laboratorians) who would have an identified higher risk for exposure because of work-related contact with smallpox patients or infectious materials. CDC asked ACIP to consider three questions and develop options under each. The results of its deliberations, presented as options, follow each question: Question 1: With no known cases of smallpox worldwide, should there be any change in the current recommendation for not vaccinating members of the general public? Option 1: In the absence of a confirmed smallpox case, or a confirmed smallpox bioterrorism attack, ACIP does not recommend vaccination of members of the general public (i.e., no change from the current recommendation). Option 2: In the absence of a confirmed smallpox case, or a confirmed smallpox bioterrorism attack, ACIP does not recommend that members of the general public be vaccinated; however, members of the general public 15   This section summarizes the presentation by Joel Kuritsky, Centers for Disease Control and Prevention.

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Scientific and Policy Considerations in Developing Smallpox Vaccination Options: A Workshop Report it turns out after a vaccine is distributed that the threat does not materialize, which occurred in 1976 with the swine flu vaccine. In addition, although it is typical for vaccines to be accompanied by warnings, such warnings, no matter how carefully constructed, often fail to hold up in the litigation process. There are several reasons why smallpox vaccine could be far more susceptible to litigation than the typical vaccine. First, FDA review will to some extent be attenuated and could be incomplete at the time the vaccine is actually distributed. Second, the side effects are far more serious and common than those experienced with vaccines that people have become accustomed to over the past few decades. In addition, many of the individuals experiencing side effects will be those who were not actually vaccinated and thus they will be seen by juries as completely innocent, and possibly uninformed, victims. In general, the public is not aware of the risks of smallpox vaccine. If the vaccine is distributed, there is a good chance it will be distributed quickly. It may not be provided by physicians. All of these factors make the smallpox vaccine especially susceptible to tort liability litigation, which could add up to billions of dollars if the vaccine is used on a mass scale. It is obvious that this kind of liability could threaten bankruptcy for a small vaccine firm, even for a medium-sized vaccine firm. Thus, policies are needed regarding liability exposure for smallpox vaccine. Tightly targeted tort reform could limit punitive damages, a measure unlikely to be acceptable. Another option is indemnification after liability has occurred, possibly through Executive Order 10789. The problem with this form of indemnification is that it is discretionary—there does not have to be indemnification if liability occurs. If ex post, it would apply after a firm has gone through the litigation process. It covers “reasonable” liability expenses, which makes for a great deal of uncertainty about what kind of indemnification would actually occur. Perhaps most limiting of all, it only applies to vaccines that are given to consumers and patients directly by the federal government. A third alternative would be indemnification through specific legislation, which also raises problems. Again, it would be ex post, after the firm has gone through the litigation process, and would be subject to political considerations. A fourth alternative is government assumption of risk for the smallpox vaccine, an alternative which was implemented for the swine flu vaccine and which is likely to be the most realistic alternative. Communication36 Vaccine programs, like most public health efforts, require public cooperation and participation to be effective. Indeed, public health programs have, with carefully developed communication strategies, usually succeeded in garnering public trust, cooperation, and participation. Mostly, Americans cooperate with 36   This section summarizes the presentation by Anthony Robbins, Tufts University.

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Scientific and Policy Considerations in Developing Smallpox Vaccination Options: A Workshop Report public health officials and programs, although there have been exceptions to this rule, including the reluctance of soldiers to accept anthrax vaccine. These are difficult times because the needed public trust is low. The public health community did not perform well in response to the anthrax releases. If there is any doubt, ask the postal workers. Public trust is the key ingredient for success, and constitutes one broad measure of the effectiveness of our communications. Trust depends on the public understanding what and how actions will protect people. In the case of smallpox, the public will need to understand the important distinction between protecting individuals with vaccine versus using vaccine in the population to stop the spread of disease. Public health actions should not be in conflict with public understanding, or lead to a suspicion that there are unrelated political motives or goals in play. Perhaps most importantly, to be effective, public health officials must not adopt reassurance as an objective. Elected officials often demand that public health officials reassure the public. In truth, the public is comforted only by knowing that public health officials are more concerned about and alert to threats to the public health than are individual citizens. Public health officials are never trusted if they are perceived as offering reassurance rather than vigilance and protection. As a corollary, secrecy is counterproductive and destroys trust. The public should know what the public health officials know. Many citizens may choose to trust their word, and follow their advice, but others will want more information. Experience teaches that information should not be withheld and simplification carries risks. Clear and understandable explanations are indispensable. It helps to be able to explain complex and difficult ideas, but simplification must not even appear to be a way to withhold information. With every useful simplification, communicators must be able to demonstrate a willingness to expand and explain in greater depth and complexity. A knowledgeable person can master understandable simplification as well as the complexity. Finally, politics will prevail over science in the international context. If smallpox poses a threat or a serious risk to Americans, it poses similar risks to everyone on earth. If the nation is caught up in war imagery, the other six billion people on this planet may see a focus on protecting Americans in a very different light. A vaccination strategy focused entirely on Americans seems likely to trigger international mistrust about our motives and could promote fears of genocide.

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Scientific and Policy Considerations in Developing Smallpox Vaccination Options: A Workshop Report Risk Communication37 What is going to be the best risk communication strategy once the final smallpox vaccination policy is announced? Based on the complex scientific and technical information regarding smallpox vaccine, how are public health officials going to transform this information into a message, and communicate it to the right audiences at the right time with the intended effect? Dr. Ed Baker, CDC, has said, “As we move into the 21st century, risk communication may well become the central science of public health practice.” Since September 11, the Consortium for Risk and Crisis Communication has been conducting tracking studies on the public’s attitude, awareness, and beliefs about post-September 11 events, in particular smallpox, smallpox vaccine, anthrax, and anthrax vaccine. Since September 11, there have been 572 media mentions of the smallpox vaccine (particularly as it relates to national security) in the top 20 national daily newspapers. Of interest, public health is now viewed by the public as a national security issue, which provides a strong communications leverage point for any communications campaign. Although there has been much good coverage of the issues, the public does not understand the information, suggesting that it has not been put into a publicly understandable form. A large majority of the American public lacks basic and correct information, and physicians are poorly informed, not only about the disease, but also about the adverse effects of the vaccine. A public information campaign will have to be designed to correct misperceptions, identify missing facts and concepts, fill data and information gaps, reinforce correct beliefs, emphasize peripheral ones, dispel myths and rumors, overcome resistance, and anticipate and minimize controversy. The campaign, which could begin today, requires trust in the source of information and trust in the messenger. The message should be tested for public opinion and the new policy, once decided, should be positioned within the context of public health and national security. Moreover, a common message that outlines both risks and benefits must be sent across all organizations. A “step risk” communication approach is needed, recognizing that people are at varying stages in their awareness and knowledge. The individual chosen to communicate this message must have numerous attributes. He or she must: convey calmness and resolve; recognize the enormity of events; identify the nature and source of harm; acknowledge uncertainty; be highly visible; take charge of the situation; explain why and how risk information might change; elaborate concrete steps to minimize harm and risk; keep the public informed about any new developments; expose bad news; express personal and honest emotions; deliver candid and complete answers; present clear, 37   This section summarizes the presentation by Tim Tinker, Widmeyer Communications.

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Scientific and Policy Considerations in Developing Smallpox Vaccination Options: A Workshop Report strong, and empathic messages; and anticipate the psychological impact of the communications. PUBLIC HEALTH RISKS AND BENEFITS Four speakers provided commentary on the public health risks and benefits that need to be considered in planning for a smallpox outbreak or attack. Perspective 138 When focusing on public health risks and public health benefits, it is important to remember that people “do what they do,” that not everyone will respond to the same information in the same way, which creates a challenge for public health officials. The most dangerous thing in public health is having different people doing different things during a public health crisis. This was obvious in the aftermath of the anthrax release when diverse groups of people offered the anthrax vaccine made different choices. During the anthrax crisis, public health officials told everybody to go to D.C. General Hospital, get in line, get educated, and get ciprofloxacin. They were able to communicate fairly effectively that people cannot transmit anthrax to each other. It will be more difficult communicating transmission risks for smallpox or Ebola when public health departments desperately are going to need people to do what they are asked. The traditional public health approach of prevention, education, and outreach will have to be replaced with outreach first, followed by engagement, then education and prevention. Communication does not occur if one is not engaging his or her audience. Unfortunately, the anthrax crisis was the first chance the public health community had to deliver a clear public health message across the United States and engage the American public, and they did not do it very well. Unsurprisingly, those who trust government did what they were asked and those who do not did something else. This first failure will follow us into the next public health crisis. Further, the public health community needs to consider the issues involved in communicating public health risks and engendering trust and not panic. Public health officials need to stop talking about percentages and start talking about individuals. We need to reach out to people from diverse communities in diverse ways so in the middle of a crisis, all those diverse people get up and go in one 38   This section summarizes the presentation by Ivan Walks, Ivan Walks and Associates.

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Scientific and Policy Considerations in Developing Smallpox Vaccination Options: A Workshop Report direction, because it is essential and they must believe it is essential. Trust is something that comes through consistent behavior. Perspective 239 Among members of the American Society for Microbiology those working in clinical microbiology laboratories have expressed concern about possible smallpox infection. Many of these workers are young enough to have never been vaccinated, and they are likely to be on the front line of a smallpox response. Although it is easy to consider in theory that good microbiology practice would be sufficient to avoid infection of these workers, they are not confident that this would necessarily be the case. Thus, it is important that this critical group of health care personnel feel that due consideration has been given to their protection and that they have a say in the determination of that policy. The same is true for other hospital and laboratory personnel. Not only are there all the usual considerations about the danger of the vaccination to those being immunized, but also in the hospital setting is the greater problem of potential exposure to large numbers of immunodepressed or -suppressed patients. If, in fact, the probability of a smallpox attack is low, then it might not be warranted to immunize all these hospital and laboratory personnel. On the other hand, if the probability of an attack is higher than has been suggested, an altogether different public discussion should occur. Perspective 340 If, in fact, a smallpox case arises, it is by definition going to be a bioterrorist attack and there likely will be multiple introductions at multiple sites at multiple times. Although education and consensus are important, once these events occur the media and many of the scientists who agreed at one point on the response policy will assert that they had a very different policy in mind. If there is an introduction of smallpox, the public health community will not be able to prevent the second wave and thus will encounter many vaccination complications. In public health, however, perspective is important. There were 30,000 deaths during the 1968 flu outbreak in comparison to a speculated 2 cases of smallpox or 500 cases of progressive vaccinia. On the other hand, the political reaction will be pronounced: once there is one case of smallpox everyone is going to want access to the vaccine. Consequently, mass vaccination is going to take place whether or not ring vaccination is the official policy. 39   This section summarizes the presentation by Kenneth Berns, Mt. Sinai Medical Center. 40   This section summarizes the presentation by Alfred Sommer, Johns Hopkins University.

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Scientific and Policy Considerations in Developing Smallpox Vaccination Options: A Workshop Report The priority has to be to protect those people who are initially at highest risk, the first responders. The major reason to employ ring vaccination, in the presence of what will surely rapidly become mass vaccination, is to ensure near 100 percent coverage, which will never occur with a mass vaccination campaign. Pre-exposure vaccination has very little purpose, because there is no end to the list of first responders. There are good data suggesting that post-exposure vaccination within the first four or five days is essentially 100 percent effective. An epidemic was stopped cold in Bangladesh by posting vaccinators around the clock at the doorway to the hospital. Anybody who entered the smallpox hospital, where there were hundreds of cases, got vaccinated, and none of those people ended up getting smallpox. Successful response depends on our success in deploying core public health disciplines. It requires meticulous local planning and preparation, which includes sufficient local vaccine stocks—not vaccine stocks that can be pushed out in 12 hours—but stocks located in every major metropolitan area and municipality, with needles to go with them, trained vaccinators, and surge capacity. If the anthrax events proved anything, it is that the public health community cannot plan for a specific event. Public health capacity must be expanded to respond to the unexpected. Perspective 441 Public health crises inevitably involve changing facts and situations, which contribute to the uncertainty and complexity of risk communication. For example, in the context of smallpox in 2002, versus 30 years ago, there are now more people who are on chemotherapy, recipients of organ transplants, living with HIV, and in day care, and the nation is witnessing increases in childhood asthma and eczema. Social changes have occurred as well. There is greater distrust of government. The United States population has reached 280 million people, with more and more living in urbanized environments. The fraction of the population that is immigrant with English as a second language has grown, and many of them are undocumented with no access to health care. The mobility of the population is stunning. As a result of all these changes, planners must be wary of their assumptions about “who we are, who we are trying to protect, and what we are trying to do.” And they must now deal with the concept of malignant intent, which was not factored in decades ago. Experience with swine flu vaccine taught the public health community that efforts like developing consent forms and mobilizing enough people to vaccinate enough people are incredibly difficult to mount and can be halted for political 41   This section summarizes the presentation by June Osborn, Josiah Macy, Jr. Foundation.

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Scientific and Policy Considerations in Developing Smallpox Vaccination Options: A Workshop Report reasons. Moreover, public health plans can never achieve 100 percent immunization when people do not have insurance or access to health care because city emergency rooms are closing down for cost containment reasons. Jonathan Mann used to emphasize that the infrastructure to fight AIDS had to be built to the capacity necessary for everything else that needed doing, because otherwise it would either not work at all or disappear as soon as there was a departure of personnel, money, or a particular program. There is a lot of work to be done in building the public health infrastructure and there are a lot of biological agents to worry about besides smallpox. Whatever the public health community does, it needs to build the infrastructure that society has been negligent about in terms of infectious disease in general. PUBLIC COMMENTS AND DISCUSSION Several additional issues emerged in the general discussion and are briefly summarized below. Use of Scarce Public Health Resources and Insuring Dual Use Approaches An immunization program will entail costs, thus decisions must be made about trade-offs. Spending money on a program that would potentially be very effective at addressing a single bioweapons disease might come at the expense of other public health measures that might provide more protection against a broader range of bioagents. However, developing a plan for smallpox response also readies the public health system for other infectious diseases, whether naturally occurring or deliberately spread. Vaccine Development and Approval New vaccines will be subject to an IND, which will require the usual protections for those volunteering to be research subjects, including IRB review, informed consent, and data and safety monitoring. By recruiting health care professionals into those trials it might be possible to not only test the vaccine but also potentially immunize a larger ring of individuals who by occupation are not at the highest risk (first responders) but are at greater risk of exposure than the general population. In addition, there should be provisions in the usual IND granting process—if the response is going to be in an emergent situation—to suspend some of the usual procedures and guidelines, or the vaccine will not be delivered.

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Scientific and Policy Considerations in Developing Smallpox Vaccination Options: A Workshop Report In testing new vaccines, it will be important to fine tune the dosage and correlate it with the take and reaction. Public response to the clinical reactions experienced by those receiving experimental doses will be important to consider and measure, anticipating that a more risk averse reaction is likely to occur if only the high-dose, more radical reactions are publicized. For new vaccine development, a vaccine compensation injury fund and indemnification must be available or manufacturers will continue to be wary of conducting R&D in this area. International Considerations In developing a smallpox plan for the United States, the ability of the rest of the world to also respond must be considered, especially those countries that have neither the resources nor infrastructure to conduct surveillance and containment or that might face complex cultural challenges in communicating the need for immunization, isolation, or quarantine. In setting domestic vaccine policies, public health officials must also consider what, how, and when the United States makes recommendations to other countries. Uncertainties One area of uncertainty in the many public discussions about the vaccination policy options is the risk-benefit ratio. Government officials have said that the risk of an attack is very low, but not zero. The uncertainty of the threat level, the characteristics of the virus that would be used in an attack, and the mechanisms of dispersal make it difficult to evaluate the benefit of the vaccine. Another area of uncertainty is that much of the clinical and epidemiological experience with smallpox infection and the vaccine derive from an era with very different population characteristics than today. Two key differences are the large number of Americans who have no prior immunity to smallpox and the number of people who are immune-compromised. Communication and Education The lack of an effective communication strategy can be a significant hindrance to an effective public health response, even with a fairly benign vaccine that is well accepted and without risk. Right now, the assumption is that once the nation sees crucial people getting vaccinated, everyone is going to want to be vaccinated. An alternative possibility is that when people learn about this vaccine through effective public education efforts, they will understand that the vaccine carries risks but they will also understand that if they are exposed, the vaccination is very effective within a few days and there will be enough vaccine

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Scientific and Policy Considerations in Developing Smallpox Vaccination Options: A Workshop Report for those who need it. A plan should be made for advance notification of the public about the risks and the benefits of the vaccine. Citizens should be encouraged to consider in advance whether vaccination is something they would want to pursue in the event of an outbreak or attack. An important lesson from the anthrax investigation was the importance of a strong, credible spokesperson. Once the vaccination policy is announced, it is important that it be explained thoroughly to the public, particularly to those who are at risk for adverse effects of vaccination. Depending on the policy decided upon, it will be critical that it be explained not only to those who will receive the vaccine, but also—if the plan does not involve mass vaccination—to those who are not given access. EPILOGUE A summary of the June 15, 2002 IOM meeting was presented at the June 19–20, 2002 meeting of the Advisory Committee on Immunization Practices. The ACIP made its recommendations (below) on June 20th. These recommendations are currently under consideration by CDC and the Department of Health and Human Services. Draft Supplemental Recommendations of the ACIP Use of Smallpox (Vaccinia) Vaccine, June 2002 Draft approved by ACIP on June 20, 2002 (SOURCE: http://www.cdc.gov/nip/smallpox/supp_recs.htm [accessed August 2002]) Pre-Release Vaccination of the General Population Under current circumstances, with no confirmed smallpox, and the risk of an attack assessed as low, vaccination of the general population is not recommended, as the potential benefits of vaccination do not outweigh the risks of vaccine complications. Recommendations regarding pre-outbreak smallpox vaccination are being made on the basis of an assessment that considers the risks of disease and the benefits and risks of vaccination. The live smallpox (vaccinia) vaccine virus can be transmitted from person to person. In addition to sometimes causing adverse reactions in vaccinated persons, the vaccine virus can cause adverse reactions in the contacts of vaccinated

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Scientific and Policy Considerations in Developing Smallpox Vaccination Options: A Workshop Report persons. It is assumed that the risk of serious adverse events with currently available vaccines would be similar to those previously observed and could be higher today due to the increased prevalence of persons with altered immune systems. Pre-Release Vaccination of Selected Groups to Enhance Smallpox Response Readiness Smallpox Response Teams Smallpox vaccination is recommended for persons pre-designated by the appropriate bioterrorism and public health authorities to conduct investigation and follow-up of initial smallpox cases that would necessitate direct patient contact. To enhance public health preparedness and response for smallpox control, specific teams at the federal, state and local level should be established to investigate and facilitate the diagnostic work-up of the initial suspect case(s) of smallpox and initiate control measures. These Smallpox Response Teams might include persons designated as medical team leader, public health advisor, medical epidemiologists, disease investigators, diagnostic laboratory scientist, nurses, personnel who would administer smallpox vaccines, and security/law enforcement personnel. Such teams may also include medical personnel who would assist in the evaluation of suspected smallpox cases. The ACIP recommends that each state and territory establish and maintain at least one Smallpox Response Team. Considerations for additional teams should take into account population and geographic considerations and should be developed in accordance with federal, state, and local bioterrorism plans. Designated Smallpox Healthcare Personnel at Designated Hospitals Smallpox vaccination is recommended for selected personnel in facilities pre-designated to serve as referral centers to provide care for the initial cases of smallpox. These facilities would be pre-designated by the appropriate bioterrorism and

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Scientific and Policy Considerations in Developing Smallpox Vaccination Options: A Workshop Report public health authorities, and personnel within these facilities would be designated by the hospital. As outlined in the CDC Interim Smallpox Response Plan and Guidelines state bioterrorism response plans should designate initial smallpox isolation and care facilities (e.g., type C facilities). In turn, these facilities should pre-designate individuals who would care for the initial smallpox cases. To staff augmented medical response capabilities, additional personnel should be identified and trained to care for smallpox patients. Implementation of Recommendations The ACIP recognizes that the implementation of the supplemental recommendations presented in this document requires addressing a number of issues, and that this will take time. The issues include provider and public education, health care provider training, availability of vaccine and VIG, developing the appropriate investigational new drug protocols, screening, strategies to minimize vaccine wastage, vaccine adverse event surveillance, and other logistical and administrative issues.