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PubMed2001

The threat of smallpox and bioterrorism.

Smallpox (variola) was a devastating disease with a high case-fatality rate. Although the disease was eradicated in 1977, the remaining stocks of smallpox virus constitute one of the most dangerous threats to humanity. The smallpox virus is highly specific for humans and non-pathogenic in animals. There is no antiviral treatment and a vaccine is active only if administered in the first four days post-exposure. Smallpox virus represents a potential biological weapon that could be used by terrorists, and the destruction of stocks raises political, social, scientific and ethical issues.

Biological Warfare↗
PubMed2006

Quantification of antibody responses against multiple antigens of the two infectious forms of Vaccinia virus provides a benchmark for smallpox vaccination.

Smallpox was eradicated without an adequate understanding of how vaccination induced protection. In response to possible bioterrorism with smallpox, the UK government vaccinated approximately 300 health care workers with vaccinia virus (VACV) strain Lister. Antibody responses were analyzed using ELISA for multiple surface antigens of the extracellular enveloped virus (EEV) and the intracellular mature virus (IMV), plaque reduction neutralization and a fluorescence-based flow cytometric neutralization assay. Antibody depletion experiments showed that the EEV surface protein B5 is the only target responsible for EEV neutralization in vaccinated humans, whereas multiple IMV surface proteins, including A27 and H3, are targets for IMV-neutralizing antibodies. These data suggest that it would be unwise to exclude the B5 protein from a future smallpox vaccine. Repeated vaccination provided significantly higher B5-specific and thus EEV-neutralizing antibody responses. These data provide a benchmark against which new, safer smallpox vaccines and residual immunity can be compared.

Antibodies, Viral↗
PubMed2006

What dermatologists do not know about smallpox vaccination: results from a worldwide electronic survey.

The risk of a bioterrorist attack with smallpox has increased owing to breakthroughs in the de novo synthesis of long-chain DNA molecules. Although the leading roles of dermatologists in diagnosing recent outbreaks of cutaneous anthrax and monkeypox demonstrate the importance of dermatologist preparedness for bioterrorism, dermatologist knowledge regarding smallpox vaccination has not been extensively examined. We conducted a cross-sectional worldwide electronic survey of all members of the American Academy of Dermatology with available e-mail addresses. The response rate was 23% (1,303/5,723): 34% of respondents were women, 52% were age 50 or older, 85% practiced in the US, and 90% reported English as their primary language. Less than 37% indicated the Centers for Disease Control and Prevention estimated rate of death owing to smallpox vaccination (1 in 1,000,000), and many failed to identify vaccination contraindications: previous myocardial infarction (83%), angina (83%), congestive heart failure (78%), steroid eye drop use (65%), and the non-emergency vaccination of those younger than age 18 (95%). Widespread dermatologist smallpox vaccination knowledge deficits pinpoint opportunities for educational efforts.

Adult↗
PubMed1980

The confirmation and maintenance of smallpox eradication.

In December 1979, an independent scientific commission certified global eradication of smallpox. This conclusion was accepted at the 33d World Health Assembly of the World Health Organization (WHO) in May 1980. After WHO's intensified eradication program began in 1967, special certification procedures were used in 35 countries where the disease had been endemic and in 44 others at special risk. Six laboratories are known to retain variola virus; efforts have been made to ensure strict containment of these strains. There is no evidence that smallpox will recur as an endemic disease. Nevertheless, WHO will promote surveillance of smallpox-like disease and selected laboratory research on certain orthopoxviruses. These efforts will maintain confidence that smallpox has been eradicated and confirm that there are no animal reservoirs of variola virus. A more complete understanding of the orthopoxviruses, including monkeypox virus, should also be obtained.

Child↗
PubMed2003

Quantitation of CD8+ T cell responses to newly identified HLA-A*0201-restricted T cell epitopes conserved among vaccinia and variola (smallpox) viruses.

Immunization with vaccinia virus resulted in long-lasting protection against smallpox and was the approach used to eliminate natural smallpox infections worldwide. Due to the concern about the potential use of smallpox virus as a bioweapon, smallpox vaccination is currently being reintroduced. Severe complications from vaccination were associated with congenital or acquired T cell deficiencies, but not with congenital agammaglobulinemia, suggesting the importance of T cell immunity in recovery from infection. In this report, we identified two CD8+ T cell epitopes restricted by the most common human major histocompatibility complex (MHC) class I allele, HLA-A*0201. Both epitopes are highly conserved in vaccinia and variola viruses. The frequency of vaccinia-specific CD8+ T cell responses to these epitopes measured by interferon (IFN)-gamma enzyme-linked immunospot (ELISPOT) assay and HLA/peptide tetramer staining peaked 2 wk after primary immunization and then declined, but were still detectable 1 to 3 yr after primary immunization. 2 wk after immunization, IFN-gamma-producing cells specific to these two epitopes were 14% of total vaccinia virus-specific IFN-gamma-producing cells in one donor, 35% in the second donor, and 6% in the third donor. This information will be useful for studies of human T cell memory and for the design and analyses of the immunogenicity of experimental vaccinia vaccines.

CD8-Positive T-Lymphocytes↗
PubMed2005

Generalized vaccinia, progressive vaccinia, and eczema vaccinatum are rare following smallpox (vaccinia) vaccination: United States surveillance, 2003.

Generalized vaccinia (GV), progressive vaccinia (PV), and eczema vaccinatum (EV) are adverse reactions following smallpox vaccination. We investigated all reports suggestive of GV, PV, or EV among United States civilian smallpox vaccinees during 2003 and applied standard case definitions. We identified 29 reports of possible GV among 38,440 vaccinees; 2 (7%) of the reports met the case definition. One case of GV was confirmed by identifying vaccinia from a lesion distant from the vaccine site using polymerase chain reaction. The other case was classified as probable GV, because confirmatory testing was not done. We identified 3 potential EV cases and 7 potential PV cases, none of which met the standard case definition. GV, PV, and EV were rare or absent following smallpox vaccination after careful screening of potential vaccinees. GV may be difficult to distinguish from other rashes, and confirmatory testing is recommended. Careful prevaccination screening probably contributed to the low incidence of these adverse reactions following smallpox vaccination.

Adolescent↗
PubMed2005

The Spanish royal philanthropic expedition to bring smallpox vaccination to the New World and Asia in the 19th century.

The New World was ravaged by smallpox for several centuries after the Spanish conquest. Jenner's discovery of the smallpox vaccine made possible the prevention and control of smallpox epidemics. In response to a large outbreak of smallpox in the Spanish colonies, King Charles IV appointed Francisco Xavier de Balmis to lead an expedition that would introduce Jenner's vaccine to these colonies. During the journey, the vaccine was kept viable by passing it from arm to arm in orphaned children, who were brought along expressly for that purpose and remained under the care of the orphanage's director. This expedition was the first large scale mass vaccination of its kind. The historic legacy of this pioneering event in international health should be revisited in the current era of persistent inequalities in global health.

Americas↗
PubMed2005

Willingness of private physicians to be involved in smallpox preparedness and response activities.

BACKGROUND: The public health system continues its efforts to prepare for bioterrorist events, such as a smallpox outbreak, but may need to call on other health professionals to ensure sufficient capacity to implement preparedness plans. OBJECTIVE: The goal was to understand the willingness of primary care physicians to participate in possible smallpox pre- or post-event activities. METHODS: A 23-question mail survey was sent to a national random sample of 727 internists and 720 family physicians. After three mailings, a one-page version of the survey was sent to nonrespondents. RESULTS: Response rates were 26% for questions common to both surveys and 22% for questions on the longer survey only. Respondents to the survey expressed moderate support for participating in certain smallpox pre- and post-event activities. Under a pre-event scenario, many providers would be willing to vaccinate first responders in their practice, and roughly one-third would be willing to vaccinate patients in their practice or to work in a public health clinic as a vaccinator. Most physicians, however, would be unwilling to be vaccinated themselves. Under post-event conditions, most providers would be willing to vaccinate their own patients, and many would vaccinate other community members in their practice. CONCLUSIONS: Despite the low response rate, information from this study on the smallpox preparedness activities in which physicians are most willing to participate can help to inform efforts by public health officials and private physicians to collaborate on bioterrorism preparedness efforts.

Adult↗
PubMed1980

Immune responses to measles and smallpox vaccinations in malnourished children.

Children with different levels of nutritional status were studied to determine their immune response to, and complications from, immunization with live measles vaccine and lyophilized smallpox vaccine. Two hundred forty-one children between the ages of 5 months and 9 years were examined to assess their nutritional status at the time of immunization. Sero-conversion was defined as a hemagglutination-inhibition titer to measles virus, of greater than or equal to 1:20 6 to 8 weeks after vaccination in initially sero-negative children. Of 111 initially sero-negative children 94% had an adequate immune response, shown by sero-conversion. Of 193 children without a smallpox vaccinationscar 97% were successfully immunized against smallpox. These rates of immune response were independent of age, sex, and nutritional status of the children. The geometric mean titer rise to measles immunization of groups, whose nutritional status was normal (greater than 90% of median weight for age), mildly (75 to 90%), moderately (60 to 75%), or severely (less than 60%) malnourished were 7.5, 8.8, 7.9, and 7.9, respectively. Malnutrition did not affect the children's ability to develop adequate immune response to measles of smallpox vaccine, and there were no major complications during the 8-week period of follow-up. Since measles is a very severe disease, which in malnourished children can carry a case fatality rate as high as 50%, malnutrition should be a prime indication for measles immunization, and certainly not a contraindication.

Aging↗
PubMed1995

Epidemiology of smallpox in west Pakistan. III. Outbreak detection and interlocality transmission. 1971.

During one year, 121 outbreaks of variola major were detected in 99 of the 1717 localities within a rural area of West Pakistan with a total population of approximately 1.2 million. Only 19% of the outbreaks, representing 36% of the 1040 investigated cases, were officially reported, although potential strengths in the government surveillance system were also identified. Persistence of smallpox within the area depended on introductions from the outside, and more than one-half of all outbreaks of known source could be ultimately traced to cities. Within the study area, outbreaks with the largest numbers of cases and those in the larger communities were the ones from which smallpox was most frequently transported. The frequency with which variola was introduced into localities was directly related to population size and to the presence of medical care facilities. Trips between localities by infected individuals were extremely rare events. They were made most often during the late fall and winter, primarily during the incubation period of the disease, and did not differ in purpose, means or destination from journeys unassociated with smallpox. Individuals at relatively high risk of becoming introducers included the unvaccinated (primarily children under five), the unschooled and those not native to the area. Vaccination priorities based on these findings could increase the efficiency of smallpox eradication efforts.

Disease Outbreaks↗
PubMed2002

Smallpox and the Native American.

With the arrival of Europeans in the Western Hemisphere, Native American populations were exposed to new infectious diseases, diseases for which they lacked immunity. These communicable diseases, including smallpox and measles, devastated entire native populations. In this article, we focus on the effect of smallpox on the Native Americans from the 15th through the 19th centuries. Among the "new" infectious diseases brought by the Europeans, smallpox was one of the most feared because of the high mortality rates in infected Native Americans. This fear may have been well-founded, because the Native Americans were victims of what was probably one of the earliest episodes of biological warfare. Fortunately, they were also major beneficiaries of early vaccination programs. Thus, the arrival of smallpox and the decline of the Native American populations are inexorably linked, as the history summarized here illustrates.

History, 16th Century↗
PubMedDate not supplied

Correlates of public health workforce acceptance of smallpox immunization in Virginia.

OBJECTIVE: By October 24, 2003, 38,577 of 500,000 targeted civilians received smallpox vaccine in the Pre-Event Smallpox Vaccination Campaign, Phase I. We investigated reasons for the low vaccination uptake. DESIGN: Cross-sectional survey, conducted in May 2004. SAMPLE: We surveyed 225 health care personnel, potential members of smallpox response teams in Virginia, who were offered vaccination. We assessed respondents' acceptance of vaccination and its association with factors potentially influencing vaccination: perceptions of vaccine safety, contraindications, concerns about bioterrorism, and workplace influences. RESULTS: Among nonvaccinees (n=44), 70% had a contraindication to the vaccine compared with 8% among vaccinees (n=132). The desire to prepare America for potential bioterrorist attack was associated with acceptance of smallpox vaccination (odds ratio [OR]: 17.7, 95% confidence interval [CI]: 3.6-85.9). Among respondents with contraindications, vaccinees reported more often than nonvaccinees having been asked by their supervisors to be vaccinated (OR: 5; 95% CI: 1.1-22.1) and to have been concerned that their vaccination choice would affect positively their job evaluation (OR: 11; 95% CI: 1.6-81.1). CONCLUSION: Concerns about bioterrorism and willingness to help in the preparedness effort were motivations for vaccination. Continued vigilance to avoid vaccination of those with contraindications is needed.

Adult↗
PubMed1970

Accuracy of smallpox diagnosis by immunfluorescence with a purified conjugate.

A direct fluorescent-antibody test for smallpox is described which utilizes a conjugated antivaccinia serum that was purified by diethylaminoethyl fractionation. The purity of the conjugate was analyzed by density gradient centrifugation, and specific staining of smallpox and nonsmallpox specimens was measured quantitatively by a photovoltmeter. Variola elementary bodies were identified in all of the specimens of vesicular and pustular fluid collected from 50 smallpox patients, and no false-positive diagnoses were made on specimens from 27 patients with varicella or other nonpox viral exanthems. However, 63.8% of the specimens of vesicular and pustular fluid smeared on slides in the field were unusable because of bright nonspecific fluorescence. For this reason, the fluorescent-antibody test does not compare favorably with other routine laboratory tests for smallpox.

Animals↗
PubMed1975

Response of camels to intradermal inoculation with smallpox and camelpox viruses.

Young camels were inoculated intradermally with either camelpox or smallpox virus and the courses of infection, including serological response, were compared. Camelpox virus was highly infectious; generalized disease resulted which was transmitted naturally to contact animals. Smallpox virus produced only transient lesions at the inoculation site and a less marked serological response. Nevertheless, the camels inoculated with smallpox virus subsequently resisted a severe challenge with camelpox virus, and the possibility that limited replication of smallpox virus took place is discussed. The differences demonstrated between the behavior of the vituses is discussed in the light of their otherwise close relationship and the limited information available about camelpox infections in man.

Animals↗
PubMed2003

New generation of cell culture assay for smallpox vaccine potency.

The potency of smallpox vaccines produced in the 1970s was tested by titration onto chorioallantoic membranes of fertilized hen eggs (CAM assay). The potency specification commonly approved for these vaccines was a titer above 10(8) pock-forming units per milliliter. We developed and validated a cell culture titration assay to have a more reliable potency test. The cell titration assay and the CAM assay were tested in parallel on 34 first-generation smallpox vaccine lots. These allowed us to demonstrate that a correlation does exist between the two titration techniques and to determine a new in-house specification for the cell titration method. This in vitro potency assay will allow us to test first-generation smallpox vaccines produced on the skin of living animals but will also give a hint of the potency specification that should be assigned for new generations of cell-derived smallpox vaccines.

Allantois↗
PubMed2002

Smallpox manifestations and survival during the Boston epidemic of 1901 to 1903.

Clinical records of 243 patients with smallpox consecutively admitted to the Southampton Street smallpox hospital in Boston, Massachusetts, during the 1901-1903 epidemic were reviewed. Smallpox was divided into five categories of varying severity; 47% of patients had varioloid, a relatively mild form of the disease usually occurring in previously vaccinated individuals with incomplete immunity. Survival information is available for 206 patients, of whom 36 (17.5%) died. Vaccination status, disease severity, and age were associated with survival, whereas sex, birthplace, and race were not. While full recovery often took weeks, most deaths occurred 7 to 14 days after the onset of symptoms, and all deaths occurred within 18 days of symptom onset. Smallpox was eradicated worldwide in 1977, but knowledge of the disease is essential because its cause, variola virus, is considered a potential biological weapon.

Boston↗
PubMed2003

Eczematous skin disease and recall of past diagnoses: implications for smallpox vaccination.

BACKGROUND: Persons with atopic dermatitis or eczema, regardless of disease severity or activity, may develop eczema vaccinatum if they or their close contacts receive the smallpox vaccine. According to current recommendations, a preexposure vaccination program should identify these persons and exclude them from participating. OBJECTIVE: To determine the prevalence of diagnosed atopic dermatitis and eczema in a defined population and assess the sensitivity of screening questions to identify patients who have received these diagnoses. DESIGN: Population-based prevalence survey and telephone interview. SETTING: 14 ZIP code regions in Wisconsin. PATIENTS: Persons given a diagnosis of atopic dermatitis or eczema in 2000 and 2001 were identified from a population-based cohort. Persons with a history of atopic dermatitis diagnosed since 1979 were eligible for the telephone survey. MEASUREMENTS: Prevalence of diagnosed atopic dermatitis or eczema; proportions of respondents able to recall a past diagnosis of atopic dermatitis, eczema, or recurrent rash. RESULTS: The prevalence of atopic dermatitis or eczema diagnosis in 2000 or 2001 was 0.8%. At least 2.4% of the cohort would be ineligible for smallpox vaccination because of active skin disease in themselves or household members. Among 94 adult respondents with atopic dermatitis, 55 (59%) correctly self-reported skin disease. Seventy-nine (60%) of 133 household contacts of adults with atopic dermatitis correctly reported the presence of skin disease in a household member. Parental recall of skin disease in children with atopic dermatitis was 70% (123 of 177). CONCLUSIONS: Identifying dermatologic contraindications to smallpox vaccination by relying only on a self-reported history of rash illnesses is likely to miss a substantial proportion of individuals who should not receive smallpox vaccine in a preexposure vaccination campaign.

Adolescent↗
PubMed2002

The cause of death in smallpox: an examination of the pathology record.

OBJECTIVE: Because the cause of death in smallpox remains controversial, the human pathology record was examined. METHODS: The surviving case series of smallpox pathology in humans as well as other review articles from English language journals written during the last 200 years were reviewed. RESULTS: The skin lesions in smallpox developed as a result of viral damage and inflammation. Secondary bacterial infection did not occur until the scabs started shedding. During the papular stage of skin eruption, a secondary viremia caused focal lesions in the pharynx, larynx, tongue, trachea, and esophagus in descending frequency. The virus also caused potentially lethal interstitial pneumonitis as well as tubulointerstitial nephritis. CONCLUSIONS: The cytopathic effects of smallpox cause death. The data did not support previously promulgated theories attributing death to a bacterial sepsis syndrome seeded from the pustules or immune complex deposition. In a future outbreak, antibiotic therapy would minimally influence mortality.

Bone Marrow Diseases↗