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PubMed1996

Oscillatory dynamics of smallpox and the impact of vaccination.

The evolution of smallpox epidemics in London, 1647-1893, was studied by time series analysis of deaths from the disease in the Bills of Mortality. The interepidemic interval (T) evolved progressively from 4 years to 2 years at 1800. The dynamics of epidemics during 1647-1800 are explicable in terms of the transmission of viral diseases which shows that (i) T is determined by the product of population size (N) and susceptibility (beta), (ii) T determines the mean age of catching the disease, (iii) the system will settle at its steady-state, endemic level unless the epidemics are driven. It is suggested that (i) the progressive change in T was initially caused by a rise in N and later by an increased beta related to malnutrition and (ii) the epidemics were driven by an oscillation in delta beta associated with seasonal dry conditions. The effects of variolation and vaccination became apparent after 1800: the endemic level fell progressively, the epidemics were reduced in amplitude and they were not driven. The dynamics of the disease can now be described by an SEIR model: severe outbreaks of smallpox are followed by decaying epidemics. Endemic smallpox mortality also interacts with the dynamics of the population so that a long wavelength oscillation (associated with recovery after the plague) and a 5/6 year (associated with immigration) oscillation are generated.

Disease Outbreaks↗
PubMed2006

Mass vaccination and surveillance/containment in the eradication of smallpox.

The Smallpox Eradication Program, initiated by the WHO in 1966, was originally based on mass vaccination. The program emphasized surveillance from the beginning, largely to track the success of the program and further our understanding of the epidemiology of the disease. Early observations in West Africa, bolstered by later data from Indonesia and the Asian subcontinent, showed that smallpox did not spread rapidly, and outbreaks could be quickly controlled by isolation of patients and vaccination of their contacts. Contacts were usually easy to find because transmission of smallpox usually required prolonged face-to-face contact. The emphasis therefore shifted to active searches to find cases, coupled with contact tracing, rigorous isolation of patients, and vaccination and surveillance of contacts to contain outbreaks. This shift away from mass vaccination resulted in an acceleration of the program's success.

Africa, Western↗
PubMed2005

Characterization of a vaccinia virus strain used to produce smallpox vaccine in Argentina between 1937 and 1970.

Due to recent political developments, smallpox has re-emerged as a serious threat. We recovered and characterized an old batch of smallpox vaccine, Malbrán strain, produced between 1945 and 1949. The virus was re-isolated and characterized by sequence analysis and biological activity in animals. Phylogenetic analysis using the hemagglutinin and A45R genes showed that the Malbrán strain was closely related to the Lister strain of vaccinia virus. In animals, the Malbrán strain exhibited low pathogenicity, confirming historical records. Mice immunized with the Malbrán strain survived a lethal challenge with cowpox virus. Thus, this strain of vaccinia virus remains a viable candidate as a smallpox vaccine.

Argentina↗
PubMed2006

Analysis of cases reported as generalized vaccinia during the US military smallpox vaccination program, December 2002 to December 2004.

BACKGROUND: We evaluated military personnel who developed dermatologic reactions suggestive of generalized vaccinia (GV) after smallpox vaccination. METHODS: We conducted surveillance and retrospective analysis of cases from the Vaccine Adverse Event Reporting System (a passive reporting system managed by the Centers for Disease Control and Prevention), and the military's preventive medicine channels, vaccine healthcare centers, clinical laboratory network, dermatology clinics, and pathology departments from December 2002 to December 2004. RESULTS: Of 74 cases investigated in 753,226 vaccinations, 50 (67.6%) met the case definition of possible GV (rate 66/million), 95% confidence interval (49-88/million), consistent with historically reported rates. Cases of possible GV occurred more frequently in primary vaccinees (81/million) than in those revaccinated (32/million) (relative risk 2.6, 95% confidence interval 1.2-5.9, P = .013). None met the case definition of probable or confirmed GV, including 15 with virologically negative laboratory evaluations (eg, culture, skin biopsy, or polymerase chain reaction). LIMITATIONS: The methods of case collection and retrospective nature of this study are its limitations. The clinical diagnosis of possible GV was made on the basis of the authors' interpretation of clinical notes and adverse events submitted by more than 100 different providers. Only 15 of the 74 cases of possible GV had laboratory attempts for virological confirmation. CONCLUSION: GV is still a rarely reported complication of smallpox vaccination. True GV, strictly defined, may be even less common than previously reported. We named one self-limited dermatologic manifestation confused with GV "postvaccinial nonviral pustulosis." Properly screened individuals considering smallpox vaccination may be assured most exanthemata after vaccination are benign.

Adult↗
PubMed2005

Standardization of a neutralizing anti-vaccinia antibodies titration method: an essential step for titration of vaccinia immunoglobulins and smallpox vaccines evaluation.

The possibility of mass population vaccination with smallpox vaccine implies the development of anti-vaccinia immunoglobulins for the treatment of severe side effects following vaccination. We have chosen to develop and validate the "gold standard method" (plaque reduction neutralization assay) to titrate neutralizing anti-vaccinia antibodies in two different French laboratories belonging to the Department of Defense (CRSSA) and to the French Health Products Safety Agency (Afssaps). The results of precision, linearity and accuracy of the method led to consider the method as validated. In parallel, we have prepared and lyophilized a pool of anti-vaccinia plasma samples issued from a unique donor and qualified this preparation versus the first British standard to use it as an in-house standard with a titer of 25 international units (IU). This work will allow to titrate, in IU, sera from vaccinated persons in order (i) to titrate purified anti-vaccinia immunoglobulin preparations for vaccine severe side effect treatments; (ii) to investigate the level of neutralizing antibodies in the general population; and (iii) to investigate clinical trials of new generation smallpox vaccines. In the future, this will allow comparability of studies on either smallpox vaccines or on the serological status of the population.

Animals↗
PubMed2004

[Smallpox and bioterrorism].

The variola virus was the first biological agent to be used as a military weapon. It is considered as one of the main agents that could potentially be used in the context of bioterrorism. Smallpox was declared eradicated in 1980. So, in case of a confirmed or suspected case of smallpox, a deliberate, intentional origin must be considered. The early diagnosis of the first case is essential for initiating an epidemiological alert. All physicians should be well informed of the epidemiological, clinical, diagnostic, and therapeutic aspects of smallpox.

Bioterrorism↗
PubMed2005

A novel, cell culture-derived smallpox vaccine in vaccinia-naive adults.

Despite the eradication of smallpox as a naturally occurring disease, concern persists over its potential use as a bioterrorist agent. The development of a new-generation smallpox vaccine represents an important contribution to a cogent biodefense strategy. We conducted a phase 2 randomized, double-blind, controlled trial at four sites in the United States to determine whether a clonal smallpox vaccine manufactured in cell culture, ACAM2000, is equivalent to the standard calf-lymph vaccine, Dryvax, in terms of cutaneous response rate, antibody responses and safety. Subjects received either Dryvax or one of four dose levels of ACAM2000 administered percutaneously using a bifurcated needle. All subjects in the highest ACAM2000 dose group and the Dryvax group experienced a successful vaccination. Dilution doses of ACAM2000 were associated with success rates below the 90% threshold established for efficacy. There were no differences in the proportion of subjects who developed neutralizing antibody: 94% in the highest ACAM2000 dose group (95% CI, 84-99) and 96% in the Dryvax group (95% CI, 86-100). No significant differences were seen between the effective ACAM2000 and Dryvax groups regarding the occurrence of adverse events. One subject who received ACAM2000 developed myopericarditis. In healthy, primary vaccines ACAM2000 has a similar vaccination success rate, antibody response, and safety profile to Dryvax.

Adolescent↗
PubMed2006

Highly attenuated smallpox vaccine protects rabbits and mice against pathogenic orthopoxvirus challenge.

The possible reemergence of smallpox through bioterrorism requires the preparation of adequate stockpiles of vaccine. Dryvax, the only US-licensed vaccinia virus smallpox vaccine, has an unacceptable safety profile in the pre-event setting. LC16m8 is a Japanese-licensed attenuated vaccinia virus strain that has been safely used in over 50,000 persons. Until now, efficacy of this vaccine was unproven. Using two animal models, we show that LC16m8 and Dryvax elicit comparable humoral immune responses after a single vaccination and equivalently protect against lethal poxvirus disease. Thus, LC16m8 shows promise as a safe and effective smallpox vaccine with the potential for replacing Dryvax.

Animals↗
PubMed2005

Smallpox vaccine stability after maintenance at temperatures not recommended for shipping.

Two distinct smallpox vaccine formulations were exposed to temperatures beyond the ranges specified by the manufacturers for vaccine maintenance and shipping. Under the conditions investigated, titers of both Dryvax smallpox vaccine and Aventis Pasteur smallpox vaccine remained at or above the titers recommended for successful vaccination. From these data it can be inferred that vaccine efficacy would not be expected to be adversely affected by unintended fluctuations of temperature, within the ranges studied, for a 4-day period.

Drug Stability↗
PubMed1982

Laboratory diagnosis of smallpox: role of the Virus Reference Laboratory, Colindale, 1947-70.

The Virus Reference Laboratory, Colindale, first embarked on laboratory investigations for smallpox early in 1947. From then, in conjunction with the Department of Bacteriology, University of Liverpool, it provided a complete diagnostic service throughout England and Wales until 1962, after which the service became available regionally until eradication was effected. Up to 1970 it had investigated 2696 specimens from suspected cases of smallpox and had recovered 108 strains of variola and 248 of vaccinia virus. These last were from persons suffering the complications of vaccination. Some outbreaks following smallpox importation are discussed but infection among laboratory staff during this period was not demonstrated.

England↗
PubMed2003

Planning for smallpox outbreaks.

Mathematical models of viral transmission and control are important tools for assessing the threat posed by deliberate release of the smallpox virus and the best means of containing an outbreak. Models must balance biological realism against limitations of knowledge, and uncertainties need to be accurately communicated to policy-makers. Smallpox poses the particular challenge that key biological, social and spatial factors affecting disease spread in contemporary populations must be elucidated largely from historical studies undertaken before disease eradication in 1979. We review the use of models in smallpox planning within the broader epidemiological context set by recent outbreaks of both novel and re-emerging pathogens.

Bioterrorism↗
PubMed2004

Immunogenicity of a highly attenuated MVA smallpox vaccine and protection against monkeypox.

The potential use of smallpox as a biological weapon has led to the production and stockpiling of smallpox vaccine and the immunization of some healthcare workers. Another public health goal is the licensing of a safer vaccine that could benefit the millions of people advised not to take the current one because they or their contacts have increased susceptibility to severe vaccine side effects. As vaccines can no longer be tested for their ability to prevent smallpox, licensing will necessarily include comparative immunogenicity and protection studies in non-human primates. Here we compare the highly attenuated modified vaccinia virus Ankara (MVA) with the licensed Dryvax vaccine in a monkey model. After two doses of MVA or one dose of MVA followed by Dryvax, antibody binding and neutralizing titres and T-cell responses were equivalent or higher than those induced by Dryvax alone. After challenge with monkeypox virus, unimmunized animals developed more than 500 pustular skin lesions and became gravely ill or died, whereas vaccinated animals were healthy and asymptomatic, except for a small number of transient skin lesions in animals immunized only with MVA.

Animals↗
PubMed2004

The host response to smallpox: analysis of the gene expression program in peripheral blood cells in a nonhuman primate model.

Smallpox has played an unparalleled role in human history and remains a significant potential threat to public health. Despite the historical significance of this disease, we know little about the underlying pathophysiology or the virulence mechanisms of the causative agent, variola virus. To improve our understanding of variola pathogenesis and variola-host interactions, we examined the molecular and cellular features of hemorrhagic smallpox in cynomolgus macaques. We used cDNA microarrays to analyze host gene expression patterns in sequential blood samples from each of 22 infected animals. Variola infection elicited striking and temporally coordinated patterns of gene expression in peripheral blood. Of particular interest were features that appear to represent an IFN response, cell proliferation, immunoglobulin gene expression, viral dose-dependent gene expression patterns, and viral modulation of the host immune response. The virtual absence of a tumor necrosis factor alpha/NF-kappaB-activated transcriptional program in the face of an overwhelming systemic infection suggests that variola gene products may ablate this response. These results provide a detailed picture of the host transcriptional response during smallpox infection, and may help guide the development of diagnostic, therapeutic, and prophylactic strategies.

Animals↗
PubMed2004

Exploring the potential of variola virus infection of cynomolgus macaques as a model for human smallpox.

Smallpox virus (variola) poses a significant threat as an agent of bioterrorism. To mitigate this risk, antiviral drugs and an improved vaccine are urgently needed. Satisfactory demonstration of protective efficacy against authentic variola will require development of an animal model in which variola produces a disease course with features consistent with human smallpox. Toward this end, cynomolgus macaques were exposed to several variola strains through aerosol and/or i.v. routes. Two strains, Harper and India 7124, produced uniform acute lethality when inoculated i.v. in high doses (10(9) plaque-forming units). Lower doses resulted in less fulminant, systemic disease and lower mortality. Animals that died had profound leukocytosis, thrombocytopenia, and elevated serum creatinine levels. After inoculation, variola was disseminated by means of a monocytic cell-associated viremia. Distribution of viral antigens by immunohistochemistry correlated with the presence of replicating viral particles demonstrated by electron microscopy and pathology in the lymphoid tissues, skin, oral mucosa, gastrointestinal tract, reproductive system, and liver. These particles resembled those seen in human smallpox. High viral burdens in target tissues were associated with organ dysfunction and multisystem failure. Evidence of coagulation cascade activation (D dimers) corroborated histologic evidence of hemorrhagic diathesis. Depletion of T cell-dependent areas of lymphoid tissues occurred, probably as a consequence of bystander apoptotic mechanisms initiated by infected macrophages. Elaboration of cytokines, including IL-6 and IFN-gamma, contribute to a cytokine storm formerly known as "toxemia." A more precise understanding of disease pathogenesis should provide targets for therapeutic intervention, to be used alone or in combination with inhibitors of variola virus replication.

Animals↗
PubMed2005

Genetically stable and fully effective smallpox vaccine strain constructed from highly attenuated vaccinia LC16m8.

A highly attenuated LC16m8 (m8) smallpox vaccine has been licensed in Japan because of its extremely low neurovirulence profile, which is comparable to that of replication incompetent strains of vaccinia virus. From 1973 to 1975, m8 was administrated to >100,000 infants where it induced levels of immunity similar to that of the originating Lister strain, without any serious side effects. Recently, we observed that m8 reverts spontaneously to large plaque forming clones that possess virulence equivalent to that of LC16mO, a parental virus strain of m8. Here, we report that the B5R gene is responsible for the reversion, and that we could construct a more genetically stable virus by deleting B5R from m8. The protective immunogenicity of the vaccine candidate proved to be equivalent to that of the U.S.-licensed product Dryvax, and much superior to modified vaccinia Ankara in a mouse model. Furthermore, the vaccine strain never elicited any symptoms in severe combined immunodeficiency disease mice, even at a dose 1,000-fold greater than that used in the immune protection experiments, which is in contrast to the lethal pathogenicity induced by Dryvax inoculation of severe combined immunodeficiency disease mice. Our results suggest that this vaccine strain is a good candidate as a suitable smallpox vaccine and a vector virus, and that B5R is not essential for protective immunity against smallpox.

Animals↗
PubMed2006

Smallpox transmission and control: spatial dynamics in Great Britain.

Contingency planning for the possible deliberate reintroduction of smallpox has become a priority for many national public health organizations in recent years. We used an individual-based spatial model of smallpox transmission in Great Britain and census-derived journey-to-work data to accurately describe the spatiotemporal dynamics of an outbreak of smallpox in the community. A Markov chain Monte-Carlo algorithm was developed to generate sociospatial contact networks that were consistent with demographic and commuting data. We tested the sensitivity of model predictions to key epidemiological parameters before choosing three representative scenarios from within the range explored. We examined the spatiotemporal dynamics for these illustrative scenarios and assessed the efficacy of symptomatic case isolation, contact tracing with vaccination, and reactive regional mass vaccination as policy options for control. We conclude that case isolation and contact tracing with vaccination would be sufficient to halt ongoing transmission rapidly, unless policy effectiveness was compromised by resource or other constraints. A slight reduction in the expected size and duration of an outbreak could be achieved with regional mass vaccination, but these benefits are small and do not justify the high numbers of vaccine doses required and their associated negative side effects.

Biological Warfare↗
PubMed2004

Lack of vaccinia viremia after smallpox vaccination.

Although the transmission of certain viral infections (human immunodeficiency virus, hepatitis B and C viruses, and West Nile virus) through donated blood products is well described, the risk of transmitting vaccinia virus after smallpox vaccination is unknown. Blood samples from patients receiving the smallpox vaccine were obtained before vaccination; then from one-half of the study group on alternate days for each of the first 10 days after vaccination; then from all patients on days 14 and 21 after vaccination. Samples were analyzed by culture, polymerase chain reaction, and antigen detection (electrochemiluminescence) assay for the presence of vaccinia virus. Two hundred and twenty samples from 28 volunteers were processed by all 3 laboratory detection methods and all were negative for the presence of vaccinia virus (confidence interval, 0%-12.3%). Viremia with vaccinia virus after smallpox vaccination appears to be an uncommon occurrence.

Antigens, Viral↗
PubMed2004

Randomized trial comparing vaccinia on the external surfaces of 3 conventional bandages applied to smallpox vaccination sites in primary vaccinees.

BACKGROUND: Concern about accidental contact transmission after smallpox vaccination has prompted various recommendations regarding vaccination site coverage. METHODS: On days 6-8 after their first-ever smallpox vaccination, 63 adult subjects were randomized to apply a self-adhesive bandage (n=20), gauze with adhesive tape (n=21), or gauze with a semipermeable dressing (n=22) over the vaccination site for a mean of 8+/-2 h. Swabs from the external bandage surfaces and the vaccination sites were then assessed by real time vaccinia-specific polymerase chain reaction (PCR) in blinded fashion. RESULTS: Among 58 subjects completing the study, PCR results were positive for the vaccination site in 55 (94.8%) and on 10 swabs (17.2%) from external bandage surfaces. There were no differences among the 3 bandages (P=.57). CONCLUSIONS: At 7 days after smallpox vaccination, a peak time for vaccinia shedding, a self-adhesive bandage was as effective as 2 bulkier, less convenient bandages in limiting PCR-detectable virus on the external surface.

Adult↗