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PubMed1974

Differentiation of smallpox and camelpox viruses in cultures of human and monkey cells.

The cytopathic effect of smallpox and camelpox viruses has been compared in cell cultures derived from human and monkey tissues. The two viruses could easily be distinguished in HeLa, GMK-AH1, BSC-1 and WISH cells, camelpox producing multinucleate giant cells and smallpox producing rounding up of individual cells. In other cells (LLC-MK2, HEK and 2RhK) the differences were not so marked, and in some (VERO, HEL, K and HuTh) no differences were seen.

Amnion↗
PubMed2004

Biochemical and functional analysis of smallpox growth factor (SPGF) and anti-SPGF monoclonal antibodies.

Variola, the causative agent of smallpox, is a highly infectious double-stranded DNA virus of the orthopox genus that replicates within the cytoplasm of infected cells. For unknown reasons prominent skin manifestations, including "pox," mark the course of this systemic human disease. Here we characterized smallpox growth factor (SPGF), a protein containing an epidermal growth factor (EGF)-like domain that is conserved among orthopox viral genomes, and investigated its possible mechanistic link. We show that after recombinant expression, refolding, and purification, the EGF domain of SPGF binds exclusively to the broadly expressed cellular receptor, erb-B1 (EGF receptor), with subnanomolar affinity, stimulating the growth of primary human keratinocytes and fibroblasts. High affinity monoclonal antibodies specific for SPGF reveal in vivo immunoprotection in a murine vaccinia pneumonia model by a mechanism distinct from viral neutralization. These findings suggest that blockade of pathogenic factor actions, in general, may be advantageous to the infected host.

Amino Acid Sequence↗
PubMed2006

Regulation of catalysis by the smallpox virus topoisomerase.

The poxvirus type IB topoisomerases catalyze relaxation of supercoiled DNA by cleaving and rejoining DNA strands via a pathway involving a covalent phosphotyrosine intermediate. Recently we determined structures of the smallpox virus topoisomerase bound to DNA in covalent and non-covalent DNA complexes using x-ray crystallography. Here we analyzed the effects of twenty-two amino acid substitutions on the topoisomerase activity in vitro in assays of DNA relaxation, single cycle cleavage, and equilibrium cleavage-religation. Alanine substitutions at 14 positions impaired topoisomerase function, marking a channel of functionally important contacts along the protein-DNA interface. Unexpectedly, alanine substitutions at two positions (D168A and E124A) accelerated the forward rate of cleavage. These findings and further analysis indicate that Asp(168) is a key regulator of the active site that maintains an optimal balance among the DNA cleavage, religation, and product release steps. Finally, we report that high level expression of the D168A topoisomerase in Escherichia coli, but not other alanine-substituted enzymes, prevented cell growth. These findings help elucidate the amino acid side chains involved in DNA binding and catalysis and provide guidance for designing topoisomerase poisons for use as smallpox antivirals.

Amino Acid Substitution↗
PubMed2003

Real-time PCR assay to detect smallpox virus.

We developed a highly sensitive and specific assay for the rapid detection of smallpox virus DNA on both the Smart Cycler and LightCycler platforms. The assay is based on TaqMan chemistry with the orthopoxvirus hemagglutinin gene used as the target sequence. With genomic DNA purified from variola virus Bangladesh 1975, the limit of detection was estimated to be approximately 25 copies on both machines. The assay was evaluated in a blinded study with 322 coded samples that included genomic DNA from 48 different isolates of variola virus; 25 different strains and isolates of camelpox, cowpox, ectromelia, gerbilpox, herpes, monkeypox, myxoma, rabbitpox, raccoonpox, skunkpox, vaccinia, and varicella-zoster viruses; and two rickettsial species at concentrations mostly ranging from 100 fg/ microl to 1 ng/ microl. Contained within those 322 samples were variola virus DNA, obtained from purified viral preparations, at concentrations of 1 fg/ microl to 1 ng/ microl. On the Smart Cycler platform, 2 samples with false-positive results were detected among the 116 samples not containing variola virus tested; i.e., the overall specificity of the assay was 98.3%. On the LightCycler platform, five samples with false-positive results were detected (overall specificity, 95.7%). Of the 206 samples that contained variola virus DNA ranging in concentrations from 100 fg/ microl to 1 ng/ microl, 8 samples were considered negative on the Smart Cycler platform and 1 sample was considered negative on the LightCycler platform. Thus, the clinical sensitivities were 96.1% for the Smart Cycler instrument and 99.5% for the LightCycler instrument. The vast majority of these samples were derived from virus-infected cell cultures and variola virus-infected tissues; thus, the DNA material contained both viral DNA and cellular DNA. Of the 43 samples that contained purified variola virus DNA ranging in concentration from 1 fg/ microl to 1 ng/ microl, the assay correctly detected the virus in all 43 samples on both the Smart Cycler and the LightCycler platforms. The assay may be useful for the early detection of smallpox virus infections should such infections occur as a result of a deliberate or an accidental recurrence.

Animals↗
PubMed2004

[The development of epidemiological surveillance systems for smallpox and poliomyelitis: changing concepts in operational categories].

This article describes the process by which some concepts of epidemiological surveillance are elaborated and turned into operational categories to comprise the so-called epidemiological surveillance system for two specific diseases. The authors describe some epidemiological concepts and categories which were elaborated over the course of the smallpox eradication program and more recently in the poliomyelitis eradication program. Such concepts and categories as outbreak containment, cross-notification, and case definitions are described as they fit into a series of actions which make up the epidemiological surveillance system. Finally, it is worth noting that the description developed in this article is based on personal observations, since the authors participated in the smallpox eradication program in Bangladesh and Somalia as well as in the regional poliomyelitis eradication program in the Americas.

English Abstract↗
PubMed1985

Smallpox eradication: selected management issues.

The eradication of smallpox was dependent on the attainment of a high level of herd immunity during the consolidation and maintenance phases of the eradication program, after mass vaccination effort had reduced the incidence of the disease to a few endemic areas in the world. Immunity was possible through the immunization of susceptible population. Attainment of effective immunization in both large and small countries, with both concentrated and dispersed population settlement patterns, was dependent not only on improved vaccination technology, notably the widespread availability of heat-stable freeze-dried vaccine and the use of the bifurcated needle, but also on the way eradication programs were designed and implemented. This paper will outline important components of the smallpox eradication program, particularly, information management, personnel management, and material resources management. Although they were critical to the eventual success of the program, there has been little consolidated effort to review these management strategies. The paper, to a large extent, concentrates on the eradication programs of Bangladesh, India, and West Africa, given that these come to the forefront in terms of reviewing management strategies in the internationally available literature.

Africa↗
PubMedDate not supplied

[Fusion proteins encoded by orf 129L of ectromelia and orf A30L of smallpox viruses cross-react with neutralizing monoclonal antibodies].

Open reading frame (orf) 129L of ectromelia (EV) and orf A30L of smallpox viruses (SPV) encoding fusion proteins were cloned and expressed in E. coli cells. The recombinant polypeptides (prA30L H pr129L) were purified from cell lysates by Ni-NTA chromatography. Recombinant polypeptides were able to form trimers in buffered saline and they destroyed under treatment with SDS and 2-mercaptoethanol. Reactivity of prA30L, pr129L and orthopoxvirus proteins was analyzed by ELISA and Western blotting with panel of 22 monoclonal antibodies (MAbs) against orthopoxviruses (19 against EV, 2 MAbs against vaccinia virus and 1 Mabs against cowpox virus). This data allowed us to conclude that there are 12 EV-specific epitopes of pr129L and EV fusion proteins, ten orthopox-specific epitopes of EV, VV, CPV fusion proteins, from them 9 orthopox-specific epitopes of prA30L and SPV fusion proteins. Five Mabs, which cross-reacted with orthopox-specific epitopes, were able to neutralize the VV on Vero cells and from them two MAbs has neutralizing activity against smallpox virus. Our findings demonstrate that 129L fusion protein have EV-specific epitopes, that EV 129L and SPV A30L fusion proteins have a several orthopox-specific epitopes to induce a neutralizing antibodies against human pathogenic orthopoxviruses.

Animals↗
PubMed1986

[Antibodies to measles, smallpox, influenza and arenaviruses in schizophrenic patients].

The levels of hemagglutinating antibodies to measles, smallpox, influenza viruses and of complement-fixing antibody to lymphocytic choriomeningitis, Takaribe, Amapari viruses were studied, in the blood sera of 77 schizophrenics and 44 normal donors. The investigation revealed definite differences. The schizophrenic patients had a statistically significant elevation in the titres of anti-smallpox antibodies. A certain increase in levels of antibodies to the measles virus was observed. There were no considerable differences in titres of antibodies to arenaviruses and influenza virus. A relationship between antibody production, on the one hand, and the severity and course of the disease and also the age of those examined, on the other, was noted.

Adolescent↗
PubMed1981

Comparative analysis of the degree of specific humoral immunity, content of serum immunoglobulins and isolation of vaccinia virus in children with post-vaccinal encephalitis after smallpox vaccination.

Considerable variations were found in the content of virus neutralizing antibodies (VNA) to smallpox in 35 children with postvaccinal encephalitis (PVE) which developed after vaccination against smallpox: the titre of VNA was high in 7 children, negligible in 14, and in 6 children VNA were not present 3-4 weeks after vaccination. Dependence of the production of VNA on the peculiarities of individual development and premorbid state of the patients as well as on serotherapy was analysed; the role of the inhibitory effect of immunoglobulin on the process of antibody formation was excluded. No correlation was found between the isolation of vaccinia virus from the blood, liquor and throat of the children suffering from PVE (virus was isolated from 17 children) and the level of VNA. The content of immunoglobulins A, M and G in PVE patients did not essentially differ from the corresponding age norm, though the increase in IgM and IgG in response to vaccination was absent or considerably delayed in most children. Importance of the obtained results for understanding the pathogenesis of PVE is discussed.

Adolescent↗
PubMed2002

Clinical responses to undiluted and diluted smallpox vaccine.

BACKGROUND: To evaluate the potential to increase the supply of smallpox vaccine (vaccinia virus), we compared the response to vaccination with 10(8.1), 10(7.2), and 10(7.0) plaque-forming units (pfu) of vaccinia virus per milliliter. METHODS: In this randomized, single-blind, prospective study, 680 adults who had not been previously immunized were inoculated intradermally with undiluted vaccine (mean titer, 10(8.1) pfu per milliliter), a 1:5 dilution, or a 1:10 dilution of vaccinia virus with use of a bifurcated needle, and the site was covered with a semipermeable dressing. Subjects were monitored for vesicle formation (an indicator of the success of vaccination) and adverse events for 56 days after immunization. RESULTS: Success rates did not differ significantly among the groups and ranged from 97.1 to 99.1 percent after the first vaccination. Both the undiluted and diluted vaccines were reactogenic. In addition to the formation of pustules, common adverse events included the formation of satellite lesions, regional lymphadenopathy, fever, headache, nausea, muscle aches, fatigue, and chills consistent with the presence of an acute viral illness. Generalized and localized rashes, including two cases of erythema multiforme, were also observed. CONCLUSIONS: When given by a bifurcated needle, vaccinia virus vaccine can be diluted to a titer as low as 10(7.0) pfu per milliliter (approximately 10,000 pfu per dose) and induce local viral replication and vesicle formation in more than 97 percent of persons.

Adolescent↗
PubMed1962

Smallpox in Toronto, 1962.

A 14-year-old boy was seen on August 17, 1962, with a vesicular eruption of five days' duration. The vesicles were about 0.5 cm. in diameter, loculated, mainly distributed centrifugally, and all were at the same stage of development. On August 8, he left his residence in a rural area of southern Brazil where alastrim is endemic. His last smallpox vaccination was received at least six years ago. Alastrim virus was isolated from vesicle fluid obtained on August 17 and 19 by inoculation of chorioallantoic membranes of embryonated eggs. A fourfold rising level of vaccinia antihemagglutinin in paired serum samples was consistent with infection by alastrim virus. The patient has since recovered uneventfully.

Brazil↗
PubMed2006

Keeping the memory of smallpox virus.

Smallpox virus eradication was one of the greatest successes of the 20th century. Moreover, the quest to combat its use in biological warfare, has fueled efforts to understand residual immune memory and to develop new animal models by the scientific community. Although the literature is full of animal studies of vaccinia virus infection, continuing efforts have helped to increase our knowledge regarding humoral and cellular memory to non-persistent pathogens and to study factors that might influence further vaccination strategies in humans. In addition, the potent immunostimulatory action of poxvirus vectors has led to development and evaluation of new-generation vaccine candidates, which will be discussed in this review.

Animals↗
PubMed1995

Intimidation, coercion and resistance in the final stages of the South Asian Smallpox Eradication Campaign, 1973-1975.

This paper reviews episodes during 1973-1975 when American physician-epidemiologists in South Asia, working under the auspices of the World Health Organization, intimidated local health officials and resorted to coercive methods in the final stages of the Smallpox Eradication Programme. While intimidation and coercion were successful in the short-run in ensuring disease containment, they evoked health-professional and popular resentments, and the long-term effect may have been to foster negative attitudes toward subsequent vaccination campaigns. At the very least these episodes suggest a need for paying attention to actual and perceived abuses when global health measures are introduced from 'above' into regional settings.

Asia↗
PubMed2004

[Update on smallpox vaccines].

Smallpox is among the most dangerous pathogens that could be used by bioterrorists. The former vaccines produced by scarification on the flanks of calves or sheep could be used to protect the whole French population when used with bifurcated needles. They should be replaced by a second-generation vaccine grown in cell culture and, eventually later by new and safer third-generation vaccines using non-replicative viral strains.

Animals↗
PubMedDate not supplied

Hospital recruitment for the Smallpox Pre-Event Vaccination Program: experiences from Florida, Nebraska, New Jersey, and Tennessee, December 2002-June 2003.

The Smallpox Pre-Event Vaccination Program (SPVP) for public health and hospital-based health care workers began on January 24, 2003. This report summarizes efforts made by health officials in Florida, Nebraska, New Jersey, and Tennessee to facilitate the voluntary participation of acute care hospitals in the SPVP. Seven common characteristics contributed to the success of programs in these four states: (1) early planning, building on existing competencies, and state government support, (2) carrying the program forward on a planned timeline with experienced vaccination staff, (3) use of multifaceted training activities, (4) use of mock scenarios and field exercises to avoid early problems, (5) establishment and fostering of good relationships and lines of communication with stakeholders and the mass media, (6) addressing liability and workers' compensation concerns prior to initiation of the SPVP, and (7) attention to vaccination clinic logistics.

Bioterrorism↗
PubMed2006

Immune responses to vaccinia and influenza elicited during primary versus recent or distant secondary smallpox vaccination of adults.

The kinetics and frequency of the primary response to human smallpox vaccine was compared to that among subjects re-vaccinated within the last 2 years, or after several decades. Vaccination induced local and systemic reactions that were mildest in the distant cohort and more severe in the primary vaccinees. The timing of IFN-gamma responses was similar in all three groups, but of higher frequency in the primary vaccinees. Responses to vaccinia re-immunization between those immunized <2 years ago and those immunized >10 years ago were not significantly different. Neutralizing antibodies were boosted in all groups, with the highest titers observed among the distant cohort. However, the antibody and IFN-gamma responses did not correlate strongly with the local reactions at the vaccine site. This suggests that local immune events in the tissue are distinct from the parameters measured in the peripheral blood.

Adolescent↗
PubMed2003

Pathogenesis and potential antiviral therapy of complications of smallpox vaccination.

Vaccination against smallpox may result in a variety of complications, ranging in severity from benign to lethal. Universal vaccination was halted in the US in 1972, so almost half the present population has never been vaccinated. Because side effects occur most often in first-time vaccinees, current plans for rapid large-scale vaccination in the event of bioterrorist attack raise concerns about the occurrence of a large number of adverse events. Most complications result from the excessive replication of vaccinia virus, making them potential targets for antiviral therapy. Effective treatment is especially needed for persons with atopic dermatitis or eczema, who are unusually susceptible to the initiation and spread of vaccinia infection because of defects of innate immunity in the skin, and for individuals with defective cell-mediated immunity, who are unable to eliminate vaccinia infection once it has begun. In the past, many complications were treated with vaccinia immune globulin (VIG) and/or the antiviral drug methisazone, but neither was tested in placebo-controlled trials. New antiviral drugs are now available, but have not yet been evaluated for treating vaccinia infections in humans. Both laboratory research and clinical studies are needed to help prevent serious complications in any major vaccination campaign.

Antiviral Agents↗
PubMed2004

Modelling responses to a smallpox epidemic taking into account uncertainty.

Epidemiology and modelling are currently under pressure to build consistent scenarios of control in case of deliberate release of biological weapons. In order to assess the key parameters for the control of a smallpox outbreak in a large city (2 million inhabitants), we built a stochastic model to simulate the course of an epidemic controlled by ring vaccination and case isolation. Assuming a reference scenario with 100 index cases and implementation of intervention 25 days after the attack, the model forecasts an epidemic of 730 cases with an epidemic duration of 240 days. Setting intervention 20 days later would result in an almost fourfold increase in the epidemic size. A multivariate sensitivity analysis has selected three key parameters: the basic reproduction number (i.e. the number of secondary cases infected by one case in an entirely susceptible population, equal to 3 in the reference scenario), time to intervention, and proportion of traced and vaccinated contacts.

Algorithms↗