Smallpox.
Ontology highlight
ABSTRACT:
SUBMITTER: Breman JG
PROVIDER: S-EPMC8482028 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description: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 /NF-B-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. Groups of assays that are related as part of a time series. Keywords: time_series_design
2006-01-11 | GSE4013 | GEO
Project description:Human disease likely attributable to variola virus (VARV), the etiologic agent of smallpox, has been reported in human populations for >2,000 years. VARV is unique among orthopoxviruses in that it is an exclusively human pathogen. Because VARV has a large, slowly evolving DNA genome, we were able to construct a robust phylogeny of VARV by analyzing concatenated single nucleotide polymorphisms (SNPs) from genome sequences of 47 VARV isolates with broad geographic distributions. Our results show two primary VARV clades, which likely diverged from an ancestral African rodent-borne variola-like virus either approximately 16,000 or approximately 68,000 years before present (YBP), depending on which historical records (East Asian or African) are used to calibrate the molecular clock. One primary clade was represented by the Asian VARV major strains, the more clinically severe form of smallpox, which spread from Asia either 400 or 1,600 YBP. Another primary clade included both alastrim minor, a phenotypically mild smallpox described from the American continents, and isolates from West Africa. This clade diverged from an ancestral VARV either 1,400 or 6,300 YBP, and then further diverged into two subclades at least 800 YBP. All of these analyses indicate that the divergence of alastrim and variola major occurred earlier than previously believed.
| S-EPMC2000395 | biostudies-literature
Project description:Few diseases can match the enormous impact that smallpox has had on mankind. Its influence can be seen in the earliest recorded histories of ancient civilizations in Egypt and Mesopotamia. With fatality rates up to 30%, smallpox left its survivors with extensive scarring and other serious sequelae. It is estimated that smallpox killed 500 million people in the 19th and 20th centuries. Given the ongoing concerns regarding the use of variola as a biological weapon, this review will focus on the licensed vaccines as well as current research into next-generation vaccines to protect against smallpox and other poxviruses.
| S-EPMC2764553 | biostudies-literature
Project description:BackgroundSmallpox was eradicated by 1980, but its possible use as a bioweapon has rekindled interest in the development of protective vaccines. Therefore, stockpiled calf lymph-derived vaccines and recently developed cell-cultured vaccines have been investigated to contribute information to smallpox emergency response plans, while newer (non-replication competent) vaccines are developed.ObjectivesTo assess the effects of smallpox vaccines in preventing the disease, in inducing immunity, and in regard to adverse events.Search strategyIn December 2006, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2006, Issue 4), MEDLINE, EMBASE, LILACS, and Current Controlled Trials, and handsearched Index Medicus. We also searched three databases of vaccine safety in December 2005.Selection criteriaRandomized controlled trials of smallpox vaccines versus placebo, other smallpox or non-smallpox vaccine, no intervention, or different dose of the same vaccine in people receiving smallpox vaccination irrespective of age.Data collection and analysisBoth authors independently assessed trial quality and extracted data. We combined dichotomous data using relative risk with a random-effects model.Main resultsTen trials involving 2412 participants were included. The vaccines investigated were calf-lymph derived first-generation vaccines (Dryvax, APVS, Lancy-vaxina, Lister), and cell-cultured second-generation vaccines (ACAM, CCSV). Vaccines were investigated in different dilutions. All undiluted vaccines induced a reaction in 95% of people vaccinated in terms of pustule and immunogenicity. Also 1:10 dilutions were fully efficient when the starting concentration was defined. Serious adverse events were reported in 1% to 2% of the volunteers. Fever was observed in 11% to 22% of participants, and headache in roughly half of the participants. Fever was less frequent when new vaccines were administered, but rates of headache were similar in new and old vaccines.Authors' conclusionsThe evidence shows that stockpiled vaccines have maintained their immunogenicity and new cell-cultured vaccines are similar to stockpiled vaccines in terms of vaccination success rate and immunogenicity. First- and second-generation vaccines diluted to at least 1:10 are as effective as undiluted vaccine in terms of clinical success rate and immunogenicity. Dilution did not reduce the frequency of adverse events. Success rate and immunogenicity were similar in naive and previously vaccinated persons, but there were fewer adverse events in previously vaccinated persons. The rate of adverse events found in this review reveals the need for further development and improvement of smallpox vaccines.
| S-EPMC6532594 | biostudies-literature
Project description: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 /NF-B-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. Groups of assays that are related as part of a time series. Keywords: time_series_design Using regression correlation
2006-01-10 | E-GEOD-4013 | biostudies-arrayexpress
Project description:The frequency of moderate to severe adverse reactions associated with smallpox vaccines currently stockpiled in the US, and the continued threat of bioterrorism have prompted the development of effective vaccines with improved safety profiles. LC16m8, an attenuated, replicating smallpox vaccine derived from the Lister strain of vaccinia, is currently licensed in Japan where it was safely used in over 50,000 children in the 1970s. It has been shown to have markedly less neurotoxicity than unattenuated vaccines in nonclinical studies. LC16m8 is immunogenic after a single dose, and recent studies in two different animal models have demonstrated protective efficacy equivalent to that of the only FDA-licensed smallpox vaccine. This article reviews the history and available scientific literature regarding LC16m8 and provides comparisons to other smallpox vaccines.
| S-EPMC7115618 | biostudies-literature
Project description:We present a stochastic model for the spread of smallpox after a small number of index cases are introduced into a susceptible population. The model describes a branching process for the spread of the infection and the effects of intervention measures. We discuss scenarios in which ring vaccination of direct contacts of infected persons is sufficient to contain an epidemic. Ring vaccination can be successful if infectious cases are rapidly diagnosed. However, because of the inherent stochastic nature of epidemic outbreaks, both the size and duration of contained outbreaks are highly variable. Intervention requirements depend on the basic reproduction number (R0), for which different estimates exist. When faced with the decision of whether to rely on ring vaccination, the public health community should be aware that an epidemic might take time to subside even for an eventually successful intervention strategy.
| S-EPMC3323203 | biostudies-literature
Project description:Widespread vaccination programmes led to the global eradication of smallpox, which was certified by the World Health Organisation (WHO), and, since 1978, there has been no case of smallpox anywhere in the world. However, the viable variola virus (VARV), the causative agent of smallpox, is still kept in two maximum security laboratories in Russia and the USA. Despite the eradication of the disease smallpox, clandestine stocks of VARV may exist. In a rapidly changing world, the impact of an intentional VARV release in the human population would nowadays result in a public health emergency of global concern: vaccination programmes were abolished, the percentage of immunosuppressed individuals in the human population is higher, and an increased intercontinental air travel allows for the rapid viral spread of diseases around the world. The WHO has authorised the temporary retention of VARV to enable essential research for public health benefit to take place. This work aims to develop diagnostic tests, antiviral drugs, and safer vaccines. Advances in synthetic biology have made it possible to produce infectious poxvirus particles from chemicals in vitro so that it is now possible to reconstruct VARV. The status of smallpox in the post-eradication era is reviewed.
| S-EPMC7077202 | biostudies-literature
Project description:BACKGROUND:Smallpox was declared eradicated in 1980, but variola virus (VARV), which causes smallpox, still exists. There is no known effective treatment for smallpox; therefore, tecovirimat is being developed as an oral smallpox therapy. Because clinical trials in a context of natural disease are not possible, an alternative developmental path to evaluate efficacy and safety was needed. METHODS:We investigated the efficacy of tecovirimat in nonhuman primate (monkeypox) and rabbit (rabbitpox) models in accordance with the Food and Drug Administration (FDA) Animal Efficacy Rule, which was interpreted for smallpox therapeutics by an expert advisory committee. We also conducted a placebo-controlled pharmacokinetic and safety trial involving 449 adult volunteers. RESULTS:The minimum dose of tecovirimat required in order to achieve more than 90% survival in the monkeypox model was 10 mg per kilogram of body weight for 14 days, and a dose of 40 mg per kilogram for 14 days was similarly efficacious in the rabbitpox model. Although the effective dose per kilogram was higher in rabbits, exposure was lower, with a mean steady-state maximum, minimum, and average (mean) concentration (Cmax, Cmin, and Cavg, respectively) of 374, 25, and 138 ng per milliliter, respectively, in rabbits and 1444, 169, and 598 ng per milliliter in nonhuman primates, as well as an area under the concentration-time curve over 24 hours (AUC0-24hr) of 3318 ng×hours per milliliter in rabbits and 14,352 ng×hours per milliliter in nonhuman primates. These findings suggested that the nonhuman primate was the more conservative model for the estimation of the required drug exposure in humans. A dose of 600 mg twice daily for 14 days was selected for testing in humans and provided exposures in excess of those in nonhuman primates (mean steady-state Cmax, Cmin, and Cavg of 2209, 690, and 1270 ng per milliliter and AUC0-24hr of 30,632 ng×hours per milliliter). No pattern of troubling adverse events was observed. CONCLUSIONS:On the basis of its efficacy in two animal models and pharmacokinetic and safety data in humans, tecovirimat is being advanced as a therapy for smallpox in accordance with the FDA Animal Rule. (Funded by the National Institutes of Health and the Biomedical Advanced Research and Development Authority; ClinicalTrials.gov number, NCT02474589 .).
| S-EPMC6086581 | biostudies-literature
Project description:The search for a 'third'-generation smallpox vaccine has resulted in the development and characterization of several vaccine candidates. A significant barrier to acceptance is the absence of challenge models showing induction of correlates of protective immunity against variola virus. In this light, virus neutralization provides one of few experimental methods to show specific 'in vitro' activity of vaccines against variola virus. Here, we provide characterization of the ability of a modified vaccinia virus Ankara vaccine to induce variola virus-neutralizing antibodies, and we provide comparison with the neutralization elicited by standard Dryvax vaccination.
| S-EPMC2887573 | biostudies-literature