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2.
PLoS Pathog ; 17(9): e1009633, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34547055

RESUMO

Smallpox, caused by the solely human pathogen Variola virus (VARV), was declared eradicated in 1980. While known VARV stocks are secure, smallpox remains a bioterrorist threat agent. Recent U.S. Food and Drug Administration approval of the first smallpox anti-viral (tecovirimat) therapeutic was a successful step forward in smallpox preparedness; however, orthopoxviruses can become resistant to treatment, suggesting a multi-therapeutic approach is necessary. Animal models are required for testing medical countermeasures (MCMs) and ideally MCMs are tested directly against the pathogen of interest. Since VARV only infects humans, a representative animal model for testing therapeutics directly against VARV remains a challenge. Here we show that three different humanized mice strains are highly susceptible to VARV infection, establishing the first small animal model using VARV. In comparison, the non-humanized, immunosuppressed background mouse was not susceptible to systemic VARV infection. Following an intranasal VARV challenge that mimics the natural route for human smallpox transmission, the virus spread systemically within the humanized mouse before mortality (~ 13 days post infection), similar to the time from exposure to symptom onset for ordinary human smallpox. Our identification of a permissive/representative VARV animal model can facilitate testing of MCMs in a manner consistent with their intended use.


Assuntos
Modelos Animais de Doenças , Varíola , Animais , Humanos , Camundongos , Vírus da Varíola
3.
Expert Rev Vaccines ; 20(9): 1059-1063, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34365880

RESUMO

INTRODUCTION: The Development of the SARS-CoV-2 virus vaccine and its update on an ongoing pandemic is the first subject of the world health agenda. AREAS COVERED: First, we will scrutinize the biological features of the measles virus (MV), variola virus (smallpox virus), influenza virus, and their vaccines to compare them with the SARS-CoV-2 virus and vaccine. Next, we will discuss the statistical details of measuring the effectiveness of an improved vaccine. EXPERT OPINION: Amidst the pandemic, we ought to acknowledge our prior experiences with respiratory viruses and vaccines. In the planning stage of observational Phase-III vaccine effectiveness studies, the sample size, sampling method, statistical model, and selection of variables are crucial in obtaining high-quality and valid results.


Assuntos
Vacinas contra COVID-19/imunologia , COVID-19/prevenção & controle , Imunidade Celular/imunologia , SARS-CoV-2/imunologia , COVID-19/patologia , Humanos , Vacinas contra Influenza/imunologia , Vacinação em Massa/métodos , Vírus do Sarampo/imunologia , Vacina contra Sarampo-Caxumba-Rubéola/imunologia , Orthomyxoviridae/imunologia , Vacina Antivariólica/imunologia , Vacinação , Vacinas Atenuadas/imunologia , Vírus da Varíola/imunologia
4.
Orphanet J Rare Dis ; 16(1): 354, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34362412

RESUMO

BACKGROUND: Osteomyelitis variolosa is a self-limiting disease triggered by variola virus that cannot be prevented or repaired. Smallpox has been eradicated for 40 years, and complications that remain after smallpox has been cured have become a remarkable diagnostic challenge for contemporary physicians. In this systematic review, we searched PubMed (MEDLINE), Web of Science, and Google Scholar for cases on complications, diagnosis, and treatment for osteomyelitis variolosa between January 1980 and February 2021. RESULTS: Ten papers and eleven finished cases, all patients from India, were included for comparison with the present case. In total, 100% of patients presented with bilateral elbow deformities, the ankle was the second most common site of lesion in 50%, and knee lesions accounted for 25% in this study. Flexion contracture, joint instability, secondary arthritis, and fracture are common complications of osteomyelitis variolosa, and most patients receive conservative treatment, while internal fixation has good results for combined fractures. CONCLUSIONS: Although osteomyelitis variolosa is not a direct threat to the safety of patients, severe skeletal deformities can have a significant impact on quality of life. With advances in surgical techniques, clinicians are offering an increasing number of treatment options for patients with osteomyelitis variolosa. However, most importantly, smallpox has basically been removed from the historical arena, and for areas where smallpox was once endemic, physicians need to deepen the understanding of this disease again.


Assuntos
Instabilidade Articular , Osteomielite , Varíola , Vírus da Varíola , Humanos , Qualidade de Vida
5.
Vaccine ; 39(36): 5214-5223, 2021 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-34334254

RESUMO

Smallpox, a disease caused by the variola virus, is one of the most dangerous diseases and had killed numerous people before it was eradicated in 1980. However, smallpox has emerged as the most threatening bio-terrorism agent; as the first- and second-generation smallpox vaccines have been controversial and have caused severe adverse reactions, new demands for safe smallpox vaccines have been raised and some attenuated smallpox vaccines have been developed. We have developed a cell culture-based highly attenuated third-generation smallpox vaccine candidate KVAC103 strain by 103 serial passages of the Lancy-Vaxina strain derived from the Lister in Vero cells. Several clones were selected, taking into consideration their shape, size, and growth rate in mammalian cells. The clones were then inoculated intracerebrally in suckling mice to test for neurovirulence by observing survival. Protective immune responses in adult mice were examined by measuring the levels of neutralization antibodies and IFN-γ expression. Among several clones, clone 7 was considered the best alternative candidate because there was no mortality in suckling mice against a lethal challenge. In addition, enhanced neutralizing antibodies and T-cell mediated IFN-γ production were observed in clone 7-immunized mice. Clone 7 was named "KVAC103" and was used for the skin toxicity test and full-genome analysis. KVAC103-inoculated rabbits showed reduced skin lesions compared to those inoculated with the Lister strain, Lancy-Vaxina. A whole genome analysis of KVAC103 revealed two major deleted regions that might contribute to the reduced virulence of KVAC103 compared to the Lister strain. Phylogenetic inference supported the close relationship with the Lister strain. Collectively, our data demonstrate that KVAC103 holds promise for use as a third-generation smallpox vaccine strain due to its enhanced safety and efficacy.


Assuntos
Vacina Antivariólica , Varíola , Vírus da Varíola , Animais , Anticorpos Antivirais , Chlorocebus aethiops , Camundongos , Camundongos Endogâmicos BALB C , Filogenia , Coelhos , Varíola/prevenção & controle , Vacinas Atenuadas , Vírus Vaccinia/genética , Células Vero
6.
Biochim Biophys Acta Mol Basis Dis ; 1867(11): 166218, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34311080

RESUMO

Throughout history, pandemics of infectious diseases caused by emerging viruses have spread worldwide. Evidence from previous outbreaks demonstrated that pregnant women are at high risk of contracting the diseases and suffering from adverse outcomes. However, while some viruses can cause major health complications for the mother and her fetus, others do not appear to affect pregnancy. Viral surface proteins bind to specific receptors on the cellular membrane of host cells and begin therewith the infection process. During pregnancy, the molecular features of these proteins may determine specific target cells in the placenta, which may explain the different outcomes. In this review, we display information on Variola, Influenza, Zika and Corona viruses focused on their surface proteins, effects on pregnancy, and possible target placental cells. This will contribute to understanding viral entry during pregnancy, as well as to develop strategies to decrease the incidence of obstetrical problems in current and future infections.


Assuntos
Placenta/virologia , Complicações Infecciosas na Gravidez/virologia , Proteínas do Envelope Viral/metabolismo , Viroses/virologia , Feminino , Humanos , Placenta/metabolismo , Gravidez , Complicações Infecciosas na Gravidez/metabolismo , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidade , Vírus da Varíola/metabolismo , Vírus da Varíola/patogenicidade , Viroses/metabolismo , Zika virus/metabolismo , Zika virus/patogenicidade
7.
mSphere ; 6(1)2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33536322

RESUMO

Smallpox, caused by Variola virus (VARV), was eradicated in 1980; however, VARV bioterrorist threats still exist, necessitating readily available therapeutics. Current preparedness activities recognize the importance of oral antivirals and recommend therapeutics with different mechanisms of action. Monkeypox virus (MPXV) is closely related to VARV, causing a highly similar clinical human disease, and can be used as a surrogate for smallpox antiviral testing. The prairie dog MPXV model has been characterized and used to study the efficacy of antipoxvirus therapeutics, including recently approved TPOXX (tecovirimat). Brincidofovir (BCV; CMX001) has shown antiviral activity against double-stranded DNA viruses, including poxviruses. To determine the exposure of BCV following oral administration to prairie dogs, a pharmacokinetics (PK) study was performed. Analysis of BCV plasma concentrations indicated variability, conceivably due to the outbred nature of the animals. To determine BCV efficacy in the MPXV prairie dog model, groups of animals were intranasally challenged with 9 × 105 plaque-forming units (PFU; 90% lethal dose [LD90]) of MPXV on inoculation day 0 (ID0). Animals were divided into groups based on the first day of BCV treatment relative to inoculation day (ID-1, ID0, or ID1). A trend in efficacy was noted dependent upon treatment initiation (57% on ID-1, 43% on ID0, and 29% on ID1) but was lower than demonstrated in other animal models. Analysis of the PK data indicated that BCV plasma exposure (maximum concentration [C max]) and the time of the last quantifiable concentration (AUClast) were lower than in other animal models administered the same doses, indicating that suboptimal BCV exposure may explain the lower protective effect on survival.IMPORTANCE Preparedness activities against highly transmissible viruses with high mortality rates have been highlighted during the ongoing coronavirus disease 2019 (COVID-19) pandemic. Smallpox, caused by variola virus (VARV) infection, is highly transmissible, with an estimated 30% mortality. Through an intensive vaccination campaign, smallpox was declared eradicated in 1980, and routine smallpox vaccination of individuals ceased. Today's current population has little/no immunity against VARV. If smallpox were to reemerge, the worldwide results would be devastating. Recent FDA approval of one smallpox antiviral (tecovirimat) was a successful step in biothreat preparedness; however, orthopoxviruses can become resistant to treatment, suggesting the need for multiple therapeutics. Our paper details the efficacy of the investigational smallpox drug brincidofovir in a monkeypox virus (MPXV) animal model. Since brincidofovir has not been tested in vivo against smallpox, studies with the related virus MPXV are critical in understanding whether it would be protective in the event of a smallpox outbreak.


Assuntos
Citosina/análogos & derivados , Vírus da Varíola dos Macacos/efeitos dos fármacos , Organofosfonatos/farmacologia , Organofosfonatos/farmacocinética , Varíola/tratamento farmacológico , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Benzamidas/farmacocinética , Benzamidas/farmacologia , Citosina/farmacocinética , Citosina/farmacologia , Modelos Animais de Doenças , Cães , Feminino , Isoindóis/farmacocinética , Isoindóis/farmacologia , Masculino , Vírus da Varíola/efeitos dos fármacos
10.
Bull Exp Biol Med ; 170(2): 207-210, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33263846

RESUMO

We compared absolute bioavailability of the chemical substance of the anti-smallpox preparation NIOCH-14 and chemical compound ST-246 active against orthopoxviruses after oral administration to mice in doses of 10 and 50 µg/g and intravenous administration to mice in a dose of 2 µg/g body weight. The absolute bioavailability of NIOCH-14 is comparable with the absolute bioavailability of ST-246.


Assuntos
Disponibilidade Biológica , Ácidos Dicarboxílicos/farmacocinética , Varíola/tratamento farmacológico , Animais , Área Sob a Curva , Benzamidas/farmacocinética , Calibragem , Modelos Animais de Doenças , Feminino , Infusões Intravenosas , Isoindóis/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos ICR , Fatores de Tempo , Vírus da Varíola
11.
Philos Trans R Soc Lond B Biol Sci ; 375(1812): 20190572, 2020 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-33012235

RESUMO

Smallpox, caused by the variola virus (VARV), was a highly virulent disease with high mortality rates causing a major threat for global human health until its successful eradication in 1980. Despite previously published historic and modern VARV genomes, its past dissemination and diversity remain debated. To understand the evolutionary history of VARV with respect to historic and modern VARV genetic variation in Europe, we sequenced a VARV genome from a well-described eighteenth-century case from England (specimen P328). In our phylogenetic analysis, the new genome falls between the modern strains and another historic strain from Lithuania, supporting previous claims of larger diversity in early modern Europe compared to the twentieth century. Our analyses also resolve a previous controversy regarding the common ancestor between modern and historic strains by confirming a later date around the seventeenth century. Overall, our results point to the benefit of historic genomes for better resolution of past VARV diversity and highlight the value of such historic genomes from around the world to further understand the evolutionary history of smallpox as well as related diseases. This article is part of the theme issue 'Insights into health and disease from ancient biomolecules'.


Assuntos
Evolução Molecular , Genoma Viral , Varíola/história , Vírus da Varíola/genética , Animais , Inglaterra , História do Século XVIII , Humanos , Lactente , Museus , Filogenia
12.
Curr Biol ; 30(19): R1215-R1231, 2020 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-33022266

RESUMO

The ability to sequence genomes from ancient biological material has provided a rich source of information for evolutionary biology and engaged considerable public interest. Although most studies of ancient genomes have focused on vertebrates, particularly archaic humans, newer technologies allow the capture of microbial pathogens and microbiomes from ancient and historical human and non-human remains. This coming of age has been made possible by techniques that allow the preferential capture and amplification of discrete genomes from a background of predominantly host and environmental DNA. There are now near-complete ancient genome sequences for three pathogens of considerable historical interest - pre-modern bubonic plague (Yersinia pestis), smallpox (Variola virus) and cholera (Vibrio cholerae) - and for three equally important endemic human disease agents - Mycobacterium tuberculosis (tuberculosis), Mycobacterium leprae (leprosy) and Treponema pallidum pallidum (syphilis). Genomic data from these pathogens have extended earlier work by paleopathologists. There have been efforts to sequence the genomes of additional ancient pathogens, with the potential to broaden our understanding of the infectious disease burden common to past populations from the Bronze Age to the early 20th century. In this review we describe the state-of-the-art of this rapidly developing field, highlight the contributions of ancient pathogen genomics to multidisciplinary endeavors and describe some of the limitations in resolving questions about the emergence and long-term evolution of pathogens.


Assuntos
Bactérias/patogenicidade , DNA Antigo/análise , DNA Bacteriano/genética , Animais , Bactérias/genética , Evolução Biológica , Evolução Molecular , Genoma/genética , Genoma Bacteriano/genética , Genômica/métodos , Humanos , Microbiota/genética , Mycobacterium leprae/genética , Mycobacterium tuberculosis/genética , Filogenia , Treponema/genética , Vírus da Varíola/genética , Vibrio cholerae/genética , Yersinia pestis/genética
13.
Vaccine ; 38(38): 6007-6018, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32741672

RESUMO

Smallpox, a contagious and deadly disease caused by variola virus, was eradicated by a strategy that included vaccination with vaccinia virus, a live-virus vaccine. Because the threat of bioterrorism with smallpox persists and infections with zoonotic poxvirus infections like monkeypox continue, and there may be a time when an alternative vaccine platform is needed, recombinant-subunit vaccine strategies for poxviruses have been pursued. Our prior work focused on understanding the immune responses generated to vaccine-formulations containing the virus protein L1. In this work, we examine vaccine-formulations with additional key protein targets: A33 and B5 (components of the extracellular virus) and another protein on the mature virus (A27) adjuvanted with aluminum hydroxide (AH) with and without CpG- oligonucleotide. Each vaccine was formulated to allow either adsorption or non-adsorption of the protein (and CpG) to AH. Mice given a prime and single boost produced long-lasting antibody responses. A second boost (given ~5-months after the first) further increased antibody titers. Similar to our prior findings with L1 vaccine-formulations, the most protective A33 vaccine-formulations included CpG, resulted in the generation of IgG2a-antibody responses. Unlike the prior findings with L1 (where formulations that adsorbed both the protein and the CpG to AH resulted in 100% survival after challenge and minimal weight loss), the AH-adsorption status of A33 and CpG did not play as important a role, since both AH-adsorbed and non-adsorbed groups lost weight after challenge and had similar survival. Vaccination with B5-formulations gave different results. While CpG-containing formulations were the only ones that generated IgG2a-antibody responses, the vaccine-formulation that adsorbed B5 to AH (without CpG) was as equally effective in protecting mice after challenge. These results indicate that the mechanism of how antibodies against A33 and B5 protect differ. The data also show the complexity of designing optimized vaccine-formulations containing multiple adjuvants and recombinant protein-based antigens.


Assuntos
Vacina Antivariólica , Varíola , Vírus da Varíola , Hidróxido de Alumínio , Animais , Anticorpos Antivirais , Camundongos , Camundongos Endogâmicos BALB C , Varíola/prevenção & controle , Vacinação , Vacinas de Subunidades , Vírus Vaccinia
14.
Science ; 369(6502)2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32703849

RESUMO

Smallpox, one of the most devastating human diseases, killed between 300 million and 500 million people in the 20th century alone. We recovered viral sequences from 13 northern European individuals, including 11 dated to ~600-1050 CE, overlapping the Viking Age, and reconstructed near-complete variola virus genomes for four of them. The samples predate the earliest confirmed smallpox cases by ~1000 years, and the sequences reveal a now-extinct sister clade of the modern variola viruses that were in circulation before the eradication of smallpox. We date the most recent common ancestor of variola virus to ~1700 years ago. Distinct patterns of gene inactivation in the four near-complete sequences show that different evolutionary paths of genotypic host adaptation resulted in variola viruses that circulated widely among humans.


Assuntos
Varíola , Vírus da Varíola , Evolução Biológica , Europa (Continente) , Genoma Viral , História Medieval , Humanos , Varíola/história , Varíola/virologia , Vírus da Varíola/genética
15.
Science ; 369(6502): 376-377, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32703866
17.
Multimedia | Recursos Multimídia | ID: multimedia-4314

RESUMO

Originally broadcast live on 08 May 2020, the daily press briefing on coronavirus COVID-19, direct from WHO Headquarters, Geneva Switzerland with Dr Tedros WHO Director-General, Dr Micheal Ryan, Executive Director of the Health Emergencies Programme, and Dr Maria Van Kerkhove, Technical lead COVID-19, WHO Health Emergencies Programme.


Assuntos
Betacoronavirus , Pneumonia Viral/prevenção & controle , Infecções por Coronavirus/prevenção & controle , Pandemias/prevenção & controle , Quarentena/organização & administração , Vírus da Varíola/imunologia , Vacinas , Erradicação de Doenças/instrumentação , Controle de Doenças Transmissíveis/instrumentação , Sistemas de Saúde/organização & administração
18.
Mil Med ; 185(7-8): e952-e957, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32373931

RESUMO

INTRODUCTION: Smallpox, caused by variola virus, was eradicated in 1980, but remains a category A bioterrorism agent. A decade ago, smallpox ranked second after anthrax in a multifactorial risk priority scoring analysis of category A bioterrorism agents. However, advances in genetic engineering and synthetic biology, including published methods for synthesizing an Orthopoxvirus, require the assumptions of this scoring for smallpox and other category A agents to be reviewed. MATERIALS AND METHODS: The risk priority framework was reviewed and revised to account for the capability for creation of synthetic or engineered smallpox and other category A agents. RESULTS: The absolute score for all agents increased because of gene editing and synthetic biology capability, which was not present when the framework was developed more than a decade ago, although new treatments revised scores downward for smallpox, Ebola, and botulism. In the original framework, smallpox scored 0 for global availability, given the high security around known seed stocks of variola in two laboratories in the United States and Russia. Now, smallpox can be created using synthetic biology, raising the score for this criterion to 2. Other agents too, such as Ebola, score higher for availability, based on synthetic biology capability. When advances in synthetic biology and genetic engineering are considered, smallpox and anthrax are now equally ranked the highest category A bioterrorism agents for planning and preparedness. CONCLUSIONS: Revision of a risk priority framework for category A bioterrorism agents shows that smallpox should be elevated in priority for preparedness planning, and that gene editing and synthetic biology raises the overall risk for all agents. The ranking of categories A, B, and C agents should also be revisited, as there is an endless possibility of engineered threats that may be more severe than any agent on the category A list.


Assuntos
Varíola , Vírus da Varíola , Antraz , Bioterrorismo , Humanos , Fatores de Risco , Federação Russa , Varíola/epidemiologia , Varíola/prevenção & controle , Vacina Antivariólica , Estados Unidos/epidemiologia , Vírus da Varíola/genética
19.
Bull Exp Biol Med ; 168(4): 496-499, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32147764
20.
Viruses ; 12(2)2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31991671

RESUMO

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.


Assuntos
Erradicação de Doenças , Vacina Antivariólica , Varíola/prevenção & controle , Antivirais/uso terapêutico , Derramamento de Material Biológico , Evolução Molecular , Genoma Viral , Humanos , Programas de Imunização , Risco , Varíola/diagnóstico , Varíola/tratamento farmacológico , Varíola/virologia , Vacina Antivariólica/efeitos adversos , Vacina Antivariólica/imunologia , Vacina Antivariólica/provisão & distribuição , Biologia Sintética , Vírus da Varíola/genética , Organização Mundial da Saúde
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