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1
Shchelkunov, S. N., and G. A. Shchelkunova. "We should be prepared to smallpox re-emergence." Problems of Virology, Russian journal 64, no. 5 (October 20, 2019): 206–14. http://dx.doi.org/10.36233/0507-4088-2019-64-5-206-214.
Анотація:
The review contains a brief analysis of the results of investigations conducted during 40 years after smallpox eradication and directed to study genomic organization and evolution of variola virus (VARV) and development of modern diagnostics, vaccines and chemotherapies of smallpox and other zoonotic orthopoxviral infections of humans. Taking into account that smallpox vaccination in several cases had adverse side effects, WHO recommended ceasing this vaccination after 1980 in all countries of the world. The result of this decision is that the mankind lost the collective immunity not only to smallpox, but also to other zoonotic orthopoxvirus infections. The ever more frequently recorded human cases of zoonotic orthopoxvirus infections force to renew consideration of the problem of possible smallpox reemergence resulting from natural evolution of these viruses. Analysis of the available archive data on smallpox epidemics, the history of ancient civilizations, and the newest data on the evolutionary relationship of orthopoxviruses has allowed us to hypothesize that VARV could have repeatedly reemerged via evolutionary changes in a zoonotic ancestor virus and then disappeared because of insufficient population size of isolated ancient civilizations. Only the historically last smallpox pandemic continued for a long time and was contained and stopped in the 20th century thanks to the joint efforts of medics and scientists from many countries under the aegis of WHO. Thus, there is no fundamental prohibition on potential reemergence of smallpox or a similar human disease in future in the course of natural evolution of the currently existing zoonotic orthopoxviruses. Correspondingly, it is of the utmost importance to develop and widely adopt state-of-the-art methods for efficient and rapid species-specific diagnosis of all orthopoxvirus species pathogenic for humans, VARV included. It is also most important to develop new safe methods for prevention and therapy of human orthopoxvirus infections.
2
Douglas, Kirk Osmond, Claire Cayol, Kristian Michael Forbes, Thelma Alafia Samuels, Olli Vapalahti, Tarja Sironen, and Marquita Gittens-St. Hilaire. "Serological Evidence of Multiple Zoonotic Viral Infections among Wild Rodents in Barbados." Pathogens 10, no. 6 (May 28, 2021): 663. http://dx.doi.org/10.3390/pathogens10060663.
Анотація:
Background: Rodents are reservoirs for several zoonotic pathogens that can cause human infectious diseases, including orthohantaviruses, mammarenaviruses and orthopoxviruses. Evidence exists for these viruses circulating among rodents and causing human infections in the Americas, but much less evidence exists for their presence in wild rodents in the Caribbean. Methods: Here, we conducted serological and molecular investigations of wild rodents in Barbados to determine the prevalence of orthohantavirus, mammarenavirus and orthopoxvirus infections, and the possible role of these rodent species as reservoirs of zoonotic pathogens. Using immunofluorescent assays (IFA), rodent sera were screened for the presence of antibodies to orthohantavirus, mammarenavirus (Lymphocytic choriomeningitis virus—LCMV) and orthopoxvirus (Cowpox virus—CPXV) infections. RT-PCR was then conducted on orthohantavirus and mammarenavirus-seropositive rodent sera and tissues, to detect the presence of viral RNA. Results: We identified antibodies against orthohantavirus, mammarenavirus, and orthopoxvirus among wild mice and rats (3.8%, 2.5% and 7.5% seropositivity rates respectively) in Barbados. No orthohantavirus or mammarenavirus viral RNA was detected from seropositive rodent sera or tissues using RT–PCR. Conclusions: Key findings of this study are the first serological evidence of orthohantavirus infections in Mus musculus and the first serological evidence of mammarenavirus and orthopoxvirus infections in Rattus norvegicus and M. musculus in the English-speaking Caribbean. Rodents may present a potential zoonotic and biosecurity risk for transmission of three human pathogens, namely orthohantaviruses, mammarenaviruses and orthopoxviruses in Barbados.
3
Shchelkunova, G. A., and S. N. Shchelkunov. "40 Years without Smallpox." Acta Naturae 9, no. 4 (December 15, 2017): 4–12. http://dx.doi.org/10.32607/20758251-2017-9-4-4-12.
Анотація:
The last case of natural smallpox was recorded in October, 1977. It took humanity almost 20 years to achieve that feat after the World Health Organization had approved the global smallpox eradication program. Vaccination against smallpox was abolished, and, during the past 40 years, the human population has managed to lose immunity not only to smallpox, but to other zoonotic orthopoxvirus infections as well. As a result, multiple outbreaks of orthopoxvirus infections in humans in several continents have been reported over the past decades. The threat of smallpox reemergence as a result of evolutionary transformations of these zoonotic orthopoxviruses exists. Modern techniques for the diagnostics, prevention, and therapy of smallpox and other orthopoxvirus infections are being developed today.
4
Tregubchak, T. V., T. V. Bauer, R. A. Maksyutov, and E. V. Gavrilova. "Cases of Orthopoxviral Infections around the World over a Period of 2008–2018." Problems of Particularly Dangerous Infections, no. 3 (October 23, 2021): 33–39. http://dx.doi.org/10.21055/0370-1069-2021-3-33-39.
Анотація:
The eradication of smallpox has become one of the greatest successes of modern health science. This great achievement was made possible thanks to the widespread vaccination of the population. The last case of human infection with smallpox virus occurred in 1977. In 1980, at the 33rd session of the World Health Assembly, routine vaccination against that infection was recommended to be discontinued due to severe post-vaccination complications. However, humanity remains vulnerable to other orthopoxvirus infections closely related to smallpox virus. Recently, the cases of human infection with ortopoxviruses such as monkeypox virus, cowpox virus, vaccinia virus have become more frequent. Also, cases of infection of people with previously unknown orthopoxvirus species are recorded. Zoonotic orthopoxviruses pathogenic for humans, circulating in nature, require a detailed study and monitoring of the emergence of new strains. Their occurrence against the background of the cessation of planned vaccination of the population against smallpox virus can lead to the emergence of new highly pathogenic viruses. This review contains information on cases of human infection with orthopoxviruses around the world for the period 2008–2018. It also describes epidemiological anamnesis and the relations between cases of human infection in different countries due to the spread of viruses over a wide area, the movement of people between countries, population contacts with domestic and wild animals. Also, this paper provides information on the infection of people with previously unknown strains of orthopoxviruses.
5
Khlusevich, Ya A., A. L. Matveev, E. P. Goncharova, I. K. Baykov, and N. V. Tikunova. "Immunogenicity of recombinant fragment of orthopoxvirus p35 protein in mice." Vavilov Journal of Genetics and Breeding 23, no. 4 (July 7, 2019): 398–404. http://dx.doi.org/10.18699/vj19.508.
Анотація:
Despite the elimination of smallpox, orthopoxviruses continue to be a source of biological danger for humans, as cowpox and monkey pox viruses circulate in nature and the last virus can cause both sporadic cases of human diseases and outbreaks of smallpox-like infection. In addition, periodic vaccination is necessary for representatives of some professions (scientists studying pathogenic orthopoxviruses, medical personnel, etc.). Vaccination against smallpox virus with live vaccinia virus, which was widely used during the elimination of smallpox, induces the formation of long-term immunity in vaccinated people. However, providing a high level of protection, the vaccination is often accompanied by serious post-vaccination complications, the probability of which is particularly great for individuals with compromised immunity. In this regard, the development of preparations for the prevention and treatment of infections caused by orthopoxviruses remains important today. The aim of this study was to assess the immunogenicity in the mouse model of recombinant protein р35Δ12, designed previously on the base of the cowpox virus protein p35. It was previously shown that the protein р35Δ12 was recognized by fully human neutralizing anti-orthopoxviral antibody with high affinity. In this work, recombinant protein р35Δ12 produced in E. coli cells XL1-blue and purified by chromatography was used for two-time immunization of mice. Two weeks after the second immunization, blood samples were taken from mice and serum antibodies were analyzed. It was shown by ELISA and Western-blot analysis that immunized mice sera contained IgG antibodies specific to recombinant protein р35Δ12. Confocal microscopy showed that antibodies induced by the р35Δ12 protein were able to recognize Vero E6 cells infected with the LIVP-GFP vaccinia virus. In addition, the antibodies in the serum of immunized mice were able to neutralize the infectivity of the vaccinia virus LIVP-GFP in the plaque reduction neutralization test in vitro. These experiments have demonstrated promising properties of the р35Δ12 protein if it were used as a component of vaccine for prophylaxis of orthopoxvirus infections.
6
Scaramozzino, Natale, Audrey Ferrier-Rembert, Anne-laure Favier, Corinne Rothlisberger, Stéphane Richard, Jean-Marc Crance, Hermann Meyer, and Daniel Garin. "Real-Time PCR to Identify Variola Virus or Other Human Pathogenic Orthopox Viruses." Clinical Chemistry 53, no. 4 (April 1, 2007): 606–13. http://dx.doi.org/10.1373/clinchem.2006.068635.
Анотація:
Abstract Background: Variola virus (family Poxviridae, genus Orthopoxvirus) and the closely related cowpox, vaccinia, and monkeypox viruses can infect humans. Efforts are mounting to replenish the smallpox vaccine stocks, optimize diagnostic methods for poxviruses, and develop new antivirals against smallpox, because it is feared that variola virus might be used as a weapon of bioterrorism. Methods: We developed an assay for the detection of variola virus DNA. The assay is based on TaqMan chemistry targeting the 14-kD protein gene. For the 1st stage of the assay we used genus consensus primers and a mixture of 2 probes (14-kD POX and 14-kD VAR) spanning the 14-kD protein-encoding gene for detection of all human pathogenic orthopoxviruses. We then tested positive samples with the specific orthopoxvirus-specific probe 14-kD POX to identify monkeypox, cowpox, and vaccinia viruses and with the 14-kD VAR probe to identify variola viruses. The assay was established on 4 different PCR cycler platforms. It was assessed in a study with 85 different orthopoxvirus species and strains that included variola, camelpox, cowpox, monkeypox, and vaccinia viruses at concentrations ranging from 100 ng/L to 1 μg/L. Results: The assay detected as little as 0.05 fg of DNA, corresponding to 25 copies of DNA, and enabled differentiation of variola virus from the other orthopoxviruses. Conclusions: This real-time PCR assay provides a rapid method for the early detection and differentiation of smallpox and other human pathogenic orthopoxvirus infections.
7
Smith, Scott K., Victoria A. Olson, Kevin L. Karem, Robert Jordan, Dennis E. Hruby, and Inger K. Damon. "In Vitro Efficacy of ST246 against Smallpox and Monkeypox." Antimicrobial Agents and Chemotherapy 53, no. 3 (December 15, 2008): 1007–12. http://dx.doi.org/10.1128/aac.01044-08.
Анотація:
ABSTRACT Since the eradication of smallpox and the cessation of routine childhood vaccination for smallpox, the proportion of the world's population susceptible to infection with orthopoxviruses, such as variola virus (the causative agent of smallpox) and monkeypox virus, has grown substantially. In the United States, the only vaccines for smallpox licensed by the Food and Drug Administration (FDA) have been live virus vaccines. Unfortunately, a substantial number of people cannot receive live virus vaccines due to contraindications. Furthermore, no antiviral drugs have been fully approved by the FDA for the prevention or treatment of orthopoxvirus infection. Here, we show the inhibitory effect of one new antiviral compound, ST-246, on the in vitro growth properties of six variola virus strains and seven monkeypox virus strains. We performed multiple assays to monitor the cytopathic effect and to evaluate the reduction of viral progeny production and release in the presence of the compound. ST-246 had 50% effective concentrations of ≤0.067 μM against variola virus and <0.04 μM against monkeypox virus. In a dose-dependent manner, plaque size and comet tail formation were markedly reduced in the presence of the drug at low, noncytotoxic concentrations between 0.015 and 0.05 μM. Our in vitro phenotype data suggest that ST-246 inhibits variola and monkeypox viruses similarly by reducing the production and release of enveloped orthopoxvirus and support the development of ST-246 as an antiviral therapeutic compound for the treatment of severe systemic orthopoxvirus infections.
8
Prichard, Mark N., Kathy A. Keith, Debra C. Quenelle, and Earl R. Kern. "Activity and Mechanism of Action of N-Methanocarbathymidine against Herpesvirus and Orthopoxvirus Infections." Antimicrobial Agents and Chemotherapy 50, no. 4 (April 2006): 1336–41. http://dx.doi.org/10.1128/aac.50.4.1336-1341.2006.
Анотація:
ABSTRACT N-Methanocarbathymidine [(N)-MCT] is a conformationally locked nucleoside analog that is active against some herpesviruses and orthopoxviruses in vitro. The antiviral activity of this molecule is dependent on the type I thymidine kinase (TK) in herpes simplex virus and also appears to be dependent on the type II TK expressed by cowpox and vaccinia viruses, suggesting that it is a substrate for both of these divergent forms of the enzyme. The drug is also a good inhibitor of viral DNA synthesis in both viruses and is consistent with inhibition of the viral DNA polymerase once it is activated by the viral TK homologs. This mechanism of action explains the rather unusual spectrum of activity, which is limited to orthopoxviruses, alphaherpesviruses, and Epstein-Barr virus, since these viruses express molecules with TK activity that can phosphorylate and thus activate the drug. The compound is also effective in vivo and reduces the mortality of mice infected with orthopoxviruses, as well as those infected with herpes simplex virus type 1 when treatment is initiated 24 h after infection. These results indicate that (N)-MCT is active in vitro and in vivo, and its mechanism of action suggests that the molecule may be an effective therapeutic for orthopoxvirus and herpesvirus infections, thus warranting further development.
9
Shchelkunov, S. N., T. V. Bauer, S. N. Yakubitskiy, A. A. Sergeev, A. S. Kabanov, and S. A. Pyankov. "Mutations in the A34R gene increase the immunogenicity of vaccinia virus." Vavilov Journal of Genetics and Breeding 25, no. 2 (April 29, 2021): 139–46. http://dx.doi.org/10.18699/vj21.017.
Анотація:
Vaccination is the most simple and reliable approach of protection to virus infections. The most effective agents are live vaccines, usually low-virulence organisms for humans and closely related to pathogenic viruses or attenuated as a result of mutations/deletions in the genome of pathogenic virus. Smallpox vaccination with live vaccinia virus (VACV) closely related to smallpox virus played a key role in the success of the global smallpox eradication program carried out under the World Health Organization auspices. As a result of the WHO decision as of 1980 to stop smallpox vaccination, humankind has lost immunity not only to smallpox, but also to other zoonotic, orthopoxviruscaused human infections. This new situation allows orthopoxviruses to circulate in the human population and, as a consequence, to alter several established concepts of the ecology and range of sensitive hosts for various orthopoxvirus species. Classic VACV-based live vaccine for vaccination against orthopoxvirus infections is out of the question, because it can cause severe side effects. Therefore, the development of new safe vaccines against orthopoxviral infections of humans and animals is an important problem. VACV attenuation by modern approaches carried out by targeted inactivation of certain virus genes and usually leads to a decrease in the effectiveness of VACV in vivo propagation. As a result, it can cause a diminishing of the immune response after administration of attenuated virus to patients at standard doses. The gene for thymidine kinase is frequently used for insertion/inactivation of foreign genes and it causes virus attenuation. In this research, the effect of the introduction of two point mutations into the A34R gene of attenuated strain LIVP-GFP (ТК–), which increase the yield of extracellular enveloped virions (EEV), on the pathogenicity and immunogenicity of VACV LIVP-GFP-A34R administered intranasally to laboratory mice were studied. It was shown that increase in EEV production by recombinant strain VACV LIVP-GFP-A34R does not change the attenuated phenotype characteristic of the parental strain LIVP-GFP, but causes a significantly larger production of VACV-specific antibodies.
10
Maksyutov, R. A., S. N. Yakubitskyi, I. V. Kolosova, and S. N. Shchelkunov. "Comparing New-Generation Candidate Vaccines against Human Orthopoxvirus Infections." Acta Naturae 9, no. 2 (June 15, 2017): 88–93. http://dx.doi.org/10.32607/20758251-2017-9-2-88-93.
Анотація:
The lack of immunity to the variola virus in the population, increasingly more frequent cases of human orthopoxvirus infection, and increased risk of the use of the variola virus (VARV) as a bioterrorism agent call for the development of modern, safe vaccines against orthopoxvirus infections. We previously developed a polyvalent DNA vaccine based on five VARV antigens and an attenuated variant of the vaccinia virus (VACV) with targeted deletion of six genes (VAC6). Independent experiments demonstrated that triple immunization with a DNA vaccine and double immunization with VAC6 provide protection to mice against a lethal dose (10 LD50) of the ectromelia virus (ECTV), which is highly pathogenic for mice. The present work was aimed at comparing the immunity to smallpox generated by various immunization protocols using the DNA vaccine and VAC6. It has been established that immunization of mice with a polyvalent DNA vaccine, followed by boosting with recombinant VAC6, as well as double immunization with VAC6, induces production of VACV-neutralizing antibodies and provides protection to mice against a 150 LD50 dose of ECTV. The proposed immunization protocols can be used to develop safe vaccination strategies against smallpox and other human orthopoxvirus infections.
11
Shchelkunov, Sergei N. "An Increasing Danger of Zoonotic Orthopoxvirus Infections." PLoS Pathogens 9, no. 12 (December 5, 2013): e1003756. http://dx.doi.org/10.1371/journal.ppat.1003756.
12
Schmitt, Anne, Kerstin Mätz-Rensing, and Franz-Josef Kaup. "Non-Human Primate Models of Orthopoxvirus Infections." Veterinary Sciences 1, no. 1 (June 10, 2014): 40–62. http://dx.doi.org/10.3390/vetsci1010040.
13
Kern, Earl R., Mark N. Prichard, Debra C. Quenelle, Kathy A. Keith, Kamal N. Tiwari, Joseph A. Maddry, and John A. Secrist. "Activities of Certain 5-Substituted 4′-Thiopyrimidine Nucleosides against Orthopoxvirus Infections." Antimicrobial Agents and Chemotherapy 53, no. 2 (November 24, 2008): 572–79. http://dx.doi.org/10.1128/aac.01257-08.
Анотація:
ABSTRACT As part of a program to identify new compounds that have activity against orthopoxviruses, a number of 4′-thionucleosides were synthesized and evaluated for their efficacies against vaccinia and cowpox viruses. Seven compounds that were active at about 1 μM against both viruses in human cells but that did not have significant toxicity were identified. The 5-iodo analog, 1-(2-deoxy-4-thio-β-d-ribofuranosyl)-5-iodouracil (4′-thioIDU), was selected as a representative molecule; and this compound also inhibited viral DNA synthesis at less than 1 μM but only partially inhibited the replication of a recombinant vaccinia virus that lacked a thymidine kinase. This compound retained complete activity against cidofovir- and ST-246-resistant mutants. To determine if this analog had activity in an animal model, mice were infected intranasally with vaccinia or cowpox virus and treatment with 4′-thioIDU was given intraperitoneally or orally twice daily at 50, 15, 5, or 1.5 mg/kg of body weight beginning at 24 to 120 h postinfection and was continued for 5 days. Almost complete protection (87%) was observed when treatment with 1.5 mg/kg was begun at 72 h postinfection, and significant protection (73%) was still obtained when treatment with 5 mg/kg was initiated at 96 h. Virus titers in the liver, spleen, and kidney were reduced by about 4 log10 units and about 2 log10 units in mice infected with vaccinia virus and cowpox virus, respectively. These results indicate that 4′-thioIDU is a potent, nontoxic inhibitor of orthopoxvirus replication in cell culture and experimental animal infections and suggest that it may have potential for use in the treatment of orthopoxvirus infections in animals and humans.
14
Shchelkunov, S. N., A. A. Sergeev, K. A. Titova, S. A. Pyankov, and S. N. Yakubitskiy. "Increasing protectivity of the smallpox vaccine." Medical Immunology (Russia) 24, no. 1 (March 10, 2022): 201–6. http://dx.doi.org/10.15789/1563-0625-ipo-2203.
Анотація:
At the present time, vast majority of human population lacks immunity against orthopoxvirus infections caused by variola (smallpox), monkeypox, cowpox, or buffalopox viruses. More and more mass outbreaks of orthopoxvirus infections are yearly registered among humans on different continents. To prevent transition of these outbreaks to widespread epidemics, we should develop appropriate immunoprophylaxis strategies. Currently, massive usage of the classic live vaccine based on vaccinia virus is not acceptable, due to its high reactogenicity. Therefore, it is necessary to develop the variants of vaccinia virus with reduced virulence and increased immunogenicity/protectivity. The aim of this work was to study protective effects against a lethal orthopoxvirus infection occuring after low-dose immunization of mice with vaccinia virus variants, i.e., carrying mutant A34R gene causing increased production of extracellular virions, or a A35R gene deletion encoding protein product inhibiting antigen presentation by the major histocompatibility complex class II. The LIVP viral strain used in Russia as a smallpox vaccine, and its recombinant variants (LIVP-A34R*, LIVP-dA35R and LIVP-A34R*-dA35R) were compared with intranasal or intradermal immunization of BALB/c mice at the doses of 105 or 103 PFU. 28 days following administration of viral preparations (experimental groups) or saline (control groups), the mice underwent intravital blood sampling from retroorbital venous sinus. The levels of virion-specific antibodies were determined in individual serum samples by enzyme immunoassay. On the day 30 of experiment, the mice were infected with cowpox virus at a dose of 32 LD50, which caused total death of control mice on days 6-10. In the groups immunized with the studied viruses at a dose of 105 PFU, all the animals survived, regardless of strain, or immunization method. Upon intradermal immunization (103 PFU) of mice immunized with the original LIVP virus, 83% of the animals survived, whereas all mutant strains of the vaccinia virus provided 100% protection of the mice from subsequent cowpox virus infection. Intranasal immunization of mice at a dose of 103 PFU with LIVP strain protected only 33% of animals from lethal infection with cowpox virus, while the mutant strains LIVP-A34R* and LIVP-A34R*-dA35R provided 67% protection, and the LIVP-dA35R strain has resqued 75% of the mice. The studied mutant vaccinia viruses can be considered not only new candidate vaccines against smallpox and other human orthopoxvirus infections, but also as vector platforms for creating live multivalent vaccines against other infectious diseases.
15
Jordan, Robert, Deborah Tien, Tove' C. Bolken, Kevin F. Jones, Shanthakumar R. Tyavanagimatt, Josef Strasser, Annie Frimm, Michael L. Corrado, Phoebe G. Strome, and Dennis E. Hruby. "Single-Dose Safety and Pharmacokinetics of ST-246, a Novel Orthopoxvirus Egress Inhibitor." Antimicrobial Agents and Chemotherapy 52, no. 5 (March 3, 2008): 1721–27. http://dx.doi.org/10.1128/aac.01303-07.
Анотація:
ABSTRACT ST-246 is a novel, potent orthopoxvirus egress inhibitor that is being developed to treat pathogenic orthopoxvirus infections of humans. This phase I, double-blind, randomized, placebo-controlled single ascending dose study (first time with humans) was conducted to determine the safety, tolerability, and pharmacokinetics of ST-246 in healthy human volunteers. ST-246 was administered in single oral doses of 500, 1,000, and 2,000 mg to fasting healthy volunteers and 1,000 mg to nonfasting healthy volunteers. ST-246 was generally well tolerated with no serious adverse events, and no subject was withdrawn from the study due to ST-246. The most commonly reported drug-related adverse event was neutropenia, which was found, upon further analysis, not to be treatment related. ST-246 was readily absorbed following oral administration with mean times to maximum concentration from 2 h to 3 h. Absorption was greater in nonfasting volunteers than in fasting volunteers. Administration of ST-246 resulted in exposure levels predicted to be sufficient for inhibiting orthopoxvirus replication compared to exposure levels in nonhuman primates in which ST-246 protected animals from lethal orthopoxvirus infection.
16
Shchelkunov, S. N., A. A. Sergeev, S. N. Yakubitskyi, K. A. Titova, and S. A. Pyankov. "Assessing immunogenicity and protectiveness of the vaccinia virus LIVP-GFP in three laboratory animal models." Russian Journal of Infection and Immunity 11, no. 6 (October 7, 2021): 1167–72. http://dx.doi.org/10.15789/2220-7619-aia-1668.
Анотація:
Smallpox eradication and lack of adequate animal model for smallpox infection underlies a necessity to assess immunogenic and protective properties of genetic engineering-created live attenuated smallpox vaccines in several animal models of orthopoxviral infections. Here we compared immunogenic and protective properties of the recombinant vaccinia virus (VACV) LIVP-GFP intradermally (i.d.) inoculated to mice, guinea pigs and rabbits. LIVP-GFP immunization in all animal species was applied at dose of 2 × 104 or 2 × 106 PFU. Control animals were injected with saline. Blood sampling was performed on day 28 after virus LIVP-GFP or saline inoculation. Blood samples were taken intravitally from the retro-orbital venous sinus in mice, heart in guinea pigs or marginal ear vein in rabbits. Serum samples were isolated by precipitating blood cells via centrifugation. The serum anti-VACV IgG titers were determined by ELISA. On day 30 post-immunization animals were intranasally challenged with lethal dose of host specific orthopoxvirus species. Mice were infected by cowpox virus (CPXV) strain GRI-90 at dose 68 LD50, guinea pigs – by VACV GPA at dose 56 LD50, rabbits — by VACV HB-92 at dose 100 LD50. All animals in control group died afterwards, whereas all animals immunized by attenuated recombinant virus LIVP-GFP at dose 2 × 106 PFU survived. In case of the LIVP-GFP immunization at dose 2 × 104 PFU, 88% of mice, 67% of rabbits and 50% of guinea pigs survived after being challenged with species-specific CPXV, VACV HB-92, and VACV GPA. ELISA data for the blood serum samples revealed a correlation between level of VACV-specific antibodies and level of protection in animal species. Based on the data obtained, it could be concluded that all three “animal–orthopoxvirus” models allow to provide with a proper evaluation of immunogenicity and protectiveness for generated modern attenuated vaccines against smallpox and other orthopoxviral human infections. Upon that, it was shown that BALB/c mouse strain was the most convenient investigational host species.
17
Parker, Scott, Lauren Handley, and R. Mark Buller. "Therapeutic and prophylactic drugs to treat orthopoxvirus infections." Future Virology 3, no. 6 (November 2008): 595–612. http://dx.doi.org/10.2217/17460794.3.6.595.
18
Shchelkunov, Sergei N., Stanislav N. Yakubitskiy, Kseniya A. Titova, Stepan A. Pyankov, and Alexander A. Sergeev. "Enhancing the Protective Immune Response to Administration of a LIVP-GFP Live Attenuated Vaccinia Virus to Mice." Pathogens 10, no. 3 (March 21, 2021): 377. http://dx.doi.org/10.3390/pathogens10030377.
Анотація:
Following the WHO announcement of smallpox eradication, discontinuation of smallpox vaccination with vaccinia virus (VACV) was recommended. However, interest in VACV was soon renewed due to the opportunity of genetic engineering of the viral genome by directed insertion of foreign genes or introduction of mutations or deletions into selected viral genes. This genomic technology enabled production of stable attenuated VACV strains producing antigens of various infectious agents. Due to an increasing threat of human orthopoxvirus re-emergence, the development of safe highly immunogenic live orthopoxvirus vaccines using genetic engineering methods has been the challenge in recent years. In this study, we investigated an attenuated VACV LIVP-GFP (TK-) strain having an insertion of the green fluorescent protein gene into the viral thymidine kinase gene, which was generated on the basis of the LIVP (Lister-Institute for Viral Preparations) strain used in Russia as the first generation smallpox vaccine. We studied the effect of A34R gene modification and A35R gene deletion on the immunogenic and protective properties of the LIVP-GFP strain. The obtained data demonstrate that intradermal inoculation of the studied viruses induces higher production of VACV-specific antibodies compared to their levels after intranasal administration. Introduction of two point mutations into the A34R gene, which increase the yield of extracellular enveloped virions, and deletion of the A35R gene, the protein product of which inhibits presentation of antigens by MHC II, enhances protective potency of the created LIVP-TK--A34R*-dA35R virus against secondary lethal orthopoxvirus infection of BALB/c mice even at an intradermal dose as low as 103 plaque forming units (PFU)/mouse. This virus may be considered not only as a candidate attenuated live vaccine against smallpox and other human orthopoxvirus infections but also as a vector platform for development of safe multivalent live vaccines against other infectious diseases using genetic engineering methods.
19
Kaminsky, Lauren W., Janet J. Sei, Nikhil J. Parekh, Michael L. Davies, Irene E. Reider, Tracy E. Krouse, and Christopher C. Norbury. "Redundant Function of Plasmacytoid and Conventional Dendritic Cells Is Required To Survive a Natural Virus Infection." Journal of Virology 89, no. 19 (July 22, 2015): 9974–85. http://dx.doi.org/10.1128/jvi.01024-15.
Анотація:
ABSTRACTViruses that spread systemically from a peripheral site of infection cause morbidity and mortality in the human population. Innate myeloid cells, including monocytes, macrophages, monocyte-derived dendritic cells (mo-DC), and dendritic cells (DC), respond early during viral infection to control viral replication, reducing virus spread from the peripheral site. Ectromelia virus (ECTV), an orthopoxvirus that naturally infects the mouse, spreads systemically from the peripheral site of infection and results in death of susceptible mice. While phagocytic cells have a requisite role in the response to ECTV, the requirement for individual myeloid cell populations during acute immune responses to peripheral viral infection is unclear. In this study, a variety of myeloid-specific depletion methods were used to dissect the roles of individual myeloid cell subsets in the survival of ECTV infection. We showed that DC are the primary producers of type I interferons (T1-IFN), requisite cytokines for survival, following ECTV infection. DC, but not macrophages, monocytes, or granulocytes, were required for control of the virus and survival of mice following ECTV infection. Depletion of either plasmacytoid DC (pDC) alone or the lymphoid-resident DC subset (CD8α+DC) alone did not confer lethal susceptibility to ECTV. However, the function of at least one of the pDC or CD8α+DC subsets is required for survival of ECTV infection, as mice depleted of both populations were susceptible to ECTV challenge. The presence of at least one of these DC subsets is sufficient for cytokine production that reduces ECTV replication and virus spread, facilitating survival following infection.IMPORTANCEPrior to the eradication of variola virus, the orthopoxvirus that causes smallpox, one-third of infected people succumbed to the disease. Following successful eradication of smallpox, vaccination rates with the smallpox vaccine have significantly dropped. There is now an increasing incidence of zoonotic orthopoxvirus infections for which there are no effective treatments. Moreover, the safety of the smallpox vaccine is of great concern, as complications may arise, resulting in morbidity. Like many viruses that cause significant human diseases, orthopoxviruses spread from a peripheral site of infection to become systemic. This study elucidates the early requirement for innate immune cells in controlling a peripheral infection with ECTV, the causative agent of mousepox. We report that there is redundancy in the function of two innate immune cell subsets in controlling virus spread early during infection. The viral control mediated by these cell subsets presents a potential target for therapies and rational vaccine design.
20
Golden, Joseph W., and Jay W. Hooper. "Evaluating the Orthopoxvirus Type I Interferon-Binding Molecule as a Vaccine Target in the Vaccinia Virus Intranasal Murine Challenge Model." Clinical and Vaccine Immunology 17, no. 11 (September 15, 2010): 1656–65. http://dx.doi.org/10.1128/cvi.00235-10.
Анотація:
ABSTRACT The biological threat imposed by orthopoxviruses warrants the development of safe and effective vaccines. We developed a candidate orthopoxvirus DNA-based vaccine, termed 4pox, which targets four viral structural components, A33, B5, A27, and L1. While this vaccine protects mice and nonhuman primates from lethal infections, we are interested in further enhancing its potency. One approach to enhance potency is to include additional orthopoxvirus immunogens. Here, we investigated whether vaccination with the vaccinia virus (VACV) interferon (IFN)-binding molecule (IBM) could protect BALB/c mice against lethal VACV challenge. We found that vaccination with this molecule failed to significantly protect mice from VACV when delivered alone. IBM modestly augmented protection when delivered together with the 4pox vaccine. All animals receiving the 4pox vaccine plus IBM lived, whereas only 70% of those receiving a single dose of 4pox vaccine survived. Mapping studies using truncated mutants revealed that vaccine-generated antibodies spanned the immunoglobulin superfamily domains 1 and 2 and, to a lesser extent, 3 of the IBM. These antibodies inhibited IBM cell binding and IFN neutralization activity, indicating that they were functionally active. This study shows that DNA vaccination with the VACV IBM results in a robust immune response but that this response does not significantly enhance protection in a high-dose challenge model.
21
Smith, Alvin L., Marisa St Claire, Srikanth Yellayi, Laura Bollinger, Peter B. Jahrling, Jason Paragas, Joseph E. Blaney, and Reed F. Johnson. "Intrabronchial inoculation of cynomolgus macaques with cowpox virus." Journal of General Virology 93, no. 1 (January 1, 2012): 159–64. http://dx.doi.org/10.1099/vir.0.036905-0.
Анотація:
The public health threat of orthopoxviruses from bioterrorist attacks has prompted researchers to develop suitable animal models for increasing our understanding of viral pathogenesis and evaluation of medical countermeasures (MCMs) in compliance with the FDA Animal Efficacy Rule. We present an accessible intrabronchial cowpox virus (CPXV) model that can be evaluated under biosafety level-2 laboratory conditions. In this dose-ranging study, utilizing cynomolgus macaques, signs of typical orthopoxvirus disease were observed with the lymphoid organs, liver, skin (generally mild) and respiratory tract as target tissues. Clinical and histopathological evaluation suggests that intrabronchial CPXV recapitulated many of the features of monkeypox and variola virus, the causative agent of smallpox, infections in cynomolgus macaque models. These similarities suggest that CPXV infection in non-human primates should be pursued further as an alternative model of smallpox. Further development of the CPXV primate model, unimpeded by select agent and biocontainment restrictions, should facilitate the development of MCMs for smallpox.
22
Gavrilova, E. V., R. A. Maksyutov, and S. N. Shchelkunov. "Orthopoxvirus Infections: Epidemiology, Clinical Picture, and Diagnostics (Scientific Review)." Problems of Particularly Dangerous Infections, no. 4 (December 20, 2013): 82–88. http://dx.doi.org/10.21055/0370-1069-2013-4-82-88.
23
Xiao, Yuhong, and Stuart N. Isaacs. "Therapeutic Vaccines and Antibodies for Treatment of Orthopoxvirus Infections." Viruses 2, no. 10 (October 20, 2010): 2381–403. http://dx.doi.org/10.3390/v2102381.
24
Ferraris, O., A. Ferrier-Rembert, I. Drouet, F. Jarjaval, F. Iseni, and C. Peyrefitte. "Surveillance des infections à orthopoxvirus en France en 2014." Annales de Dermatologie et de Vénéréologie 142, no. 12 (December 2015): S437. http://dx.doi.org/10.1016/j.annder.2015.10.036.
25
Jordan, Robert, Arthur Goff, Annie Frimm, Michael L. Corrado, Lisa E. Hensley, Chelsea M. Byrd, Eric Mucker, et al. "ST-246 Antiviral Efficacy in a Nonhuman Primate Monkeypox Model: Determination of the Minimal Effective Dose and Human Dose Justification." Antimicrobial Agents and Chemotherapy 53, no. 5 (February 17, 2009): 1817–22. http://dx.doi.org/10.1128/aac.01596-08.
Анотація:
ABSTRACT Therapeutics for the treatment of pathogenic orthopoxvirus infections are being sought. In the absence of patients with disease, animal models of orthopoxvirus disease are essential for evaluation of the efficacies of antiviral drugs and establishment of the appropriate dose and duration of human therapy. Infection of nonhuman primates (NHP) by the intravenous injection of monkeypox virus has been used to evaluate a promising therapeutic drug candidate, ST-246. ST-246 administered at 3 days postinfection (which corresponds to the secondary viremia stage of disease) at four different doses (from 100 mg/kg of body weight down to 3 mg/kg) once a day for 14 days was able to offer NHP 100% protection from a lethal infection with monkeypox virus and reduce the viral load and lesion formation. In NHP, the administration of ST-246 at a dose of 10 mg/kg/day for 14 days resulted in levels of blood exposure comparable to the levels attained in humans administered 400 mg in the fed state. These results suggest that administration of an oral dosage of 400 mg once daily for 14 days will be effective for the prevention or treatment of smallpox or monkeypox infections in humans.
26
Karem, Kevin L., Mary Reynolds, Zach Braden, Gin Lou, Nikeva Bernard, Joanne Patton, and Inger K. Damon. "Characterization of Acute-Phase Humoral Immunity to Monkeypox: Use of Immunoglobulin M Enzyme-Linked Immunosorbent Assay for Detection of Monkeypox Infection during the 2003 North American Outbreak." Clinical Diagnostic Laboratory Immunology 12, no. 7 (July 2005): 867–72. http://dx.doi.org/10.1128/cdli.12.7.867-872.2005.
Анотація:
ABSTRACT A monkeypox outbreak occurred in the United States in 2003. Patient's sera were sent to the Centers for Disease Control and Prevention as a part of outbreak response measures. Clinical and epidemiologic information was abstracted from the case investigation forms. Serum samples from patients were tested by using an immunoglobulin M (IgM)-capture and an IgG enzyme-linked immunosorbent assay ELISA against Orthopoxvirus antigen. The detection of antiviral IgG and IgM antibodies and the kinetics of the antiviral IgG and IgM antibody responses were evaluated. Patients were classified as confirmed, probable, or suspect cases or were excluded as cases based on laboratory test results and epidemiologic and clinical criteria. A total of 37 confirmed case patients with monkeypox were identified, and 116 patients were excluded as case patients based on molecular testing or insufficient epidemiology and clinical data to warrant classification as a suspect or probable case. Of 37 confirmed case patients, 36 had a known history (presence or absence) of smallpox vaccination. Of those, 29 of the 36 either had or developed an IgG response, while 34 of the 36 developed an IgM response, regardless of vaccination status. Serum collected ≥5 days for IgM detection or serum collected ≥8 days after rash onset for IgG detection was most efficient for the detection of monkeypox virus infection. IgM ELISA detects recent infection with orthopoxviruses and, in this case, recent infection with monkeypox virus. In addition, analysis of paired sera for IgG and IgM detected seroconversion, another indicator of recent infection. The ELISA results correlated with the virologic PCR and viral culture results, indicating its diagnostic capabilities for monkeypox and potentially other orthopoxvirus infections due to zoonotic transmission or bioterrorism events.
27
Schatzmayr, Hermann G., Bruno R. Simonetti, Danielle C. Abreu, José P. Simonetti, Sandra R. Simonetti, Renata V. C. Costa, Márcia Cristina R. Gonçalves, et al. "Animal infections by vaccinia-like viruses in the state of Rio de Janeiro: an expanding disease." Pesquisa Veterinária Brasileira 29, no. 7 (July 2009): 509–14. http://dx.doi.org/10.1590/s0100-736x2009000700004.
Анотація:
In the present study we investigated the presence of infections by vaccinia-like viruses in dairy cattle from 12 counties in the state of Rio de Janeiro in the last 9 years. Clinical specimens were collected from adult animals with vesicular/pustular lesions mainly in the udder and teats, and from calves with lesions around the nose and mouth. A plaque reduction neutralization test (PRNT) was applied to search for antibodies to Orthopoxvirus; the vesicular/pustular fluids and scabs were examined by PCR, electron microscopy (EM) and by inoculation in VERO cells for virus isolation. Antibodies to Orthopoxvirus were detected in most cases. The PCR test indicated a high nucleotide homology among the isolates and the vaccinia viruses (VACV) used as controls. By EM, typical orthopoxvirus particles were observed in some specimens. The agents isolated in tissue culture were confirmed as vaccinia-like viruses by EM and PCR. The HA gene of the vaccinia-like Cantagalo/IOC virus isolated in our laboratory was sequenced and compared with other vaccinia-like isolates, showing high homology with the original Cantagalo strain, both strains isolated in 1999 from dairy cattle. Antibodies to Orthopoxvirus were detected in one wild rodent (genus Akodon sp.) collected in the northwestern region of the state, indicating the circulation of poxvirus in this area. Nonetheless, PCR applied to tissue samples collected from the wild rodents were negative. Vesicular/pustular lesions in people in close contact with animals have been also recorded. Thus, the vaccinia-like virus infections in cattle and humans in the state seem to be an expanding condition, resulting in economic losses to dairy herds and leading to transient incapacitating human disease. Therefore, a possible immunization of the dairy cattle in the state should be carefully evaluated.
28
Baker, Robert O., Mike Bray, and John W. Huggins. "Potential antiviral therapeutics for smallpox, monkeypox and other orthopoxvirus infections." Antiviral Research 57, no. 1-2 (January 2003): 13–23. http://dx.doi.org/10.1016/s0166-3542(02)00196-1.
29
Smee, Donald F., Mike Bray, and John W. Huggins. "Antiviral Activity and Mode of Action Studies of Ribavirin and Mycophenolic Acid against Orthopoxviruses in Vitro." Antiviral Chemistry and Chemotherapy 12, no. 6 (December 2001): 327–35. http://dx.doi.org/10.1177/095632020101200602.
Анотація:
Two inhibitors of cellular inosine monophosphate dehydrogenase, mycophenolic acid (MPA) and ribavirin, were evaluated for inhibitory activity against orthopoxviruses. Unrelated antipoxvirus agents tested for comparison included 6-azauridine, cidofovir (HPMPC) and cyclic HPMPC. MPA inhibited camelpox, cowpox, monkeypox and vaccinia viruses by 50% in plaque reduction assays at 0.2–3 μM in African green monkey kidney (Vero 76) and mouse 3T3 cells. Ribavirin was considerably more active in 3T3 cells (50% inhibition at 2-l2 μM) than in Vero 76 cells (inhibitory at 30–250 μM) against these viruses. In cytotoxicity assays, MPA and ribavirin were more toxic to replicating cells than to stationary cell monolayers, with greater toxicity seen in 3T3 than in Vero 76 cells. The superior antiviral potency and increased toxicity of ribavirin in 3T3 cells was related to greater accumulation of mono-, di- and triphosphate forms of the drug compared with Vero 76 cells. For both MPA and ribavirin, virus inhibition was closely correlated to the extent of suppression of intracellular guanosine triphosphate (GTP) pools. Treatment with extracellular guanosine (which restored intracellular GTP levels) did not lead to complete reversal of the anticowpox virus activity of ribavirin. This suggests that other modes of virus inhibition also appear to contribute to the anti-orthopoxvirus activity of ribavirin. Biological differences in mode of action and immunosuppressive potential between ribavirin and MPA may account for why the former compound is active against orthopoxvirus infections in animals and the latter inhibitor is not.
30
Almehmadi, Mazen, Mamdouh Allahyani, Ahad Amer Alsaiari, Mohammed Kanan Alshammari, Abrar Saleh Alharbi, Khansa Hamza Hussain, Lojain Ibrahim Alsubaihi, et al. "A Glance at the Development and Patent Literature of Tecovirimat: The First-in-Class Therapy for Emerging Monkeypox Outbreak." Viruses 14, no. 9 (August 25, 2022): 1870. http://dx.doi.org/10.3390/v14091870.
Анотація:
Monkeypox disease (MPX) is currently considered a global threat after COVID-19. European Medicines Agency (EMA) approved Tecovirimat in capsule dosage form (200 mg) as the first treatment for MPX in January 2022. This article highlights Tecovirimat’s development and patent literature review and is believed to benefit the scientists working on developing MPX treatments. The literature for Tecovirimat was gathered from the website of SIGA Technologies (developer of Tecovirimat), regulatory agencies (EMA, United States Food and Drug Administration (USFDA), and Health Canada), PubMed, and freely accessible clinical/patent databases. Tecovirimat was first recognized as an anti-orthopoxvirus molecule in 2002 and developed by SIGA Technologies. The USFDA and Health Canada have also recently approved Tecovirimat to treat smallpox in 2018 and 2021, respectively. The efficacy of Tecovirimat was verified in infected non-human primates (monkeys) and rabbits under the USFDA’s Animal Rule. Most clinical studies have been done on Tecovirimat’s safety and pharmacokinetic parameters. The patent literature has revealed inventions related to the capsule, injection, suspension, crystalline forms, amorphous form, and drug combinations (Tecovirimat + cidofovir) and process for preparing Tecovirimat. The authors foresee the off-label use of Tecovirimat in the USA and Canada for MPX and other orthopoxvirus infections. The authors also trust that there is immense scope for developing new Tecovirimat-based treatments (new drug combinations with other antivirals) for orthopoxvirus and other viral diseases. Drug interaction studies and drug resistance studies on Tecovirimat are also recommended. Tecovirimat is believed to handle the current MPX outbreak and is a new hope of biosecurity against smallpox or orthopoxvirus-related bioterrorism attack.
31
Suslov, Evgenii V., Evgenii S. Mozhaytsev, Dina V. Korchagina, Nikolay I. Bormotov, Olga I. Yarovaya, Konstantin P. Volcho, Olga A. Serova, et al. "New chemical agents based on adamantane–monoterpene conjugates against orthopoxvirus infections." RSC Medicinal Chemistry 11, no. 10 (2020): 1185–95. http://dx.doi.org/10.1039/d0md00108b.
32
Yakubitskiy, S. N., I. V. Kolosova, R. A. Maksyutov, and S. N. Shchelkunov. "Attenuation of Vaccinia Virus." Acta Naturae 7, no. 4 (December 15, 2015): 113–21. http://dx.doi.org/10.32607/20758251-2015-7-4-113-121.
Анотація:
Since 1980, in the post-smallpox vaccination era the human population has become increasingly susceptible compared to a generation ago to not only the variola (smallpox) virus, but also other zoonotic orthopoxviruses. The need for safer vaccines against orthopoxviruses is even greater now. The Lister vaccine strain (LIVP) of vaccinia virus was used as a parental virus for generating a recombinant 1421ABJCN clone defective in five virulence genes encoding hemagglutinin (A56R), the IFN--binding protein (B8R), thymidine kinase (J2R), the complement-binding protein (C3L), and the Bcl-2-like inhibitor of apoptosis (N1L). We found that disruption of these loci does not affect replication in mammalian cell cultures. The isogenic recombinant strain 1421ABJCN exhibits a reduced inflammatory response and attenuated neurovirulence relative to LIVP. Virus titers of 1421ABJCN were 3 lg lower versus the parent VACV LIVP when administered by the intracerebral route in new-born mice. In a subcutaneous mouse model, 1421ABJCN displayed levels of VACV-neutralizing antibodies comparable to those of LIVP and conferred protective immunity against lethal challenge by the ectromelia virus. The VACV mutant holds promise as a safe live vaccine strain for preventing smallpox and other orthopoxvirus infections.
33
da Fonseca, Flávio Guimarães, and Luis Adan Flores. "Immune responses to acute orthopoxvirus infections: what lessons can be learned?" Future Virology 9, no. 8 (August 2014): 699–702. http://dx.doi.org/10.2217/fvl.14.49.
34
Rosone, Francesca, Marcello Giovanni Sala, Giusy Cardeti, Pasquale Rombolà, Marina Cittadini, Azzurra Carnio, Roberta Giordani, and Maria Teresa Scicluna. "Sero-Epidemiological Survey of Orthopoxvirus in Stray Cats and in Different Domestic, Wild and Exotic Animal Species of Central Italy." Viruses 13, no. 10 (October 19, 2021): 2105. http://dx.doi.org/10.3390/v13102105.
Анотація:
Orthpoxvirus infection can spread more easily in a population with a waning immunity with the subsequent emergence/re-emergence of the viruses pertaining to this genus. In the last two decades, several cases of Orthopoxvirus, and in particular Cowpoxvirus infections in humans were reported in different parts of the world, possibly due to the suspension of smallpox vaccinations. To date, in Italy, few investigations were conducted on the presence of these infections, and because of this a serosurvey was carried out to evaluate Cowpoxvirus infection in feline colonies situated in the province of Rome, since these are also susceptible to other zoonotic viruses belonging to Orthopoxvirus, and from which humans may contract the infection. The sample design was set at an expected minimum seroprevalence of 7.5%, a 5% standard error and 95% confidence level. In parallel, a serological investigation was conducted using convenience sampling in domestic, exotic and wild susceptible animals of the Latium and Tuscany Regions, which are areas in the jurisdiction of the Istituto Zooprofilattico Sperimentale del Lazio e della Toscana, coordinating this study. The serological methods employed were indirect immunofluorescence for 36 sera of nonhuman primate and virus neutralization for 1198 sera of different species. All the 1234 sera examined were negative for the presence of antibodies against Cowpoxvirus, indicating its limited circulation in the areas of investigation. The methodology applied for the serosurveillance could be adopted in the case of outbreaks of this infection and for the evaluation of the spread of this infection in the area of interest, to obtain essential information crucial for animal and public health policies according to the One Health concept.
35
MacNeill, Amy L. "Comparative Pathology of Zoonotic Orthopoxviruses." Pathogens 11, no. 8 (August 9, 2022): 892. http://dx.doi.org/10.3390/pathogens11080892.
Анотація:
This review provides a brief history of the impacts that a human-specific Orthopoxvirus (OPXV), Variola virus, had on mankind, recalls how critical vaccination was for the eradication of this disease, and discusses the consequences of discontinuing vaccination against OPXV. One of these consequences is the emergence of zoonotic OPXV diseases, including Monkeypox virus (MPXV). The focus of this manuscript is to compare pathology associated with zoonotic OPXV infection in veterinary species and in humans. Efficient recognition of poxvirus lesions and other, more subtle signs of disease in multiple species is critical to prevent further spread of poxvirus infections. Additionally included are a synopsis of the pathology observed in animal models of MPXV infection, the recent spread of MPXV among humans, and a discussion of the potential for this virus to persist in Europe and the Americas.
36
Neyts, Johan, Erik Verbeken, and Erik De Clercq. "Effect of 5-Iodo-2′-Deoxyuridine on Vaccinia Virus (Orthopoxvirus) Infections in Mice." Antimicrobial Agents and Chemotherapy 46, no. 9 (September 2002): 2842–47. http://dx.doi.org/10.1128/aac.46.9.2842-2847.2002.
Анотація:
ABSTRACT There is a concern that there may be unregistered stocks of smallpox that can be used for bioterrorism or biological warfare. According to the WHO Advisory Committee on Variola Research, there is a need to develop strategies to treat smallpox infections should they reappear. It would also be important to have an effective drug at hand for the treatment of monkeypox disease in humans. We show here that 5-iodo-2′-deoxyuridine (IDU) is a potent inhibitor of vaccinia virus (VV) replication and that IDU inhibits VV DNA synthesis in a dose-dependent way. The in vivo protective effect of IDU was assessed in the VV tail lesion model in immunocompetent mice and in a lethal model for VV infection in SCID (severe combined immune deficiency) mice that had been infected either intranasally, intraperitoneally, or intravenously. Subcutaneous treatment with IDU at 150 and 100 mg/kg of body weight markedly reduced the number of tail lesions in immunocompetent NMRI mice. Untreated intranasally VV-infected SCID mice died at 20.8 ± 3.1 days after infection (mean ± standard deviation). Treatment with IDU (subcutaneously, 150 mg/kg/day [from day 0 to 4] and 75 mg/kg/day [from day 6 to 11]) delayed-virus induced mortality by 15 days (mean day of death ± standard deviation, 35.8 ± 6.7; P < 0.0001). This protective effect was associated with (i) an improvement of lung histology and (ii) a marked reduction in lung viral titers. IDU also delayed VV-induced mortality when mice had either been infected intraperitoneally or intravenously. Even when the start of treatment with IDU (in intraperitoneally VV-infected mice) was postponed until 2 or 4 days after infection, an important delay in virus-induced mortality was noted.
37
Kania, Konrad, Maria Kalicka, Tomasz Korzec, Przemyslaw Raczkiewicz, and Monika Kuc. "Skin lesions caused by Orthopoxvirus, cowpox - case report from Poland." Journal of Education, Health and Sport 11, no. 9 (September 3, 2021): 43–48. http://dx.doi.org/10.12775/jehs.2021.11.09.006.
Анотація:
Background:Despite the elimination of smallpox, other orthopoxviruses, including cowpox virus, still infect humans. Wild rodents are its natural reservoir. Infections in humans are commonly reported from contact with sick domestic cats, rarely directly from rats. Cow pox in humans is a rare zoonotic disease, the diagnosis of which is problematic due to its rarity and thus the lack of clinical experience.Case report:Presented with a summary of the available clinical data on a 15-year-old boy who became infected with cowpox by a domestic cat.The patient developed cutaneous macular changes in the facial area. Within 3 weeks of the onset of symptoms, the lesions progressed through the papular, vesicular and pustular stages before forming a hard black eschars (2 cm in diameter) with erythema and edema and regional lifadenopathy. Differential diagnosis consisting of cat scratch disease, anthrax and brucellosis excluded microbiological examination. The lesions left scars after 8 weeks of continuous topical antiseptic treatment.Conclusions:The clinical course may be complicated, and the improvement takes 4 to 8 weeks. Infection which entered through the skin changes was the cause of antibiotic therapy. Cowpox should be suspected in patients with poorly healing skin lesions accompanied by a painful black eschars with erythema and local lymphadenopathy.
38
Mätz-Rensing, K., A. Schmitt, H. Ellerbrok, M. Kramski, C. Stahl-Hennig, and F. J. Kaup. "Calpox Virus Marmoset Model: A New Primate Animal Model for Orthopoxvirus Infections." Journal of Comparative Pathology 152, no. 1 (January 2015): 55. http://dx.doi.org/10.1016/j.jcpa.2014.10.058.
39
Kern, Earl, Mark Prichard, Debra Quenelle, Kathy Keith, Kamal Tiwari, Joseph Maddry, and John Secrist. "Activity of Certain 5-Substituted-4′-Thio Pyrimindine Nucleosides against Orthopoxvirus Infections." Antiviral Research 82, no. 2 (May 2009): A72. http://dx.doi.org/10.1016/j.antiviral.2009.02.178.
40
Gruber, Cesare, Emanuela Giombini, Marina Selleri, Simon Tausch, Andreas Andrusch, Alona Tyshaieva, Giusy Cardeti, et al. "Whole Genome Characterization of Orthopoxvirus (OPV) Abatino, a Zoonotic Virus Representing a Putative Novel Clade of Old World Orthopoxviruses." Viruses 10, no. 10 (October 6, 2018): 546. http://dx.doi.org/10.3390/v10100546.
Анотація:
Orthopoxviruses (OPVs) are diffused over the complete Eurasian continent, but previously described strains are mostly from northern Europe, and few infections have been reported from Italy. Here we present the extended genomic characterization of OPV Abatino, a novel OPV isolated in Italy from an infected Tonkean macaque, with zoonotic potential. Phylogenetic analysis based on 102 conserved OPV genes (core gene set) showed that OPV Abatino is most closely related to the Ectromelia virus species (ECTV), although placed on a separate branch of the phylogenetic tree, bringing substantial support to the hypothesis that this strain may be part of a novel OPV clade. Extending the analysis to the entire set of genes (coding sequences, CDS) further substantiated this hypothesis. In fact the genome of OPV Abatino included more CDS than ECTV; most of the extra genes (mainly located in the terminal genome regions), showed the highest similarity with cowpox virus (CPXV); however vaccinia virus (VACV) and monkeypox virus (MPXV) were the closest OPV for certain CDS. These findings suggest that OPV Abatino could be the result of complex evolutionary events, diverging from any other previously described OPV, and may indicate that previously reported cases in Italy could represent the tip of the iceberg yet to be explored.
41
Lustig, Shlomo, Christiana Fogg, J. Charles Whitbeck, Roselyn J. Eisenberg, Gary H. Cohen, and Bernard Moss. "Combinations of Polyclonal or Monoclonal Antibodies to Proteins of the Outer Membranes of the Two Infectious Forms of Vaccinia Virus Protect Mice against a Lethal Respiratory Challenge." Journal of Virology 79, no. 21 (November 1, 2005): 13454–62. http://dx.doi.org/10.1128/jvi.79.21.13454-13462.2005.
Анотація:
ABSTRACT Previous studies demonstrated that antibodies to live vaccinia virus infection are needed for optimal protection against orthopoxvirus infection. The present report is the first to compare the protective abilities of individual and combinations of specific polyclonal and monoclonal antibodies that target proteins of the intracellular (IMV) and extracellular (EV) forms of vaccinia virus. The antibodies were directed to one IMV membrane protein, L1, and to two outer EV membrane proteins, A33 and B5. In vitro studies showed that the antibodies to L1 neutralized IMV and that the antibodies to A33 and B5 prevented the spread of EV in liquid medium. Prophylactic administration of individual antibodies to BALB/c mice partially protected them against disease following intranasal challenge with lethal doses of vaccinia virus. Combinations of antibodies, particularly anti-L1 and -A33 or -L1 and -B5, provided enhanced protection when administered 1 day before or 2 days after challenge. Furthermore, the protection was superior to that achieved with pooled immune gamma globulin from human volunteers inoculated with live vaccinia virus. In addition, single injections of anti-L1 plus anti-A33 antibodies greatly delayed the deaths of severe combined immunodeficiency mice challenged with vaccinia virus. These studies suggest that antibodies to two or three viral membrane proteins optimally derived from the outer membranes of IMV and EV, may be beneficial for prophylaxis or therapy of orthopoxvirus infections.
42
Shchelkunov, S. N., S. N. Yakubitskiy, T. V. Bauer, A. A. Sergeev, A. S. Kabanov, L. E. Bulichev, I. A. Yurganova, et al. "The Influence of an Elevated Production of Extracellular Enveloped Virions of the Vaccinia Virus on Its Properties in Infected Mice." Acta Naturae 12, no. 4 (December 22, 2020): 120–32. http://dx.doi.org/10.32607/actanaturae.10972.
Анотація:
The modern approach to developing attenuated smallpox vaccines usually consists in targeted inactivation of vaccinia virus (VACV) virulence genes. In this work, we studied how an elevated production of extracellular enveloped virions (EEVs) and the route of mouse infection can influence the virulence and immunogenicity of VACV. The research subject was the LIVP strain, which is used in Russia for smallpox vaccination. Two point mutations causing an elevated production of EEVs compared with the parental LIVP strain were inserted into the sequence of the VACV A34R gene. The created mutant LIVP-A34R strain showed lower neurovirulence in an intracerebral injection test and elevated antibody production in the intradermal injection method. This VACV variant can be a promising platform for developing an attenuated, highly immunogenic vaccine against smallpox and other orthopoxvirus infections. It can also be used as a vector for designing live-attenuated recombinant polyvalent vaccines against various infectious diseases.
43
Babkin, Igor V., Irina N. Babkina, and Nina V. Tikunova. "An Update of Orthopoxvirus Molecular Evolution." Viruses 14, no. 2 (February 14, 2022): 388. http://dx.doi.org/10.3390/v14020388.
Анотація:
Although variola virus (VARV) has been eradicated through widespread vaccination, other orthopoxviruses pathogenic for humans circulate in nature. Recently, new orthopoxviruses, including some able to infect humans, have been found and their complete genomes have been sequenced. Questions about the orthopoxvirus mutation rate and the emergence of new threats to humankind as a result of the evolution of circulating orthopoxviruses remain open. Based on contemporary data on ancient VARV DNA and DNA of new orthopoxvirus species, an analysis of the molecular evolution of orthopoxviruses was carried out and the timescale of their emergence was estimated. It was calculated that the orthopoxviruses of the Old and New Worlds separated approximately 40,000 years ago; the recently discovered Akhmeta virus and Alaskapox virus separated from other orthopoxviruses approximately 10,000–20,000 years ago; the rest of modern orthopoxvirus species originated from 1700 to 6000 years ago, with the exception of VARV, which emerged in approximately 300 AD. Later, there was a separation of genetic variants of some orthopoxvirus species, so the monkeypox virus West African subtype originated approximately 600 years ago, and the VARV minor alastrim subtype emerged approximately 300 years ago.
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Lapa, Daniele, Anna Beltrame, Alessandra Arzese, Fabrizio Carletti, Antonino Di Caro, Giuseppe Ippolito, Maria Rosaria Capobianchi, and Concetta Castilletti. "Orthopoxvirus Seroprevalence in Cats and Veterinary Personnel in North-Eastern Italy in 2011." Viruses 11, no. 2 (January 25, 2019): 101. http://dx.doi.org/10.3390/v11020101.
Анотація:
Orthopoxviruses (OPV) are emerging zoonotic pathogens, and an increasing number of human infections is currently reported in Europe and in other continents, warranting heightened attention on this topic. Following two OPV infections reported in veterinarians scratched by sick cats in 2005 and 2007 in North-Eastern-Italy, involving a previously undescribed OPV, a similar strain was isolated by a sick cat from the same territory in 2011, i.e., 6 years later, raising attention on OPV circulation in this region. A surveillance program was launched to assess the OPV seroprevalence among the veterinarians working in local veterinary clinics and in the local wild and domestic cat population; seroprevalence was 33.3% in veterinarians and 19.5% in cats. Seroprevalence in cats was unevenly distributed, peaking at 40% in the area where OPV-infected cats had been observed.
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Chaudhri, Geeta, Vikas Tahiliani, Preethi Eldi, and Gunasegaran Karupiah. "Vaccine-Induced Protection against Orthopoxvirus Infection Is Mediated through the Combined Functions of CD4 T Cell-Dependent Antibody and CD8 T Cell Responses." Journal of Virology 89, no. 3 (November 26, 2014): 1889–99. http://dx.doi.org/10.1128/jvi.02572-14.
Анотація:
ABSTRACTAntibody production by B cells in the absence of CD4 T cell help has been shown to be necessary and sufficient for protection against secondary orthopoxvirus (OPV) infections. This conclusion is based on short-term depletion of leukocyte subsets in vaccinated animals, in addition to passive transfer of immune serum to naive hosts that are subsequently protected from lethal orthopoxvirus infection. Here, we show that CD4 T cell help is necessary for neutralizing antibody production and virus control during a secondary ectromelia virus (ECTV) infection. A crucial role for CD4 T cells was revealed when depletion of this subset was extended beyond the acute phase of infection. Sustained depletion of CD4 T cells over several weeks in vaccinated animals during a secondary infection resulted in gradual diminution of B cell responses, including neutralizing antibody, contemporaneous with a corresponding increase in the viral load. Long-term elimination of CD8 T cells alone delayed virus clearance, but prolonged depletion of both CD4 and CD8 T cells resulted in death associated with uncontrolled virus replication. In the absence of CD4 T cells, perforin- and granzyme A- and B-dependent effector functions of CD8 T cells became critical. Our data therefore show that both CD4 T cell help for antibody production and CD8 T cell effector function are critical for protection against secondary OPV infection. These results are consistent with the notion that the effectiveness of the smallpox vaccine is related to its capacity to induce both B and T cell memory.IMPORTANCESmallpox eradication through vaccination is one of the most successful public health endeavors of modern medicine. The use of various orthopoxvirus (OPV) models to elucidate correlates of vaccine-induced protective immunity showed that antibody is critical for protection against secondary infection, whereas the role of T cells is unclear. Short-term leukocyte subset depletion in vaccinated animals or transfer of immune serum to naive, immunocompetent hosts indicates that antibody alone is necessary and sufficient for protection. We show here that long-term depletion of CD4 T cells over several weeks in vaccinated animals during secondary OPV challenge reveals an important role for CD4 T cell-dependent antibody responses in effective virus control. Prolonged elimination of CD8 T cells alone delayed virus clearance, but depletion of both T cell subsets resulted in death associated with uncontrolled virus replication. Thus, vaccinated individuals who subsequently acquire T cell deficiencies may not be protected against secondary OPV infection.
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Gigante, Gao, Tang, McCollum, Wilkins, Reynolds, Davidson, McLaughlin, Olson, and Li. "Genome of Alaskapox Virus, A Novel Orthopoxvirus Isolated from Alaska." Viruses 11, no. 8 (August 1, 2019): 708. http://dx.doi.org/10.3390/v11080708.
Анотація:
Since the eradication of smallpox, there have been increases in poxvirus infections and the emergence of several novel poxviruses that can infect humans and domestic animals. In 2015, a novel poxvirus was isolated from a resident of Alaska. Diagnostic testing and limited sequence analysis suggested this isolate was a member of the Orthopoxvirus (OPXV) genus but was highly diverged from currently known species, including Akhmeta virus. Here, we present the complete 210,797 bp genome sequence of the Alaska poxvirus isolate, containing 206 predicted open reading frames. Phylogenetic analysis of the conserved central region of the genome suggested the Alaska isolate shares a common ancestor with Old World OPXVs and is diverged from New World OPXVs. We propose this isolate as a member of a new OPXV species, Alaskapox virus (AKPV). The AKPV genome contained host range and virulence genes typical of OPXVs but lacked homologs of C4L and B7R, and the hemagglutinin gene contained a unique 120 amino acid insertion. Seven predicted AKPV proteins were most similar to proteins in non-OPXV Murmansk or NY_014 poxviruses. Genomic analysis revealed evidence suggestive of recombination with Ectromelia virus in two putative regions that contain seven predicted coding sequences, including the A-type inclusion protein.
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Karem, Kevin L., Mary Reynolds, Christine Hughes, Zach Braden, Pragati Nigam, Shane Crotty, John Glidewell, Rafi Ahmed, Rama Amara, and Inger K. Damon. "Monkeypox-Induced Immunity and Failure of Childhood Smallpox Vaccination To Provide Complete Protection." Clinical and Vaccine Immunology 14, no. 10 (August 22, 2007): 1318–27. http://dx.doi.org/10.1128/cvi.00148-07.
Анотація:
ABSTRACT Following the U.S. monkeypox outbreak of 2003, blood specimens and clinical and epidemiologic data were collected from cases, defined by standard definition, and household contacts of cases to evaluate the role of preexisting (smallpox vaccine-derived) and acquired immunity in susceptibility to monkeypox disease and clinical outcomes. Orthopoxvirus-specific immunoglobulin G (IgG), IgM, CD4, CD8, and B-cell responses were measured at ∼7 to 14 weeks and 1 year postexposure. Associations between immune responses, smallpox vaccination, and epidemiologic and clinical data were assessed. Participants were categorized into four groups: (i) vaccinated cases, (ii) unvaccinated cases, (iii) vaccinated contacts, and (iv) unvaccinated contacts. Cases, regardless of vaccination status, were positive for orthopoxvirus-specific IgM, IgG, CD4, CD8, and B-cell responses. Antiorthopoxvirus immune responses consistent with infection were observed in some contacts who did not develop monkeypox. Vaccinated contacts maintained low levels of antiorthopoxvirus IgG, CD4, and B-cell responses, with most lacking IgM or CD8 responses. Preexisting immunity, assessed by high antiorthopoxvirus IgG levels and childhood smallpox vaccination, was associated (in a nonsignificant manner) with mild disease. Vaccination failed to provide complete protection against human monkeypox. Previously vaccinated monkeypox cases manifested antiorthopoxvirus IgM and changes in antiorthopoxvirus IgG, CD4, CD8, or B-cell responses as markers of recent infection. Antiorthopoxvirus IgM and CD8 responses occurred most frequently in monkeypox cases (vaccinated and unvaccinated), with IgG, CD4, and memory B-cell responses indicative of vaccine-derived immunity. Immune markers provided evidence of asymptomatic infections in some vaccinated, as well as unvaccinated, individuals.
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Yu, Joyce, and Suresh Mahendra Raj. "Efficacy of three key antiviral drugs used to treat orthopoxvirus infections: a systematic review." Global Biosecurity 1, no. 1 (February 14, 2019): 28. http://dx.doi.org/10.31646/gbio.12.
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Putkuri, Niina, Heli Piiparinen, Antti Vaheri, and Olli Vapalahti. "Detection of human orthopoxvirus infections and differentiation of smallpox virus with real-time PCR." Journal of Medical Virology 81, no. 1 (November 21, 2008): 146–52. http://dx.doi.org/10.1002/jmv.21385.
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Vigne, Solenne, Raphaële Germi, Sophie Duraffour, Sylvie Larrat, Graciela Andrei, Robert Snoeck, Daniel Garin, and Jean-Marc Crance. "Specific Inhibition of Orthopoxvirus Replication by a Small Interfering RNA Targeting the D5R Gene." Antiviral Therapy 13, no. 3 (April 2008): 357–68. http://dx.doi.org/10.1177/135965350801300307.
Анотація:
Background Concerns about the potential use of smallpox in bioterrorism have stimulated interest in the development of novel antiviral treatments. Currently, there are no effective therapies against smallpox and new treatment strategies are greatly needed. Methods In this study, specifically designed small interfering RNAs (siRNAs), targeting five proteins essential for orthopoxvirus replication, were investigated for their ability to inhibit vaccinia virus strain Western Reserve (VACVWR) replication. Results Among these siRNAs, 100 nM siD5R-2, an siRNA targeting the D5 protein, decreased VACVWR replication up to 90% when used either prophylactically or therapeutically in human lung carcinoma A549 cells. This siRNA induced a striking concentration-dependent inhibition of VACVWR replication and a prolonged prophylactic antiviral effect that lasted for 72 h, at a concentration of 100 nM. Confocal microscopy of Alexa–siD5R-2-treated VACVWR-infected cells confirmed a decrease in viral replication. Furthermore, siD5R-2 was shown to specifically reduce the D5R mRNA and protein expression using real-time reverse tran-scriptase-PCR and western blotting analysis, without inducing interferon-β in A549 cells. We also demonstrated the antiviral potency of siD5R-2 against different pathogenic orthopoxviruses, such as cowpox and monkeypox viruses, which were inhibited up to 70% at the lowest concentration (1 nM) tested. Finally, siD5R-2 showed antiviral effects in VACVWR-infected human keratinocyte and fibroblast cell cultures. Conclusions These results suggest that siD5R-2 could be a potential candidate to treat poxvirus infections.