Poxviruses from the Concept of One Health.

In the last 4 years, the world has experienced two pandemics of bat-borne viruses. Firstly, in 2019 the SARS-CoV-2 pandemic started and has been causing millions of deaths around the world. In 2022, a Monkeypox pandemic rose in various countries of the world. Those pandemics have witnessed movements and initiatives from healthcare and research institutions to establish a worldwide understanding to battle any future pandemics and biological threats. One Health concept is a modern, comprehensive, unifying ways to improve humans, animals, and ecosystems' health. This concept shows how much they are intertwined and related to one another, whether it is an environmental, or a pathological relation. This review aims to describe Poxviridae and its impact on the One Health concept, by studying the underlying causes of how poxviruses can affect the health of animals, humans, and environments. Reviewing the effect of disease transmission between animal to human, human to human, and animal to animal with pox viruses as a third party to achieve a total understanding of infection and viral transmission. Thus, contributing to enhance detection, diagnosis, research, and treatments regarding the application of One Health.

Efficacy and Safety of the Smallpox Vaccine for Postexposure Prophylaxis in Monkeypox: Protocol for an Open-Labeled, Single-Armed Study.

BACKGROUND: In May 2022, a case of monkeypox (currently known as "mpox") with no history of overseas travel was reported in the United Kingdom, followed by reports of infections reported in Europe, the United States, and other countries worldwide. Due to the significant overlap in immune responses among viruses of the genus Orthopoxvirus (including smallpox virus, mpox virus, and vaccinia virus), it is believed that cross-immunity can be achieved by administering the smallpox virus vaccine. In Japan, a smallpox vaccine (LC16m8 strain vaccine) has been approved; however, there was no regulatory approval for the mpox vaccine during the design of this study. Although it is believed that individuals exposed to the mpox virus may receive smallpox vaccination as mpox prophylaxis, the existing evidence is not clear. OBJECTIVE: The primary objective was to evaluate the efficacy of the LC16m8 strain vaccine, approved for smallpox in Japan, for postexposure prophylaxis against mpox when administered to close contacts of individuals with mpox. The secondary objective was to investigate the safety of the vaccine for postexposure prophylaxis against mpox. METHODS: The study aimed to enroll 100 vaccinated participants who had been identified as close contacts of individuals with mpox. Consent was obtained, and the participants are inoculated with the vaccine. Daily recordings of symptoms (body temperature, headache, rash, and side effects) were made until day 21 and then again on day 28. Furthermore, additional evaluations of adverse events were performed by the investigators on days 7, 14, 21, and 28. Considering that the maximum incubation period for mpox is 21 days, the primary end point is the presence or absence of the disease 21 days after close contact. The primary analysis focused on cases within 4 days of intense contact as it has been reported that vaccination within this timeframe can reduce the incidence of the disease. RESULTS: The first trial participant was enrolled on July 28, 2022, and the research period concluded in March 2023. The study results will be published in a peer-reviewed scientific journal. CONCLUSIONS: This study allowed us to investigate the efficacy and safety of the LC16m8 strain vaccine in postexposure prophylaxis against mpox. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs031220137; https://jrct.niph.go.jp/en-latest-detail/jRCTs031220137. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46955.

Corrigendum: Anti-viral drug discovery against monkeypox and smallpox infection by natural curcumin derivatives: a computational drug design approach.

[This corrects the article DOI: 10.3389/fcimb.2023.1157627.].

Monkeypox: another pandemic in the making?

Monkeypox is a zoonotic disease caused by the monkeypox virus, which is a member of the Poxviridae family of viruses. It is transmitted through direct or indirect contact with fluid secretions. Initial symptoms include fever, chills, headache, and malaise, followed by a maculopapular rash that starts on the face and progresses centrifugally. Polymerase chain reaction is the preferred laboratory test for the diagnosis, and management is mostly supportive. The clinical presentation of monkeypox is quite similar to that of another member of the Poxviridae family: smallpox, which wreaked havoc in the 20th century, before being eradicated with the help of the vaccinia virus vaccine in 1977. This vaccine protects not only against smallpox but also monkeypox; therefore, when use of this vaccine was discontinued, monkeypox had a new susceptible population to infect and way to proliferate and evolve. Initially the disease spread in Africa, but now the more evolved monkeypox is quickly spreading to other countries. On July 23, 2022, the World Health Organization declared this multicountry outbreak a public health emergency of international concern. Given its mutating ability and high transmissibility, we need to quickly devise measures to control this virus before it turns into a pandemic.

Anti-viral drug discovery against monkeypox and smallpox infection by natural curcumin derivatives: A Computational drug design approach.

Background: In the last couple of years, viral infections have been leading the globe, considered one of the most widespread and extremely damaging health problems and one of the leading causes of mortality in the modern period. Although several viral infections are discovered, such as SARS CoV-2, Langya Henipavirus, there have only been a limited number of discoveries of possible antiviral drug, and vaccine that have even received authorization for the protection of human health. Recently, another virial infection is infecting worldwide (Monkeypox, and Smallpox), which concerns pharmacists, biochemists, doctors, and healthcare providers about another epidemic. Also, currently no specific treatment is available against Monkeypox. This research gap encouraged us to develop a new molecule to fight against monkeypox and smallpox disease. So, firstly, fifty different curcumin derivatives were collected from natural sources, which are available in the PubChem database, to determine antiviral capabilities against Monkeypox and Smallpox. Material and method: Preliminarily, the molecular docking experiment of fifty different curcumin derivatives were conducted, and the majority of the substances produced the expected binding affinities. Then, twelve curcumin derivatives were picked up for further analysis based on the maximum docking score. After that, the density functional theory (DFT) was used to determine chemical characterizations such as the highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO), softness, and hardness, etc. Results: The mentioned derivatives demonstrated docking scores greater than 6.80 kcal/mol, and the most significant binding affinity was at -8.90 kcal/mol, even though 12 molecules had higher binding scores (-8.00 kcal/mol to -8.9 kcal/mol), and better than the standard medications. The molecular dynamic simulation is described by root mean square deviation (RMSD) and root-mean-square fluctuation (RMSF), demonstrating that all the compounds might be stable in the physiological system. Conclusion: In conclusion, each derivative of curcumin has outstanding absorption, distribution, metabolism, excretion, and toxicity (ADMET) characteristics. Hence, we recommended the aforementioned curcumin derivatives as potential antiviral agents for the treatment of Monkeypox and Smallpox virus, and more in vivo investigations are warranted to substantiate our findings.

Emergence and dissemination of monkeypox, an intimidating global public health problem.

The monkeypox virus (MPXV) is the cause of a zoonotic infection similar to smallpox. Although it is endemic to Africa, it has recently begun to circulate in other parts of the world. In July 2022, the World Health Organization declared monkeypox an international public health emergency. This review aims to provide an overview of this neglected zoonotic pathogen. MPXV circulates as two distinct clades, the Central African and West African, with case fatality rates of 10.6% and 3.6%, respectively. The risk of infection is greater for those who work with animals or infected individuals. The virus' entry into the human body provokes both natural and acquired immunity. Although natural killer cells, CD4 + T cells, and CD8 + T cells play an essential role in eradicating MPXV, there is still a gap in the understanding of the host immune response to the virus. Currently, there are no specific therapeutic guidelines for treating monkeypox; however, some antiviral drugs such as tecovirimat and cidofovir may help to abate the severity of the disease. The use of nonpharmaceutical interventions and immunization can reduce the risk of infection. Increased surveillance and identification of monkeypox cases are crucial to understand the constantly shifting epidemiology of this resurging and intimidating disease. The present review provides a detailed perspective on the emergence and circulation of MPXV in human populations, infection risks, human immune response, disease diagnosis and prevention strategies, and future implications, and highlights the importance of the research community engaging more with this disease for an effective global response.

Viruela símica: revisión bibliográfica / Monkeypox: Bibliographic Review

La viruela símica es una enfermedad que ocurre en los monos, sin embargo también se han presentado casos en humanos desde 1970, transformándose en una zoonosis de origen viral, la sintomatología es similar a la viruela pero menos grave. Objetivo: Proporcionar información actualizada sobre la viruela símica, situación epidemiológica, sintomatología, letalidad, diagnóstico, tratamiento y medidas de prevención Materiales y métodos: Se realizó una búsqueda de literatura científica en las bases de datos Organización Mundial de la Salud, Google Académico y PubMed, se eligieron los descriptores o palabras relacionadas con la enfermedad y se realizó la búsqueda para la descripción de reportes de casos y brotes producidas por la viruela símica. Resultados: Desde que se reportó el primer caso en humanos, han existido brotes en el continente africano, fuera de éste, se han reportados varios casos y brotes en otros países, la mayoría en los Estados Unidos. El último evento se reporta en mayo de 2022 y es de preocupación mundial, debido a la aparición en varios países no endémicos. Conclusiones: La presencia de casos de viruela símica en humanos se ha mantenido desde su aparición, la ausencia de un tratamiento específico y vacunas autorizadas para su administración, podrían generar un aumento en la morbimortalidad(AU)

Monkeypox is a disease that occurs in monkeys, however there have also been cases in humans since 1970, becoming a zoonosis of viral origin, the symptoms are similar to smallpox but less severe. Objective: To provide updated information on monkeypox, epidemiological situation, symptomatology, lethality, diagnosis, treatment and prevention measures. Materials and methods: A search of scientific literature was carried out in the World Health Organization, Google Scholar and PubMed databases. , the descriptors or words related to the disease were chosen and the search was performed for the description of case reports and outbreaks caused by monkeypox. Results: Since the first human case was reported, there have been outbreaks on the African continent, outside of Africa, several cases and outbreaks have been reported in other countries, most in the United States. The last event is reported in May 2022 and is of global concern, due to the appearance in several non-endemic countries. Conclusions: The presence of cases of monkeypox in humans has been maintained since its appearance, the absence of a specific treatment and vaccines authorized for its administration, could generate an increase in morbidity and mortality(AU)

Conocimiento sobre viruela del mono en profesionales de la salud, Lima-Perú / Knowledge about monkeypox among health professionals, Lima-Peru

Introducción: la pandemia por SARS-CoV 2 nos demostró que no estábamos preparados, que no se repita. Objetivo: conocer el nivel de conocimiento sobre etiología, síntomas, tratamiento y prevención de la enfermedad viruela del mono en profesionales de la salud. El estudio: observacional-descriptivo, incluyó 251 profesionales de la salud, ambos sexos participación voluntaria. Se elaboró un cuestionario incluyéndose las variables edad, sexo y preguntas sobre la enfermedad viruela del mono; análisis descriptivos de los datos. Hallazgos: bajo conocimiento sobre etiología, síntomas, tratamiento y prevención de la enfermedad. Menor conocimiento sobre formas de contagio (21,9%), tiempo de incubación (21,9%), características del virus (24,3%) y diagnóstico laboratorial (25,1%); mayor conocimiento sobre contagiosidad en periodo de incubación (61,0%), presencia de erupciones como característica de la enfermedad (53,8%) y no existencia de tratamiento específico (52,2%). Conclusión: conocimiento bajo; urge la formulación de estrategias para poder enfrentar, de ser necesario, los posibles casos.

Background:the SARS-CoV 2 pandemic showed us that we were not prepared, that it will not happen again. to know the level of knowledge about Objective:the etiology, symptoms, treatment and prevention of monkeypox disease in health professionals. observational-descriptive, included 251 The study:health professionals, both sexes, voluntary participation. Aquestionnaire was developed including the variables age, sex and questions about the monkeypox disease, descriptive analysis of the data. Finding: low knowledge about the etiology, symptoms, treatment and prevention of the disease. Less knowledge about forms of contagion (21.9%), incubation time (21.9%), characteristics of the virus (24.3%) and laboratory diagnosis (25.1%); greater knowledge about contagiousness in the incubation period (61.0%), presence of rashes as a characteristic of the disease (53.8%) and lack of specific treatment (52.2%). Conclusion: low knowledge; The formulation of strategies is urgently needed to be able to face possible cases, if necessary.

Evolution of human respiratory virus epidemics.

Background: Pathogens are often assumed to evolve towards reduced virulence, but counterexamples abound. Faced with a new pathogen, such as SARS-CoV-2, it is crucial to be able to forecast the case fatality rate (CFR) and the overall disease burden. Considerable effort has been invested towards developing a mathematical framework for predicting virulence evolution. Although many approaches accurately recapitulate complex outcomes, most rely on an assumed trade-off between CFR and infection rate. It is often impractical to empirically validate this constraint for human pathogens. Methods: A compartment model with parameters tuning the degree to which symptomatic individuals are isolated and the duration of immunity is constructed and evaluated at both short timescales and at equilibrium. Results: We reveal kinetic constraints whereby variation of multiple parameters in concert leads to decreased CFR and increased pathogen fitness, whereas independent variation of the parameters decreases pathogen fitness. Smallpox, SARS-CoV-2, and influenza are analyzed as diverse representatives of human respiratory viruses. We show that highly virulent viruses, such as smallpox, are often constrained by the host behavior, whereas moderately virulent viruses, such as SARS-CoV-2, appear to be typically constrained by the relationship between the duration of immunity and CFR. Conclusions: Evolution of human respiratory epidemics appears to be often kinetically constrained and a reduction in CFR should not be assumed. These results agree with previous work demonstrating an increase in virulence for smallpox and further predict that SARS-CoV-2 is likely to continue presenting a substantial disease burden. Herd immunity against SARS-CoV-2 and viruses with similar life history traits might be unachievable without vaccination. However, partial isolation of symptomatic individuals can have a major effect on the epidemic dynamics not only by reducing the number of fatalities in the short term but also by changing the evolutionary trajectory of moderate CFR viruses towards reduced CFR.

Role of Electrostatic Hotspots in the Selectivity of Complement Control Proteins Toward Human and Bovine Complement Inhibition.

Poxviruses are dangerous pathogens, which can cause fatal infection in unvaccinated individuals. The causative agent of smallpox in humans, variola virus, is closely related to the bovine vaccinia virus, yet the molecular basis of their selectivity is currently incompletely understood. Here, we examine the role of the electrostatics in the selectivity of the smallpox protein SPICE and vaccinia protein VCP toward the human and bovine complement protein C3b, a key component of the complement immune response. Electrostatic calculations, in-silico alanine-scan and electrostatic hotspot analysis, as introduced by Kieslich and Morikis (PLoS Comput. Biol. 2012), are used to assess the electrostatic complementarity and to identify sites resistant to local perturbation where the electrostatic potential is likely to be evolutionary conserved. The calculations suggest that the bovine C3b is electrostatically prone to selectively bind its VCP ligand. On the other hand, the human isoform of C3b exhibits a lower electrostatic complementarity toward its SPICE ligand. Yet, the human C3b displays a highly preserved electrostatic core, which suggests that this isoform could be less selective in binding different ligands like SPICE and the human Factor H. This is supported by experimental cofactor activity assays revealing that the human C3b is prone to bind both SPICE and Factor H, which exhibit diverse electrostatic properties. Additional investigations considering mutants of SPICE and VCP that revert their selectivity reveal an "electrostatic switch" into the central modules of the ligands, supporting the critical role of the electrostatics in the selectivity. Taken together, these evidences provide insights into the selectivity mechanism of the complement regulator proteins encoded by the variola and vaccinia viruses to circumvent the complement immunity and exert their pathogenic action. These fundamental aspects are valuable for the development of novel vaccines and therapeutic strategies.

[We should be prepared to smallpox re-emergence.]

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.

POXVIRUS DISEASE OF SQUIRRELS (POXVIRIDAE, CHORDOPOXVIRINAE, SQPV - SQUIRREL POXVIRUS).

A new taxon of the subfamily Chordopoxvirinae that may represent a new genus of smallpox viruses is considered in this review. The distribution of gray squirrels (Sciurus carolinensis) throughout the UK during the 20th century and the decrease in the population of red squirrels (Sciurus vulgaris) is one of the most well-documented cases of ecological change of local fauna by the introduced species. The tendency to expand the distribution of the smallpox virus from Great Britain to the Western part of Europe has been noted. The genetic peculiarities of the genome of the poxvirus of squirrels, which determine its biological properties, as well as evolutionary relationships with other poxviruses, are separately described. Determination of the size of the genome by restriction analysis, sequencing of the whole genome, determination of the content of G/C nucleotide pairs, and functional mapping of the majority of genes made it possible to construct a phylogenetic tree. Phylogenetic analysis shows that this is a new representative of the subfamily Chordоpoxvirinae located between the viruses of the molluscum contagiosum and parapoxviruses. Serological and molecular biological methods are used to reveal and identify the causative agent of smallpox. The use of electron microscopy is limited in grey squirrels, due to the absence of organ damage and reproduction of the virus. Identification of the DNA of the causative agent of poxvirus of squirrels based on the use of different types of polymerase chain reaction (nested and in real time) overcomes all these limitations.

40 Years without Smallpox.

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.

Poxvirus viability and signatures in historical relics.

Although it has been >30 years since the eradication of smallpox, the unearthing of well-preserved tissue material in which the virus may reside has called into question the viability of variola virus decades or centuries after its original occurrence. Experimental data to address the long-term stability and viability of the virus are limited. There are several instances of well-preserved corpses and tissues that have been examined for poxvirus viability and viral DNA. These historical specimens cause concern for potential exposures, and each situation should be approached cautiously and independently with the available information. Nevertheless, these specimens provide information on the history of a major disease and vaccination against it.

Infecção em humanos por varíola bovina na região de Ibertioga, estado de Minas Gerais / Human infection with bovine smallpox in the Ibertioga region, State of Minas Gerais, Brazil

Introdução e objetivo: a varíola bovina é uma zoonose causada pela proliferação do vírus do gênero ortopoxvírus, sendo os bovinos a fonte primária de infecção humana. É importante apresentar relatos de casos dessa doença para que os profissionais de saúde, em especial os médicos, fiquem atentos para seu diagnóstico e tratamento corretos. Resultados: quatro casos de varíola bovina em humanos foram identificados e comprovados por exames sorológicos na região de Ibertioga, Minas Gerais. Todos os pacientes apresentavam sintomas em comum, como febre alta, falta de apetite, mialgia e lesões de pele. Conclusão: deve ser dada mais atenção aos casos dessa zoonose, no sentido de seu correto diagnóstico, adequada terapia de suporte e boa orientação para os pacientes, para que possa se evitar a transmissão intrafamiliar, bem como para animais com os quais venham a ter contato, considerando que a quase totalidade dos casos ocorre em áreas rurais.

Introduction and objective: Bovine smallpox is a zoonosis caused by Ortopxvirus proliferation, bovines being the primary source for human infection. Case reports of this disease are important to raise health professionals? consciousness of correct diagnosis and treatment.Results: Four cases of human infection with bovine smallpox were identified and confirmed by serologic exams in the Ibertioga region, State of Minas Gerais, Brazil Patients shared common symptoms such as high fever, decreased appetite, myalgia, and skin injury. Conclusion:The cases of this zoonosis should be paid more attention in order to enhance diagnosis, support therapy and guidance for patients witha view to avoiding intra-familiar and further animal transmission (as virtually all cases are reported in rural areas).

In celebration of the 200th anniversary of Edward Jenner's Inquiry into the causes and effects of the variolae vaccinae.

This review commemorates the 200th anniversary of Edward Jenner's development of a vaccine for variola, the cause of smallpox, and the 20th anniversary of its eradication. Jenner's original 23 case reports are briefly revisited within the context of earlier attempts to prevent this dreaded disease and in light of the current understanding of vaccinology and immunology. In addition, with molecular biological information available about many pox viruses and detailed sequence knowledge of some, it is now possible to appreciate Jenner's prescient accomplishments more fully.