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The largest outbreak of monkeypox in history began in May, 2022, and has rapidly spread across the globe ever since. The purpose of this Review is to briefly describe human immune responses to orthopoxviruses; provide an overview of the vaccines available to combat this outbreak; and discuss the various clinical data and animal studies evaluating protective immunity to monkeypox elicited by vaccinia virus-based smallpox vaccines, address ongoing concerns regarding the outbreak, and provide suggestions for the appropriate use of vaccines as an outbreak control measure. Data showing clinical effectiveness (~85%) of smallpox vaccines against monkeypox come from surveillance studies conducted in central Africa in the 1980s and later during outbreaks in the same area. These data are supported by a large number of animal studies (primarily in non-human primates) with live virus challenge by various inoculation routes. These studies uniformly showed a high degree of protection and immunity against monkeypox virus following vaccination with various smallpox vaccines. Smallpox vaccines represent an effective countermeasure that can be used to control monkeypox outbreaks. However, smallpox vaccines do cause side-effects and the replication-competent, second-generation vaccines have contraindications. Third-generation vaccines, although safer for use in immunocompromised populations, require two doses, which is an impediment to rapid outbreak response. Lessons learned from the COVID-19 pandemic should be used to inform our collective response to this monkeypox outbreak and to future outbreaks.

Human monkeypox (MPX) cases are escalating worldwide. Smallpox vaccination, which was compulsory in Austria until 1981, was reported to confer 85% cross-protection against MPX.To assess the impact of smallpox vaccine-induced protection, the age-dependent vaccine-induced immunity against human MPX and the probability of infection according to age in the general population of Vienna, Austria, were determined using a modified susceptible-infected-removed model.Within the population born before 1981, the average vaccine-induced protective effect was calculated at 50.4%, whereas in the population born thereafter, protection was lacking. The overall probability of infection after exposure to an infected patient was calculated at 73.8%, which exceeds the threshold value of 46.9% for an index patient to infect at least one other person (R ≥1.0).Our model shows that if no additional interventions are taken, the collective immunization status of the population alone will not suffice to contain human MPX. Although the majority of cases have occurred in a subpopulation, given the steadily increasing incidence, dissemination into the general population remains possible, as observed before with HIV. Our model emphasizes the need for adequate containment measures and may aid in specific risk assessment because it can easily be adapted to other populations and cohorts worldwide.

Monkeypox virus (MPXV), genetic closely linked to the notorious variola (smallpox) virus, currently causes several clusters and outbreaks in the areas outside Africa and is noted to be phylogenetically related to the West African clade. To prepare for the upsurge of the cases of monkeypox in the Europe and North America, two vaccines, Jynneos® in the U.S. (Imvamune® in Canada or Imvanex® in the Europe) and ACAM2000® (Acambis, Inc.) initially developed in the smallpox eradication program, can provide protective immunity to monkeypox, and their production and availability are rapidly scaled up in the response to the emerging threat. So far, these two vaccines are recommended for people at a high risk for monkeypox, instead of universal vaccination. Tecovirimat, an inhibitor of extracellular virus formation, and brincidofovir, a lipid conjugate of cidofovir, both are in vitro and in vivo active against MPXV, and are suggested for immunocompromised persons, who are at risk to develop severe diseases. However, current general consensus in the response to the monkeypox outbreak among public health systems is early identification and isolation of infected patients to prevent its spread.

Since the eradication of smallpox in 1980, monkeypox has been the most prevalent zoonosis caused by orthopoxviruses. The virus has been largely endemic to the rainforests of Central and West Africa with occasional exportation to other countries. The disease typically runs a self-limited course with case fatality rates ranging from 4 to 11%. Currently, the world is faced with a multi-country outbreak of monkeypox, whose extent and impact remains to be seen.The objective of this article is to discuss the changing epidemiology of the monkeypox virus, with special reference to the current outbreak.Since the beginning of this outbreak which started on May 7th, till 14th of June 2022, a total of 1879 cases of monkeypox have been reported worldwide, spanning across 35 non-endemic, and commonly involving men who have sex with men. The magnitude of this unprecedented outbreak has highlighted the lacunae in our understanding of the viral epidemiology and ecology. What was earlier a rare sporadic zoonotic disease is now an emergent pathogen with documented human-to-human transmission potential, both in household as well as nosocomial settings. Waning immunity due to cessation of smallpox vaccination, wide host range of the virus, undetected circulation in wildlife in pan-geographic areas, emergence of better adapted strains of the virus due to unchecked replication in the HIV positive immunocompromised population along with deforestation and human encroachment of reservoir areas are some of the plausible reasons for an increased incidence of the disease. Unflinching government commitment, healthcare worker training, education of the masses, stockpiling of the available vaccine and drug, intersectoral co-ordination in lines of the One Health approach are simultaneously needed to avert the current spread of monkeypox. There is also a compelling need to strengthen surveillance systems to curb future outbreaks.

Monkeypox is caused by a pox virus closely related to smallpox virus and spreads from animals to humans, and humans to humans following close contact. Prior smallpox vaccination gives partial protection against monkeypox. The steady increase in monkeypox cases in Africa over the past few decades were ignored by the global scientific community till this year, when more than 16,000 cases have been reported from nonendemic countries. Monkeypox has recently been labelled as a public health emergency of international concern by the WHO. While most of the current cases are in men who have sex with men, there is the larger threat of the disease spilling into the general population. The disease is characterized by a short febrile illness with lymphadenopathy followed by a rash which spreads centrifugally and passes through phases of macules, papules, vesicles, and pustules. Recovery occurs in most patients within 2-4 wk. Complications are more likely in children, pregnant women, and the immunocompromised. Specific diagnosis is by detection of viral DNA by PCR. Treatment is largely symptomatic. Tecorivimat is a promising antiviral drug. Vaccination with the currently available smallpox vaccines is recommended for high-risk groups, health care workers, and close contacts. Control of the monkeypox outbreak needs a multipronged effort comprising enhanced surveillance, quick diagnosis, isolation of affected people, ring immunization, and adoption of "one health" approach.

Monkeypox virus (MPXV) is closely related to the infamous variola (smallpox) virus, causing a febrile rash illness in humans similar to but milder than smallpox. In the twentieth century, human monkeypox had been mostly a rare zoonotic disease confined to forested areas in West and Central Africa. However, the case number and geographic range have increased significantly in this century, coincided with the waning of the smallpox vaccine-induced immunity in the global population. The outbreak of human monkeypox in multiple countries since May 2022 has been unusual in its large case number and the absence of direct links to endemic countries, raising concerns for a possible change in monkeypox transmission pattern that could pose a greater global threat. Here, we review aspects of MPXV biology that are relevant for risk assessment and preparedness for a monkeypox epidemic, with an emphasis on recent progress in understanding of the virus host range, evolutionary potential, and neutralization targets.

The development of new zoonotic diseases such as coronavirus disease 2019 (COVID-19) and monkeypox that can cause epidemics and high mortality rates have significantly threatened global health security. However, the increasing number of people with no immunity to poxvirus because of the end of the smallpox vaccination programme has created a vulnerable population for the monkeypox outbreak. On 23 July 2022, it was announced that the World Health Organization’s director-general has determined that the multicountry outbreak of monkeypox constitutes a Public Health Emergency of International Concern. The monkeypox virus is an orthopoxvirus that causes a disease with symptoms similar to smallpox but less severe. Many unanswered questions remain regarding monkeypox’s pathogenesis, transmission and host reservoir. There is currently no evidence that transmission by individuals can sustain zoonotic infections during human-to-human transmissions; the continued emergence of these pathogens highlights the interconnectedness of animals and humans. The increasing number of monkeypox cases outside the endemic region has highlighted the need for effective global capacity building to prevent the spread of the disease and its impact on global health security. The priority now is to stop the spread of the disease and protect frontline healthcare workers and the most vulnerable individuals. This article aims to comprehensively analyse the various aspects of the transmission and epidemiology of monkeypox. It also explores possible diagnostic techniques, therapeutics and prevention strategies. A key recommendation is that primary care and public health professionals are expected to increase their efforts to be vigilant and contain any potential outbreaks.&nbsp

We report a case of monkeypox in the United States in a patient who had been vaccinated with ACAM2000 smallpox vaccine 8 years earlier. Despite his vaccination status, he still contracted disease. He showed prodromal symptoms preceding development of painless penile lesions that later coalesced.

Certain laboratorians and health care personnel can be exposed to orthopoxviruses through occupational activities. Because orthopoxvirus infections resulting from occupational exposures can be serious, the Advisory Committee on Immunization Practices (ACIP) has continued to recommend preexposure vaccination for these persons since 1980 (1), when smallpox was eradicated (2). In 2015, ACIP made recommendations for the use of ACAM2000, the only orthopoxvirus vaccine available in the United States at that time (3). During 2020-2021, ACIP considered evidence for use of JYNNEOS, a replication-deficient Vaccinia virus vaccine, as an alternative to ACAM2000. In November 2021, ACIP unanimously voted in favor of JYNNEOS as an alternative to ACAM2000 for primary vaccination and booster doses. With these recommendations for use of JYNNEOS, two vaccines (ACAM2000 and JYNNEOS) are now available and recommended for preexposure prophylaxis against orthopoxvirus infection among persons at risk for such exposures.

Indigenous and aboriginal peoples of the Americas and Pacific died at enormous rates soon after joining the global pathogen pool in the seventeenth to nineteenth centuries from respiratory infections such as smallpox, measles, and influenza. It was widely assumed that this represented a selection process against primitive societies. Darwinian selection for specific genetic resistance factors seems an unlikely hypothesis given that some populations stabilized quickly over two to three generations. European-origin populations whose childhood was marked by epidemiological isolation also suffered high infectious disease mortality from respiratory pathogens. American soldiers with smallpox, South African (Boer) children with measles, and New Zealand soldiers with influenza suggest that epidemiological isolation resulting in few previous respiratory infections during childhood may be a consistent mortality risk factor. Modern studies of innate immunity following Bacillus Calmette–Guérin (BCG) in infancy point toward rapid immune adaptation rather than evolutionary selection as an explanation for excessive first contact epidemic mortality from respiratory pathogens.

Zoonotic orthopoxvirus outbreaks have occurred repeatedly worldwide, including monkeypox in Africa and the United States, cowpox in Europe, camelpox in the Middle East and India, buffalopox in India, vaccinia in South America, and novel emerging orthopoxvirus infections in the United States, Europe, Asia, and South America. Waning smallpox immunity may increase the potential for animal-to-human transmission followed by further community transmission person-to-person (as demonstrated by monkeypox and buffalopox outbreaks) and by contact with fomites (as demonstrated by camelpox, cowpox, and, possibly, Alaskapox). The objectives of this review are to describe the disease ecology, epidemiology, clinical manifestations, prevention, and control of human infections with animal orthopoxviruses and to discuss the association with diminished population herd immunity formerly induced by vaccinia vaccination against smallpox. Internet search engines were queried with key words, and case reports, case series, seroprevalence studies, and epidemiologic investigations were found for review.

Cowpox virus (CPXV) has an animal reservoir and is typically transmitted to humans by contact with infected animals. In 2017, CPXV infection of a pregnant woman in France led to the death of her fetus. Fetal death after maternal orthopoxvirus (smallpox) vaccination has been reported; however, this patient had not been vaccinated. Investigation of the patient’s domestic animals failed to demonstrate prevalence of CPXV infection among them. The patient’s diagnosis was confirmed by identifying CPXV DNA in all fetal and maternal biopsy samples and infectious CPXV in biopsy but not plasma samples. This case of fetal death highlights the risk for complications of orthopoxvirus infection during pregnancy. Among orthopoxviruses, fetal infection has been reported for variola virus and vaccinia virus; our findings suggest that CPXV poses the same threats for infection complications as vaccinia virus.

When people think about hazards, the types that easily come to their mind include natural hazards, such as earthquakes, tornados, and tsunamis, and manmade ones, such as plane crashes, bomb explosions, and exposure to toxic industrial chemicals. Disease outbreaks are a source of hazards that are often overlooked, and the largely forgotten smallpox was an example of such disease. This article provides a review of the emergency management practices that curtailed the potentially devastating spread of smallpox at Meschede, Germany in 1970. Lessons that can be transferred to the COVID-19 pandemic are also discussed.

In August 2020, Africa was declared free of poliomyelitis (polio), bringing to fruition a goal that took more than 30 years to achieve. This Perspective chronicles global, continental, national and community actions taken by diverse stakeholders that finally led to the elimination of transmission of wild poliovirus in Africa. The cascade of events started with the development of polio vaccines and the realization that polio, much like smallpox, could be eradicated. After a 1988 pledge by the World Health Assembly to eradicate polio globally, concerted and deliberate efforts were made in Africa to achieve this goal. This included the use of evidence-based approaches for the harmonization and standardization of public health strategies, using a network of polio laboratories and emergency operation centres and actively pursuing underserved populations. Innovative solutions to counter challenges such as conflict and vaccine hesitancy may be of use in future public health interventions., This Perspective chronicles the journey to the elimination of transmission of wild poliovirus in Africa, with a critical discussion of the global, continental, national and community actions that were required and the lessons learnt along the way.

Mining has had a great influence on human societies permeating the riches of the soil and culture in equal proportion. This has led to profound changes in the individuals dedicated to this work and the locations where it takes place. In this historical review, we describe the socio-cultural and health characteristics, as well as the diseases associated with gold mining in Marmato (Caldas) during the 19th century. Poor salubrity conditions and tropical and infectious diseases were constant during the whole century.La minería ha tenido una gran influencia en las sociedades humanas, permeando por igual las riquezas del suelo y la cultura, lo que ha tenido profundas implicaciones para los individuos dedicados a esta labor y para los lugares en los que se lleva a cabo. En el presente artículo, se describen las características socioculturales y de sanidad, así como las enfermedades más frecuentes en las minas de oro de Marmato (Caldas) durante el siglo XIX. Las precarias condiciones de salubridad y las enfermedades tropicales infecciosas persistieron en la población durante todo el siglo.

Funder: Universitätsklinikum Schleswig-Holstein - Campus Kiel (6509), BACKGROUND: The pathogen landscape in the Early European Middle Ages remains largely unexplored. Here, we perform a systematic pathogen screening of the rural community Lauchheim "Mittelhofen," in present-day Germany, dated to the Merovingian period, between fifth and eighth century CE. Skeletal remains of individuals were subjected to an ancient DNA metagenomic analysis. Genomes of the detected pathogens were reconstructed and analyzed phylogenetically. RESULTS: Over 30% of the individuals exhibit molecular signs of infection with hepatitis B virus (HBV), parvovirus B19, variola virus (VARV), and Mycobacterium leprae. Seven double and one triple infection were detected. We reconstructed four HBV genomes and one genome each of B19, VARV, and M. leprae. All HBV genomes are of genotype D4 which is rare in Europe today. The VARV strain exhibits a unique pattern of gene loss indicating that viruses with different gene compositions were circulating in the Early Middle Ages. The M. leprae strain clustered in branch 3 together with the oldest to-date genome from the UK. CONCLUSIONS: The high burden of infectious disease, together with osteological markers of physiological stress, reflect a poor health status of the community. This could have been an indirect result of the climate decline in Europe at the time, caused by the Late Antique Little Ice Age (LALIA). Our findings suggest that LALIA may have created an ecological context in which persistent outbreaks set the stage for major epidemics of severe diseases such as leprosy and smallpox hundreds of years later.

The genus Orthopoxvirus contains several human pathogens, including vaccinia, monkeypox, cowpox, and variola virus, the causative agent of smallpox. Although there are a few effective vaccines, widespread prophylactic vaccination has ceased and is unlikely to resume, making therapeutics increasingly important to treat poxvirus disease. Here, we described efforts to improve the potency of the anti-poxvirus small molecule CMLDBU6128. This class of small molecules, referred to as pyridopyrimidinones (PDPMs), showed a wide range of biological activities. Through the synthesis and testing of several exploratory chemical libraries based on this molecule, we identified several compounds that had increased potency from the micromolar into the nanomolar range. Two compounds, designated (12) and (16), showed inhibitory concentrations of 326 nM and 101 nM, respectively, which was more than a 10-fold increase in potency to CMLDBU6128 with an inhibitory concentration of around 6 μM. We also expanded our investigation of the breadth of action of these molecules and showed that they can inhibit the replication of variola virus, a related orthopoxvirus. Together, these findings highlighted the promise of this new class of antipoxviral agents as broad-spectrum small molecules with significant potential to be developed as antiviral therapy. This would add a small molecule option for therapy of spreading diseases, including monkeypox and cowpox viruses, that would also be expected to have efficacy against smallpox.

The current outbreak of monkeypox (MPX) infection has emerged as a global matter of concern in the last few months. MPX is a zoonosis caused by the MPX virus (MPXV), which is one of the Orthopoxvirus species. Thus, it is similar to smallpox caused by the variola virus, and smallpox vaccines and drugs have been shown to be protective against MPX. Although MPX is not a new disease and is rarely fatal, the current multi-country MPX outbreak is unusual because it is occurring in countries that are not endemic for MPXV. In this work, we reviewed the extensive literature available on MPXV to summarize the available data on the major biological, clinical and epidemiological aspects of the virus and the important scientific findings. This review may be helpful in raising awareness of MPXV transmission, symptoms and signs, prevention and protective measures. It may also be of interest as a basis for performance of studies to further understand MPXV, with the goal of combating the current outbreak and boosting healthcare services and hygiene practices. Trial registration:ClinicalTrials.gov identifier: NCT02977715.. Trial registration:ClinicalTrials.gov identifier: NCT03745131.. Trial registration:ClinicalTrials.gov identifier: NCT00728689.. Trial registration:ClinicalTrials.gov identifier: NCT02080767..

Smallpox was eradicated40 years ago but it is not a reason to forget forever about orthopoxviruses pathogenic to humans. Though in 1980 the decision of WHO to cease vaccination against smallpox had seemed logical, it led to the decrease of cross immunity against other infections caused by orthopoxviruses. As a result, in 2022 the multi-country monkeypox outbreak becomes a topic of great concern. In spite of existing FDA-approved drugs for the treatment of such diseases, the search for new small-molecule orthopoxvirus inhibitors continues. In the course of this search a series of novel 2-aryl-1-hydroxyimidazole derivatives containing ester or carboxamide moieties in position 5 of heterocycle has been synthesized and tested for activity against Vaccinia virus in Vero cell culture. Some of the compounds under consideration revealed a selectivity index higher than that of the reference drug Cidofovir. The highest selectivity index SI = 919 was exhibited by ethyl 1-hydroxy-4-methyl-2-[4-(trifluoromethyl)phenyl]-1H-imidazole-5-carboxylate 1f. The most active compound also demonstrated inhibitory activity against the cowpox virus (SI = 20) and the ectromelia virus (SI = 46).

OBJECTIVES To evaluate the rates of myopericarditis (primary objective) and rates of cardiovascular and neurological adverse events (secondary objectives) in temporal association with ACAM2000® smallpox vaccine. METHODS Observational cohort study conducted through monthly surveillance from 2009 to 2017 of electronic medical records of military service members (SM) for pre-specified cardiac and neurological International Classification of Diseases (ICD) codes reported in the 30 days following smallpox vaccination. ICD codes potentially predictive of myopericarditis and codes for encephalitis, Guillain-Barre syndrome, and sudden death were classified into Group 1. All other cardiovascular and neurological ICD codes were classified into Group 2. Medical records containing Group 1 codes were individually reviewed to confirm coding accuracy and to seek additional data in support of myopericarditis adjudication, which was performed by an independent clinical panel. Chart reviews were not performed for Group 2 codes, which were reported in aggregate only. RESULTS 897,227 SM who received ACAM2000 smallpox vaccine and 450,000 SM who received Dryvax smallpox vaccine were included in the surveillance population. The rate of adjudicated myopericarditis among ACAM2000 smallpox vaccine recipients was 20.06/100,000 and was significantly higher for males (21.8/100,000) than females (8.5/100,000) and for those

This history of vaccinology article outlines the work of William Money (1790-1843), who conducted a study related to smallpox disease, immunity, and vaccination. His hitherto unpublished study demonstrated that smallpox could be contracted more than once; notably, results from his studies showed that vaccination was not dangerous. He was also the author of a celebrated Vade Mecum in human anatomy. Here, we outline the work he conducted in England: from serving as the house surgeon at Northampton Infirmary to his post as a surgeon at the Royal Metropolitan Hospital in London.

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

For the American colonies, smallpox implied a process that dramatically destabilized their sociodemographic dynamics, which explains why scientific development took place around the causative virus. Each book about smallpox in Nariño’s library was a tool in the fight against smallpox undertaken by the founding father. After reviewing the article “About the bicentennial of the independence of Colombia: The reading practices of Antonio Nariño and the development of a vaccine that is presumably effective against smallpox” (1), I set myself to study Antonio Nariño’s medical knowledge further. Through the approach to the works that Nariño used to educate himself on smallpox and the development of a biographical sketch of each of them, I analyzed the process of variolization in the Kingdom of Nueva Granada and the need to manufacture a vaccine locally.La viruela significó para las colonias americanas un proceso que desestabilizaba de forma dramática las dinámicas sociodemográficas de las colonias, lo que incentivó el desarrollo de estudios científicos sobre el virus causante. Cada libro acerca de la viruela en la biblioteca de Nariño constituyó una herramienta en la lucha contra el virus emprendida por el prócer. Tras la revisión del artículo "A propósito del bicentenario de la independencia de Colombia: las prácticas de lectura de Antonio Nariño y el desarrollo de una vacuna presuntamente efectiva contra la viruela" (1) quise comentar y profundizar en torno al saber médico de Nariño mediante el acercamiento a las obras a las que recurrió para instruirse sobre la enfermedad. A partir de la semblanza de cada una de ellas, analicé el proceso de variolización en el Reino de la Nueva Granada y la necesidad de fabricar una vacuna propia.

We compared the COVID-19 experience in the first year of the current pandemic in the US with the smallpox experience of the 18th century, focusing on the US military but recognizing civilian and military populations are not separate and distinct. Despite the epidemics being separated by 21/2 centuries and with great advancements in technology having occurred over that time, we observed similarities which led us to several conclusions: • Infectious disease outbreaks will continue to occur and novel agents, naturally occurring or manipulated by humans, will threaten military and civilian populations nationally and globally. • Infectious disease outbreaks can affect both military and civilian populations, persist for long periods, and be catastrophic to military peacetime and wartime operations. • Effective surveillance is a prerequisite for early identification and subsequent meaningful responses to novel and reemerging threat agents and diseases. • Socio-cultural, religious, or political factors may limit the implementation of effective interventions in military or civilian populations. Public health officials must assess impediments to implementation of interventions and develop plans to overcome them.

The World Health Organization, has declared the recent multiregional outbreak of monkeypox, a global public health emergency. Monkeypox is a zoonotic viral infection endemic to the west and central Africa. It belongs to the Poxviridae family, the Chordopoxvirinae subfamily, and the Orthopoxvirus genus. The Poxviridae family generally consists of complex, large, enveloped, and linear double-stranded DNA viruses. The initial clinical symptoms of monkeypox are often fever, severe headache, lymphadenopathy, myalgia, and fatigue. The skin lesions typically erupt within 1–3 days of the onset of fever. The rash tends to be more localized on the face and extremities than on the trunk. Monkeypox is often a self-limiting infection, and symptoms last from 2 to 4 weeks. It is isolated from various species, but the exact natural host is uncertain. Monkeypox is transmitted by close contact with infected humans or animals. Currently, no specific medication is available for monkeypox, and the existing therapeutics are the anti-viral agents approved for smallpox infection, including tecovirimat, cidofovir, and brincidofovir. Additionally, the U.S. Food and Drug Administration has approved Vaccinia Immune Globulin Intravenous for treating vaccination complications. It is diagnosed by PCR. There are currently two vaccines licensed by the U.S. Food and Drug Administration. According to the WHO guidance, the first-generation smallpox vaccines held in national reserves of some countries are not recommended as they do not meet the current safety and manufacturing standards. The interim guidance indicates that new and safer (second- and third generation) vaccines for smallpox, may be beneficial for monkeypox prevention, including JYNNEOS, which has been approved for the prevention of monkeypox. Human monkeypox was first reported in 1970. Since then, it has caused several outbreaks, mainly in central and west Africa. The first monkeypox outbreak outside of Africa occurred in the United States in 2003, linked to contact with infected pet prairie dogs. More recently (2018-2021), monkeypox cases have been reported in travelers from Nigeria to the United Kingdom, Israel, Singapore, and the US. Since May 2022, multiple monkeypox cases have been confirmed in several non-endemic countries, raising the concern of an emerging global pandemic. This review is an updated overview of our current state of knowledge regarding monkeypox virology, pathophysiology, clinical characteristics, epidemiology, vaccines, diagnosis, and treatment options.

ImportanceOrthopox viruses include smallpox virus, a once feared but now eradicated virus, as well as monkeypox virus. Monkeypox is an emerging virus initially isolated in 1958, previously unrecognized outside sub-Saharan Africa until a worldwide outbreak in May 2022. It is important to review known neurologic consequences of both these viruses, as complications of smallpox may be relevant to monkeypox, though complications of monkeypox may be rarer and perhaps less severe.ObservationsThis was a literature review of the known neurologic complications of smallpox, which include encephalitis, transverse myelitis, and acute disseminated encephalomyelitis among others; historical complications of smallpox vaccination, including postvaccinal encephalomyelitis; and the known neurologic complications of monkeypox, which include headaches and mood disturbances, as well as rare presentations of encephalitis, transverse myelitis, and seizures. Of concern is the possibility of viral persistence and systemic complications in immunocompromised individuals. Also provided were considerations for diagnosis, current treatment, and prevention of monkeypox.Conclusions and RelevanceMonkeypox should be considered in high-risk populations who present with neurologic syndromes. Diagnosis may require serology and polymerase chain reaction testing of blood and spinal fluid. Antiviral therapy should be initiated early in the course of the illness.

Starting from mid-May 2022, cases of human monkeypox started to rise in several non-endemic countries. By mid-July, more than 17000 confirmed/suspect cases have been reported by at least 82 countries worldwide, with a regular incremental trend. In order to contain the disease diffusion, risk evaluation is crucial to undertake informed decisions and effective communication campaigns. However, since orthopoxvirus infections so far have attracted low attention, due to the eradication of smallpox 40 years ago, and to the confinement of human monkeypox almost exclusively to endemic areas, several unresolved issues concerning natural history, ecology and pathogenesis remain. To this respect, we identified some open questions and reviewed the relevant literature on monkeypoxvirus and/or related orthopoxviruses. The results will be discussed in the perspective of their relevance to public health decisions, particularly those related to non-pharmacological interventions.

Despite the eradication in 1980, developing safe and effective smallpox vaccines remains an active area of research due to the recent outbreaks and the public health concern that smallpox viruses could be used as bioterrorism weapons. Identifying immunogenic peptides (epitopes) would create a foundation for the development of a robust peptide-based vaccine. We previously identified a library of naturally-processed, human leukocyte antigen class I-presented vaccinia-derived peptides from infected B cells. In the current study, we evaluated the immunogenicity of these T-cell peptides in both transgenic mouse models and human peripheral blood mononuclear cells. A vaccine based on four selected peptides provided 100% protection against a lethal viral challenge. In addition, responses from memory T cells remained unchanged up to five months. Our results validate a practical approach for identifying and verifying immunogenic peptides for vaccine development and highlight the potential of peptide-based vaccines for various infectious diseases.

The 2022 global human monkeypox outbreak emphasizes the importance of maintaining poxvirus research, including enriching a basic understanding of animal models for developing and advancing therapeutics and vaccines. Intravenous administration of monkeypox virus in macaques is arguably one of the best animal models for evaluating the efficacy of medical countermeasures. Here we addressed one criticism of the model, a requirement for a high-titer administration of virus, as well as improving our understanding of monkeypox virus pathogenesis. To do so, we infected macaques with a challenge dose containing a characterized inoculum enriched for the extracellular form of monkeypox virus. Although there were some differences between diseases caused by the enriched preparation compared with a relatively similar unpurified preparation, we were unable to reduce the viral input with the enriched preparation and maintain severe disease. We found that inherent factors contained within the serum of nonhuman primate blood affect the stability of the monkeypox extracellular virions. As a first step to study a role of the extracellular form in transmission, we also showed the presence of this form in the oropharyngeal swabs from nonhuman primates exposed to monkeypox virus.

On June 21, 2022, Singapore reported its second ever case of imported monkeypox and first linked to the ongoing multi-country outbreak that has since been declared a public health emergency of international concern. There was quick initiation of public health measures including identification and quarantine of contacts, with post-exposure smallpox vaccination.

Background Since May 2022, a new outbreak of monkeypox has been reported in several countries, including Spain. The clinical and epidemiological characteristics of the cases in this outbreak may differ from those in earlier reports. Objectives To document the clinical and epidemiological characteristics of cases of monkeypox in the current outbreak. Methods We conducted a prospective cross-sectional study in multiple medical facilities in Spain to describe the cases of monkeypox in the 2022 outbreak. Results In total, 185 patients were included. Most cases started with primarily localized homogeneous papules, not pustules, in the probable area of inoculation, which could be cutaneous or mucous, including single lesions. Generalized small pustules appeared later in some of them. Heterogeneous lesions occurred during this generalized phase. All patients had systemic symptoms. Less common lesions included mucosal ulcers (including pharyngeal ulcers and proctitis) and monkeypox whitlows. Four patients were hospitalized, none died. Smallpox vaccination and well-controlled HIV disease were not associated with markers of severity. Contact during sex is the most likely mechanism of transmission. In this outbreak, cases have been described in men who have sex with men and are strongly associated with high-risk sexual behaviours. Seventy-six per cent of the patients had other sexually transmitted diseases upon screening. Conclusions The clinical findings in this outbreak differ from previous findings and highly suggest contact transmission and initiation at the entry site. The characterization of the epidemiology of this outbreak has implications for control. What is already known about this topic? Monkeypox eruption is described as consisting of pustules.The roles of HIV and previous smallpox vaccination in the prognosis are unknown.The transmission route was initially described as respiratory droplets and was later suggested to be via sexual contact. What does this study add? Initial lesions at the probable inoculation area were homogeneous and papular (pseudopustules). Generalized small pustules appeared later in some of them. Heterogeneous lesions occurred during this generalized phase. All patients had systemic symptoms.Less common signs included mucosal ulcers (including pharyngeal ulcers and proctitis) and monkeypox whitlows. Well-controlled HIV and previous smallpox vaccination were not associated with severity. No patient died.The data support the hypothesis of transmission via contact during sex. Although this might change, the outbreak is currently limited mostly to men who have sex with men, with high-risk factors for sexually transmitted diseases.

Monkeypox is a viral zoonosis, with symptoms similar to those seen in smallpox patients, although the clinical presentation may be less severe. Until recently, human monkeypox infection was rare, and primarily occurred in Central and West Africa.An international outbreak began in May 2022, and monkeypox has now been detected on every continent except Antarctica. The first recognized case from the current outbreak was confirmed in the United Kingdom on 6 May 2022, in an adult with travel links to Nigeria, but it has been suggested that cases had been spreading in Europe for months. On 23 July 2022 the Director-General of the World Health Organization declared the monkeypox outbreak a public health emergency of international concern.There are no treatments specifically for monkeypox virus infections. However, monkeypox and smallpox viruses are genetically similar, and therapeutics developed to combat smallpox may be used to treat monkeypox. This manuscripts reviews what is known about these potential treatments, including tecovirimat and brincidofovir, based on a literature search of PubMed through 9 August 2022, and explores how these therapeutics may be used in the future to address the expanding monkeypox pandemic.

An ongoing monkeypox outbreak in non-endemic countries has resulted in the declaration of a public health emergency of international concern by the World Health Organization (WHO). Though monkeypox has long been endemic in regions of sub-Saharan Africa, relatively little is known about its ecology, epidemiology, and transmission. Here, we consider the relevant research on both monkeypox and smallpox, a close relative, to make inferences about the current outbreak. Undetected circulation combined with atypical transmission and case presentation, including mild and asymptomatic disease, have facilitated the spread of monkeypox in non-endemic regions. A broader availability of diagnostics, enhanced surveillance, and targeted education, combined with a better understanding of the routes of transmission, are critical to identify at-risk populations and design science-based countermeasures to control the current outbreak.

Background In May, 2022, several European countries reported autochthonous cases of monkeypox, which rapidly spread globally. Early reports suggest atypical presentations. We aimed to investigate clinical and virological characteristics of cases of human monkeypox in Spain. Methods This multicentre, prospective, observational cohort study was done in three sexual health clinics in Madrid and Barcelona, Spain. We enrolled all consecutive patients with laboratory-confirmed monkeypox from May 11 to June 29, 2022. Participants were offered lesion, anal, and oropharynx swabs for PCR testing. Participant data were collected by means of interviews conducted by dermatologists or specialists in sexually transmitted infections and were recorded using a standard case report form. Outcomes assessed in all participants with a confirmed diagnosis were demographics, smallpox vaccination, HIV status, exposure to someone with monkeypox, travel, mass gathering attendance, risk factors for sexually transmitted infections, sexual behaviour, signs and symptoms on first presentation, virological results at multiple body sites, co-infection with other sexually transmitted pathogens, and clinical outcomes 14 days after the initial presentation. Clinical outcomes were followed up until July 13, 2022. Findings 181 patients had a confirmed monkeypox diagnosis and were enrolled in the study. 166 (92%) identified as gay men, bisexual men, or other men who have sex with men (MSM) and 15 (8%) identified as heterosexual men or heterosexual women. Median age was 37.0 years (IQR 31.0-42.0). 32 (18%) patients reported previous smallpox vaccination, 72 (40%) were HIV-positive, eight (11%) had a CD4 cell count less than 500 cells per mu L, and 31 (17%) were diagnosed with a concurrent sexually transmitted infection. Median incubation was 7.0 days (IQR 5.0-10.0). All participants presented with skin lesions; 141 (78%) participants had lesions in the anogenital region, and 78 (43%) in the oral and perioral region. 70 (39%) participants had complications requiring treatment: 45 (25%) had a proctitis, 19 (10%) had tonsillitis, 15 (8%) had penile oedema, six (3%) an abscess, and eight (4%) had an exanthem. Three (2%) patients required hospital admission. 178 (99%) of 180 swabs from skin lesions collected tested positive, as did 82 (70%) of 117 throat swabs. Viral load was higher in lesion swabs than in pharyngeal specimens (mean cycle threshold value 23 [SD 4] vs 32 [6], absolute difference 9 [95% CI 8-10]; p

Poxviruses (PXVs) are mostly known for the variola virus, being the cause of smallpox; however, re-emerging PXVs have also shown a great capacity to develop outbreaks of pox-like infections in humans. The situation is alarming; PXV outbreaks have been involving both endemic and non-endemic areas in recent decades. Stopped smallpox vaccination is a reason offered mainly for this changing epidemiology that implies the protective role of immunity in the pathology of PXV infections. The immune system recognizes PXVs and elicits responses, but PXVs can antagonize these responses. Here, we briefly review the immunology of PXV infections, with emphasis on the role of pattern-recognition receptors, macrophages, and natural killer cells in the early response to PXV infections and PXVs' strategies influencing these responses, as well as taking a glance at other immune cells, which discussion over them mainly occurs in association with PXV immunization rather than PXV infection. Throughout the review, numerous evasion mechanisms are highlighted, which might have implications for designing specific immunotherapies for PXV in the future.

Descriptions of monkeypox 2022 outbreak have been increasingly reported with unusual presentations and therefore a risk of misdiagnosis. Diagnosis is primarily based on risk factors, including men having sex with men and high-risk contact, with the presence of cutaneous lesions and/or rashes including the genitals in a context of fever.