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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.

Vaccinia virus has been used as a smallpox vaccine. Now that smallpox has been eradicated, the vaccinia virus is expected to be used as a bioterrorism countermeasure and a recombinant vaccine vector for other infectious diseases, such as viral hemorrhagic fevers. Many vaccinia virus strains were used as smallpox vaccines in the smallpox eradication campaign coordinated by the World Health Organization. These strains can be classified into generations, according to the history of improving production methods and efforts to reduce the adverse reactions. Significantly, the third-generation of smallpox vaccine strains, which include modified vaccinia Ankara (MVA) and LC16m8, are currently popular as recombinant vaccine vectors due to their well-balanced safety and immunogenicity profiles. The present review firstly focuses on the characteristics of the smallpox vaccine generations. The historical background of the development of the third-generation smallpox vaccine strains is detailed, along with the history of the transition of the vaccinia virus generation used as vectors for hemorrhagic fever vaccines to the third generation. Among the vaccinia viruses, MVA is currently the most commonly used vector for developing hemorrhagic fever vaccines, including dengue fever, yellow fever, Ebola viral disease, Lassa fever, Rift Valley fever, and Crimean-Congo hemorrhagic fever. LC16m8 is a vaccine candidate for severe fever with thrombocytopenia syndrome. The current status and recent advances in the development of these hemorrhagic fever vaccines using third-generation vaccinia strains are discussed.

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.

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.

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.

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

Infectious pandemics result in hundreds and millions of deaths, notable examples of the Spanish Flu, the Black Death and smallpox. The current pandemic, caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), is unprecedented even in the historical term of pandemics. The unprecedentedness is featured by multiple surges, rapid identification of therapeutic options and accelerated development of vaccines. Remdesivir, originally developed for Ebola viral disease, is the first treatment of COVID-19 (Coronavirus disease 2019) approved by the United States Food and Drug Administration. As demonstrated by in vitro and preclinical studies, this therapeutic agent is highly potent with a broad spectrum activity against viruses from as many as seven families even cross species. However, randomized controlled trials have failed to confirm the efficacy and safety. Remdesivir improves some clinical signs but not critical parameters such as mortality. This antiviral agent is an ester/phosphorylation prodrug and excessive hydrolysis which increases cellular toxicity. Remdesivir is given intravenously, leading to concentration spikes and likely increasing the potential of hydrolysis-based toxicity. This review has proposed a conceptual framework for improving its efficacy and minimizing toxicity not only for the COVID-19 pandemic but also for future ones caused by remdesivir-sensitive viruses.

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.

Background: The entire planet is now under significant threat of a terrible CoVid-19 epidemic Because of small clandestine organisms known as viruses. Only 1% of the population has been discovered, leaving the other 95% unexplored. The most difficult aspect of dealing with these minuscule organisms is their unpredictability, as viruses mutate quickly. Poliomyelitis, smallpox, measles, meningitis, and a few other deadly viral and bacterial diseases were successfully eradicated as a result of the immunisation push. The goal of this review article is to look at both the positive and negative aspects of vaccines. In order to improve the production, examine the quality of WHO vaccine recommendations in clinical practise guidelines (CPGs). Methods: A systematic review of available microbial agent vaccines and pipelines (WHO, 2020) as well as the National Centre for Complementary and Integrative Health's websites was conducted. The US Department of Health and Human Services' Assessment of Guidance, Study, and Evaluation was compared to the Eligible WHO and FDA guidelines providing treatment and/or management recommendations. Approval stage for vaccination products. Food and Drug Administration, United States of America. Understanding vaccine research: How are AIDS vaccines tested? IAVI Article, first volume, 2003. WHO,1998 Recommendations for the quality control of 26 DNA vaccine volumes [17] Vaccines, 3rd Edition, Shock 12th Edition, and “History of Vaccination” in 111 volumes of proceedings are also recommended. Vaccines against almost 27 microbes are approved and ongoing research on vaccines against almost 130 microbial agents is ongoing (WHO, 2020; FDA, 2017). The decision to move to ART (Anti-Retroviral Treatment) regimens is based on the recommendations for clinical, immunological, and virological failure. Assay style output using DBS as opposed to plasma using a 1000 copies / mL viral load threshold [30]. Conclusion: The high-scoring suggestions could be used as a foundation for future vaccine use in the context of various microbial illnesses in vaccine development. In addition to the graphical representation of the vaccine plan, various tools for designing guidance are being used to get insight. Key words: Vaccines, WHO Guidelines, Development stages, Challenges, COVID Vaccines

Vaccination has played a crucial role in the improvement of global health. Some of the world's deadliest diseases, like smallpox and rinderpest, have been eradicated with the help of vaccines, and many others have been restrained. The appearance of the strain of coronavirus disease 2019 (COVID-19) severe acute respiratory syndrome coronavirus 2 and its impact on global health have made the development of effective and safe vaccines crucial for this new lethal disease. So far, there are three main types of COVID-19 vaccines in use around the world: messenger RNA-based vaccines, adenoviral vector vaccines, and inactivated whole-virus vaccines. Some of them have passed through phase 3 of safety and efficacy trials and are widely used for prophylaxis of COVID-19 infection. A plethora of cutaneous adverse events have been reported, most of them mild or moderate injection-site reactions. Some rare delayed inflammatory reactions such as "COVID arm" have also been reported, posing questions on their pathophysiology and clinical importance. Some rare serious adverse events, such as vaccine-induced prothrombotic immune thrombocytopenia and anaphylaxis, have been described raising great concerns on the safety of some widely spread vaccines. More data need to be collected with further and more detailed analysis. The overall risk of such severe adverse reactions remains extremely low, and the benefits of the existing vaccines in combating the widespread threat of COVID-19 continue to outweigh the risk of their side effects.

Major pandemics have tremendous effects on society. They precipitated the early decline of the Western Roman Empire and helped spread Christianity. There are countless such examples of infectious diseases altering the course of history. The impact of epidemics on education however is less well documented. This present historical account of the past 800 years looks specifically at how some aspects of education were shaped from the early medieval epidemics such as leprosy and the Black Plague to the Spanish Flu and COVID-19. Leprosy changed religious education, and the Black Plague may have contributed to the rise of medical schools, hospitals, public health education, and led to the implementation of lazarettos and the quarantine. The smallpox epidemic helped usher in public health education for immunization, while the 1918 Spanish Flu precipitated the rise of education by correspondence, and recently COVID-19 has catapulted remote digital learning to the forefront of higher education.

Introduction. Vaccination is now entering the third century of its practice and it is the most important medical intervention that has ever been implemented. Due to vaccines, the incidence of infectious diseases, which have killed hundreds of millions throughout the history has been dramatically reduced and made a substantial contribution to life expectancy. Recently, new technologies have emerged in the development of vaccines that are being implemented in the control of the COVID-19 pandemic. The successful immunoprophylaxis and the better understanding of the immune response mechanisms suggest that vaccination would also help in curing cancer and chronic diseases in the nearest future. Material and methods. There were analyzed 43 scientific articles on both vaccination and its future potential. Results. On 8 May 1980, the World Health Organization certified that smallpox had been eradicated globally. For the first time in history, the humankind defeated a disease. It was certainly the greatest medical achievement of the twentieth century. Recently, however, new technologies have emerged in the development of vaccines, based on mRNA, viral vectors and other technologies. Conclusions. Vaccines are the most important medical achievement ever made with a great impact in eradicating and controlling emerging and re-emerging infectious diseases.

Introduction. The article examines the understudied issues of how and to what extent epidemic diseases used to spread across Kalmyk uluses (‘districts’) in the late 19th – early 20th centuries, with special attention be paid to employed control and monitoring methods. The problem was covered in a number of published reports delivered at the First Congress of Astrakhan physicians to have worked in Kalmyk-inhabited lands during the period under study, and the former contain their shared their experiences and valuable findings. Historians hardly ever approached the topic in just a few papers. Goals. So, the work aims at a detailed survey of epidemic diseases in the Kalmyk Steppe of Astrakhan Governorate in the late 19th – early 20th centuries. Materials and Methods. The study employs a set of general scientific and specific historical research methods. The observance of the historicism principle made it possible to avoid modern misinterpretations of the century-old events examined, while system-analysis techniques and interdisciplinary approaches resulted in that certain specific events of Kalmyk life were analyzed as parts of an overall picture. The article mainly explores and newly introduces materials of the Medical Department — a healthcare agency within the Kalmyk People’s Administration — currently stored at the National Archive of Kalmykia. Results. Despite the remoteness of Kalmyk nomadic settlements (Kalm. khoton) from administrative centers and first-aid stations, healthcare practitioners still were efficient enough to promptly respond in case of epidemic outbreaks. Besides treatment proper, the medical, administrative and police personnel were largely responsible for quarantine and disinfection activities, medical examination and supervision of people living around the periphery of the effective disease area. Conclusions. The analysis of materials dealing with the issue reveals Kalmyk districts were widely affected by epidemic diseases, such as typhus, smallpox, measles, diphtheria and others, while cholera and plague were not that often. It should be admitted that the frequent occurrence of those diseases in medical records across the Kalmyk Steppe was determined by their endemicity to have resulted from a number of reasons.

The Chilean Abbe Ignacio Molina (1740-1829) developed a brilliant career as naturalist in the University of Bologna, where he arrived when the Jesuit Order was expelled from the Spanish colonies in 1767, until he was accused of heresy because some ideas about evolution expressed in one of his late works, at the same time with Lamarck and 44 years before Darwin. In his youth Molina was affected in a severe way by smallpox, leaving us in two poems a vivid story of his suffering, not only by the disease itself but also for the useless therapeutic measures, some disagreeable, like enemas; other injurious, as bleeding and topic vinegar of the four thieves. A handful of the more significant verses from the two Latin Elegies "De peste variolarum" and "De peste variolis vulgo dicta" is analyzed: its literary value is scarce, its reading is bored, and its real merit only historic.

COVID-19 is not the world's first pandemic, not its worst, or likely to be its last. In fact, there have been many pandemics throughout history with lessons for the current one. The most destructive pandemic of all time, at least in terms of the number of people killed in the shortest time, was the “Spanish flu“ pandemic of 1918/1919. Why did it happen? What lessons did it teach us? And could it happen again? These questions are addressed in the context of the current COVID-19 pandemic and several other nearly equally devastating pandemics of earlier times

Before the 20(th) century many deaths in England, and most likely a majority, were caused by infectious diseases. The focus here is on the biggest killers, plague, typhus, smallpox, tuberculosis, cholera, typhoid, dysentery, childhood infections, pneumonia, and influenza. Many other infectious diseases including puerperal fever, relapsing fever, malaria, syphilis, meningitis, tetanus and gangrene caused thousands of deaths. This review of preventive measures, public health interventions and changes in behavior that reduced the risk of severe infections puts the response to recent epidemic challenges in historical perspective. Two new respiratory viruses have recently caused pandemics: an H1N1 influenza virus genetically related to pig viruses, and a bat-derived coronavirus causing COVID-19. Studies of infectious diseases emerging in human populations in recent decades indicate that the majority were zoonotic, and many of the causal pathogens had a wildlife origin. As hunter-gatherers, humans contracted pathogens from other species, and then from domesticated animals and rodents when they began to live in settled communities based on agriculture. In the modern world of large inter-connected urban populations and rapid transport, the risk of global transmission of new infectious diseases is high. Past and recent experience indicates that surveillance, prevention and control of infectious diseases are critical for global health. Effective interventions are required to control activities that risk dangerous pathogens transferring to humans from wild animals and those reared for food.

General vaccination of population with vaccinia virus leaded to the eradication of smallpox, then it was finished because of the danger of adverse events. The recurrence of research interest in smallpox vaccine is due to the research of using the virus as a weapon of bioterrorism and the increased frequency of orthopoxvirus infections whereas the population immunity decline. The vaccinia virus is also used as a vector for creating recombinant vaccines. Understanding the pathway and predicting the immune response it will be able to avoid possible adverse events and excessive immunization. The aim of the study was to assess the correlations between humoral immunity, clinical signs during a vaccination period, sex and age characteristics of adults who had received several doses of vaccinia virus. We studied a vaccination clinical data of 135 subjects revaccinated with a smallpox vaccine from twice to 10 times. A total of 95% and 5% vaccine recipients experienced mild or moderate vaccination period, respectively. Inoculation skin lesions was noted at 127 subjects (94.1%). Among them more than 22% vaccine recipients experienced local or systemic adverse events. Compared to mild group moderate group had larger hyperemia (p = 0.04), scab (p = 0.01), healing time (p = 0.001). The age subjects with a moderate vaccination period is less than mild (p = 0.03), the chance of lymphadenopathy development is higher within moderate vaccination period (p 0.001). Vaccinia neutralizing antibody titers were determined for 54 subjects using plaque reduction neutralization tests. There was a noted tendency of higher protective antibody values at women compared with men. Negative correlation between the antibody titers and the hyperemia size was revealed. Frequently axillary adenopathy is assotiated with higher protective antibody values. Vaccinia neutralizing antibody titers value are not associated with the presence and size of the lesion, the scab falling time, age and the number of previous vaccinations. The clinical variability and the immune response using the same vaccine and the same pattern vaccination would be explained by individual genetic differences that should be further explored.

A lo largo de la historia diferentes pandemias han asolado a la humanidad. De todas ellas, salvo de la Covid-19, pues aún no ha habido tiempo de llevarla a la gran pantalla, ha habido numerosas representaciones en el cine comercial, algunas muy relevantes desde el punto de vista de la calidad cinematográfica y de la calidad científica con la que están documentados los guiones. Sería inalcanzable enumerar todas y cada una de ellas. Por tanto, en este artículo se plantea ofrecer a los lectores un ejemplo de cada una de estas pandemias (Peste, Viruela, Cólera, Gripe y VIH) que pueden ser útiles para la docencia y para la educación sanitaria de la población.

The bioterrorism is threatened / premeditated utilization of biological agents/ weapons including viruses, bacteria, toxins and various other microorganisms to reason deaths and/or illness in plants, animals, humans etc. As majority of the agents/products used as biological agents are zoonotics, there is major concern about the possibility to use animals as the source. Livestock owners and veterinarians may be the first among those who identify initial cases of act of bioterrorism. Biological agents can be categorized into three classes. Biological agents of category (A) can cause easy transmission from animal to human except smallpox; as it has no reservoir of animal, human to human, cause increased mortality and can cause major health impact globally. Agents in category (B) cause moderate transmission; causing moderate morbidity and low mortality. Agents in category (C) belong to characteristics which can be engineered for spreading them globally or into massive community. We lack the adequate capability for prevention of these biological attacks, but prevention measures should be taken for decreasing the risks. For restriction of access of dangerous biological weapons to population, increased laboratory testing or scrutiny for causative agents, high control for investigations and proper measurement of prevention are necessary. Along with human measures and testing, veterinary laboratories should be included in surveillance on national level.

The reemergence of smallpox as a bioterrorism attack is now an increasing and legitimate concern. Advances in synthetic biology have now made it possible for the virus to be synthesized in a laboratory, with methods publicly available. Smallpox introduction into a susceptible population, with increased immunosuppression and an aging population, raises questions of how vaccination should be used in an epidemic situation when supply may be limited. We constructed three modified susceptible-latent-infectious-recovered (SEIR) models to simulate targeted, ring and mass vaccination in response to a smallpox outbreak in Sydney, Australia. We used age-specific distributions of susceptibility, infectivity, contact rates, and tested outputs under different assumptions. The number of doses needed of second- and third-generation vaccines are estimated, along with the total number of deaths at the end of the epidemic. We found a faster response is the key and ring vaccination of traced contacts is the most effective strategy and requires a smaller number of doses. However if public health authorities are unable to trace a high proportion of contacts, mass vaccination with at least 125,000 doses delivered per day is required. This study informs a better preparedness and response planning for vaccination in a case of a smallpox outbreak in a setting such as Sydney.

Background: Monkeypox (MPX) is a viral zoonoses characterized by pustular rashes similar to smallpox. It is endemic in the Democratic Republic of Congo and West Africa. The outbreak of MPX was first reported outside Africa in 2003 following horizontal infection of Prairie dogs by imported African rodents. Two distinct clades are known, the Central (more severe) and the West African clade (Mild). In Nigeria, the first confirmed case of MPX was in a 4-year old child in 1971. This was followed by a lull of 39 years. Since September 2017, sporadic outbreaks have been reported in 17 states across Nigeria. As at week 36 of 2019, Akwa Ibom reported ten suspected cases with one lab-confirmed. Methods: We revised MPX case definition and constituted a team comprising of State DSNO, Laboratory and RRT from NCDC. We identified retrospective cases from the state line list, their contacts traced and samples collected. We carried out a case-control study on the 3 cases in Mkpat Enin LGA. Twenty-one (21) pre-tested (KAP) questionnaire was administered to health care workers (HCW) and community members to access knowledge awareness and risk perception of MPX. HCWs were trained, and community sensitization carried out. We accessed the capacity of IDH Uyo to manage MPX cases and conducted a case-control study to determine the odds of association of MPX with individuals in contact with confirmed MPX cases at Mkpat Enin LGA. Results: Eight new cases identified during active case search were negative of MPX. The level of awareness of MPX amongst HCW was high (n=20); pre-test score 16.5(85%) and 18 (90%) posttest. Knowledge of clinical presentation of MPX amongst HCW was also high 17(85%). There was a high-risk perception of MPX 18(90%), assessment of best practice 16 (76%) and proper sample collection 15 (75%). CM awareness of MPX (n=20) was at 12(62%), health-seeking behaviour at 2(11%) and the consumption of giant rats and monkeys at 12(86%). There was a weak association of transmission of infection by MPX cases to individuals in contact with them {(OR=0.333, (0.0673, 1.6516), Fisher exact 0.1756}. We identified a general apathy by HCW (Nurses) at the IDH Uyo to accept and manage MPX cases. Conclusion: The high HCW and community awareness negates the poor health-seeking behaviour of members of Ekpat Enin community due to paucity of funds to access health care or rejection by HF within the area. Monkeys and giant rats are delicacies high within the community hence a risk factor in MPX zoonoses. Consequently, individuals who consume such delicacies or come into contact with confirmed cases are at times likely to contact MPX.

Objectives To compare rates of myopericarditis, severe and serious dermatological or neurological events, and other adverse events in deploying US military personnel who received or did not receive ACAM2000® (Smallpox [Vaccinia] Vaccine, Live) vaccine and to evaluate potential risk factors for development of myopericarditis. Methods Prospective observational cohort study enrolling up to 15,000 ACAM2000 recipients (Cohort 1) and up to 5000 persons otherwise eligible for ACAM2000 vaccination but not vaccinated due to recency of vaccination or characteristics of their contacts (Cohort 2). Data and specimens were collected initially and 10 (6–17) days later. Those with clinical or laboratory evidence of possible myopericarditis were referred for further evaluation and adjudication by a blinded independent review committee. The adjusted odds ratio for myopericarditis was determined by a logistic regression model controlling for age, race, gender, and exercise regimen. Results 14,667 subjects provided initial data and specimens (Cohort 1, 10,825; Cohort 2, 3842); 12,110 (Cohort 1, 8945; Cohort 2, 3165) completed Visit 2 per-protocol. A total of 125 (Cohort 1, 111; Cohort 2, 14) were referred for myopericarditis adjudication, yielding 54 (Cohort 1, 44, Cohort 2, 10) subclinical myopericarditis, 5 suspected myocarditis, 1 confirmed myocarditis, and 1 suspected pericarditis. Unadjusted myopericarditis rates were: Cohort 1, 5.7/1000 (95% CI, 4.3–7.5); Cohort 2, 3.2/1000 (95% CI, 1.7–5.8). Unadjusted and adjusted odds ratios for myopericarditis were 1.8 (95% CI: 0.9–3.6) and 1.3 (95% CI: 0.6–2.6), respectively. One hundred seventeen subjects (1.1%) in Cohort 1 and 13 (0.3%) in Cohort 2 experienced at least 1 serious adverse event. No instances of serious and severe neurological or dermatological adverse events were reported. Conclusions In this carefully screened, generally young and healthy service-member population, ACAM2000 vaccination was associated with modest non-significant increases in the risk of myopericarditis (adjusted OR, 1.3; unadjusted OR, 1.8); all but seven cases were subclinical. Clinical trials registration: ClinicalTrials.gov NCT00928577.

Tecovirimat (TPOXX®; ST-246) was approved for the treatment of symptomatic smallpox by the USFDA in July of 2018 and has been stockpiled by the US government for use in a smallpox outbreak. While there has not been a reported case of smallpox since 1978 it is still considered a serious bioterrorism threat.A brief history of smallpox from its proposed origins as a human disease through its eradication in the late 20th century is presented. The current smallpox threat and the current public health response plans are described. The discovery, and development of tecovirimat through NDA submission and subsequent approval for treatment of smallpox are discussed. Google Scholar and PubMed were searched over all available dates for relevant publications.Approval of tecovirimat to treat smallpox represents an important milestone in biosecurity preparedness. Incorporating tecovirimat into the CDC smallpox response plan, development of pediatric liquid and intravenous formulations, and approval for post-exposure prophylaxis would provide additional health security benefit.Tecovirimat shows broad efficacy against orthopoxviruses in vitro and in vivo and could be developed for use against emerging orthopoxvirus diseases such as monkeypox, vaccination-associated adverse events, and side effects of vaccinia oncolytic virus therapy.

Background The pandemic associated with the new SARS-CoV-2 coronavirus continues to spread worldwide. The most favorable epidemic control scenario, which provides long-term protection against COVID-19 outbreak, is the development and distribution of an effective and safe vaccine. The need to develop a new COVID-19 vaccine is pressing; however, it is likely to take a long time, possibly several years. This is due to the time required to demonstrate the safety and efficacy of the proposed vaccine. and the time required to manufacture and distribute millions of doses. Objectives To accelerate this development and associated safety testing, the deliberate infection of healthy volunteers has been suggested. The purpose of this short communication is to describe the ethical aspects of this type of testing, Results Deliberate infection of volunteers with a dangerous virus such as SARS-CoV-2 was initially considered unethical by researchers; but the current pandemic is so different from previous ones that these studies are considered ethical if certain criteria are met. Participants in human challenge studies must be relatively young, in good health and must receive the highest quality medical care, with frequent monitoring. Tests should also be performed with great caution and specialized medical supervision. Besides, the fact that obtaining vaccines faster through deliberate infection studies of healthy people has greater benefits than risks, has been demonstrated by obtaining other vaccines in other historical pandemics such as: smallpox, influenza, malaria, typhoid fever, Dengue fever and Zika. Conclusions One possibility to shorten the time required for the development of COVID-19 vaccines is to reduce clinical phases II and III by using human challenge studies through eliberate infection of healthy volunteers with SARS-CoV-2 after administration of the candidate vaccine. Accelerating the development of a COVID-19 vaccine even for a few weeks or months would have a great beneficial impact on public health by saving many lives. Graphical abstract

Today's COVID-19 pandemic offers many similarities with previous pandemics hitting our country. In particular, the smallpox epidemics during the 1700s threatened the lives of multitudes and created panic and fear in the society, similar to the situation caused by the coronavirus. Remedies that were instituted, especially inoculations, were met with opposition and even violence when first introduced. The newspapers were filled with headlines reflecting the disputes. There was a "six feet rule" during the smallpox epidemics, although it had a different meaning than today. Politicians and other leaders of the society were engaged in the war against the infection. Boston became involved in the fight against the smallpox by Dr. Zabdiel Boylston's and Rev. Cotton Mather's introduction of inoculations. When George Washington realized the benefits of the procedure and ordered mass inoculations of the Continental Army, it became an important factor in winning not only the fight against smallpox but the Revolutionary War as well. Looking back at history, realizing that we have survived previous outbreaks of devastating diseases, can provide hope during the current pandemic.

In developed countries, it is said that "threats of infectious diseases are already thought as things of the past". However, as you can see in the case of Ebola hemorrhagic fever that occurred in West Africa, this is a big mistake. Among infectious diseases, only smallpox has been successfully eradicated worldwide. In addition to the three major infectious diseases of HIV/AIDS, tuberculosis, and malaria, there is another group called emerging and reemerging infectious diseases. Recently, neglected tropical diseases (NTDs) have been listed as threats by the WHO, as have drug-resistant bacteria. The spread of these pathogens is increasing due to an increase in global travel. Malaria and more than half of the NTDs are parasitic diseases, such as trypanosomiasis and soil-borne helminthiasis. These are caused by parasites, with eukaryotes similar to their host mammals. In the case of these NTDs, protective immune responses induced by differences between a pathogen and host do not work well, and there is no vaccine against parasites. As for drugs developed to treat these diseases, because the properties of enzymes and target receptors are very similar, and effective drugs simultaneously show efficacy against both the disease and the host, severe side effects often occur. Therefore, the search for targets specifically present in parasites, and screening for drugs that inhibit their physiological functions, is extremely important. Here, as an example of the development of antiparasitic drugs, I will introduce a study on malaria.

The whole world has entered a terrible crisis with a huge and increasing amount of human deaths and economic loss in fighting the pandemic of COVID‐19 caused by the novel coronavirus termed SARS‐CoV‐2. The live pathogen vaccine (LPV) strategy, which originated in ancient China for fighting smallpox, has been applied successfully in the USA military recruits for decades to control acute respiratory diseases caused by types 4 and 7 adenoviruses. This strategy has also been widely employed in veterinary medicine. These facts suggest a fast way out of the current pandemic crisis, namely that SARS‐CoV‐2 could be directly used as a live vaccine. Beyond the two traditional mechanisms to guarantee the LPV's safety (SARS‐CoV‐2 is not highly pathogenic; the LPV is inoculated bypassing the respiratory sites of pathology), three novel mechanisms to further ensure the LPV's safety are available (the virus replication is inhibited with early use of an antiviral drug; symptomatic LPV recipients are cured with convalescent plasma; the LPV is inoculated in hot seasons). This LPV strategy has multiple potential advantages over other options, and could reduce greatly the morbidity and mortality as well as economic loss caused by the pandemic. The safety and efficacy of this strategy should be investigated strictly using animal experiments and clinical trials, and even if the experiments and trials all support the strategy, it should be implemented with enough cautiousness. This article is protected by copyright. All rights reserved.

Vaccination is the most effective measure against infectious diseases. Due to vaccinations, smallpox was eliminated, poliomyelitis and tetanus morbidity decreased dramatically. According to WHO, 12 million children around the world annually die from infectious diseases. Of these, 7.5 million lives are lost to diseases against which we do not yet have vaccines, but more than 4 million people die from preventable diseases. Immunization is currently considered to be one of the most effective and cost-effective medical interventions in the epidemic process. The more economically developed a country is, the more diseases is its population protected from with the help of immunoprophylaxis. In order to create herd immunity, WHO recommends that at least 95 % of individuals should be vaccinated. However, in the Lviv region andUkrainethere is a negative tendency to reduce the coverage of preventive vaccinations up to 45–53%, which is a danger of the emergence and epidemic spread of preve ntable diseases. The objective: was to analyze the legislative framework on immunoprophylaxis, the peculiarities of planning preventive vaccinations, the requirements for vaccination offices and modern contraindications for vaccination. Materials and methods. Legal documents on immunoprophylaxis were analysed, 210 family doctors were surveyed on immunoprophylaxis awareness. Conclusions. There is a necessity of continuous professional development of physicians on immunoprophylaxis, including training, theoretical improvement courses, internships in European countries and Ukrainian vaccination centers.

Brincidofovir (BCV) is a lipid conjugate of cidofovir with good oral bioavailability, enabling optimal intracellular levels of the active drug. Lower rates of nephrotoxicity and myelotoxicity make it a favorable alternative. Despite a greater safety profile among pediatric hematopoietic cell transplant recipients, the oral formulation has been associated with increased gastrointestinal toxicity in adult hematopoietic cell transplant recipients. Oral BCV continues to be developed as a countermeasure against smallpox, while a potentially safer intravenous preparation has been out licensed to another company. BCV has demonstrated great in vitro potency against double-stranded DNA viruses, especially adenovirus. Because of its importance for immunocompromised patients, this review aims to evaluate BCV’s clinical and safety profile to support its continued development.

Biotechnology has demonstrated its importance for health development, especially in the discovery of new drugs and production of vaccines. On account of the occurrence of many diseases that have killed millions of people in the world, vaccines were developed to control infections and prevent diseases caused by viruses, bacteria, protozoans and fungi, and even eradicate them, as is the case of smallpox. Vaccines can be of first, second and third generation. Currently, vaccine manufacturing can be directed to the use of DNA containing the gene that encodes an antigenic protein. The present work is a literature review, with the objective to present the first-, second- and third-generation vaccines, as well as to make an analysis of the use of these vaccines in Brazil.

Monkey pox is a rare viral zoonotic disease of which clinical manifestations are similar to smallpox, it is transmitted to humans by direct contact with the body of an infected animal, but the transmission can also be human-to-human. The Democratic Republic of Congo is the most endemic country in the world where almost all provinces are affected by this scourge. However, in the administrative configuration currently, monkey pox has not been detected in Nord Ubangi province yet. This cross-sectional study focuses on three cases of patients diagnosed with monkey pox virus at Businga General Hospital in Nord Ubangi province. The findings show that all the three patients were male with a primary education level and their average age was 9±3.46 years. They had some epidemiological characteristics specific to monkey pox, including high fevers, rashes, pruritus and abdominal pain. After two weeks of symptomatic treatment, each patient was able to get out without further complications. For the best of our knowledge, this is the first report on the cases of Monkey pox in Nord Ubangi Province.

In March 2015, a patient in Colombia with HIV/AIDS was hospitalized for disseminated ulcers after milking cows that had vesicular lesions on their udders. Vaccinia virus was detected, and the case met criteria for progressive vaccinia acquired by zoonotic transmission. Adherence to an optimized antiretroviral regimen resulted in recovery. © 2020 Centers for Disease Control and Prevention (CDC). All rights reserved.

Epidemics of paralytic poliomyelitis (polio) first emerged in the late 19th and early 20th centuries in the United States and the Scandinavian countries. They continued through the first half of the 20th century becoming global. A major epidemic occurred in Australia in 1951 but significant outbreaks were reported from the late 1930s to 1954. The poliovirus is an enterovirus that is usually transmitted by the faecal–oral route but only one in about 150 infections results in paralysis when the central nervous system is invaded. The Salk inactivated polio vaccine (IPV) became available in Australia in 1956 and the Sabin live attenuated oral polio vaccine (OPV) was introduced in 1966. After decades of stability, many survivors of the earlier epidemics experience late-onset sequelae including post-polio syndrome. The World Health Organization launched the global polio eradication initiative (GPEI) in 1988 based on the easily administered OPV. The GPEI has resulted in a dramatic decrease in cases of wild polio so that only Pakistan and Afghanistan report such cases in 2020. However, a major challenge to eradication is the reversion of OPV to neurovirulent mutants resulting in circulating vaccine-derived poliovirus (cVDPV). A novel, genetically stabilised OPV has been developed recently to stop the emergence and spread of cVDPV and OPV is being replaced by IPV in immunisation programs worldwide. Eradication of poliomyelitis is near to achievement and the expectation is that poliomyelitis will join smallpox as dreaded epidemic diseases of the past that will be consigned to history.

This article analyses the seasonal peculiarities of infant mortality and identifies periods of children’s increased vulnerability to adverse factors during the year. The article assesses infant mortality rate and the impact of various causes in the formation of the situation with infant mortality. Referring to the database of Barnaul parish register books, the author analyses deaths of Orthodox believers between 1869 and 1911. During the period in question, Russia was characterised by a high level of infant mortality, and in Siberia and Barnaul it was ultrahigh. In the early twentieth century, European Russia and the Urals faced a decline in infant mortality. In Barnaul, the rate of the decline was significantly lower. Seasonal infant mortality rates showed increased infant mortality from May to August with peak values in June. Summer months accounted for 50.8% of deaths, spring for 21.7%, winter for 15%, and autumn for 12.5%. In the summer, more than 80% of cases in the structure of infant mortality resulted from infectious and intestinal diseases with an overwhelming percentage of intestinal infections (79%). The percentage of deaths from intestinal infections (smallpox, measles) and bacterial diseases (diphtheria, whooping cough, scarlet fever) was less significant. Most of the deaths from respiratory diseases occurred in spring, followed by winter mortality and autumn mortality. The seasonality rate of child mortality (aged between 1 and 4) shows high values in June and July. In the summer, infant mortality was 1.4 times higher than child mortality and 2.1 higher than total mortality. A quarter of infant mortality was neonatal. The extreme level of the infant mortality rate in Barnaul was accounted for primarily by post-neonatal mortality cases.

Naturally occurring smallpox has been eradicated but research stocks of variola virus (VARV), the causative agent of smallpox, still exist in secure laboratories. Clandestine stores of the virus or resurrection of VARV via synthetic biology are possible and have led to concerns that VARV could be used as a biological weapon. The US government has prepared for such an event by stockpiling smallpox vaccines and TPOXX®, SIGA Technologies' smallpox antiviral drug. While vaccination is effective as a pre-exposure prophylaxis, protection is limited when administered following exposure. Safety concerns preclude general use of the vaccine unless there is a smallpox outbreak. TPOXX is approved by the FDA for use after confirmed diagnosis of smallpox disease. Tecovirimat, the active pharmaceutical ingredient in TPOXX, targets a highly conserved orthopoxviral protein, inhibiting long-range dissemination of virus. Although indications for use of the vaccine and TPOXX do not overlap, concomitant use is possible, especially if the TPOXX indication is expanded to include post-exposure prophylaxis. It is therefore important to understand how vaccine and TPOXX may interact. In studies presented here, monkeys were vaccinated with the ACAM2000TM live attenuated smallpox vaccine and concomitantly treated with tecovirimat or placebo. Immune responses to the vaccine and protective efficacy versus a lethal monkeypox virus (MPXV) challenge were evaluated. In two studies, primary and anamnestic humoral immune responses were similar regardless of tecovirimat treatment while the third study showed reduction in vaccine elicited humoral immunity. Following lethal MPXV challenge, all (12 of 12) vaccinated/placebo treated animals survived, and 12 of 13 vaccinated/tecovirimat treated animals survived. Clinical signs of disease were elevated in tecovirimat treated animals compared to placebo treated animals. This suggests that TPOXX may affect the immunogenicity of ACAM2000 if administered concomitantly. These studies may inform on how vaccine and TPOXX are used during a smallpox outbreak.

Background It is unclear whether human immunodeficiency virus (HIV) infection results in permanent loss of T-cell memory or if it affects preexisting antibodies to childhood vaccinations or infections. Methods We conducted a matched cohort study involving 50 pairs of HIV-infected and HIV-uninfected women. Total memory T-cell responses were measured after anti-CD3 or vaccinia virus (VV) stimulation to measure T cells elicited after childhood smallpox vaccination. VV-specific antibodies were measured by means of enzyme-linked immunosorbent assay (ELISA). Results There was no difference between HIV-infected and HIV-uninfected study participants in terms of CD4+ T-cell responses after anti-CD3 stimulation (P = .19) although HIV-infected participants had significantly higher CD8+ T-cell responses (P = .03). In contrast, there was a significant loss in VV-specific CD4+ T-cell memory among HIV-infected participants (P = .04) whereas antiviral CD8+ T-cell memory remained intact (P > .99). VV-specific antibodies were maintained indefinitely among HIV-uninfected participants (half-life, infinity; 95% confidence interval, 309 years to infinity) but declined rapidly among HIV-infected participants (half-life; 39 years; 24–108 years; P = .001). Conclusions Despite antiretroviral therapy–associated improvement in CD4+ T-cell counts (nadir, 350/μL after antiretroviral therapy), antigen-specific CD4+ T-cell memory to vaccinations or infections that occurred before HIV infection did not recover after immune reconstitution, and a previously unrealized decline in preexisting antibody responses was observed.

Recently, concern has been raised about the emergence of human monkeypox virus and the occasionally severe clinical presentation bearing resemblance to that of smallpox. In 2018 3 patients in the UK were diagnosed with monkeypox, and the frequency and geographic distribution of cases across West and Central Africa have increased in recent years. In Nigeria, most monkeypox patients are aged

The first written record of intervention against what later came to be known as an infectious disease was in the early seventeenth century by a Buddhist nun. She dried 3 to 4 wk old scabs from patients with mild smallpox and asked well people to inhale the powder. More than a century later in 1796, Edward Jenner described vaccination against smallpox by using cowpox that later was found to be caused by cowpox virus which is non-pathogenic for humans. Another century later in 1890, Robert Koch published the Koch's Postulates allowing the study of pathogenic bacteria and subsequently the study of agents to fight them. The first chemical cure for disease was reported by Paul Erhlich in 1909 in the form of an arsenic compound to treat syphilis. One hundred and ten years since then a lot has happened in the area of preventing and treating infectious diseases with significant contribution to increase in human lifespan. This is the only area of medicine in which treatment (antimicrobial agent) is used to eradicate a replicating biological agent inside the human host. The potential of this second biological agent to mutate under the selection pressure of antibiotics making them resistant was recognized in the 1940s. But the indiscriminate use of antibiotics for over 70 y has led to the present crisis of resistance in major pathogens with increased morbidity and mortality. In this review, we have incorporated all the possible avenues that might be useful in the future. However, none is more important than relearning the judicious use of antibiotics based on microbiology, pharmacology, and genetics.

Vaccinia virus (VACV) is an orthopoxvirus used in smallpox vaccines, as a vector for novel cancer treatments, and for experimental vaccine research (1). The Advisory Committee on Immunization Practices (ACIP) recommends smallpox vaccination for laboratory workers who handle replication-competent VACV (1). For bioterrorism preparedness, the U.S. government stockpiles tecovirimat, the first Food and Drug Administration-approved antiviral for treatment of smallpox (caused by variola virus and globally eradicated in 1980*,†) (2). Tecovirimat has activity against other orthopoxviruses and can be administered under a CDC investigational new drug protocol. CDC was notified about an unvaccinated laboratory worker with a needlestick exposure to VACV, who developed a lesion on her left index finger. CDC and partners performed laboratory confirmation, contacted the study sponsor to identify the VACV strain, and provided oversight for the first case of laboratory-acquired VACV treated with tecovirimat plus intravenous vaccinia immunoglobulin (VIGIV). This investigation highlights 1) the misconception among laboratory workers about the virulence of VACV strains; 2) the importance of providing laboratorians with pathogen information and postexposure procedures; and 3) that although tecovirimat can be used to treat VACV infections, its therapeutic benefit remains unclear.

Concerns about bioterrorism and outbreaks of zoonotic orthopoxvirus require safe and efficacious smallpox vaccines. We previously reported the clinical efficacy and safety profiles of LC16m8, a live, attenuated, cell culture-derived, smallpox vaccine, examined in over 3000 healthy Japanese adults with various vaccination histories. In this study, serum of approximately 200 subjects pre and post LC16m8 vaccination were subjected to a vaccinia virus-specific protein array to evaluate the proteome-wide immunogenicity. The relationships between antigen-specific antibodies and plaque reduction neutralization titers were analyzed. LC16m8 induced antibodies to multiple vaccinia antigens in primary-vaccinated individuals and yielded effective booster responses in previously vaccinated individuals, demonstrating similar antibody profiles to those reported for other vaccinia virus strains. Several immunodominant antigens were indicated to be important for neutralization of the intracellular mature virion. The similarity of antibody profiles between LC16m8 and other smallpox vaccine strains supports the immunogenicity and protective efficacy of LC16m8.

All living beings are at risk for experiencing infections; humans are no exception. The prestige and credibility of modern medicine is built in large part on achievements in preventing and treating infectious diseases. For most of human history, there was little that could be done to prevent and treat infections. Millions of humans, of all ages, have died from infections; and in some parts of the world, infection-related deaths remain common. Advances in preventing and treating infectious diseases include improved sanitization, sterilization, pasteurization, immunization, and antibiotics. Vaccination has played a major role in the prevention of lethal diseases, such as smallpox, diphtheria, cholera, and influenza. Because of developing or waning immune function, the young and the old are at particularly high risk of experiencing infections. Influenza and pneumonia remain common causes of death in older adults. Influenza, in particular, has the potential to result in premature mortality for all age groups, including those who are older and particularly those who live in congregate settings. Vaccination is important in promoting healthy aging. J Am Geriatr Soc 68:207-214, 2019.

Background: Ludwig van Beethoven was born 250 years ago on December 17th, 1770 in Bonn, Germany. Although he was one of the most brilliant composers of all time, his life was shaped by many illnesses. Many know that Beethoven was hard of hearing and later deaf and that he could not longer hear his own works. However, there are many diseases that were little and or not known and that still shaped his life significantly.Methods: This article reports the medical history of this artist, based on authoritative scientific sources.Results: Even when he was young, Beethoven fell ill with smallpox, which gave his face a typical appearance. Since 1804/1805 he had been unable to see properly and was wearing glasses. The first hearing disorders appeared in 1796, treatment began in 1800. From 1814, hearing loss worsened significantly. The cause of hearing disorders is still unclear. From the age of 25, there was colic, diarrhea and fever, probably caused by a chronic pancreatitis. It is certain that Beethoven suffered from hepatitis and cirrhosis of the liver, certainly significantly influenced by alcohol consumption. Liver cirrhosis and esophageal varices were the consequences, and certainly also psychological changes to his difficult personality. In 1825, there was a cough of blood, nosebleeds and ascites and until 1827, 30-40 l of ascites were punctured.. On March 26, 1827, Beethoven died in the liver coma.Conclusions: Beethoven was a brilliant musician and composer who had many illnesses in his life. Above all, his hearing impairment significantly influenced his life. He had also frequent gastroenterological diseases, especially pancreatitis, hepatitis and live cirrhosis. Alcohol certainly played an important role in his life and influenced many illnesses.

Myocarditis and pericarditis have been linked recently to COVID-19 vaccines without exploring the underlying mechanisms, or compared to cardiac adverse events post-non-COVID-19 vaccines. We introduce an informatics approach to study post-vaccine adverse events on the systems biology level to aid the prioritization of effective preventive measures and mechanism-based pharmacotherapy by integrating the analysis of adverse event reports from the Vaccine Adverse Event Reporting System (VAERS) with systems biology methods. Our results indicated that post-vaccine myocarditis and pericarditis were associated most frequently with mRNA COVID-19 vaccines followed by live or live-attenuated non-COVID-19 vaccines such as smallpox and anthrax vaccines. The frequencies of cardiac adverse events were affected by vaccine, vaccine type, vaccine dose, sex, and age of the vaccinated individuals. Systems biology results suggested a central role of interferon-gamma (INF-gamma) in the biological processes leading to cardiac adverse events, by impacting MAPK and JAK-STAT signaling pathways. We suggest that increasing the time interval between vaccine doses minimizes the risks of developing inflammatory adverse reactions. We also propose glucocorticoids as preferred treatments based on system biology evidence. Our informatics workflow provides an invaluable tool to study post-vaccine adverse events on the systems biology level to suggest effective mechanism-based pharmacotherapy and/or suitable preventive measures.