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Objectives: The aim was to estimate the effect of reported history of smallpox vaccination prior to 1980 on clinical expression of mpox., Methods: We included all confirmed mpox cases identified by the national mpox surveillance system in France between May and July 2022. Cases tested positive for monkeypox virus or orthopoxviruses by PCR. Cases were interviewed by phone using a questionnaire documenting demographics, symptoms and exposures. To estimate the effect of smallpox vaccination on the presence of marked mpox symptoms (association of fever, lymphadenopathy and extensive mucocutaneous lesions), we estimated prevalence ratios (PRs) and 95% CIs using Poisson regression models with robust standard errors., Results: There were 1888 confirmed mpox cases with date of symptom onset between 7 May and 31 July 2022. Overall, 7% (93/1394) presented marked mpox symptoms. Among patients who provided information about their vaccination status, 14% (207/1469) reported smallpox vaccination prior to 1980. The proportion of cases with marked symptoms was 2% (3/170) among those reporting smallpox vaccination prior to 1980 and 8% (76/974) among those who reported no vaccination. The proportion of marked symptoms was four times lower among cases reporting previous smallpox vaccination than in cases reporting no vaccination (PR, 0.24; 95% CI: 0.08-0.76). There was no evidence of an effect of smallpox vaccination on development of complications (PR, 0.65; 95% CI: 0.35-1.22) or hospitalization due to mpox (PR, 0.64; 95% CI: 0.23-1.80)., Discussion: Our results suggest that smallpox vaccination during childhood attenuated the clinical expression of monkeypox virus infection, but there was no evidence of an effect on complications or hospitalization., (Copyright © 2024 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Modified Vaccinia Ankara Bavarian Nordic (MVA-BN) as a smallpox and mpox vaccine has been approved in its liquid-frozen (LF) formulation in the US, Canada, and EU. A freeze-dried (FD) formulation may offer additional benefits, such as a longer shelf life and reduced dependence on cold chain storage and transport. In a phase 2 clinical trial, 651 vaccinia-naïve participants were vaccinated with two doses of MVA-BN LF or FD, 4 weeks apart. The objectives were to compare MVA-BN FD with LF in terms of vaccine-induced immune responses, safety, and reactogenicity. Non-inferiority of the immune response was assessed by the 95% CI of the geometric mean ratios. Both formulations induced robust vaccinia-specific humoral and cellular immune responses. At peak humoral responses (Week 6), geometric means of total antibody titers were 1096 (95% CI 1013, 1186) from the FD group and 877 (95% CI 804, 956) from the LF group, achieving the primary endpoint of non-inferiority of MVA-BN FD compared to MVA-BN LF. At peak cellular responses (Week 2), geometric means of T cell spot forming units were 449 (95% CI 341, 590) from the FD group and 316 (95% CI 234, 427) from the LF group. Both formulations of MVA-BN were well tolerated, with similar unsolicited AEs and solicited systemic reactions in both groups but slightly more local reactions in the FD group. No vaccine-related serious adverse events (SAEs) or vaccine-related AE of special interest were reported. The FD formulation of MVA-BN was shown to be equivalent to MVA-BN LF.

A large outbreak of monkeypox occurred in 2022, and most people lack immunity to orthopoxvirus. Smallpox vaccination is essential for preventing further smallpox outbreaks. This study evaluated the effectiveness, protection, safety, and cross-immunogenicity of smallpox vaccine in preventing monkeypox infection. PubMed, Embase, Scopus, and Web of Science were searched from database inception to 10 March 2024. We included studies involving "monkeypox virus" and "vaccinations", and excluded reviews, animal studies, and articles with missing or duplicate data. A total of 37 studies with 57,693 participants were included in the final analysis. The effectiveness data showed that monkeypox infection rates were lower in the smallpox-vaccinated group than in the unvaccinated group (risk ratio [RR]: 0.46; 95% confidence interval [CI]: 0.31-0.68). The protection data showed that smallpox vaccination effectively reduced the risk of severe monkeypox infection (RR: 0.61; 95% CI: 0.42-0.87). Third-generation vaccines showed greater efficacy (RR: 0.36, 95% CI: 0.22-0.56) than first-generation vaccines. The number of doses of smallpox vaccine has no significant effect on monkeypox. Safety data showed that adverse reactions after smallpox vaccination were mainly mild and included local erythema, swelling, induration, itching, and pain. Meanwhile, we found that smallpox vaccination could induce the production of neutralizing antibodies against monkeypox. Our findings offer compelling evidence supporting the clinical application of the smallpox vaccine for preventing monkeypox and advocate that high-risk groups should be prioritized for receiving one dose of the smallpox vaccine if the vaccine stockpile is low.

The smallpox vaccine developed by Jenner in 1798 was successfully introduced in France in 1800 with the support of Napoleon Bonaparte. The medals and tokens (coin-like medals) issued to encourage early-day vaccination activities are described in the context of the changing political situation in that country. In 1800 a private society of subscribers, led by the Duke of La Rochefoucauld-Liancourt was created, along with a Vaccine Committee charged with evaluating the safety and efficacy of vaccination before deciding if vaccination should be extended to the entire population. The Vaccine Committee published a positive report in 1803, and in 1804, the Ministry of the Interior established the "Society for the extinction of smallpox in France by means of the propagation of the vaccine". The creation of the Society made smallpox vaccination an official activity of the empire, facilitating collaboration between government agencies. The vaccine institution, established by Napoleon in 1804, continued its functions until 1820 when the Royal Academy of Medicine was created and took over those functions. This case exemplifies the collaboration that was needed between science and politics to rapidly bring the recently developed smallpox vaccine to the needed population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Smallpox is a highly contagious human disease caused by the variola virus. Although the disease was eliminated in 1979 due to its highly contagious nature and historical pathogenicity, with a mortality rate of up to 30%, this virus is an important candidate for biological weapons. Currently, vaccines are the critical measures to prevent this virus infection and spread. In this study, we designed a peptide vaccine using immunoinformatics tools, which have the potential to activate human immunity against variola virus infection efficiently. The design of peptides derives from vaccine-candidate proteins showing protective potential in vaccinia WR strains. Potential non-toxic and nonallergenic T-cell and B-cell binding and cytokine-inducing epitopes were then screened through a priority prediction using special linkers to connect B-cell epitopes and T-cell epitopes, and an appropriate adjuvant was added to the vaccine construction to enhance the immunogenicity of the peptide vaccine. The 3D structure display, docking, and free energy calculation analysis indicate that the binding affinity between the vaccine peptide and Toll-like receptor 3 is high, and the vaccine receptor complex is highly stable. Notably, the vaccine we designed is obtained from the protective protein of the vaccinia and combined with preventive measures to avoid side effects. This vaccine is highly likely to produce an effective and safe immune response against the variola virus infection in the body., Importance: In this work, we designed a vaccine with a cluster of multiple T-cell/B-cell epitopes, which should be effective in inducing systematic immune responses against variola virus infection. Besides, this work also provides a reference in vaccine design for preventing monkeypox virus infection, which is currently prevalent., Competing Interests: The authors declare no conflict of interest.

The human monkeypox virus (Mpox) is classified as a member of the Poxviridae family and belongs to the Orthopoxvirus genus. Mpox possesses double-stranded DNA, and there are two known genetic clades: those originating in West Africa and the Congo Basin, commonly known as Central African clades. Mpox may be treated with either the vaccinia vaccination or the therapeutics. Modifying the smallpox vaccine for treating and preventing Mpox has shown to be beneficial because of the strong link between smallpox and Mpox viruses and their categorization in the same family. Cross-protection against Mpox is effective with two Food and Drug Administration (FDA)-approved smallpox vaccines (ACAM2000 and JYNNEOSTM). However, ACAM2000 has the potential for significant adverse effects, such as cardiac issues, whereas JYNNEOS has a lower risk profile. Moreover, Mpox has managed to resurface, although with modified characteristics, due to the discontinuation and cessation of the smallpox vaccine for 40 years. The safety and efficacy of the two leading mRNA vaccines against SARS-CoV-2 and its many variants have been shown in clinical trials and subsequent data analysis. This first mRNA treatment model involves injecting patients with messenger RNA to produce target proteins and elicit an immunological response. High potency, the possibility of safe administration, low-cost manufacture, and quick development is just a few of the benefits of RNA-based vaccines that pave the way for a viable alternative to conventional vaccines. When protecting against Mpox infection, mRNA vaccines are pretty efficient and may one day replace the present whole-virus vaccines. Therefore, the purpose of this article is to provide a synopsis of the ongoing research, development, and testing of an mRNA vaccine against Mpox., (© 2024. The Author(s).)

The smallpox infection with the variola virus was one of the most fatal disorders until a global eradication was initiated in the twentieth century. The last cases were reported in Somalia 1977 and as a laboratory infection in the UK 1978; in 1980, the World Health Organization (WHO) declared smallpox for extinct. The smallpox virus with its very high transmissibility and mortality is still a major biothreat, because the vaccination against smallpox was stopped globally in the 1980s. For this reason, new antivirals (cidofovir, brincidofovir, and tecovirimat) and new vaccines (ACAM2000, LC16m8 and Modified Vaccine Ankara MVA) were developed. For passive immunization, vaccinia immune globulin intravenous (VIGIV) is available. Due to the relationships between orthopox viruses such as vaccinia, variola, mpox (monkeypox), cowpox, and horsepox, the vaccines (LC16m8 and MVA) and antivirals (brincidofovir and tecovirimat) could also be used in the mpox outbreak with positive preliminary data. As mutations can result in drug resistance against cidofovir or tecovirimat, there is need for further research. Further antivirals (NIOCH-14 and ST-357) and vaccines (VACΔ6 and TNX-801) are being developed in Russia and the USA. In conclusion, further research for treatment and prevention of orthopox infections is needed and is already in progress. After a brief introduction, this chapter presents the smallpox and mpox disease and thereafter full overviews on antiviral treatment and vaccination including the passive immunization with vaccinia immunoglobulins., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Smallpox was a significant cause of mortality for over three thousand years, amounting to 10% of deaths yearly. Edward Jenner discovered smallpox vaccination in 1796, which rapidly became a smallpox infection preventive practice throughout the world and eradicated smallpox infection by 1980. After smallpox eradication, monkeypox vaccines have been used primarily in research and in outbreaks in Africa, where the disease is endemic. In the present, the vaccines are being used for people who work with animals or in high-risk areas, as well as for healthcare workers treating patients with monkeypox. Among all orthopoxviruses (OPXV), monkeypox viral (MPXV) infection occurs mainly in cynomolgus monkeys, natural reservoirs, and occasionally causes severe multi-organ infection in humans, who were the incidental hosts. The first case of the present epidemic of MXPV was identified on May 7, 2022, and rapidly increased the number of cases. In this regard, the WHO declared the outbreak, an international public health emergency on July 23, 2022. The first monkeypox vaccine was developed in the 1960s by the US Army and was based on the vaccinia virus, which is also used in smallpox vaccines. In recent years, newer monkeypox vaccines have been developed based on other viruses such as Modified Vaccinia Ankara (MVA). These newer vaccines are safer and can provide longer-lasting immunity with fewer side effects. For the future, there is ongoing research to improve the current vaccines and to develop new ones. One notable advance has been the development of a recombinant vaccine that uses a genetically modified vaccinia virus to express monkeypox antigens. This vaccine has shown promising results in pre-clinical trials and is currently undergoing further testing in clinical trials. Another recent development has been the use of a DNA vaccine, which delivers genetic material encoding monkeypox antigens directly into cells. This type of vaccine has shown effectiveness in animal studies and is also undergoing clinical testing in humans. Overall, these recent advances in monkeypox vaccine development hold promise for protecting individuals against this potentially serious disease., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Smallpox was a highly contagious disease caused by the variola virus. The disease affected millions of people over thousands of years and variola virus ranked as one of the deadliest viruses in human history. The complete eradication of smallpox in 1980, a major triumph in medicine, was achieved through a global vaccination campaign using a less virulent poxvirus, vaccinia virus. Despite this success, the herd immunity established by this campaign has significantly waned, and concerns are rising about the potential reintroduction of variola virus as a biological weapon or the emergence of zoonotic poxviruses. These fears were further fueled in 2022 by a global outbreak of monkeypox virus (mpox), which spread to over 100 countries, thereby boosting interest in developing new vaccines using molecular approaches. However, poxviruses are complex and creating modern vaccines against them is challenging. This review focuses on the structural biology of the six major neutralization determinants on poxviruses (D8, H3, A27, L1, B5, and A33), the localization of epitopes targeted by neutralizing antibodies, and their application in the development of subunit vaccines.

Monkeypox is a zoonosis that is spread mainly through direct contact with fluids and skin lesions of infected people with vesicles still active. Although the virus was isolated for the first time in 1958 and the first human case was identified in a child in 1970, in the Democratic Republic of the Congo, the disease has progressively increased its incidence in Africa reaching in May 2022 sustained transmission outside this continent. As it is a newly introduced virus in our health system, it is necessary to learn the epidemiological pattern in a different environment from that of traditionally endemic areas and to know the available antiviral treatments, as well as the prophylactic measures that could be considered, knowing that as a virus emerging in our regions, scientific evidence is still limited. There are antivirals that have been shown, in animal models, to effectively combat the disease with very good clinical tolerance. This disease has also forced us to review the characteristics of smallpox vaccines, because they have shown a protective effect against monkeypox. For this reason, it is important to have a document that compiles all the scientific information published in this regard., (Copyright © 2022 Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. Published by Elsevier España, S.L.U. All rights reserved.)

The Madrid Gazette published a Supplement on October 14, 1806, regarding the arrival of the Director of the Royal Expedition Vaccine Philanthropy, Francisco Xavier Balmis, and the reception held by King Carlos IV. Balmis had completed his journey across the Spanish overseas territories, taking the vaccine against smallpox from arm to arm with the help of a human chain of children. During this journey, Balmis also established Vaccination Boards and endeavoured to identify cows with cowpox. The publication endorsed the policies of a declining Bourbon monarchy and marked the peak of Balmis' professional career. Both sides emerged victorious: the Crown showcased itself as the sponsor and organiser of this altruistic journey, in line with prior scientific expeditions; and Balmis secured his place in Public Health history as the director of the first international vaccination campaign. This did not mean the culmination of the expedition, as other members were still administering vaccinations in the Philippines and South America. The main objective of this study was to assess the importance of the newspaper Madrid Gazette, outline the contents of the publication, authenticate the origins of the documentary sources underpinning its composition, and confirm its impact and citations throughout 19th-century Spanish publications. The components of the publication, its origins, as well as Balmis' involvement in its creation, have been substantiated. The Supplement's importance is defined by its utility as a resource for commemorating and appreciating the expedition.

The management of the coronavirus pandemic required huge worldwide vaccination efforts. In this endeavour, healthcare workers faced the twofold challenge of reaching remote areas, and persuading people to take the vaccine. As it happens, this is nothing new in the history of medicine. Health workers may indeed continue to take inspiration from Francisco Xavier Balmis, a Spanish physician of the 19th century who realised the importance of Jenner's vaccine against smallpox, and led a successful expedition to administer the vaccines in the Spanish colonial possessions of the Western hemisphere and Asia. This article presents a biographical sketch of Balmis, focusing on his expedition.

Monkeypox is an emerging threat to humans since a new outbreak in May 2022. It is hypothesised that increasing the immunologically naive population after the cessation of the smallpox vaccination campaign in the 1980s is one of the leading causes of it. A literature search was conducted using different electronic databases including MEDLINE (through PubMed), SCOPUS, Web of Science, Cochrane library, and EMBASE for relevant studies. After duplication removal, abstract and title screening, and full-text screening were done, the data were extracted, tabulated, and analysed. The risk of bias was assessed following the Risk of Bias Assessment tool for Non-randomised Studies. We found a total of 1068 relevant articles and finally, we included 6 articles including 2083 participants. The studies suggested that smallpox is 80.7% efficacious to prevent human monkeypox and the immunity provided by prior smallpox vaccination is long-lasting. Moreover, the smallpox vaccination decreases the risk of human monkeypox by 5.2-folds. Two cross-sectional studies based on the Democratic Republic of the Congo (DRC) including a total of around 1800 monkeypox cases found that unvaccinated participants had 2.73 and 9.64-fold increased risk of monkeypox compared to the vaccinated participants. Other studies in USA and Spain also demonstrated that unvaccinated people were more prone to develop monkeypox than vaccinated people. Furthermore, monkeypox incidence has increased by 20 folds, 30 years after the cessation of the smallpox vaccination campaign in DRC. Evidence-based preventive and therapeutic agents are still not available for human monkeypox. Further study should be done to explore the role of the smallpox vaccine in preventing human monkeypox., (© 2023 The Authors. Reviews in Medical Virology published by John Wiley & Sons Ltd.)

The Royal Philanthropic Vaccine Expedition is considered in the history of medicine as the first international health expedition aimed at the global elimination of a contagious disease: smallpox. However, the initiatives carried out in this way before the arrival of the Balmis Expedition, by surgeons from the Spanish Navy, are less well known. Thus, the main objective of this research work is to offer an overview of the different anti-variolic vaccination initiatives prior to the campaign financed by the Spanish crown from these health facilities. Using the heuristic and hermeneutic method, our article is based on primary sources contrasted with specialised literature. The results obtained are presented in a narrative style from each of the surgeons identified as decisive in the implementation of the vaccine, thus providing a divergent and unpublished historiographic approach. As the facts described show, before the arrival of Balmis the vaccine substance was introduced in those countries thanks to the initiative of various surgeons: in Puerto Rico by Francisco Oller; in Cartagena and Santa Marta in Colombia by Ángel Hidalgo; in Venezuela by Alonso Ruiz; in Cuba by Tomás Romay and Bernardo de Cózar; in the Viceroyalty of New Granada (Colombia) by Lorenzo Vergés; in Guatemala by Miguel José Monzón and José María Ledesma; in the Viceroyalty of New Spain by Alejandro García Arboleya and Antonio Serrano; in Peru by Pedro Belomo; in Río de la Plata by Cristóbal Martín de Montúfar; in the Chilean region of Coquimbo by José María Gómez; and in the Philippines by Cristóbal Regidor. Finally, it should be noted that these surgeons and the approach presented are part of a historiography based on the personal actions of professionals trained, for the most part, at the Medical-Surgical School of Cadiz.

People are expected to have been previously vaccinated with a Vaccinia-based vaccine, as until 1980 smallpox vaccination was a standard protocol in China. It is unclear whether people with smallpox vaccine still have antibody against vaccinia virus (VACV) and cross-antibody against monkeypox virus (MPXV). Herein, we assessed the binding antibodies with antigen of VACV-A33 and MPXV-A35 in the general population and HIV-1 infected patients. Firstly, we detected VACV antibody with A33 protein to evaluate the efficiency of smallpox vaccination. The result show that 29% (23 of 79) of hospital staff (age ≥ 42 years) and 63% (60 of 95) of HIV-positive patients (age ≥ 42 years) from Guangzhou Eighth People's Hospital were able to bind A33. However, among the subjects below 42 years of age, 1.5% (3/198) of the hospital volunteer samples and 1% (1/104) of the samples from HIV patients were positive for antibodies against A33 antigen. Then, we assessed the specific cross-reactive antibodies against MPXV A35 protein. 24% (19 of 79) hospital staff (age〉 = 42 years) and 44% (42 of 95) of HIV-positive patients (age〉 = 42 years) were positive. 98% (194/198) of the hospital staff and 99% (103/104) of the HIV patients had no A35-binding antibodies. Further, we found significant sex differences for the reactivity to A35 antigen were observed in HIV population, but no significant sex differences in hospital staff. Further, we analyzed the positivity rate of anti-A35 antibody of men who have sex with men (MSM) and non-MSM in HIV patients (age〉 = 42years). We found that 47% of no-MSM population and 40% of MSM population were positive for A35 antigen, with no significant difference. Lastly, we found only 59 samples were positive for anti-A33 IgG and anti-A35 IgG in all participants. Together, we demonstrated A33 and A35 antigens binding antibodies were detected in HIV patients and general population who were older than 42 years, and cohort studies only provided data of serological detection to support early response to monkeypox outbreak., (© 2023 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Serological testing of Singaporeans who received childhood smallpox vaccination found anti-vaccinia IgG binding and neutralizing activity indicating long-term humoral immunity. There was correlation between IgG and neutralizing titers indicating IgG could be used as a surrogate marker for humoral immunity. In 2019, Singapore experienced a case of imported monkeypox. As with smallpox, disease can be prevented through vaccination, which was mandatory for Singaporean infants until 1981. However, the degree of residual immunity in older vaccinated Singaporeans remains unknown. Sera from individuals born 1946-1984 were therefore tested and those born prior to 1981 were found to have higher anti-vaccinia IgG and neutralizing activity titers. This suggests that protective humoral immunity remains, which could reduce disease severity in an orthopoxvirus outbreak. Correlation between IgG and neutralizing titers was observed indicating that serology could be used as a surrogate marker for immunity., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This paper examines how smallpox vaccination has been implemented in China from a technological perspective. It is an attempt not only to investigate the impact of technology and instruments on medical advances, but also to deepen the understanding of modern Chinese society through smallpox vaccination. Smallpox vaccination helps people develop immunity to smallpox by inoculating into them pus from cowpox which is an infectious disease that affects cows. In 1805, Alexander Pearson succeeded in smallpox vaccination using the arm-to-arm transfer method for the first time in China thanks to the arrival of the vaccine in Macao. As Pearson and Quixi, who followed in the footsteps of Pearson, used the arm-to-arm method, they did not have much interest in vaccine containers. However, the vaccine administration technique changed: the vaccine obtained from people was inoculated into cows, and then again, into people. It thus resulted in the manufacturing of various vaccine containers including glass vials and tubes. The development of tools contributed to the expansion of cowpox vaccination. In addition, cowpox vaccines were imported directly from foreign countries. Advertisements which remain to date indicate that vaccines were widely imported. Pharmacies promoted vaccines, contending that the sale and import of vaccines was for the Chinese people. On the other hand, there were voices against imported vaccines, saying that they were expensive and foreign-made. Under the banner of patriotism and nationalism, people demanded that vaccines be made in China, which led to the production of vaccines in large cities such as Shanghai and Beijing. Along with the aforementioned efforts to obtain vaccines, techniques for smallpox vaccination can also be understood in the Chinese context. For example, traditional Chinese medicine maintains that acupuncture can be used as a vaccination lancet. Since traditional Chinese medicine already embraced the use of cowpox for protection against smallpox, they advocated using acupuncture instead of western instruments in order to expand the influence of traditional Chinese medicine. The belief that inoculation should be done into acupuncture points in the upper arms shows the significant influence of traditional Chinese medicine. On the other hand, Chinese people being reluctant to leave vaccine marks show the general view of what was considered as beautiful at the time, rather than the Chinese traditional perspective. Consequently, smallpox vaccine techniques in China, while following the technological advancement in general, could not help but be adapted to the Chinese context under the influence of modern Chinese society. Thus, smallpox vaccine techniques provide clues for understanding modern Chinese society. As such, historians who conduct research mainly with literature should also take interest in medical technology and instruments as well.

Vaccination is the most celebrated and denigrated achievement of medicine and public health - not only today, but since Edward Jenner's time (1798). In fact, the idea of injecting a mild form of "disease" into a healthy person was attacked even earlier than the discovery of vaccines. The forerunner of Jenner's vaccination with bovine lymph was the inoculation of smallpox material from person to person, which, known in Europe since the beginning of the eighteenth century, was a target of harsh criticism. The reasons for criticizing the Jennerian vaccination and its mandatory practice were medical, anthropological, biological (vaccination is not safe), religious and ethical (it is wrong to inoculate a healthy person with disease), and political (vaccination is a threat to individual freedom). As such, anti-vaccination groups emerged in England, where inoculation was adopted early, as well as overall in Europe and in the United States. This paper focuses on the lesser known debate that arose in Germany in the years 1852-53 about the medical practice of vaccination. This is an a important topic of public health that has aroused a wide debate and comparison especially in recent years and now with pandemic on Sars-Cov-2 (Covid-19) and will probably be the subject of further reflection and consideration in the coming years., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Since early May 2022, some monkeypox virus (MPXV) infections have been reported from countries where the disease is not endemic. Within 2 months, the number of patients has increased extensively, becoming the most considerable MPXV outbreak described. Smallpox vaccines demonstrated high efficacy against MPXVs in the past and are considered a crucial outbreak control measure. However, viruses isolated during the current outbreak carry distinct genetic variations, and the cross-neutralizing capability of antibodies remains to be assessed. Here we report that serum antibodies elicited by first-generation smallpox vaccines can neutralize the current MPXV more than 40 years after vaccine administration., (© 2023 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Background: After the global elimination of smallpox, monkeypox has become the most threatening orthopoxvirus to human health. Very few studies have been reported on pregnant women and newborns. In the case of monkeypox infection, the virus can cause serious adverse pregnancy events in women, which can lead to fetal or neonatal death., Data Sources: We made a comprehensive review after an extensive literature search in the PubMed/Medline database and websites concerning smallpox and monkeypox., Results: Two case reports reported a total of nine pregnant women, six of whom had fetal deaths. In the autopsy of a stillbirth, researchers found that the placenta was infected with monkeypox virus, but the mechanism of infection remains unclear. Smallpox vaccine should be administered to acutely exposed pregnant women and newborns. Several novel recombinant vaccinia immunogloblin (rVIG) and human-specific monoclonal antibodies are being developed for the prevention and treatment of monkeypox virus infection. After the fetus was delivered, the newborn should take a bath as soon as possible to remove the amniotic fluid and dirt from the body. The appropriate isolation protocol for the newborn should be selected according to the infection status of the mother. It is not known whether monkeypox virus is present in breast milk, and pasteurized breast milk can be given to newborns when breastfeeding is considered., Conclusion: This review presents an overview of monkeypox in the perinatal period and guides the future research direction., (© 2022. Children's Hospital, Zhejiang University School of Medicine.)

According to the World Health Organization, 83,339 laboratory-confirmed cases, including 72 deaths, of mpox (formerly known as monkeypox), have been reported from 110 locations globally as of 20 December 2022, making the disease a public health concern. Most of the cases (56,171, 67.4%) were reported from countries in North America. Limited data on vaccine effectiveness in the current mpox outbreak are available. However, the modified vaccinia virus (smallpox vaccine) has been predicted to prevent or reduce the severity of the mpox infection. The present study of systematic review and meta-analysis aimed to evaluate the modified vaccinia vaccine's safety and efficacy on mpox by using reported randomized clinical trials. Following guidelines from the Cochrane Collaboration and PRISMA, multiple databases including PubMed, PLOS ONE, Google Scholar, British Medical Journal, and the U. S. National Library of Medicine were searched. Out of 13,294 research articles initially identified, 187 were screened after removing duplicates. Following the inclusion and exclusion criteria, the meta-analysis included ten studies with 7430 patients. Three researchers independently assessed the risk of bias in the included study. The pooled results suggest that the vaccinia-exposed group had fewer side effects when compared to the vaccinia naïve group (odds ratio: 1.66; 95% CI: 1.07-2.57; p = 0.03). Overall, the modified vaccinia has proven safe and effective in both vaccinia naïve and previously exposed groups, with higher efficacy in the previously exposed groups.

Since vaccination remains the only effective protection against orthopox virus-induced diseases such as smallpox or monkeypox, the strategic use and stockpiling of these vaccines remains of significant public health importance. The approved liquid-frozen formulation of Bavarian Nordic's Modified Vaccinia Ankara (MVA-BN) smallpox vaccine has specific cold-chain requirements, while the freeze-dried (FD) formulation of this vaccine provides more flexibility in terms of storage conditions and shelf life. In this randomized phase 3 trial, the immunogenicity and safety of 3 consecutively manufactured lots of the FD MVA-BN vaccine was evaluated. A total of 1129 healthy adults were randomized to 3 treatment groups (lots 1 to 3) and received 2 vaccinations 4 weeks apart. For both neutralizing and total antibodies, a robust increase of geometric mean titer (GMT) was observed across all lot groups 2 weeks following the second vaccination, comparable to published data. For the primary results, the ratios of the neutralizing antibody GMTs between the lot group pairs ranged from 0.936 to 1.115, with confidence ratios well within the pre-specified margin of equivalence. Results for total antibodies were similar. In addition, seroconversion rates were high across the 3 lots, ranging between 99.1 % and 99.7 %. No safety concerns were identified; particularly, no inflammatory cardiac disorders were detected. The most common local solicited adverse events (AEs) reported across lot groups were injection site pain (87.2%) and erythema (73.2%), while the most common general solicited adverse events were myalgia, fatigue, and headache in 40.6% to 45.5% of all participants, with no meaningful differences among the lot groups. No related serious AEs were reported. In conclusion, the data demonstrate consistent and robust immunogenicity and safety results with a freeze-dried formulation of MVA-BN. Clinical Trial Registry Number: NCT03699124., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The recent emergence of monkeypox (MPX) has created a global threat. The number of infected and suspected cases of MPX is increasing in different parts of the world, especially in non-African countries. However, vaccines are available to fight against this disease. It has been observed that smallpox vaccines can be used to protect against MPX. The present article highlights the significant points and various issues for vaccines and vaccinations that should be considered related to MPX. This paper illustrates current vaccines for smallpox that can be utilized to protect against MPX infection. The article also describes the different significant research on MPXV, especially smallpox vaccines, and its outcome in MPX infection. We have also tried to depict the smallpox vaccination eradication model through the statistical interface using smallpox eradication data from Central and West Africa between 1967 and 1972. We suggest that these models might be helpful for the eradication of MPX in the middle to low-economic countries. Simultaneously, we have also discussed vaccination preparedness in different countries like the USA, UK, Canada, Denmark, Germany, etc. Our report might be helpful to scientists and policymakers in understanding the vaccines and vaccination against MPX and formulating effective strategies to fight against the disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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., (© 2022. The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation.)

Smallpox is an ancient scourge known since the Antiquity. It is caused by a highly contagious airborne poxvirus. This strictly human disease exists in two forms: variola major (Asian smallpox) with mortality of 20-45%, and an attenuated form called variola minor or alatrim with mortality of 1-2%, which only recently appeared in Europe and America towards the end of the 19th century. The first smallpox pandemic was the "Antonine plague", which swept through the Roman Empire in the 2nd century AD, after which smallpox became endemic in the Old World, causing seasonal and regional epidemics in Europe, affecting mostly young children until the 19th century. The discovery of the New World in 1492 and the opening of the African slave trade favored in 1518 the contamination by smallpox of the native Amerindian populations, who were massively decimated during the following centuries. In the absence of any effective treatment, preventive methods were developed from the 18th century. First, variolation was used, a dangerous procedure that consists in inoculating intradermally a small quantity of virus from convalescent patients. In the early 19th century, Edward Jenner popularized the practice of inoculating cowpox, a mild cow disease. This procedure proved to be very effective and relatively safe, leading to the decline of smallpox during the 19th century. In the 20th century, a ten-year WHO vaccination campaign led to the total eradication of smallpox in 1977. During that century, smallpox caused an estimated 300-500 million deaths worldwide. Using molecular approach, it has been discovered that the smallpox virus emerged 3000-4000 years ago in East Africa and is closely related to the taterapox virus from African gerbils and to the camelpox virus, which causes variola in camelids. Today, smallpox virus strains are stored in freezers at the CDC in Atlanta and at the Vector Center in Koltsovo, Siberia. That is why smallpox remains a potential threat to the highly susceptible human species, as a result of an accident or malicious use of the virus as a biological weapon., Competing Interests: Disclosure of interest The author has no conflict of interest., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

For over two decades, researchers have sought to improve smallpox vaccines and also develop therapies to ensure protection against smallpox or smallpox-like disease. The 2022 human monkeypox pandemic is a reminder that these efforts should persist. Advancing such therapies have involved animal models primarily using surrogate viruses such as monkeypox virus. The intravenous monkeypox model in macaques produces a disease that is clinically similar to the lesional phase of fulminant human monkeypox or smallpox. Two criticisms of the model have been the unnatural route of virus administration and the high dose required to induce severe disease. Here, we purified monkeypox virus with the goal of lowering the challenge dose by removing cellular and viral contaminants within the inoculum. We found that there are advantages to using unpurified material for intravenous exposures.

In 1972, Yugoslavia experienced the largest outbreak of smallpox in the history of Europe following the Second World War and its first smallpox outbreak after 1930. The origin of the infection is believed to be a pilgrim who visited countries in the Middle East. In this epidemic in Yugoslavia, from 16th February to 11 th April 1972, a total of 175 people fell ill, 35 (20%) of whom died. Measures against the outbreak were based on the strategy that was common in the final phase of the smallpox eradication program. It started with active surveillance and rapid identification of new cases. Measures, such as mass vaccination and quarantine of direct contacts, were promptly taken. In a few weeks, 18 million people had been vaccinated and approximately 15,000 had been quarantined. Yugoslavia was declared free of smallpox on 9 th May 1972. The global community today is confronted with serious threats from infectious diseases, which can appear as outbreaks and pandemics., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

This article re-examines from a new perspective the efforts of James Smith (1771-1841), a Maryland doctor, to eradicate smallpox in the United States. As one of the few successful cowpox inoculators at the turn of the nineteenth century, Smith recognized the necessity for a public vaccine institution that could ensure the safe production and continuous preservation and circulation of vaccine matter. Thus, he devoted himself to creating statewide and national vaccine institutions funded by the state and federal governments. He established the National Vaccine Institution (NVI), but despite his efforts, the NVI existed only a short time from 1813 to 1822. Previous studies on Smith have focused on the 1813 Vaccination Act (An Act to Encourage Vaccination) and the NVI, and have evaluated them as failed projects or historically missed opportunities. However, this kind of approach does not justly place the act and institutions within Smith's larger plan and do not fully discuss the role of the NVI in his system of promoting vaccination in the United States. This article analyzes how he responded to the problems hindering cowpox vaccination, including spurious vaccine, failed vaccination, and low public acceptance of cowpox vaccine. In doing so, this study shows that Smith attempted to establish a universal and systematic vaccination system connecting citizens, government, and medical personnel through the NVI, as well as ensuring a safe and regular supply of vaccine.

Although providing long-lasting immunity, smallpox vaccination was associated with local and systemic reactions and rarely with severe complications, including progressive vaccinia and postvaccinia encephalitis. As the Dryvax smallpox vaccine consists of a population of variants, we investigated a particularly pathogenic isolate called clone 3 (CL3). Virus replication was monitored by inserting the gene encoding firefly luciferase (Luc) into the genomes of CL3 and ACAM2000, the second-generation smallpox vaccine derived from a less virulent clone. Greater luminescence occurred following intranasal or intraperitoneal inoculation of mice with CL3-Luc than ACAM2000-Luc. Previous genome sequencing of CL3 and ACAM2000 revealed numerous differences that could affect pathogenicity. We focused on a 4.2-kbp segment, containing several open reading frames, in CL3 that is absent from ACAM2000 and determined that lower virulence of the latter was associated with a truncation of the interferon α/β (IFN-α/β) decoy receptor. Truncation of the decoy receptor in CL3-Luc and repair of the truncated version in ACAM2000-Luc decreased and increased virulence, respectively. Blockade of the mouse type 1 IFN receptor increased the virulence of ACAM2000-Luc to that of CL3-Luc, consistent with the role of IFN in attenuating the former. The severities of disease following intracranial inoculation of immunocompetent mice and intraperitoneal inoculation of T cell-depleted mice were also greater in viruses expressing the full-length decoy receptor. Previous evidence for the low affinity of a similarly truncated decoy receptor for IFN and the presence of a full-length decoy receptor in virus isolated from a patient with progressive vaccinia support our findings. IMPORTANCE Attenuated live viruses make effective vaccines, although concerns exist due to infrequent complications, particularly in individuals with immunological defects. Such complications occurred with smallpox vaccines, which were shown to be comprised of populations of variants. Clone 3, isolated from Dryvax, the vaccine most widely used in the United States during the smallpox eradication campaign, was particularly pathogenic in animal models. We demonstrated that the full-length IFN-α/β decoy receptor in CL3 and a truncation of the receptor in the clone used for the second-generation smallpox vaccine ACAM2000 account for their difference in pathogenicity. Viruses expressing the full-length decoy receptor were more virulent following intranasal, intraperitoneal, or intracranial inoculation of mice than ACAM2000, and disease was exacerbated following T cell depletion. Correspondingly, the full-length decoy receptor is present in smallpox vaccines with high rates of side effects and in a Dryvax clone obtained from a lesion in a patient with progressive vaccinia.

The availability of effective smallpox vaccines was a critical element of the successful eradication of smallpox in 1980. Antibody responses play a primary role in protective immunity and neutralizing antibody is an established correlate of protection against smallpox. In this study we used a poxvirus proteome array to assess the antibody response to individual viral proteins in a cohort of 1,037 smallpox vaccine recipients. Several statistically significant differences were observed in the antibody response to immunodominant proteins between men and women, including B5R-a major target of neutralizing antibody in vaccinia immune globulin, and the membrane proteins D8L and A27L, both of which have been used as vaccine antigens providing protection in animal models. We also noted differences across racial/ethnic groups. In this cohort, which consisted of both ACAM2000 and Dryvax recipients, we noted minute differences in the antibody responses to a restricted number of viral proteins, providing additional support for the use of ACAM2000 as a replacement smallpox vaccine. Furthermore, our data indicate that poxvirus proteome microarrays can be valuable for screening and monitoring smallpox vaccine-induced humoral immune responses in large-scale serologic surveillance studies and prove useful in the guidance of developing novel smallpox candidate vaccines., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: There are limited data regarding immunological correlates of protection for the modified vaccinia Ankara (MVA) smallpox vaccine., Methods: A total of 523 vaccinia-naive subjects were randomized to receive 2 vaccine doses, as lyophilized MVA given subcutaneously, liquid MVA given subcutaneously (liquid-SC group), or liquid MVA given intradermally (liquid-ID group) 28 days apart. For a subset of subjects, antibody-dependent cellular cytotoxicity (ADCC), interferon-γ release enzyme-linked immunospot (ELISPOT), and protein microarray antibody-binding assays were conducted. Protein microarray responses were assessed for correlations with plaque reduction neutralization titer (PRNT), enzyme-linked immunosorbent assay, ADCC, and ELISPOT results., Results: MVA elicited significant microarray antibody responses to 15 of 224 antigens, mostly virion membrane proteins, at day 28 or 42, particularly WR113/D8L and WR101H3L. In the liquid-SC group, responses to 9 antigens, including WR113/D8L and WR101/H3L, correlated with PRNT results. Three were correlated in the liquid-ID group. No significant correlations were observed with ELISPOT responses. In the liquid-ID group, WR052/F13L, a membrane glycoprotein, correlated with ADCC responses., Conclusions: MVA elicited antibodies to 15 vaccinia strain antigens representing virion membrane. Antibody responses to 2 proteins strongly increased and significantly correlated with increases in PRNT. Responses to these proteins are potential correlates of protection and may serve as immunogens for future vaccine development., Clinical Trials Registration: NCT00914732., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

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-Barré 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 < 40 years of age (21.1/100,000) than for those 40 years or older (6.3/100,000). Overall rates for any cardiovascular event (Group 1 plus Group 2) were 113.5/100,000 for ACAM2000 vaccine and 439.3/100,000 for Dryvax vaccine; rate ratio, 0.26 (95% CI, 0.24-0.28). The rates of subjects with one or more defined neurological events were 2.12/100,000 and 1.11/100,000 for ACAM2000 and Dryvax vaccines respectively; rate ratio, 1.91 (95% CI, 0.71-5.10)., Conclusions: Electronic records surveillance of the entire vaccinated SM population over a ten-year period found rates of myopericarditis, of defined neurological events, and of overall cardiac events that were consistent with those of prior passive surveillance studies involving Dryvax or ACAM2000 smallpox vaccines., Clinical Trials Registration: ClinicalTrials.gov NCT00927719., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The world confronts today a disease which was unknown as recently as early 2019. Now that there is a safe and effective vaccine against COVID-19, lessons can usefully be drawn from previous well documented vaccination efforts. Of these, the best documented and most successful is the Smallpox Eradication Program (SEP). A review was made of publications by major players in smallpox eradication, respecting the important differences between the disease, this review revealed several points of connection. Cultural factors loomed large both in the eradication of smallpox and progress, to date, in the control of COVID-19. Other points of similarity included political commitment, the set-up of strong surveillance mechanisms, and assurance of uniformly high quality vaccines tested and approved by the World Health Organization. The future of COVID-19 control depends, in part, on lessons learned from previous vaccination efforts. A review of those efforts will avoid repetition of past errors and permit adoption of best practices from the past. Such analyses must, of course, respect the important differences between COVID-19 and smallpox., Competing Interests: The author declares no competing interest., (Copyright: Robert Davis et al.)

Smallpox, a disease caused by the variola virus, is one of the most dangerous diseases and had killed numerous people before it was eradicated in 1980. However, smallpox has emerged as the most threatening bio-terrorism agent; as the first- and second-generation smallpox vaccines have been controversial and have caused severe adverse reactions, new demands for safe smallpox vaccines have been raised and some attenuated smallpox vaccines have been developed. We have developed a cell culture-based highly attenuated third-generation smallpox vaccine candidate KVAC103 strain by 103 serial passages of the Lancy-Vaxina strain derived from the Lister in Vero cells. Several clones were selected, taking into consideration their shape, size, and growth rate in mammalian cells. The clones were then inoculated intracerebrally in suckling mice to test for neurovirulence by observing survival. Protective immune responses in adult mice were examined by measuring the levels of neutralization antibodies and IFN-γ expression. Among several clones, clone 7 was considered the best alternative candidate because there was no mortality in suckling mice against a lethal challenge. In addition, enhanced neutralizing antibodies and T-cell mediated IFN-γ production were observed in clone 7-immunized mice. Clone 7 was named "KVAC103" and was used for the skin toxicity test and full-genome analysis. KVAC103-inoculated rabbits showed reduced skin lesions compared to those inoculated with the Lister strain, Lancy-Vaxina. A whole genome analysis of KVAC103 revealed two major deleted regions that might contribute to the reduced virulence of KVAC103 compared to the Lister strain. Phylogenetic inference supported the close relationship with the Lister strain. Collectively, our data demonstrate that KVAC103 holds promise for use as a third-generation smallpox vaccine strain due to its enhanced safety and efficacy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mr. O’Dell has no conflict of interest. Dr. Williams has no conflict of interest. Dr. Poland is the chair of a Safety Evaluation Committee for novel investigational vaccine trials being conducted by Merck Research Laboratories. Dr. Poland offers consultative advice on vaccine development to Merck & Co., Medicago, GlaxoSmithKline, Sanofi Pasteur, Emergent Biosolutions, Dynavax, Genentech, Eli Lilly and Company, Janssen Global Services LLC, Kentucky Bioprocessing, AstraZeneca, and Genevant Sciences, Inc. Dr. Poland holds patents related to vaccinia and measles peptide vaccines. Dr. Poland has received grant funding from ICW Ventures for preclinical studies on a peptide-based COVID-19 vaccine. These activities have been reviewed by the Mayo Clinic Conflict of Interest Review Board and are conducted in compliance with Mayo Clinic Conflict of Interest policies., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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.

A monkeypox outbreak in Nigeria during 2017-2020 provides an illustrative case study for emerging zoonoses. We built a statistical model to simulate declining immunity from monkeypox at 2 levels: At the individual level, we used a constant rate of decline in immunity of 1.29% per year as smallpox vaccination rates fell. At the population level, the cohort of vaccinated residents decreased over time because of deaths and births. By 2016, only 10.1% of the total population in Nigeria was vaccinated against smallpox; the serologic immunity level was 25.7% among vaccinated persons and 2.6% in the overall population. The substantial resurgence of monkeypox in Nigeria in 2017 appears to have been driven by a combination of population growth, accumulation of unvaccinated cohorts, and decline in smallpox vaccine immunity. The expanding unvaccinated population means that entire households, not just children, are now more susceptible to monkeypox, increasing risk of human-to-human transmission.

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.

Objectives: To estimate the impact of a smallpox attack in Mumbai, India, examine the impact of case isolation and ring vaccination for epidemic containment and test the health system capacity under different scenarios with available interventions., Setting: The research is based on Mumbai, India population., Interventions: We tested 50%, 70%, 90% of case isolation and contacts traced and vaccinated (ring vaccination) in the susceptible, exposed, infected, recovered model and varied the start of intervention between 20, 30 and 40 days after the initial attack., Primary and Secondary Outcome Measures: We estimated and incorporated in the model the effect of past vaccination protection, age-specific immunosuppression and contact rates and Mumbai population age structure in modelling disease morbidity and transmission., Results: The estimated duration of an outbreak ranged from 127 days to 8 years under different scenarios, and the number of vaccine doses needed for ring vaccination ranged from 16 813 to 8 722 400 in the best-case and worst-case scenarios, respectively. In the worst-case scenario, the available hospital beds in Mumbai would be exceeded. The impact of a smallpox epidemic may be severe in Mumbai, especially compared with high-income settings, but can be reduced with early diagnosis and rapid response, high rates of case finding and isolation and ring vaccination., Conclusions: This study tells us that if smallpox re-emergence occurs, it may have significant health and economic impact, the extent of which will depend on the availability and delivery of interventions such as a vaccine or antiviral agent, and the capacity of case isolation and treatment. Further research on health systems requirements and capacity across the diverse states and territories of India could improve the preparedness and management strategies in the event of re-emergent smallpox or other serious emerging infections., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background Aims: E3L is an immediate-early protein of vaccinia virus (VV) that is detected within 0.5 h of infection, potentially before the many immune evasion genes of vaccinia can exert their protective effects. E3L is highly conserved among orthopoxviruses and hence could provide important protective T-cell epitopes that should be retained in any subunit or attenuated vaccine. We have therefore evaluated the immunogenicity of E3L in healthy VV-vaccinated donors., Methods: Peripheral blood mononuclear cells from healthy volunteers (n = 13) who had previously received a smallpox vaccine (Dryvax) were activated and expanded using overlapping E3L peptides and their function, specificity and antiviral activity was analyzed. E3L-specific T cells were expanded from 7 of 12 (58.3%) vaccinated healthy donors. Twenty-five percent of these produced CD8+ T-cell responses and 87.5% produced CD4+ T cells. We identified epitopes restricted by HLA-B35 and HLA-DR15., Results: E3L-specific T cells killed peptide-loaded target cells as well as vaccinia-infected cells, but only CD8+ T cells could prevent the spread of infectious virus in virus inhibition assays. The epitopes recognized by E3L-specific T cells were shared with monkeypox, and although there was a single amino acid change in the variola epitope homolog, it was recognized by vaccinia-specific T-cells., Conclusions: It might be important to include E3L in any deletion mutant or subunit vaccine and E3L could provide a useful antigen to monitor protective immunity in humans., Competing Interests: The authors have no commercial, proprietary, or financial interest in the products or companies described in this article., (38; Gene Therapy. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: At the time of the study, DMG, NT, AS, and MDD were employees of Sanofi Pasteur and IR-L was an employee of United BioSource Corporation, a contractee of Sanofi Pasteur; DJF and LNP were employees of the US Department of Defense; GL and GD were employees of Emergent BioSolutions., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Vaccination has transformed public health, most notably including the eradication of smallpox. Despite its profound historical importance, little is known of the origins and diversity of the viruses used in smallpox vaccination. Prior to the twentieth century, the method, source and origin of smallpox vaccinations remained unstandardised and opaque. We reconstruct and analyse viral vaccine genomes associated with smallpox vaccination from historical artefacts. Significantly, we recover viral molecules through non-destructive sampling of historical materials lacking signs of biological residues. We use the authenticated ancient genomes to reveal the evolutionary relationships of smallpox vaccination viruses within the poxviruses as a whole.

Smallpox eradication, coordinated by the WHO and certified 40 years ago, led to the cessation of routine smallpox vaccination in most countries. It is estimated that over 70% of the world's population is no longer protected against smallpox, and through cross-immunity, to closely related orthopox viruses such as monkeypox. Monkeypox is now a re-emerging disease. Monkeypox is endemic in as yet unconfirmed animal reservoirs in sub-Saharan Africa, while its human epidemiology appears to be changing. Monkeypox in small animals imported from Ghana as exotic pets was at the origin of an outbreak of human monkeypox in the USA in 2003. Travellers infected in Nigeria were at the origin of monkeypox cases in the UK in 2018 and 2019, Israel in 2018 and Singapore in2019. Together with sporadic reports of human infections with other orthopox viruses, these facts invite speculation that emergent or re-emergent human monkeypox might fill the epidemiological niche vacated by smallpox. An ad-hoc and unofficial group of interested experts met to consider these issues at Chatham House, London in June 2019, in order to review available data and identify monkeypox-related research gaps. Gaps identified by the experts included:The experts further agreed on the need for a better understanding of the genomic evolution and changing epidemiology of orthopox viruses, the usefulness of in-field genomic diagnostics, and the best disease control strategies, including the possibility of vaccination with new generation non-replicating smallpox vaccines and treatment with recently developed antivirals., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Authors Elsgaard, Hochrein, Maclennan and Powell are employees of Bavarian Nordic, manufacturer of a vaccine registered as Jynneos for smallpox and monkeypox indications in the USA (Imvanex for smallpox only in Europe and Imvamune for smallpox only in Canada. Simpson works as a consultant for Bavarian Nordic., (Copyright © 2020.)

For the first 80-90 years after Jenner's discovery of vaccination in 1796, the main strategy used to disseminate and maintain the smallpox vaccine was arm-to-arm vaccination, also known as Jennerian or humanized vaccination. A major advance occurred after 1860 with the development of what was known as "animal vaccine", which referred to growing vaccine material from serial propagation in calves before use in humans. The use of "animal vaccine" had several advantages over arm-to-arm vaccination: it would not transmit syphilis or other human diseases, it ensured a supply of vaccine even in the absence of the spontaneous occurrence of cases of cowpox or horsepox, and it allowed the production of large amounts of vaccine. The "animal vaccine" concept was introduced in the United States in 1870 by Henry Austin Martin. Very rapidly a number of "vaccine farms" were established in the U.S. and produced large quantities of "animal vaccine". These "vaccine farms" were mostly established by medical doctors who saw an opportunity to respond to an increasing demand of smallpox vaccine from individuals and from health authorities, and to make a profit. The "vaccine farms" evolved from producing only smallpox "animal vaccine" to manufacturing several other biologics, including diphtheria- and other antitoxins. Two major incidents of tetanus contamination happened in 1901, which led to the promulgation of the Biologics Control Act of 1902. The US Secretary of the Treasury issued licenses to produce and sell biologicals, mainly vaccines and antitoxins. Through several mergers and acquisitions, the initial biologics licensees eventually evolved into some of the current major American industrial vaccine companies. An important aspect that was never clarified was the source of the vaccine stocks used to manufacture the smallpox "animal vaccines". Most likely, different smallpox vaccine stocks were repeatedly introduced from Europe, resulting in polyclonal vaccines that are now recognized as "variants" more appropriately than "strains". Further, clonal analysis of modern "animal vaccines" indicate that they are probably derived from complex recombinational events between different strains of vaccinia and horsepox. Modern sequencing technologies are now been used by us to study old smallpox vaccine specimens in an effort to better understand the origin and evolution of the vaccines that were used to eradicate the smallpox., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The re-emergence of smallpox is an increasing and legitimate concern due to advances in synthetic biology. Vaccination programs against smallpox using the vaccinia virus vaccine ceased with the eradication of smallpox and, unlike many other countries, Australia did not use mass vaccinations. However, vaccinated migrants contribute to population immunity. Testing for vaccinia antibodies is not routinely performed in Australia, and few opportunities exist to estimate the level of residual population immunity against smallpox. Serological data on population immunity in Australia could inform management plans against a smallpox outbreak. Vaccinia antibodies were measured in 2003 in regular plasmapheresis donors at the Australian Red Cross Blood Service from New South Wales (NSW). The data were analysed to estimate the proportion of Australians in NSW with detectable serological immunity to vaccinia. The primary object of this study was to measure neutralising antibody titres against vaccinia virus. Titre levels in donor samples were determined by plaque reduction assay. To estimate current levels of immunity to smallpox infection, the decline in geometric mean titres (GMT) over time was projected using two values for the antibody levels estimated on the basis of different times since vaccination. The results of this study suggest that there is minimal residual immunity to the vaccinia virus in the Australian population. Although humoral immunity is protective against orthopoxvirus infections, cell-mediated immunity and immunological memory likely also play roles, which are not quantified by antibody levels. These data provide an immunological snapshot of the NSW population, which could inform emergency preparedness planning and outbreak control, especially concerning the stockpiling of vaccinia vaccine.

Introduction: The social history of written culture reflects the reading and writing habits and practices that allow us to appropriate the texts to build our sense of community. Hence, the library of individuals reflects their reading habits, their way of imagining nature, their relationship with political and religious power, and their involvement with society. Objective: To interpret Antonio Nariño’s reading practices by means of the medical books in his library to approach the way he developed a presumably effective vaccine against smallpox. Materials and methods: We made a bibliographic description of the documents “Confiscación y embargo de bienes de Nariño” and “Papeles, libros y bienes de Sebastián López Ruiz en poder de Nariño” from the Nariño Archive of the Universidad Nacional de Colombia. Results: Out of the 39 books about Medicine (seven treatises on surgery, 12 compendia of practical exercise, 11 disease manuals, seven compendia of medical topics, and two books on childbirth) three were smallpox treatises. Conclusion: Antonio Nariño’s medical and scientific practice reflects his reading and writing habits, his skills and competences, and his cultural attitudes, which promoted the notion of public health. The study of Nariño as a self-taught physician allowed for relating the scientific production techniques (development of the vaccine) and the cultural materiality (state of the art) based on the medical texts in his library.

This research explores the case of the 1903 smallpox outbreak on the SS Korea , a transpacific carrier making runs between Southeast Asia, East Asia, Hawaii, and the United States. These regions were connected to a degree that no one had ever imagined through the SS Korea . Honolulu, Hawaii, was one of the most important territories in US maritime history and served as a waypoint between Asia and San Francisco on the mainland. As increasing numbers of people traveled by sea, various microbes were communicated across the Pacific Ocean. International tourists traveling across the ocean to Hawaii and the United States were alerted to infectious diseases, smallpox being one of the most significant of such diseases. The story of the SS Korea serves as an important lens through which to explore the early twentieth century transpacific world connected through Honolulu. Focusing on the spread of smallpox via international travelers, this research studies aspects of the public health system that were developed to contain smallpox infection on international ships and the application of smallpox vaccination as a method for infectious disease control. More importantly, in bringing attention to the uncertainty surrounding the diagnosis of smallpox, this research argues for the necessity of historians to build a more comprehensive medical historical context for disease control systems that includes the limits of medical science in making diagnoses of infectious diseases, the uncertainties arising from a lack of this component, and the implementation of health policies and preventative medical technologies.