Poxvirus Vaccines: Past, Present, and Future.

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.

Treatment and Vaccination for Smallpox and Monkeypox.

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.

Levels of antibodies against the monkeypox virus compared by HIV status and historical smallpox vaccinations: a serological study.

Men who have sex with men and people living with HIV are disproportionately affected in the 2022 multi-country monkeypox epidemic. The smallpox vaccine can induce cross-reactive antibodies against the monkeypox virus (MPXV) and reduce the risk of infection. Data on antibodies against MPXV induced by historic smallpox vaccination in people with HIV are scarce. In this observational study, plasma samples were collected from people living with and without HIV in Shenzhen, China. We measured antibodies binding to two representative proteins of vaccinia virus (VACV; A27L and A33R) and homologous proteins of MPXV (A29L and A35R) using an enzyme-linked immunosorbent assay. We compared the levels of these antibodies between people living with and without HIV. Stratified analyses were performed based on the year of birth of 1981 when the smallpox vaccination was stopped in China. Plasma samples from 677 people living with HIV and 746 people without HIV were tested. A consistent pattern was identified among the four antibodies, regardless of HIV status. VACV antigen-reactive and MPXV antigen-reactive antibodies induced by historic smallpox vaccination were detectable in the people born before 1981, and antibody levels reached a nadir during or after 1981. The levels of smallpox vaccine-induced antibodies were comparable between people living with HIV and those without HIV. Our findings suggest that the antibody levels against MPXV decreased in both people living with and without HIV due to the cessation of smallpox vaccination.

Introduction of the smallpox vaccine in Napoleonic France, as recorded in contemporary medals.

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.

[La expedición Balmis en el Suplemento a la Gazeta de Madrid (14 de octubre de 1806), difusión hispana.] / The Balmis expedition in the Supplement to the Gazeta de Madrid (October 14, 1806), Hispanic diffusion.

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.

La Gazeta de Madrid publicó un Suplemento el 14 de octubre de 1806 dando noticia de la llegada y recepción al Director de la Real Expedición Filantrópica de la Vacuna, Francisco Xavier Balmis, por parte del Rey Carlos IV. Había finalizado su periplo dando la vuelta al mundo por los territorios españoles de ultramar, llevando la vacuna contra la viruela brazo a brazo con la ayuda de una cadena humana de niños, creando Juntas de Vacunación e intentando encontrar vacas con cowpox. La publicación refrendó las políticas de una monarquía borbónica en decadencia y significó el momento álgido de la carrera profesional de Balmis. Ambas partes ganaban: la Corona publicitándose como financiadora y organizadora del viaje altruista en línea con expediciones científicas anteriores; Balmis pasando a la historia de la Salud Pública como director de la primera campaña internacional de vacunación. No fue el final de la expedición, ya que el resto de los expedicionarios aún seguían vacunando en Filipinas y América del Sur. El objetivo de este estudio fue analizar la importancia de la Gazeta de Madrid como periódico, describir los contenidos de la noticia, verificar el origen de las fuentes documentales que apoyaron su redacción y comprobar el impacto y citas que tuvo a lo largo del siglo XIX en publicaciones en idioma español. Los componentes de la noticia, su proveniencia, así como la participación de Balmis en su redacción han quedado probados. La importancia del Suplemento estribó en su utilidad como recurso para recordar y poner en valor la expedición.

Lest we forget: Odunbaku Oguntona Sapara William (1895-1935) beyond the demystification of deity.

Oguntola Odunbaku Sapara Williams (born Alexander Johnson Williams, 1861-1935) was a Fellow of the Royal Institute of Public Health. This paper attempts to highlight the effort of an African doctor to fight disease outbreaks during the African colonial era. His uninterrupted 32 years career as a colonial medical officer in one of the British colonies in West Africa, provided superintendence for the eradication of smallpox as a result of this, he was credited with the demystification of metaphysical involvement in the smallpox epidemic and thus eradication of smallpox in the Lagos colony. He also provided leadership for the control of bubonic plague, and tuberculosis epidemics and pioneered initiatives to reduce maternal and infant mortality by vaccination, enactment of public health law, environmental sanitation, and health education in Southwest Nigeria.

Las epidemias de viruela y la introducción de la vacuna en el Virreinato del Río de la Plata / Smallpox epidemics and vaccine introduction in the Viceroyalty of the Río de la Plata

La viruela fue una de las enfermedades epidémicas más temidas desde la antigüedad debido a su alta mortalidad y a las secuelas que dejaba en aquellos que lograban sobrevivir. En el presente trabajo se abordará el ingreso de esta enfermedad en nuestro continente, así como su manifestación a través de epidemias, brotes y focos endémicos. Al mismo tiempo se verá qué reacciones provocó dentro del ámbito médico durante los años del Virreinato del Río de la Plata. Se analizarán los problemas que surgieron con el uso de la vacuna importada, así como el hallazgo de nuestra vacuna local, finalizando con los comienzos de la organización de los servicios de vacunación obligatoria. (AU)

Smallpox was one of the most feared epidemic diseases since ancient times due to its high mortality and the sequelae caused in those that managed to survive. In the present work, the introduction of this disease into our continent will be addressed as well as its manifestation through epidemics, outbreaks, and endemic foci. At the same time, the reactions this disease caused inside the medical field during the years of the Viceroyalty of the Río de la Plata will be observed. The problems that arose from the usage of the imported vaccine and the discovery of our local vaccine will be analyzed, and it will finish with the beginnings of the organization of the mandatory vaccination services. (AU)

Kaspar Hauser, the Child of Europe: Are smallpox vaccination scars the clue to a 2-century-old mystery?

We have explored the 19th century mystery of the identity of Kaspar Hauser, the so-called Child of Europe, from the perspective of the smallpox vaccination. We have highlighted the improbability that he was secretly inoculated based on the vaccination policies and methodologies applied at the time. This consideration allows for a reflection on the whole case and the importance of vaccination scars in ascertaining immunization against one of humanity's deadliest killers, especially given the recent monkeypox outbreak.

Pandemic potential of poxviruses: From an ancient killer causing smallpox to the surge of monkeypox.

Smallpox caused by the variola virus (VARV) was one of the greatest infectious killers of mankind. Historical records trace back smallpox for at least a millennium while phylogenetic analysis dated the ancestor of VARV circulating in the 20th century into the 19th century. The discrepancy was solved by the detection of distinct VARV sequences first in 17th-century mummies and then in human skeletons dated to the 7th century. The historical records noted marked variability in VARV virulence which scientists tentatively associated with gene losses occurring when broad-host poxviruses narrow their host range to a single host. VARV split from camel and gerbil poxviruses and had no animal reservoir, a prerequisite for its eradication led by WHO. The search for residual pockets of VARV led to the discovery of the monkeypox virus (MPXV); followed by the detection of endemic smallpox-like monkeypox (mpox) disease in Africa. Mpox is caused by less virulent clade 2 MPXV in West Africa and more virulent clade 1 MPXV in Central Africa. Exported clade 2 mpox cases associated with the pet animal trade were observed in 2003 in the USA. In 2022 a world-wide mpox epidemic infecting more than 80,000 people was noted, peaking in August 2022 although waning rapidly. The cases displayed particular epidemiological characteristics affecting nearly exclusively young men having sex with men (MSM). In contrast, mpox in Africa mostly affects children by non-sexual transmission routes possibly from uncharacterized animal reservoirs. While African children show a classical smallpox picture, MSM mpox cases show few mostly anogenital lesions, low-hospitalization rates and 140 fatal cases worldwide. MPXV strains from North America and Europe are closely related, derived from clade 2 African MPXV. Distinct transmission mechanisms are more likely causes for the epidemiological and clinical differences between endemic African cases and the 2022 epidemic cases than viral traits.

Poxes great and small: The stories behind their names.

The word "pox" indicated, during the late 15th century, a disease characterized by eruptive sores. When an outbreak of syphilis began in Europe during that time, it was called by many names, including the French term "la grosse verole" ("the great pox"), to distinguish it from smallpox, which was termed "la petite verole" ("the small pox"). Chickenpox was initially confused with smallpox until 1767, when the English physician William Heberden (1710-1801) provided a detailed description of chickenpox, differentiating it from smallpox. The cowpox virus was used by Edward Jenner (1749-1823) to develop a successful vaccine against smallpox. He devised the term "variolae vaccinae" ("smallpox of the cow") to denote cowpox. Jenner's pioneering work on a smallpox vaccine has led to the eradication of this disease and opened the way to preventing other infectious diseases, such as monkeypox, a poxvirus that is closely related to smallpox and that is currently infecting persons around the world. This contribution tells the stories behind the names of the various "poxes" that have infected humans: the great pox (syphilis), smallpox, chickenpox, cowpox, and monkeypox. These infectious diseases not only share a common "pox" nomenclature, but are also closely interconnected in medical history.

Analysis of variola virus molecular evolution suggests an old origin of the virus consistent with historical records.

Archaeovirology efforts provided a rich portrait of the evolutionary history of variola virus (VARV, the cause of smallpox), which was characterized by lineage extinctions and a relatively recent origin of the virus as a human pathogen (~1700 years ago, ya). This contrasts with historical records suggesting the presence of smallpox as early as 3500 ya. By performing an analysis of ancestry components in modern, historic, and ancient genomes, we unveil the progressive drifting of VARV lineages from a common ancestral population and we show that a small proportion of Viking Age ancestry persisted until the 18th century. After the split of the P-I and P-II lineages, the former experienced a severe bottleneck. With respect to the emergence of VARV as a human pathogen, we revise time estimates by accounting for the time-dependent rate phenomenon. We thus estimate that VARV emerged earlier than 3800 ya, supporting its presence in ancient societies, as pockmarked Egyptian mummies suggest.

Voltaire and the politicization of medicine and science.

The 17th and 18th centuries witnessed an intellectual movement known as the Enlightenment that made possible future revolutions such as the scientific. No person better characterizes the Enlightenment than Voltaire (1696-1976) who, in his book Philosophical Letters published in 1734, venerated the liberalism of English institutions while criticizing the ancien régime of France. He was convinced that the personal freedom the English enjoyed was responsible for their country's success, pointing to inoculation for smallpox and advances in science as evidence. His choice of smallpox inoculation and science as exemplars of empiricism, which maintained that knowledge is obtained through sensory experience, is revealing as it pinpoints political flashpoints that persist to this day. This paper explores how inoculation and science were employed by Voltaire to advance his political idea of liberty.

Racial Disparity, Social Determinates of Health, and Slavery During the Boston Smallpox Epidemics of the Eighteenth Century.

When Benjamin Franklin published the mortality rates from smallpox during the Boston smallpox epidemic of 1752, he revealed that Blacks not only had a higher mortality rate from smallpox (12.8%, 62/485; 8.9% for whites, 452/5,059), but once inoculated, had less protection from fatal disease (mortality rate 5.0%, 7/139; 1.2% for whites, 23/1,954). His report was thus the first publication to document racial disparities in a disease and its treatment. The differential outcomes came about in the context of slavery, poverty, and war, the predecessors of the social determinates of health that we observe today.During the 1752 outbreak only 28 percent of the Boston's occupants were inoculated, a level that failed to protect the community. When the contagion returned in 1764, the town selectmen decided to provide inoculations at no cost to all that needed them. That year inoculated smallpox reached 87 percent of the total caseload. "This lowered the death rate for smallpox so markedly,' wrote John Blake, historian at the National Library of Medicine, "that for the first time a smallpox year failed to stand out as one of unusual mortality." One final observation came from Franklin's data: the unexpectedly high prevalence of inoculations among Blacks (6.8% of those inoculated, 146/2,143; 8.5% of all those contracting the disease, 693/8,201). Boston's whites had made certain enslaved Blacks were inoculated, evidence the extent to which slavery was essential to the economy of colonial Boston.

A great inspiration for today's vaccination efforts: Biographical sketch of Francisco Xavier Balmis (1753-1819).

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.

Historical Lessons on Vaccine Hesitancy: Smallpox, Polio, and Measles, and Implications for COVID-19.

Vaccine hesitancy continues to pose a formidable obstacle to increasing national COVID-19 vaccination rates in the US, but this is not the first time that American vaccination efforts have confronted resistance and apathy. This study examines the history of US vaccination efforts against smallpox, polio, and measles, highlighting persistent drivers of vaccine hesitancy as well as factors that helped overcome it. The research reveals that logistical barriers, negative portrayals in the media, and fears about safety stymied inoculation efforts as early as the 18th century and continue to do so. However, vaccine hesitancy has been markedly diminished when trusted community leaders have guided efforts, when ordinary citizens have felt personally invested in the success of the vaccine, and when vaccination efforts have been tied to broader projects to improve public health and social cohesion. Deliberately cultivating such factors could be an effective strategy for lessening opposition today, when COVID-19's distinctive characteristics make addressing vaccine hesitancy more urgent than it has ever been.

Convincing the "Herd" of immunity: Lessons from smallpox vaccination in 19th century Germany.

Although vaccination is a cost-effective way to control infectious diseases, it is often met with popular resistance. Studying smallpox in 19th century Germany, this paper explores how economic incentives contribute to this phenomenon. The paper adds to the literature by combining mathematical epidemiology and unpublished archival evidence from two German states - Baden and Wurttemberg. The two states are an intriguing case because their initial conditions and vaccination laws were similar. Despite this, Baden experienced lower smallpox prevalence and higher vaccination uptake than Wurttemberg. The epidemiological model predicts that incentives to vaccinate decline rapidly when immunization reduces prevalence. The archival evidence reveals that Baden offset this decline by creating a public vaccination system which reduced costs for vaccinees and vaccinators alike. This suggests that the high fixed costs of centralized immunization policies can be compensated by economies of scale and popular acceptance.

Military Epidemics, Then and Now: Smallpox and COVID-19.

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

Vaccine and smallpox vaccination in nineteenth century Bahia. / Vacina e vacinação antivariólica na Bahia oitocentista.

This article aims to discuss the perceptions and actions of public authorities regarding the process of introduction, production, conservation, distribution, and application of the smallpox vaccine; the emergence of institutions associated with the vaccine and vaccination; and its main obstacles in Bahia in the nineteenth century. The article emphasizes the local and regional dynamics of this process. It addresses the problem of smallpox in colonial Bahia, the arrival of the Jennerian vaccine, the diffusion of the vaccination method, the establishment of health institutions, and the disease control measures implemented as of 1808. In the context of the post-independence and Imperial Brazil, this article addresses smallpox outbreaks and discusses the problems related to vaccine and vaccination listed by the governors of the province of Bahia and local efforts to introduce the animal vaccine. This article is based on printed primary sources published in Bahia in the nineteenth century, as well as through dialogues with specialized literature.

O objetivo do artigo é discutir as percepções e ações do poder público sobre o processo de introdução, produção, conservação, distribuição e aplicação da vacina contra a varíola, o surgimento de instituições ligadas à vacina e à vacinação e seus principais entraves na Bahia do século XIX. O artigo enfatiza a dinâmica local e regional desse processo e aborda o problema da varíola na Bahia colonial, a chegada da vacina jenneriana, a difusão do método de vacinação, a constituição de instituições de saúde e as medidas de controle da doença implantadas a partir de 1808. No contexto do pós-independência e do Brasil Imperial, aborda os surtos de varíola e discute os problemas da vacina e da vacinação relacionados pelos presidentes da província da Bahia e os esforços locais para introduzir a vacina animal. O artigo se baseia em fontes primárias impressas publicadas na Bahia no século XIX e no diálogo com a literatura especializada.

Vaccination in the 19th century in Italy and the role of the catholic church in public health: a historical overview.

Using the case of the vaccine against smallpox as an example, this article explores how the attitude and the politics of the Vatican State towards vaccination changed between the 18th and 19th century. Despite some notable exceptions, the Catholic Church became progressively involved in supporting vaccination in Italy, exerting its temporal and spiritual authority to develop healthcare policies and to convince a population that still considered the vaccine as potentially harmful. The brief historical overview on vaccine and vaccination shows that during the XIX century the Catholic church and in particular, the political decision of the Pope, engaged temporal and spiritual power, high authority and persuasive influence to encourage the population, more than anyone the hesitant people, to get vaccine against smallpox. Although with the due differences determined by the path of time and by the scientific, educational and social advances of modern-day, this view from the past can provide us, with actual COVID pandemic, a reason of deep thinking and also how to face the present COVID-19 pandemic and to prepare for forcoming future. Actually, it shows us how the terrible smallpox epidemic was handled and finally overcome, thanks to vaccination.