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.

Effectiveness of historical smallpox vaccination against mpox clade II in men in Denmark, France, the Netherlands and Spain, 2022.

BackgroundIn 2022, a global monkeypox virus (MPXV) clade II epidemic occurred mainly among men who have sex with men. Until early 1980s, European smallpox vaccination programmes were part of worldwide smallpox eradication efforts. Having received smallpox vaccine > 20 years ago may provide some cross-protection against MPXV.AimTo assess the effectiveness of historical smallpox vaccination against laboratory-confirmed mpox in 2022 in Europe.MethodsEuropean countries with sufficient data on case vaccination status and historical smallpox vaccination coverage were included. We selected mpox cases born in these countries during the height of the national smallpox vaccination campaigns (latest 1971), male, with date of onset before 1 August 2022. We estimated vaccine effectiveness (VE) and corresponding 95% CI for each country using logistic regression as per the Farrington screening method. We calculated a pooled estimate using a random effects model.ResultsIn Denmark, France, the Netherlands and Spain, historical smallpox vaccination coverage was high (80-90%) until the end of the 1960s. VE estimates varied widely (40-80%, I2 = 82%), possibly reflecting different booster strategies. The pooled VE estimate was 70% (95% CI: 23-89%).ConclusionOur findings suggest residual cross-protection by historical smallpox vaccination against mpox caused by MPXV clade II in men with high uncertainty and heterogeneity. Individuals at high-risk of exposure should be offered mpox vaccination, following national recommendations, regardless of prior smallpox vaccine history, until further evidence becomes available. There is an urgent need to conduct similar studies in sub-Saharan countries currently affected by the MPXV clade I outbreak.

Patterns of smallpox mortality in London, England, over three centuries.

Smallpox is unique among infectious diseases in the degree to which it devastated human populations, its long history of control interventions, and the fact that it has been successfully eradicated. Mortality from smallpox in London, England was carefully documented, weekly, for nearly 300 years, providing a rare and valuable source for the study of ecology and evolution of infectious disease. We describe and analyze smallpox mortality in London from 1664 to 1930. We digitized the weekly records published in the London Bills of Mortality (LBoM) and the Registrar General's Weekly Returns (RGWRs). We annotated the resulting time series with a sequence of historical events that might have influenced smallpox dynamics in London. We present a spectral analysis that reveals how periodicities in reported smallpox mortality changed over decades and centuries; many of these changes in epidemic patterns are correlated with changes in control interventions and public health policies. We also examine how the seasonality of reported smallpox mortality changed from the 17th to 20th centuries in London.

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.

Letters from Balmis to Gutiérrez: fracture of the friendship between two vaccine expeditionary personages.

The Royal Philanthropic Vaccine Expedition (1803-1813) becomes relevant in these pandemic times due to the breadth of its geographical dimension and its nature of a health expedition inspired by a pioneering public health objective of its time: to spread the newly discovered vaccine against smallpox. Undertaken by a small number of participants, the expedition was directed by Francisco Xavier Balmis, who was accompanied, among others, by Antonio Gutiérrez Robredo, his favorite disciple. This research, carried out using primary sources, explores the relationship between both, which went from mutual trust to enmity due to a trivial conflict. The study of previous correspondence and late resolution of the lawsuit filed by Balmis against Gutiérrez allows us to delve into their biographical profiles. As a direct consequence of that litigation, Gutiérrez never went back to Spain, although he became a professor in Mexico; in contrast, Balmis enjoyed honors and recognition in Madrid.

En estos tiempos de pandemia, la Real Expedición Filantrópica de la Vacuna (1803-1813) cobra vigencia por la amplitud de su dimensión geográfica y por su carácter de expedición sanitaria inspirada en un objetivo de salud pública pionero en su época: propagar la recién descubierta vacuna contra la viruela. Acometida por un reducido número de expedicionarios, fue dirigida por Francisco Xavier Balmis, a quien acompañaba, entre otros, Antonio Gutiérrez Robredo, su discípulo predilecto. Esta investigación, realizada con fuentes primarias, explora la relación entre ambos, la cual pasó de la mutua confianza a la enemistad debido a un conflicto nimio. El estudio de la correspondencia previa y la tardía resolución del pleito interpuesto por Balmis contra Gutiérrez permite ahondar en sus perfiles biográficos. Como consecuencia directa de aquel litigio, Gutiérrez nunca retornó a España, aunque llegó a ser catedrático en México; por el contrario, Balmis disfrutó honores y reconocimientos en Madrid.

The Smallpox Epidemics in America in the 1700s and the Role of the Surgeons: Lessons to be Learned During the Global Outbreak of COVID-19.

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

Epidemics And Disability.

This essay argues that considering disability and disability history needs to be part of any history of epidemics. Recent scholarship has shown the many intersections of disability history and history of medicine. This essay argues that disability plays many roles in an epidemic from establishing pre-existing conditions, to affecting the acute phase of the disease, to creating lingering disabilities in the long aftermath. Histories of epidemics that ignore the many ways in which disability affects the experience of an epidemic are incomplete.

Smallpox Readiness: Modern Strategies Against an Ancient Disease.

This Viewpoint highlights the potential for unintentional or deliberate release of variola virus (smallpox), discusses current medical countermeasures for smallpox, and calls for greater flexibility from the US and its partners in developing safe, reliable, affordable, and equitable countermeasures.

Epidemic cycles and environmental pressure in colonial Quebec.

OBJECTIVES: Research on historical populations in Europe finds that infectious disease epidemics appear to induce predictable cycles in age-specific mortality. We know little, however, about whether such cycles also occurred in less dense founder populations of North America. We used high-quality data on the Quebecois population from 1680 to 1798 to examine the extent to which age-specific mortality showed predictable epidemic cycles. We further examined whether environmental pressures-temperature, lack of precipitation, or crop failure-may have set the stage for the emergence of epidemics. METHODS: We applied autoregressive, integrated, moving average time series methods to annual counts of period mortality for the following age groups: < 1 year, 1 to < 5 years, 5 to < 15 years, 15 to < 50 years, and 50 years and above. These methods controlled for other patterns (e.g., trend) before empirically identifying cycles. RESULTS: Results indicate a strong seven-year cycle in mortality among infants and children under seven years of age. Warm temperatures (across Quebec overall) and relatively dry years (in Eastern Quebec) also predicted an increased risk of mortality in infancy and childhood, although these environmental variables appear to act independently of the epidemic cycle pattern. DISCUSSION: Findings indicate a strong seven-year epidemic cycle in historical Quebec which afflicted naïve birth cohorts not previously exposed to the prior epidemic. We contend that smallpox epidemics likely contributed to this cycle. The seven-year cycle occurred only in the latter half of the test period (post 1740) with increasing size of the colony and population concentration in urban areas.

From Smallpox to Big Data: The Next 100 Years of Epidemiologic Methods.

For more than a century, epidemiology has seen major shifts in both focus and methodology. Taking into consideration the explosion of "big data," the advent of more sophisticated data collection and analytical tools, and the increased interest in evidence-based solutions, we present a framework that summarizes 3 fundamental domains of epidemiologic methods that are relevant for the understanding of both historical contributions and future directions in public health. First, the manner in which populations and their follow-up are defined is expanding, with greater interest in online populations whose definition does not fit the usual classification by person, place, and time. Second, traditional data collection methods, such as population-based surveillance and individual interviews, have been supplemented with advances in measurement. From biomarkers to mobile health, innovations in the measurement of exposures and diseases enable refined accuracy of data collection. Lastly, the comparison of populations is at the heart of epidemiologic methodology. Risk factor epidemiology, prediction methods, and causal inference strategies are areas in which the field is continuing to make significant contributions to public health. The framework presented herein articulates the multifaceted ways in which epidemiologic methods make such contributions and can continue to do so as we embark upon the next 100 years.

The XIX century smallpox prevention in Naples and the risk of transmission of human blood-related pathogens.

Vaccines are the most successful strategy developed in Medicine to prevent and even eradicate the most dreadful epidemic infectious diseases. The history of smallpox vaccination in Naples is quite unique. Although Galbiati established the retro-vaccination (1803) and developed the "calf" lymph vaccine, recognized and implemented since 1864 as the optimal smallpox vaccine in the following hundred years, Naples general population was mainly vaccinated with "human" lymph from abandoned children until 1893. Mini-epidemics of syphilis and serum hepatitis were periodically reported as results of arm-to-arm procedure. The risk of transmission of blood-related pathogens was higher in Naples where >80% of abandoned children, used as repository of cowpox virus, were dying in their first year of life. Recent vaccinology standards finally eliminated the risk of adventitious contaminating pathogens. Implementation of hepatitis B vaccination since 1991 eventually contributed to current HBV prevalence in Campania region <1%, within the range of the European Countries.