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.

Evaluation of monkeypox- and vaccinia-virus neutralizing antibodies before and after smallpox vaccination: A sero-epidemiological study.

Since May 2022, several countries outside of Africa experienced multiple clusters of monkeypox virus (MPXV)-associated disease. In the present study, anti-MPXV and anti-vaccinia virus (VACV) neutralizing antibody responses were evaluated in two cohorts of subjects from the general Italian population (one half born before the WHO-recommended end of smallpox vaccination in 1980, the other half born after). Higher titers (either against MPXV or VACV) were observed in the cohort of individuals born before the interruption of VACV vaccination. An association between VACV and MPXV antibody levels was observed, suggesting that the smallpox vaccination may confer some degree of cross-protection against MPXV infection. Results from this study highlight low levels of immunity toward the assessed Orthopoxviruses, especially in young adults, advocating the introduction of a VACV- or MPXV-specific vaccine in case of resurgence of monkeypox disease outbreaks.

Role of the Laboratory in the Diagnosis of Poxvirus Infections.

Although WHO-led global efforts led to eradication of smallpox over four decades ago, other poxviruses, especially monkeypox, have re-emerged to occupy the ecological niche vacated by smallpox. Many of these viruses produce similar lesions thus mandating a prompt laboratory confirmation. There has been considerable evolution in the techniques available to diagnose these infections and differentiate between them. With the 2022 multi-country outbreak of monkeypox, significant efforts were made to apprise the laboratory diagnosis of the virus and numerous real-time-PCR-based assays were made commercially available. This chapter discusses the sample collection and biosafety aspects along with the repertoire of diagnostic modalities, both traditional and emerging, for poxviruses which a special focus on monkeypox. The advantages and disadvantages of each technique have been illustrated. We have also reflected upon the newer advances and the existing lacunae.

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.

History of smallpox vaccination and marked clinical expression of mpox among cases notified in France from May to July 2022.

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.

Adverse drug reaction profile of third-generation smallpox vaccines used in France during the 2022 monkeypox epidemic.

Due to the start of the monkeypox epidemic in 2022, we retrospectively analyzed the adverse drug reactions (ADRs) reported in France after monkeypox vaccinations with the third-generation smallpox vaccine. Ninety-eight cases, representing 172 ADRs, were reported. ADRs were mostly expected reactogenicity reactions occurring within days after the first dose of vaccine and having a quick favorable outcome. Unexpected facial palsy and vaccination failure are discussed.

Orthopox viruses: is the threat growing?

BACKGROUND: Smallpox was a major cause of human mortality until its eradication, but the threat of orthopox viruses has not disappeared. Since the eradication of smallpox and the cessation of the related vaccination campaigns, the threat has been growing, as evidenced by the currently ongoing worldwide Mpox outbreak. In addition to threats of an evolving Mpox, we must also be aware of a myriad of other threats that remain. Many countries still lack biosecurity regulations reflecting the recent technological advances, and the threat of bioterrorism remains ever present. Reconstruction of smallpox is a distinct possibility, as are other scenarios whereby other orthopox viruses may be made more fit for transmission in humans. OBJECTIVES: To outline and discuss potential biosafety and biosecurity threats posed by orthopox viruses. SOURCES: Published scientific literature, news articles, and international agreements. CONTENT AND IMPLICATIONS: It would be wise to take steps to mitigate these threats now. Vaccination campaigns should be considered in areas with frequent orthopox outbreaks, and more efforts must be made to put a final end to the Mpox outbreak. In many countries, national biosafety and biosecurity regulations may need to be revised and strengthened to better reflect the threats posed by new technologies, including controls on synthesis of smallpox sequences. Furthermore, more international cooperation and aid is needed. The present global Mpox outbreak could likely have been prevented had areas where Mpox is endemic not been neglected. Future outbreaks could be much worse.

Vaccines for Mpox - An Unmet Global Need.

In 1970, the first case of mpox (formerly known as monkeypox) was documented in an infant in Equateur Province, Democratic Republic of Congo (DRC).1 Infections with clade I monkeypox virus (MPXV) are endemic in the rainforest regions of central Africa and result from both zoonotic and human-to-human transmission. The cessation of smallpox vaccination in 1980 because of the eradication of smallpox has led to an increase in the number of individuals who are orthopox immune naïve and is felt to be responsible for a recent increase in mpox cases in the DRC. Comparisons of active surveillance in Sankuru Province from 2005 through 2007 revealed a 20-fold increase in the incidence of mpox compared with the 1980s, with a 5-fold-lower incidence among those with a smallpox vaccination scar.2.

Tracing the journey of poxviruses: insights from history.

The historical significance of the poxviruses is profound, largely due to the enduring impact left by smallpox virus across many centuries. The elimination of smallpox is a remarkable accomplishment in the history of science and medicine, with centuries of devoted efforts resulting in the development and widespread administration of smallpox vaccines. This review provides insight into the pivotal historical events involving medically significant poxviruses. Understanding the remarkable saga of combatting smallpox is crucial, serving as a guidepost for potential future encounters with poxvirus infections. There is a continual need for vigilant observation of poxvirus evolution and spillover from animals to humans, considering the expansive range of susceptible hosts. The recent occurrence of monkeypox cases in non-endemic countries stands as a stark reminder of the ease with which infections can be disseminated through international travel and trade. This backdrop encourages introspection about our journey and the current status of poxvirus research.

Human mpox: global trends, molecular epidemiology and options for vaccination.

The eradication of smallpox and the cessation of vaccination have led to the growth of the susceptible human population to poxviruses. This has led to the increasing detection of zoonotic orthopoxviruses. Among those viruses, monkeypox virus (MPV) is the most commonly detected in Western and Central African regions. Since 2022, MPV is causing local transmission in newly affected countries all over the world. While the virus causing the current outbreak remains part of clade II (historically referred to as West African clade), it has a significant number of mutations as compared to other clade II sequences and is therefore referred to as clade IIb. It remains unclear whether those mutations may have caused a change in the virus phenotype. Vaccine effectiveness data show evidence of a high cross-protection of vaccines designed to prevent smallpox against mpox. These vaccines therefore represent a great opportunity to control human-to-human transmission, provided that their availability has short time-frames and that mistakes from the recent past (vaccine inequity) will not be reiterated.

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.

Poc (Pox), a term for various infectious diseases in the history of public health and epidemiology: the dreaded Smallpox, the almost unknown Alastrim and the Mpox.

Introduction: In 2022, the appearance of cases of Mpox outside the countries where the disease is endemic, and of some cases of human-to-human transmission, alerted the scientific community to a virus that is closely related to the smallpox virus. Mpox is a zoonosis and can be transmitted to humans. Following the eradication of smallpox in 1980 and the subsequent cessation of smallpox vaccination, it is emerging as the most important Orthopoxvirus in terms of public health impact. Methods: In outlining the current situation of Mpox in the world, the authors frame the virus responsible within a broader reflection on the Orthopoxvirus family, focusing particular attention on the Variola virus, which formerly caused millions of deaths. Discussion: Since Edward Jenner initiated the practice of vaccination, a progressive and careful vaccination campaign has led to the eradication not only of human smallpox but also of a minor form, called Alastrim, which was caused by the same virus. The mode of transmission of Mpox has been debated. At first, it seemed that the disease mainly, though not exclusively, affected men who had sex with other men. This conviction has been partially revised and the WHO recently changed the name of the disease from Monkeypox to Mpox, thereby alleviating the stigma involved. Conclusion: The recent human cases of Mpox have prompted greater surveillance and research into the biology of MPXV and other closely related poxviruses. Studies have focused on the natural history of the virus, its transmission, pathogenesis, host interactions and evolution, and on the development of drugs and vaccines to prevent its spread.

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)

Emergence of mpox in the post-smallpox era-a narrative review on mpox epidemiology.

BACKGROUND: The 2022 mpox outbreak drew global attention to this neglected pathogen. While most of the world was taken by surprise, some countries have seen this pathogen emerge and become endemic several decades prior to this epidemic. OBJECTIVES: This narrative review provides an overview of mpox epidemiology since its discovery through the 2022 global outbreak. SOURCES: We searched PubMed for relevant literature about mpox epidemiology and transmission through 28 February 2023. CONTENT: The emergence of human mpox is intertwined with the eradication of smallpox and the cessation of the global smallpox vaccination campaign. The first human clade I and II monkeypox virus (MPXV) infections were reported as zoonoses in Central and West Africa, respectively, around 1970 with sporadic infections reported throughout the rest of the decade. Over the next five decades, Clade I MPXV was more common and caused outbreaks of increasing size and frequency, mainly in the Democratic Republic of the Congo. Clade II MPXV was rarely observed, until its re-emergence and ongoing transmission in Nigeria, since 2017. Both clades showed a shift from zoonotic to human-to-human transmission, with potential transmission through sexual contact being observed in Nigeria. In 2022, clade II MPXV caused a large human outbreak which to date has caused over 86,000 cases in 110 countries, with strong evidence of transmission during sexual contact. By February 2023, the global epidemic has waned in most countries, but endemic regions continue to suffer from mpox. IMPLICATIONS: The changing epidemiology of mpox demonstrates how neglected zoonosis turned into a global health threat within a few decades. Thus, mpox pathophysiology and transmission dynamics need to be further investigated, and preventive and therapeutic interventions need to be evaluated. Outbreak response systems need to be strengthened and sustained in endemic regions to reduce the global threat of mpox.

Epidemiologic and Clinical Features of Mpox in Adults Aged >50 Years - United States, May 2022-May 2023.

During May 2022-May 2023, approximately 30,000 mpox cases were reported in the United States, predominantly among young adult men. Persons aged >50 years might experience more severe mpox disease because of a higher prevalence of comorbidities. Conversely, they could have residual protection from childhood smallpox vaccination against monkeypox virus infection and severe mpox, as has been suggested by investigation of some previous mpox outbreaks. To examine the characteristics of mpox cases among adults aged >50 years, analysts compared mpox epidemiology and clinical outcomes among all adults aged ≥18 years, by age group. Further, outcomes were compared among adults aged >50 years by JYNNEOS vaccination status. During May 10, 2022-May 17, 2023, among 29,984 adults with probable or confirmed mpox reported to CDC, 2,909 (9.7%) were aged >50 years, 96.3% of whom were cisgender men. Compared with adults aged 18-50 years, adults aged >50 years had higher prevalences of immunocompromising conditions (p<0.001) and HIV infection (p<0.001). Among adults with mpox aged >50 years, 27.6% had received JYNNEOS vaccination; this group had lower prevalences of constitutional symptoms (p<0.001), pruritus (p<0.001), and hospitalization (p = 0.002) compared with those who had not received JYNNEOS vaccine. Currently recommended JYNNEOS vaccination among all adults at risk for mpox should be encouraged, irrespective of childhood smallpox vaccination status.

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.

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.

[Mpox, 40 years after smallpox eradication]. / Mpox, 40 ans après l'éradication de la variole humaine.

In 2022, mpox - a neglected tropical zoonosis - emerged to the world stage. From 1980, the disease was periodically noted, with increasing frequency, in endemic regions of Africa. In 2017, a large outbreak in Nigeria marks a turning point in the evolution of mpox and seems to be at the origin of the 2022 pandemic. The factors for mpox emergence are complex and include loss of cross-protection conferred by smallpox vaccination, increased exposure to the animal reservoir, and increased human-to-human transmission due to behavioral factors. While the current epidemic seems under control, an evolution towards a more transmissible or more virulent virus is not excluded. The 2022 pandemic is an opportunity to initiate and strengthen mpox surveillance, prevention and care management among all affected populations.

En 2022, le mpox ­ une zoonose tropicale négligée ­ a émergé sur la scène mondiale. Depuis 1980, la maladie a été notifiée avec une fréquence croissante dans les régions endémiques d'Afrique. En 2017, une large épidémie au Nigeria marque un tournant dans l'évolution du mpox et semble à l'origine de la pandémie 2022. Les facteurs d'émergence du mpox sont complexes et incluent la perte de la protection croisée conférée par la vaccination antivariolique, une exposition accrue au réservoir animal et une augmentation de la transmission interhumaine due à des facteurs comportementaux. Alors que l'épidémie actuelle semble sous contrôle, une évolution vers un virus plus transmissible ou plus virulent n'est pas exclue. La pandémie 2022 est une opportunité pour initier et renforcer la surveillance, la prévention et la prise en charge clinique du mpox auprès de toutes les populations affectées.