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 presence of marked mpox symptoms (association of fever, lymphadenopathy and extensive mucocutaneous lesions), we estimated prevalence ratios (PR) and 95% confidence intervals (CI) using Poisson regression models with robust standard errors. RESULTS: There were 1,888 confirmed mpox cases with date of symptom onset between 7 May and 31 July 2022. Overall, 7% (93/1,394) presented marked mpox symptoms. Among cases who provided information about their vaccination status, 14% (207/1,469) 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 hospitalisation due to mpox (PR 0.64, 95%CI: 0.23-1.80). CONCLUSIONS: 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 hospitalisation.

In Commemoration of Dr. Mostafa Pourtaghva Shahrestani, a Pioneer in Infectious Disease Research.

It is important to honor the contributions of scientific leaders who have dedicated their lives to advancing knowledge and serving their country. One way is to document their experiences and personalities in a documentary format, which can serve as a historical record and an inspiration for future generations. Dr. Mostafa Pourtaghva Shahrestani, a renowned physician and specialist in infectious diseases and tropical medicine, has made significant contributions to public health in Iran. He has played a crucial role in controlling infectious diseases such as smallpox, tuberculosis, rabies, plague, and cholera. Throughout his career, he has held various executive positions, including the head of Pasteur Hospital and the director of the Pasteur Institute of Iran. Dr. Pourtaghva's life is a testament to his unwavering dedication to public health services, as evidenced by his continuous effort, love, and interest in honest work. His inspiring story can serve as a model for those who seek to follow in his footsteps.

Age-related antibody response to Orthopoxviruses and implications for public health measures: Insights from a South Korean study.

BACKGROUND: After the eradication of smallpox, there have been no specific public health measures for any Orthopoxviruses (OPXVs). Therefore, it is necessary to countermeasure OPXV infections after Mpox (formerly monkeypox) occurrences, such as the latest global outbreak in 2022-2023. This study aimed to provide crucial insights for the development of effective public health policy making against mpox in populations residing in regions where the virus is not prevalent. METHODS: This study used enzyme-linked immunosorbent assays (ELISA) to examine smallpox and mpox antibodies in Koreans with three different age groups. We analyzed 56 sera obtained from a tertiary care hospital in South Korea between September 2022 and April 2023. Plasma levels of antibodies against the viral proteins of smallpox (variola cytokine response-modifying protein B) and MPXV (A29) were measured using enzyme-linked immunosorbent assays. RESULTS: Plasma samples from participants in their early 40 s and older exhibited higher reactivity to viral antigens than those from younger participants. Furthermore, there was a strong positive correlation in antibody positivity for the two different viruses across the sera. CONCLUSIONS: The presence of low antibody levels in participants ˂40 years may hinder their ability to defend against OPXV. Therefore, it is imperative to implement effective public health measures to mitigate the transmission of OPXV within the community. These findings serve as fundamental information for devising strategies to combat mpox efficiently, particularly in regions where the virus is not prevalent.

Whole genome sequencing of recombinant viruses obtained from co-infection and superinfection of Vero cells with modified vaccinia virus ankara vectored influenza vaccine and a naturally occurring cowpox virus.

Modified vaccinia virus Ankara (MVA) has been widely tested in clinical trials as recombinant vector vaccine against infectious diseases and cancers in humans and animals. However, one biosafety concern about the use of MVA vectored vaccine is the potential for MVA to recombine with naturally occurring orthopoxviruses in cells and hosts in which it multiplies poorly and, therefore, producing viruses with mosaic genomes with altered genetic and phenotypic properties. We previously conducted co-infection and superinfection experiments with MVA vectored influenza vaccine (MVA-HANP) and a feline Cowpox virus (CPXV-No-F1) in Vero cells (that were semi-permissive to MVA infection) and showed that recombination occurred in both co-infected and superinfected cells. In this study, we selected the putative recombinant viruses and performed genomic characterization of these viruses. Some putative recombinant viruses displayed plaque morphology distinct of that of the parental viruses. Our analysis demonstrated that they had mosaic genomes of different lengths. The recombinant viruses, with a genome more similar to MVA-HANP (>50%), rescued deleted and/or fragmented genes in MVA and gained new host ranges genes. Our analysis also revealed that some MVA-HANP contained a partially deleted transgene expression cassette and one recombinant virus contained part of the transgene expression cassette similar to that incomplete MVA-HANP. The recombination in co-infected and superinfected Vero cells resulted in recombinant viruses with unpredictable biological and genetic properties as well as recovery of delete/fragmented genes in MVA and transfer of the transgene into replication competent CPXV. These results are relevant to hazard characterization and risk assessment of MVA vectored biologicals.

For Exposed and Deserted Young Children: Research at the London Foundling Hospital.

BACKGROUND: Little is known about research in Foundling Hospitals during the 18th century. SUMMARY: The London "Hospital for the Maintenance and Education of Exposed and Deserted Young Children" opened in 1741, after fundraising by the former shipmaster Thomas Coram and a Charter by King George II. From 1741 to 1756, fewer than 100 infants a year were admitted by lot. With onset of the Seven Years' War in 1756, the House of Commons resolved and financed the admission of all deserted babies. The number of admitted babies rose to 4,000 per year, and their mortality increased. The Institution was not intended as a research and teaching facility but soon became a site for gaining knowledge of young infants. Appointed physicians included Richard Conyers, William Cadogan, William Watson, and William Buchan. Their research focused on frequent conditions in the hospital's infirmary such as scabies, fever, measles, chilblains and scorbutic eruptions, and set standards for infant care and nutrition in the English-speaking world during the 18th century. They described the dangers connected with tight swaddling, meconium purgation, artificial feeding, and the difficulty to obtain wet nurses in the big cities. A major topic was their fight against smallpox, then fatal for 80% if infected infants, and the development of an effective technique of inoculation. KEY MESSAGES: Research at the London Foundling Hospital differed from modern understanding of controlled clinical trials but revealed systematic, hypothesis-driven approaches in the mid-18th century. As in other Foundling Hospitals, absent parental interference facilitated innovations.

Smallpox Geographies: vaccination, borders and Indigenous peoples in Australia's coastal north.

Australia's approach to its biosecurity and borders has always been two-pronged - quarantine first, vaccination second. This article asks what this combination looked like in practice by exploring two neglected smallpox vaccination campaigns directed towards Indigenous peoples in the early twentieth century. We argue these were important campaigns because they were the first two pre-emptive, rather than reactionary, vaccination programs directed towards First Nations people. Second, both episodes occurred in Australia's northern coastline, where the porous maritime geography and proximity to Southeast Asia posed a point of vulnerability for Australian health officials. While smallpox was never endemic, (though epidemic), in Australia, it was endemic at various times and places across Southeast Asia. This shifting spectre of smallpox along the northern coastline was made even more acute for state and federal health officials because of the existing polyethnic relationships, communities, and economies. By vaccinating Indigenous peoples in this smallpox geography, they were envisioned and embedded into a 'hygienic' border for the protection of white Australia, entwining the two-prongs as one approach. In this article, we place public health into a recent scholarship that has 'turned the map upside down' to re-spatialise Australia's history and geography to the north and its global connections, while demonstrating how particular coastlines and their connections were drawn into a national imaginary through a health lens.

Navigating resistance in global health governance: Certification of smallpox eradication in China.

Certification is an essential stage in disease eradication efforts, encompassing epidemiological, managerial, and political complexities. The certification of smallpox eradication in the People's Republic of China (PRC, or China) exemplifies the multifaceted nature of the certification. Despite eradicating smallpox in the early 1960s, before the Global Smallpox Eradication Programme (SEP) intensified in 1967, China was one of the last countries certified as smallpox-free by the World Health Organization (WHO) in 1979. The WHO encountered notable resistance during the certification of smallpox eradication in China. This article examines the underlying motivations propelling China's resistance, the factors that contributed to the shifts in its stance, the challenges navigated by the WHO, and the ultimate achievement of certification despite controversies surrounding its transparency and credibility. Through the case of the certification of smallpox eradication, the article provides a historical context of China's selective engagement in global health governance, emphasising the critical importance of building a trusting relationship between the WHO and its member states. It offers insights for fostering effective collaboration among diverse stakeholders driven by varied political agendas in addressing shared global health challenges such as the coronavirus disease (COVID-19) pandemic.

Mpox-specific immune responses elicited by vaccination or infection in people living with HIV.

In the recent mpox outbreak, people living with HIV (PLWH) were at high risk both for contracting infection and for suffering a more severe disease course. We studied cellular and humoral immune responses elicited by mpox infection (n = 5; n = 3 PLWH) or smallpox vaccination (n = 17; all PLWH) in a cohort of men who have sex with men. All PLWH were successfully treated, with stable CD4 counts and undetectable HIV viral loads. 11/17 vaccinated individuals had received childhood smallpox vaccination. In this group of individuals, both two-dose MVA-vaccination and natural infection evoked mpox-specific immune responses mediated by B cells as well as CD4 and CD8 T cells. This study improves our understanding of smallpox vaccination mediated cross-reactivity to other orthopox viruses, and the long-lasting durability of childhood smallpox vaccination mediated immune responses including in PLWH.

The Current State and Progress of Mpox Vaccine Research.

On July 23, 2022, the World Health Organization (WHO) declared the monkeypox (mpox) outbreak a "Public Health Emergency of International Concern." Since 2022, outbreaks of mpox in many countries around the world have primarily resulted in fatalities among immunocompromised individuals, such as untreated HIV/AIDS patients. Since the eradication of smallpox was declared by the WHO in 1980, the global vaccination against smallpox has been gradually discontinued. China also stopped routine smallpox vaccination in 1981. The protective effect of the smallpox vaccine has decreased over time due to aging and declining immunity in those who were vaccinated. For individuals, timely vaccination against smallpox is an effective means of protection against mpox. However, due to safety concerns with the smallpox vaccine and the limitations of current mpox vaccines, there is no vaccine that is safe, effective, and has low side effects applied in clinical settings. This article provides a comprehensive review of the development of mpox virus (MPXV) vaccines, their application in special populations, and the current state of vaccine research, considering the etiology, transmission, and prevention of the MPXV. Vaccination, as an effective method of epidemic prevention, can provide long-term immune protection and effectively reduce the severity of infection. However, as there is no licensed specific MPXV vaccine available globally, the vaccines currently used for mpox prevention are mostly smallpox vaccines. These smallpox vaccines can offer some degree of protection against mpox by activating cross-protection in the body.

Orally available nucleoside analog UMM-766 provides protection in a murine model of orthopox disease.

Although smallpox has been eradicated, other orthopoxviruses continue to be a public health concern as exemplified by the ongoing Mpox (formerly monkeypox) global outbreak. While medical countermeasures (MCMs) previously approved by the Food and Drug Administration for the treatment of smallpox have been adopted for Mpox, previously described vulnerabilities coupled with the questionable benefit of at least one of the therapeutics during the 2022 Mpox outbreak reinforce the need for identifying and developing other MCMs against orthopoxviruses. Here, we screened a panel of Merck proprietary small molecules and identified a novel nucleoside inhibitor with potent broad-spectrum antiviral activity against multiple orthopoxviruses. Efficacy testing of a 7-day dosing regimen of the orally administered nucleoside in a murine model of severe orthopoxvirus infection yielded a dose-dependent increase in survival. Treated animals had greatly reduced lesions in the lung and nasal cavity, particularly in the 10 µg/mL dosing group. Viral levels were also markedly lower in the UMM-766-treated animals. This work demonstrates that this nucleoside analog has anti-orthopoxvirus efficacy and can protect against severe disease in a murine orthopox model.IMPORTANCEThe recent monkeypox virus pandemic demonstrates that members of the orthopoxvirus, which also includes variola virus, which causes smallpox, remain a public health issue. While currently FDA-approved treatment options exist, risks that resistant strains of orthopoxviruses may arise are a great concern. Thus, continued exploration of anti-poxvirus treatments is warranted. Here, we developed a template for a high-throughput screening assay to identify anti-poxvirus small-molecule drugs. By screening available drug libraries, we identified a compound that inhibited orthopoxvirus replication in cell culture. We then showed that this drug can protect animals against severe disease. Our findings here support the use of existing drug libraries to identify orthopoxvirus-targeting drugs that may serve as human-safe products to thwart future outbreaks.

The association between BCG scars and self-reported chronic diseases: A cross-sectional observational study within an RCT of Danish health care workers.

INTRODUCTION: The live-attenuated vaccines Bacillus Calmette-Guérin (BCG) and Vaccinia have been associated with beneficial non-specific effects. We assessed the prevalence of BCG and Vaccinia vaccine scars in a cohort of Danish health care workers and investigated the association between the presence of vaccine scars and self-reported chronic diseases. METHODS: Cross-sectional study utilizing baseline data collected during 2020-2021 at enrollment in a BCG trial aiming to assess the effect of BCG vaccination on absenteeism and infectious disease morbidity during the SARS-COV-2 pandemic. In Denmark, Vaccinia was discontinued in 1977, and BCG was phased out in the early 1980s. We used logistic regression analysis (adjusted for sex, birth year, and smoking status) to estimate the association between scar status and chronic diseases, providing adjusted Odds Ratios (aORs) with 95 % Confidence Intervals, for participants born before 1977, and born from 1965 to 1976. RESULTS: The cohort consisted of 1218 participants (206 males; 1012 females) with a median age of 47 years (Q1-Q3: 36-56). Among participants born 1965-1976 (n = 403), who experienced the phase-outs, having BCG and/or Vaccinia scar(s) vs. having no vaccine scars yielded an aOR of 0.51 (0.29-0.90) of self-reported chronic disease; an effect primarily driven by BCG. In the same birth cohort, having vaccine scar(s) was most strongly associated with a lower prevalence of chronic respiratory and allergic diseases; the aORs being 0.39 (0.16-0.97) and 0.39 (0.16-0.91), respectively. CONCLUSION: Having a BCG scar was associated with a lower prevalence of self-reported chronic disease.

History, politics, and variolation vaccination hesitancy in the American South during the American Civil War.

Examining the history of vaccination in the Civil War reveals lessons about why citizens resisted vaccination and how physicians tried to respond to the problems associated with combating epidemic diseases like smallpox. The Confederate government and physicians failed to effectively advocate to the public and collect information in an organized manner, and they suffered failures in getting enough citizens and soldiers vaccinated. Some Confederate physicians like Joseph Jones studied vaccination, but this came after the war, and the Confederate government failed to embrace and combat vaccine hesitancy. In some cases, more radical political elements tried to control the conversation through newspaper articles. Criticisms of vaccination likely continued to haunt the perceptions of vaccination in the Southern United States.

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.

Live attenuated smallpox vaccine candidate (KVAC103) efficiently induces protective immune responses in mice.

Smallpox, caused by the variola virus belonging to the genus Orthopoxvirus, is an acute contagious disease that killed 300 million people in the 20th century. Since it was declared to be eradicated and the national immunization program against it was stopped, the variola virus has become a prospective bio-weapon. It is necessary to develop a safe vaccine that protects people from terrorism using this biological weapon and that can be administered to immunocompromised people. Our previous study reported on the development of an attenuated smallpox vaccine (KVAC103). This study evaluated cellular and humoral immune responses to various doses, frequencies, and routes of administration of the KVAC103 strain, compared to CJ-50300 vaccine, and its protective ability against the wild-type vaccinia virus Western Reserve (VACV-WR) strain was evaluated. The binding and neutralizing-antibody titers increased in a concentration-dependent manner in the second inoculation, which increased the neutralizing-antibody titer compared to those after the single injection. In contrast, the T-cell immune response (interferon-gamma positive cells) increased after the second inoculation compared to that of CJ-50300 after the first inoculation. Neutralizing-antibody titers and antigen-specific IgG levels were comparable in all groups administered KVAC103 intramuscularly, subcutaneously, and intradermally. In a protective immunity test using the VACV-WR strain, all mice vaccinated with CJ-50300 or KVAC103 showed 100% survival. KVAC103 could be a potent smallpox vaccine that efficiently induces humoral and cellular immune responses to protect mice against the VACV-WR strain.

Monkeypox: Can we count on the current smallpox immunization?

Two vaccines ACAM 2000 and JYNNEOS have obtained approval from the Food and Drug Administration as preventive measures against monkeypox, contributing significantly to the management of the monkeypox epidemic. Nonetheless, research has demonstrated that smallpox vaccination offers approximately 88.8% protection against monkeypox, while immunization with these vaccines generates relatively low levels of neutralizing antibodies. In this work, we performed a comprehensive comparison of antigens between the 2022-2023 monkeypox strains and the smallpox vaccine strains. Our analysis has revealed considerable amino acid changes in all 27 antigens, including core and envelope proteins. Amino acid substitutions within B cell epitopes were observed in 26 of these antigens, with at least half of the antigen substitutions occurring within B cell epitopes in 20 out of the 26 antigens analyzed. These findings may raise potential concerns regarding the efficacy of these vaccines.

Residual Immunity from Smallpox Vaccination and Possible Protection from Mpox, China.

Among persons born in China before 1980 and tested for vaccinia virus Tiantan strain (VVT), 28.7% (137/478) had neutralizing antibodies, 71.4% (25/35) had memory B-cell responses, and 65.7% (23/35) had memory T-cell responses to VVT. Because of cross-immunity between the viruses, these findings can help guide mpox vaccination strategies in China.

Medical aspects of the tour by Martin Martin (c 1660-1719) of the Western and Northern Islands of Scotland, Circa 1695.

This review is based investigations on the Western Isles, Scotland, by Martin Martin, a notable Scottish Highlander, academic and medical doctor, of the 17th-18th century. His extensive observations of the geography and peoples of these Isles were recorded in his books, "On the Description of the Western Islands of Scotland Circa 1695" and "A Late Voyage to St Kilda". In these books and subsequent papers there were some noteworthy observations on the occurrence (and as he says non-occurrence) of "epidemical" diseases and conditions afflicting the peoples of The Isle of Skye and the Western Isles of Scotland in this period, and these are discussed in this review. Martin also gives details of a wide variety of remedies that were observed or reported by inhabitants around that time. Some of these remedies are interesting for their relevance to the period but others are of doubtful merit. These are reviewed here more for their significance in the understanding of the diseases and conditions of humans and even in some cases animals at that time. Introductions by Charles Withers and R.W. Munro, 11 and re-assessments of the contributions of Martin and colleagues of that time have given insight into the health and condition of peoples of the Western Isles of Scotland(the Occidental) (Martin 1695; Martin 1716).

What determines mpox vaccination uptake? Assessing the effect of intent-to-vaccinate versus other determinants among men who have sex with men.

BACKGROUND: In response to the mpox outbreak, vaccination was offered in the Netherlands to men who have sex with men (MSM) at increased risk for mpox. Successful vaccination campaigns are leveraged by high intent-to-vaccinate, yet intent might not always lead to uptake. Therefore, we assessed the impact of intent-to-vaccinate and other factors on vaccination uptake among participants of the Amsterdam Cohort Studies (ACS). METHOD: In July 2022, prior to the mpox vaccination campaign, we distributed an online survey regarding mpox intent-to-vaccinate, as well as e.g. beliefs, attitude, subjective norms, and perception of risk among ACS participants (all MSM). Vaccination uptake was self-reported during study visits after August 2022. The association between vaccination intent and uptake, and determinants of intent, was jointly assessed using a structural equation model (SEM) based on components of the Theory of Planned Behavior (TPB). In a second SEM, determinants of intent were allowed to have a direct effect on vaccination uptake. RESULTS: 492 MSM (median age = 46 years) were included in analyses. 380 (77%) had high intent-to-vaccinate and 238 (48%) received at least one vaccine dose. In the first model with a direct relation between intent and uptake only, TBP components predicted intent as expected, and high intent-to-vaccinate was significantly associated with getting vaccinated (ß = 1.1, 95%CI = 0.6-1.5). However, 175/380 (46%) participants with high intent-to-vaccinate did not get vaccinated. The second model had an improved model fit compared to the first model. The effect of intent on uptake was non-significant, and only perceiving to be at higher risk of infection significantly increased vaccination uptake later on (ß = 0.42, 95%CI = 0.26-0.59). Having a steady relationship decreased the probability of vaccination (ß = -0.59, 95%CI = -1.0- -0.18). CONCLUSIONS: While intent-to-vaccinate for mpox was high among MSM, high intent did not necessarily result in vaccine uptake. Mpox risk perception might have played a more pivotal role in getting vaccinated, which may be related to the evolution of vaccination eligibility criteria and accessibility to the vaccine.

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.

Monkeypox: A comprehensive review of a multifaceted virus.

In May 2022, the world witnessed the re-emergence of the zoonotic disease monkeypox. While this was not the first epidemic of this disease, what differentiated the outbreak was the rapid global spread and increase of cases, which led the WHO to declare monkeypox a global health emergency. Although the disease spreads mainly through inadequately cooked meat of various rodent species, this virus also shows droplet, respiratory, sexual, and even vertical transmission. Monkeypox further multiplies in lymphoproliferative organs and presents with a classical smallpox-like rash, fever, headache, and muscle aches. Diagnosis is confirmed with a polymerase-chain-reaction test and is managed largely supportively with possible usage of some antivirals and immunoglobulins. Moreover, some pre-exposure and postexposure prophylactic vaccines have been developed. This paper aims to conduct an in-depth review of the historical epidemics, transmission, pathophysiology, clinical presentation, and management of the monkeypox disease.