Serological responses to smallpox A33 antigen and monkeypox A35 antigen in healthy people and people living with HIV-1 from Guangzhou, China.

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

Mpox neglect and the smallpox niche: a problem for Africa, a problem for the world.

Mpox (formerly known as monkeypox) is a zoonotic viral disease endemic in parts of Africa. In May, 2022, the world was alerted to circulation of monkeypox virus in many high-income countries outside of Africa. Continued spread resulted in a WHO declaration of a Public Health Emergency of International Concern. Although there has been much attention on the global outbreak, most of the focus has been on high-income countries outside of Africa, despite the fact that monkeypox virus has been causing disease in parts of Africa for at least 50 years. Furthermore, the long-term consequences of this event, especially the risk that mpox fills the niche vacated through smallpox eradication, have not been sufficiently considered. The heart of the problem is the historical neglect of mpox in Africa where the disease is endemic, and the actual and potential consequences if this neglect is left uncorrected.

Immune interference in effectiveness of influenza and COVID-19 vaccination.

Vaccines are known to function as the most effective interventional therapeutics for controlling infectious diseases, including polio, smallpox, rabies, tuberculosis, influenza and SARS-CoV-2. Smallpox has been eliminated completely and polio is almost extinct because of vaccines. Rabies vaccines and Bacille Calmette-Guérin (BCG) vaccines could effectively protect humans against respective infections. However, both influenza vaccines and COVID-19 vaccines are unable to eliminate these two infectious diseases of their highly variable antigenic sites in viral proteins. Vaccine effectiveness (VE) could be negatively influenced (i.e., interfered with) by immune imprinting of previous infections or vaccinations, and repeated vaccinations could interfere with VE against infections due to mismatch between vaccine strains and endemic viral strains. Moreover, VE could also be interfered with when more than one kind of vaccine is administrated concomitantly (i.e., co-administrated), suggesting that the VE could be modulated by the vaccine-induced immunity. In this review, we revisit the evidence that support the interfered VE result from immune imprinting or repeated vaccinations in influenza and COVID-19 vaccine, and the interference in co-administration of these two types of vaccines is also discussed. Regarding the development of next-generation COVID-19 vaccines, the researchers should focus on the induction of cross-reactive T-cell responses and naive B-cell responses to overcome negative effects from the immune system itself. The strategy of co-administrating influenza and COVID-19 vaccine needs to be considered more carefully and more clinical data is needed to verify this strategy to be safe and immunogenic.

Human monkeypox virus in the shadow of the COVID-19 pandemic.

BACKGROUND: The end of smallpox in 1980 and the subsequent stopping of vaccination against smallpox was followed by the emergence of monkeypox (mpox), a viral disease of animal origin, meaning that it is transmitted from animal to human. The symptoms of mpox are similar to smallpox, except that they are less severe in terms of clinical features. In the case of public health, the mpox virus is one of the most important orthopoxviruses (such as variola, cowpox, and vaccinia) that come from the family Poxviridae. Mpox occurs mostly in central Africa and sometimes in tropical rainforests or some urban areas. Also, there are threats other than COVID-19, that must be addressed and prevented from spreading, as there has been an outbreak of mpox cases since May 7, 2022, throughout the USA, Europe, Australia, and part of Africa. OBJECTIVES: In this review, we will discuss mpox between the past, the present and during the COVID-19 pandemic. Also, it offers an updated summary of the taxonomy, etiology, transmission, and epidemiology of mpox illness. In addition, the current review aims to highlight the importance of emerging pandemics in the same era such as mpox and COVID-19. METHODS: A literature search was done for the study using online sources like PubMed and Google Scholar. Publications in English were included. Data for study variables were extracted. After the duplicate articles were eliminated, full-text screening was performed on the papers' titles and abstracts. RESULTS: The evaluation included a series documenting mpox virus outbreaks, and both prospective and retrospectiveinvestigations. CONCLUSIONS: monkeypox is a viral disease caused by the monkeypox virus (MPXV), which is primarily found in central and western Africa. The disease is transmitted from animals to humans and presents symptoms similar to those of smallpox, including fever, headache, muscle aches, and a rash. Monkeypox can lead to complications such as secondary integument infection, bronchopneumonia, sepsis, and encephalitis, as well as corneal infection that can result in blindness. There is no specific clinically proven treatment for monkeypox, and treatment is primarily supportive. However, antiviral drugs and vaccines are available for cross-protection against the virus, and strict infection control measures and vaccination of close contacts of affected individuals can help prevent and control outbreaks.

Anti-viral drug discovery against monkeypox and smallpox infection by natural curcumin derivatives: A Computational drug design approach.

Background: In the last couple of years, viral infections have been leading the globe, considered one of the most widespread and extremely damaging health problems and one of the leading causes of mortality in the modern period. Although several viral infections are discovered, such as SARS CoV-2, Langya Henipavirus, there have only been a limited number of discoveries of possible antiviral drug, and vaccine that have even received authorization for the protection of human health. Recently, another virial infection is infecting worldwide (Monkeypox, and Smallpox), which concerns pharmacists, biochemists, doctors, and healthcare providers about another epidemic. Also, currently no specific treatment is available against Monkeypox. This research gap encouraged us to develop a new molecule to fight against monkeypox and smallpox disease. So, firstly, fifty different curcumin derivatives were collected from natural sources, which are available in the PubChem database, to determine antiviral capabilities against Monkeypox and Smallpox. Material and method: Preliminarily, the molecular docking experiment of fifty different curcumin derivatives were conducted, and the majority of the substances produced the expected binding affinities. Then, twelve curcumin derivatives were picked up for further analysis based on the maximum docking score. After that, the density functional theory (DFT) was used to determine chemical characterizations such as the highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO), softness, and hardness, etc. Results: The mentioned derivatives demonstrated docking scores greater than 6.80 kcal/mol, and the most significant binding affinity was at -8.90 kcal/mol, even though 12 molecules had higher binding scores (-8.00 kcal/mol to -8.9 kcal/mol), and better than the standard medications. The molecular dynamic simulation is described by root mean square deviation (RMSD) and root-mean-square fluctuation (RMSF), demonstrating that all the compounds might be stable in the physiological system. Conclusion: In conclusion, each derivative of curcumin has outstanding absorption, distribution, metabolism, excretion, and toxicity (ADMET) characteristics. Hence, we recommended the aforementioned curcumin derivatives as potential antiviral agents for the treatment of Monkeypox and Smallpox virus, and more in vivo investigations are warranted to substantiate our findings.

Differential Diagnosis, Prevention, and Treatment of mpox (Monkeypox): A Review for Dermatologists.

The current 2022 mpox (monkeypox) outbreak has been officially recognized as a public health emergency. The mpox clinical symptoms include high fever, fatigue, chills, headache, swollen lymph nodes, muscle aches, and a disseminated painful rash. However, recent cases of mpox have shown a shift in clinical symptoms, with anogenital skin lesions emerging as the predominant feature. Due to the predominant skin manifestations of mpox, dermatologists could be crucial in detecting new mpox cases and educating frontline healthcare professionals about mpox. The mpox virus is continuously evolving and has several variants. Genome sequencing has revealed that the Clade IIb variant is responsible for the 2022 mpox outbreak. Mpox spread may occur through animal-to-human and human-to-human transmission; however, unlike coronavirus disease 2019 (COVID-19), long-range airborne transmission has not been reported. Healthcare professionals are at higher risk of becoming infected since they are usually in close contact with both the patients and potentially contaminated fomites (e.g., examination table, gowns, gloves). Both public and healthcare professionals should take preventive and avoidance measures to limit the spread. Mpox is usually self-limiting and may require only symptomatic treatment; however, it may cause severe complications in special populations such as immunocompromised individuals. For severe infection, clinicians may consider antiviral drugs (off-label), tecovirimat and brincidofovir, originally approved for smallpox treatment. Two smallpox vaccines, ACAM2000® and JYNNEOSTM, can be used as pre-exposure prophylaxis against mpox. JYNNEOSTM, which carries approval for mpox use, has less adverse effect potential than ACAM2000®, and may also be used as post-exposure prophylaxis, preferably within 4 days of exposure.

The monkeypox diagnosis, treatments and prevention: A review.

The world is currently dealing with a second viral outbreak, monkeypox, which has the potential to become an epidemic after the COVID-19 pandemic. People who reside in or close to forest might be exposed indirectly or at a low level, resulting in subclinical disease. However, the disease has lately emerged in shipped African wild mice in the United States. Smallpox can cause similar signs and symptoms to monkeypox, such as malaise, fever, flu-like signs, headache, distinctive rash, and back pain. Because Smallpox has been eliminated, similar symptoms in a monkeypox endemic zone should be treated cautiously. Monkeypox is transmitted to humans primarily via interaction with diseased animals. Infection through inoculation via interaction with skin or scratches and mucosal lesions on the animals is conceivable significantly once the skin barrier is disrupted by scratches, bites, or other disturbances or trauma. Even though it is clinically unclear from other pox-like infections, laboratory diagnosis is essential. There is no approved treatment for human monkeypox virus infection, however, smallpox vaccination can defend counter to the disease. Human sensitivity to monkeypox virus infection has grown after mass vaccination was discontinued in the 1980s. Infection may be prevented by reducing interaction with sick patients or animals and reducing respiratory exposure among people who are infected.

The Pasteurian contribution to the history of vaccines.

Vaccination, the transmission of "vaccine", a benign disease of cows, to immunize human beings against smallpox, was invented by Jenner at the end of the eighteenth century. Pasteur, convinced that the vaccine microbe was an attenuated form of the smallpox microbe, showed that, similarly, attenuated forms of other microbes immunized against animal diseases. When applying this principle to rabies, he realized that, in this case, the vaccine was in fact composed of dead microbes. One of his students immediately exploited this result to devise a vaccine against typhoid. The vaccines against diphtheria and tetanus, in 1921, opened a new route, that of immunization with molecules from the pathogenic microbes. Molecular biology then allowed the production of the immunogenic molecules by microorganisms such as yeast, or immunization by genetically modified viruses or messenger RNA inducing our own cells to produce these molecules.

La vaccination, transmission de la vaccine, maladie bénigne des vaches, pour immuniser les humains contre la variole, a été inventée par Jenner à la fin du XVIII e siècle. Pasteur, convaincu que le microbe de la vaccine est une forme atténuée de celui de la variole, montre que des formes atténuées d'autres microbes immunisent des animaux contre des maladies. Lors de l'application à la rage, il comprend que la préparation vaccinale qu'il utilise dans ce cas est en fait constituée de microbes tués. Conclusion aussitôt exploitée par l'un de ses élèves dans la conception d'un vaccin contre la typhoïde. Les vaccins contre la diphtérie et le tétanos, en 1921, ouvrent une troisième voie, celle de l'immunisation par des molécules provenant des microbes pathogènes. La biologie moléculaire va permettre la production de ces molécules immunogènes par des micro-organismes tels que des levures, ou bien l'immunisation par des virus génétiquement modifiés ou par de l'ARN messager, conduisant nos propres cellules à produire ces molécules.

History of vaccine and immunization: Vaccine-hesitancy discussion in Germany in XIX century.

Vaccination is the most celebrated and denigrated achievement of medicine and public health - not only today, but since Edward Jenner's time (1798). In fact, the idea of injecting a mild form of "disease" into a healthy person was attacked even earlier than the discovery of vaccines. The forerunner of Jenner's vaccination with bovine lymph was the inoculation of smallpox material from person to person, which, known in Europe since the beginning of the eighteenth century, was a target of harsh criticism. The reasons for criticizing the Jennerian vaccination and its mandatory practice were medical, anthropological, biological (vaccination is not safe), religious and ethical (it is wrong to inoculate a healthy person with disease), and political (vaccination is a threat to individual freedom). As such, anti-vaccination groups emerged in England, where inoculation was adopted early, as well as overall in Europe and in the United States. This paper focuses on the lesser known debate that arose in Germany in the years 1852-53 about the medical practice of vaccination. This is an a important topic of public health that has aroused a wide debate and comparison especially in recent years and now with pandemic on Sars-Cov-2 (Covid-19) and will probably be the subject of further reflection and consideration in the coming years.

The outbreak of monkeypox: A clinical overview.

The development of new zoonotic diseases such as coronavirus disease 2019 (COVID-19) and monkeypox that can cause epidemics and high mortality rates have significantly threatened global health security. However, the increasing number of people with no immunity to poxvirus because of the end of the smallpox vaccination programme has created a vulnerable population for the monkeypox outbreak. On 23 July 2022, it was announced that the World Health Organization's director-general has determined that the multicountry outbreak of monkeypox constitutes a Public Health Emergency of International Concern. The monkeypox virus is an orthopoxvirus that causes a disease with symptoms similar to smallpox but less severe. Many unanswered questions remain regarding monkeypox's pathogenesis, transmission and host reservoir. There is currently no evidence that transmission by individuals can sustain zoonotic infections during human-to-human transmissions; the continued emergence of these pathogens highlights the interconnectedness of animals and humans. The increasing number of monkeypox cases outside the endemic region has highlighted the need for effective global capacity building to prevent the spread of the disease and its impact on global health security. The priority now is to stop the spread of the disease and protect frontline healthcare workers and the most vulnerable individuals. This article aims to comprehensively analyse the various aspects of the transmission and epidemiology of monkeypox. It also explores possible diagnostic techniques, therapeutics and prevention strategies. A key recommendation is that primary care and public health professionals are expected to increase their efforts to be vigilant and contain any potential outbreaks.

Prevention and Treatment of Monkeypox: A Systematic Review of Preclinical Studies.

The outbreak of monkeypox, coupled with the onslaught of the COVID-19 pandemic is a critical communicable disease. This study aimed to systematically identify and review research done on preclinical studies focusing on the potential monkeypox treatment and immunization. The presented juxtaposition of efficacy of potential treatments and vaccination that had been tested in preclinical trials could serve as a useful primer of monkeypox virus. The literature identified using key terms such as monkeypox virus or management or vaccine stringed using Boolean operators was systematically reviewed. Pubmed, SCOPUS, Cochrane, and preprint databases were used, and screening was performed in accordance with PRISMA guidelines. A total of 467 results from registered databases and 116 from grey literature databases were screened. Of these results, 72 studies from registered databases and three grey literature studies underwent full-text screening for eligibility. In this systematic review, a total of 27 articles were eligible according to the inclusion criteria and were used. Tecovirimat, known as TPOXX or ST-246, is an antiviral drug indicated for smallpox infection whereas brincidofovir inhibits the viral DNA polymerase after incorporation into viral DNA. The ability of tecovirimat in providing protection to poxvirus-challenged animals from death had been demonstrated in a number of animal studies. Non-inferior with regard to immunogenicity was reported for the live smallpox/monkeypox vaccine compared with a single dose of a licensed live smallpox vaccine. The trial involving the live vaccine showed a geometric mean titre of vaccinia-neutralizing antibodies post two weeks of the second dose of the live smallpox/monkeypox vaccine. Of note, up to the third generation of smallpox vaccines-particularly JYNNEOS and Lc16m8-have been developed as preventive measures for MPXV infection and these vaccines had been demonstrated to have improved safety compared to the earlier generations.

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.

Prevention of monkeypox with vaccines: a rapid review.

The largest outbreak of monkeypox in history began in May, 2022, and has rapidly spread across the globe ever since. The purpose of this Review is to briefly describe human immune responses to orthopoxviruses; provide an overview of the vaccines available to combat this outbreak; and discuss the various clinical data and animal studies evaluating protective immunity to monkeypox elicited by vaccinia virus-based smallpox vaccines, address ongoing concerns regarding the outbreak, and provide suggestions for the appropriate use of vaccines as an outbreak control measure. Data showing clinical effectiveness (~85%) of smallpox vaccines against monkeypox come from surveillance studies conducted in central Africa in the 1980s and later during outbreaks in the same area. These data are supported by a large number of animal studies (primarily in non-human primates) with live virus challenge by various inoculation routes. These studies uniformly showed a high degree of protection and immunity against monkeypox virus following vaccination with various smallpox vaccines. Smallpox vaccines represent an effective countermeasure that can be used to control monkeypox outbreaks. However, smallpox vaccines do cause side-effects and the replication-competent, second-generation vaccines have contraindications. Third-generation vaccines, although safer for use in immunocompromised populations, require two doses, which is an impediment to rapid outbreak response. Lessons learned from the COVID-19 pandemic should be used to inform our collective response to this monkeypox outbreak and to future outbreaks.

A Glance at the Development and Patent Literature of Tecovirimat: The First-in-Class Therapy for Emerging Monkeypox Outbreak.

Monkeypox disease (MPX) is currently considered a global threat after COVID-19. European Medicines Agency (EMA) approved Tecovirimat in capsule dosage form (200 mg) as the first treatment for MPX in January 2022. This article highlights Tecovirimat's development and patent literature review and is believed to benefit the scientists working on developing MPX treatments. The literature for Tecovirimat was gathered from the website of SIGA Technologies (developer of Tecovirimat), regulatory agencies (EMA, United States Food and Drug Administration (USFDA), and Health Canada), PubMed, and freely accessible clinical/patent databases. Tecovirimat was first recognized as an anti-orthopoxvirus molecule in 2002 and developed by SIGA Technologies. The USFDA and Health Canada have also recently approved Tecovirimat to treat smallpox in 2018 and 2021, respectively. The efficacy of Tecovirimat was verified in infected non-human primates (monkeys) and rabbits under the USFDA's Animal Rule. Most clinical studies have been done on Tecovirimat's safety and pharmacokinetic parameters. The patent literature has revealed inventions related to the capsule, injection, suspension, crystalline forms, amorphous form, and drug combinations (Tecovirimat + cidofovir) and process for preparing Tecovirimat. The authors foresee the off-label use of Tecovirimat in the USA and Canada for MPX and other orthopoxvirus infections. The authors also trust that there is immense scope for developing new Tecovirimat-based treatments (new drug combinations with other antivirals) for orthopoxvirus and other viral diseases. Drug interaction studies and drug resistance studies on Tecovirimat are also recommended. Tecovirimat is believed to handle the current MPX outbreak and is a new hope of biosecurity against smallpox or orthopoxvirus-related bioterrorism attack.

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.

Phylogenomic analysis of the monkeypox virus (MPXV) 2022 outbreak: Emergence of a novel viral lineage?

Monkeypox is a zoonotic disease with clinical manifestations similar to smallpox in humans. Since May 13, 2022, an increasing number of suspected and confirmed cases have been reported, affecting non-endemic regions across the globe. More strikingly, reports from the current outbreak reveal unique aspects regarding transmission dynamics and an unprecedented, rapidly expanding and sustained community transmission. As demonstrated through the still-ongoing COVID-19 pandemic, genomic surveillance has been an essential resource for monitoring and tracking the evolution of pathogens of public health relevance. Herein, we performed a phylogenomic analysis of available Monkeypox virus (MPXV) genomes to determine their evolution and diversity. Our analysis revealed that all MPXV genomes grouped into three monophyletic clades: two previously characterized clades and a newly emerging clade harboring genomes from the ongoing 2022 multi-country outbreak with 286 genomes comprising the hMPXV-1A clade and the newly classified lineages: A.1 (n = 6), A.1.1 (n = 1), A.2 (n = 3) and B.1 (n = 262), where lineage B.1 includes all MPXV genomes from the 2022 outbreak. Finally, it was estimated that B.1 lineage of this clade emerged in Europe on 03/02/2022 [95%CI = 11/13/2021 to 05/10/2022]. The exceptional surge of cases and the broader geographical expansion suggest multifactorial factors as drivers of the current outbreak dynamics. Such factors may include the cessation of smallpox vaccination and its potential spread across particular networks. Integrating pertinent epidemiological information with genomic surveillance information will help generate real-time data to help implement adequate preventive and control measures by optimizing public health decisions to mitigate this outbreak.

Historical review: Towards the 50th anniversary of the last major smallpox outbreak (Yugoslavia, 1972).

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

Pacific Eclipse - A tabletop exercise on smallpox pandemic response.

BACKGROUND: In December 2019, we ran Pacific Eclipse, a pandemic tabletop exercise using smallpox originating in Fiji as a case study. Pacific Eclipse brought together international stakeholders from health, defence, law enforcement, emergency management and a range of other organisations. AIM: To review potential gaps in preparedness and identify modifiable factors which could prevent a pandemic or mitigate the impact of a pandemic. METHODS: Pacific Eclipse was held on December 9-10 in Washington DC, Phoenix and Honolulu simultaneously. The scenario began in Fiji and becomes a pandemic. Mathematical modelling of smallpox transmission was used to simulate the epidemic under different conditions and to test the effect of interventions. Live polling, using Poll Everywhere software that participants downloaded onto their smart phones, was used to gather participant decisions as the scenario unfolded. Stakeholders from state and federal government and non-government organisations from The United States, The United Kingdom, Australia, New Zealand, Canada, as well as industry and non-government organisations attended. RESULTS: The scenario progressed in three phases and participants were able to make decisions during each phase using live polling. The polling showed very diverse and sometimes conflicting decision making. Factors influential to pandemic severity were identified and categorised as modifiable or unmodifiable. A series of recommendations were made on the modifiable determinants of pandemic severity and how these can be incorporated into pandemic planning. These included preventing an attack through intelligence, law enforcement and legislation, improved speed of diagnosis, speed and completeness of case finding and case isolation, speed and security of vaccination response (including stockpiling), speed and completeness of contact tracing, protecting critical infrastructure and business continuity, non-pharmaceutical interventions (social distancing, PPE, border control) and protecting first responders. DISCUSSION: Pacific Eclipse illustrated the impact of a pandemic of smallpox under different response scenarios, which were validated to some extent by the COVID-19 pandemic. The framework developed from the scenario draws out modifiable determinants of pandemic severity which can inform pandemic planning for the ongoing COVID-19 pandemic and for future pandemics.

The nineteenth-century experience of the kingdom of the two Sicilies on mandatory vaccination: An Italian phenomenon?

The current health emergency caused by COVID-19 disease shows several similarities with well-known epidemics of the past. The knowledge of their management and overcoming could give us useful tools to face the present COVID-19 pandemic. The Bourbon king Ferdinand I planned the first free large-scale mass vaccination programme conducted in Italy and one of the first in Europe to counteract smallpox. The vaccination campaign was characterized by many difficulties and the efforts made by the Southern Kingdoms governors were enormous. For example, the "ante litteram communication campaign", aimed at convincing the so-called "hesitant" people and at confuting the arguments of vaccination opponents, was impressive. In 1821, the compulsory vaccination significantly reduced smallpox infections and death rates. Subsequently, several experiences followed this initiative, not without doubts and debates. Smallpox was finally eradicated worldwide only on the 9th December 1979. Despite to other countries, the "mandatory vaccination" is a topic often debated by Italian scientific and social communities.