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Potential threat of smallpox bioterrorism and concerns related to the adverse effects of currently licensed live-virus vaccines suggest the need to develop novel vaccines with better efficacy against smallpox. Use of DNA vaccines containing specific antigen-encoding plasmids prevents the risks associated with live-virus vaccines, offering a promising alternative to conventional smallpox vaccines. In this study, we investigated the efficiency of toll-like receptor (TLR) ligands in enhancing the immunogenicity of smallpox DNA vaccines. BALB/c mice were immunized with a DNA vaccine encoding the vaccinia virus L1R protein, along with the cytosine-phosphate-guanine (CpG) motif as a vaccine adjuvant, and their immune response was analyzed. Administration of B-type CpG oligodeoxynucleotides (ODNs) as TLR9 ligands 24 h after DNA vaccination enhanced the Th2-biased L1R-specific antibody immunity in mice. Moreover, B-type CpG ODNs improved the protective effects of the DNA vaccine against the lethal Orthopoxvirus challenge. Therefore, use of L1R DNA vaccines with CpG ODNs as adjuvants is a promising approach to achieve effective immunogenicity against smallpox infection., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (Copyright © 2024 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

The smallpox vaccine developed by Jenner in 1798 was successfully introduced in France in 1800 with the support of Napoleon Bonaparte. The medals and tokens (coin-like medals) issued to encourage early-day vaccination activities are described in the context of the changing political situation in that country. In 1800 a private society of subscribers, led by the Duke of La Rochefoucauld-Liancourt was created, along with a Vaccine Committee charged with evaluating the safety and efficacy of vaccination before deciding if vaccination should be extended to the entire population. The Vaccine Committee published a positive report in 1803, and in 1804, the Ministry of the Interior established the "Society for the extinction of smallpox in France by means of the propagation of the vaccine". The creation of the Society made smallpox vaccination an official activity of the empire, facilitating collaboration between government agencies. The vaccine institution, established by Napoleon in 1804, continued its functions until 1820 when the Royal Academy of Medicine was created and took over those functions. This case exemplifies the collaboration that was needed between science and politics to rapidly bring the recently developed smallpox vaccine to the needed population., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Smallpox is a highly contagious human disease caused by the variola virus. Although the disease was eliminated in 1979 due to its highly contagious nature and historical pathogenicity, with a mortality rate of up to 30%, this virus is an important candidate for biological weapons. Currently, vaccines are the critical measures to prevent this virus infection and spread. In this study, we designed a peptide vaccine using immunoinformatics tools, which have the potential to activate human immunity against variola virus infection efficiently. The design of peptides derives from vaccine-candidate proteins showing protective potential in vaccinia WR strains. Potential non-toxic and nonallergenic T-cell and B-cell binding and cytokine-inducing epitopes were then screened through a priority prediction using special linkers to connect B-cell epitopes and T-cell epitopes, and an appropriate adjuvant was added to the vaccine construction to enhance the immunogenicity of the peptide vaccine. The 3D structure display, docking, and free energy calculation analysis indicate that the binding affinity between the vaccine peptide and Toll-like receptor 3 is high, and the vaccine receptor complex is highly stable. Notably, the vaccine we designed is obtained from the protective protein of the vaccinia and combined with preventive measures to avoid side effects. This vaccine is highly likely to produce an effective and safe immune response against the variola virus infection in the body., Importance: In this work, we designed a vaccine with a cluster of multiple T-cell/B-cell epitopes, which should be effective in inducing systematic immune responses against variola virus infection. Besides, this work also provides a reference in vaccine design for preventing monkeypox virus infection, which is currently prevalent., Competing Interests: The authors declare no conflict of interest.

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., Competing Interests: Declaration of Competing Interest The authors have declared no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., (© 2024 The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.)

Increased human-to-human transmission of monkeypox virus (MPXV) is cause for concern, and antibodies directed against vaccinia virus (VACV) are known to confer cross-protection against Mpox. We used 430 serum samples derived from the Scottish patient population to investigate antibody-mediated cross-neutralization against MPXV. By combining electrochemiluminescence immunoassays with live-virus neutralization assays, we show that people born when smallpox vaccination was routinely offered in the United Kingdom have increased levels of antibodies that cross-neutralize MPXV. Our results suggest that age is a risk factor of Mpox infection, and people born after 1971 are at higher risk of infection upon exposure.

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., (Copyright © 2024 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Aims: To evaluate whether antibodies specific for the vaccinia virus (VV) are still detectable after at least 45 years from immunization. To confirm that VV-specific antibodies are endowed with the capacity to neutralize Mpox virus (MPXV) in vitro. To test a possible role of polyclonal non-specific activation in the maintenance of immunologic memory., Methods: Sera were collected from the following groups: smallpox-vaccinated individuals with or without latent tuberculosis infection (LTBI), unvaccinated donors, and convalescent individuals after MPXV infection. Supernatant of VV- or MPXV-infected Vero cells were inactivated and used as antigens in ELISA or in Western blot (WB) analyses. An MPXV plaque reduction neutralization test (PRNT) was optimized and performed on study samples. VV- and PPD-specific memory T cells were measured by flow cytometry., Results: None of the smallpox unvaccinated donors tested positive in ELISA or WB analysis and their sera were unable to neutralize MPXV in vitro. Sera from all the individuals convalescing from an MPXV infection tested positive for anti-VV or MPXV IgG with high titers and showed MPXV in vitro neutralization capacity. Sera from most of the vaccinated individuals showed IgG anti-VV and anti-MPXV at high titers. WB analyses showed that positive sera from vaccinated or convalescent individuals recognized both VV and MPXV antigens. Higher VV-specific IgG titer and specific T cells were observed in LTBI individuals., Conclusions: ELISA and WB performed using supernatant of VV- or MPXV-infected cells are suitable to identify individuals vaccinated against smallpox at more than 45 years from immunization and individuals convalescing from a recent MPXV infection. ELISA and WB results show a good correlation with PRNT. Data confirm that a smallpox vaccination induces a long-lasting memory in terms of specific IgG and that antibodies raised against VV may neutralize MPXV in vitro. Finally, higher titers of VV-specific antibodies and higher frequency of VV-specific memory T cells in LTBI individuals suggest a role of polyclonal non-specific activation in the maintenance of immunologic memory.

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., Competing Interests: K.P.K., D.O., C.R.Q., J.P.T., and C.C. are employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Rahway, NJ, USA, and may own stock or hold stock options in Merck & Co. Inc., Rahway, NJ, USA.

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., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Brazil ranked third in the number of Monkeypox infected worldwide in early September 2022 and eighth in multiple deaths. Brazilian Ministry of Health prepared a public policy to face the smallpox outbreak. This paper aims to analyze the governmental public policy' impacts on Monkeypox using survival analysis. The information in the database was collected from epidemiological bulletins on the official websites of the Brazilian Ministry of Health and the World Health Organization (WHO). The survival analysis with parametric statistical analysis, semiparametric with Cox regression, and nonparametric analysis were used. The inference of causality was perceived by the impact caused by the national public policy with the proportional reduction in the number of cases in the treatment group (Chi-sq = 117.783, p < 0.001), contrary to what was perceived in the control group, as well as survival about the time of the states that elaborated their plans based on what was made available by the government. The need to evaluate government projects should be within the scope of project management in Brazilian states and provide for more assertive decision-making in the fight against smallpox., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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.

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.

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., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Historically, biological agents have been used to target various populations. One of the earliest examples could be the catastrophic effect of smallpox in Australia in the eighteenth century (as alleged by some historians). Modern biological techniques can be used to both create or provide protection against various agents of biological warfare. Any microorganism (viruses, bacteria, and fungi) or its toxins can be used as biological agents. Minnesota Department of Health has listed Smallpox (variola major) as a category A bioterrorism agent, even though it has been eradicated in 1980 through an extensive vaccination campaign. Category A agents are considered the highest risk to public health. Laboratory-associated outbreaks of poxviruses could cause unprecedented occupational hazards. Only two WHO-approved BSL-4 facilities in the United States and Russia are allowed to perform research on the variola virus. So, poxviruses present themselves as a classical case of a dual-use dilemma, since research with them can be used for both beneficial and harmful purposes. Although the importance of ethics in scientific research requires no further elaboration, ethical norms assume greater significance during experimentation with poxviruses. In this chapter, we will update the readers on the sensitive nature of conducting research with poxviruses, and how these viruses can be a source of potential biological weapons. Finally, specified ethical guidelines are explored to ensure safe research practices in virology., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Poxviridae family includes several viruses that infecting humans usually causes skin lesions only, but in some cases their clinical course is complicated by viral pneumonia (with or without bacterial superinfections). Historically variola virus has been the poxviridae most frequently associated with the development of pneumonia with many large outbreaks worldwide before its eradication in 1980. It is still considered a biological threat for its potential in biological warfare and bioterrorism. Smallpox pneumonia can be severe with the onset of acute respiratory distress syndrome (ARDS) and death. Vaccinia virus, used for vaccination against smallpox exceptionally, in immunocompromised patients, can induce generalized (with also lung involvement) severe disease after vaccination. MPXV virus occasionally can cause pneumonia particularly in immunocompromised patients. The pathophysiology of poxviridae pneumonia is still an area of active research; however, in animal models these viruses can cause both direct damage to the lower airways epithelium and a hyperinflammatory syndrome, like a cytokine storm. Multiple mechanisms of immune evasion have also been described. The treatment of poxviridae pneumonia is mainly based on careful supportive care. Despite the absence of randomized clinical trials in patients with poxviridae pneumonia there are antiviral drugs, such as tecovirimat, cidofovir and brincidofovir, FDA-approved for use in smallpox and also available under an expanded access protocol for treatment of MPXV. There are 2 (replication-deficient modified vaccinia Ankara and replication-competent vaccinia virus) smallpox vaccines FDA-approved with the first one also approved for prevention of MPXV in adults that are at high risk of infection., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Variola virus is an anthroponotic agent that belongs to the orthopoxvirus family. It is an etiological agent of smallpox, an ancient disease that caused massive mortality of human populations. Twentieth century has witnessed the death of about 300 million people due to the unavailability of an effective vaccine. Early detection is the primary strategy to prevent an outbreak of smallpox. Variola virus forms the characteristic pus-filled pustules and centrifugal rash distribution in the infected patients while transmission occurs mainly through respiratory droplets during the early stage of infection. No antiviral drugs are approved for variola virus till date. Generation of first-generation vaccines helped in the eradication of smallpox which was declared by the World Health Organization., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

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., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

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., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Smallpox was a highly contagious disease caused by the variola virus. The disease affected millions of people over thousands of years and variola virus ranked as one of the deadliest viruses in human history. The complete eradication of smallpox in 1980, a major triumph in medicine, was achieved through a global vaccination campaign using a less virulent poxvirus, vaccinia virus. Despite this success, the herd immunity established by this campaign has significantly waned, and concerns are rising about the potential reintroduction of variola virus as a biological weapon or the emergence of zoonotic poxviruses. These fears were further fueled in 2022 by a global outbreak of monkeypox virus (mpox), which spread to over 100 countries, thereby boosting interest in developing new vaccines using molecular approaches. However, poxviruses are complex and creating modern vaccines against them is challenging. This review focuses on the structural biology of the six major neutralization determinants on poxviruses (D8, H3, A27, L1, B5, and A33), the localization of epitopes targeted by neutralizing antibodies, and their application in the development of subunit vaccines.

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., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Importance: Modern smallpox vaccines, such as those used against mpox, are made from vaccinia viruses, but it is still unknown whether cowpox, horsepox, or vaccinia viruses were used in the early 20th century or earlier. The mystery began to be solved when the genomes of six historical smallpox vaccines used in the United States from 1850 to 1902 were determined. Our work analyzed in detail the genomes of these six historical vaccines, revealing a complex genomic structure. Historical vaccines are highly similar to horsepox in the core of their genomes, but some are closer to the structure of vaccinia virus at the ends of the genome. One of the vaccines is a recombinant virus with parts of variola virus recombined into its genome. Our data add valuable information for understanding the evolutionary path of current smallpox vaccines and the genetic makeup of the potentially extinct group of horsepox viruses., Competing Interests: The authors declare no conflict of interest.

The Madrid Gazette published a Supplement on October 14, 1806, regarding the arrival of the Director of the Royal Expedition Vaccine Philanthropy, Francisco Xavier Balmis, and the reception held by King Carlos IV. Balmis had completed his journey across the Spanish overseas territories, taking the vaccine against smallpox from arm to arm with the help of a human chain of children. During this journey, Balmis also established Vaccination Boards and endeavoured to identify cows with cowpox. The publication endorsed the policies of a declining Bourbon monarchy and marked the peak of Balmis' professional career. Both sides emerged victorious: the Crown showcased itself as the sponsor and organiser of this altruistic journey, in line with prior scientific expeditions; and Balmis secured his place in Public Health history as the director of the first international vaccination campaign. This did not mean the culmination of the expedition, as other members were still administering vaccinations in the Philippines and South America. The main objective of this study was to assess the importance of the newspaper Madrid Gazette, outline the contents of the publication, authenticate the origins of the documentary sources underpinning its composition, and confirm its impact and citations throughout 19th-century Spanish publications. The components of the publication, its origins, as well as Balmis' involvement in its creation, have been substantiated. The Supplement's importance is defined by its utility as a resource for commemorating and appreciating the expedition.

Background: After the eradication of smallpox in China in 1979, vaccination with the vaccinia virus (VACV) Tiantan strain for the general population was stopped in 1980. As the monkeypox virus (MPXV) is rapidly spreading in the world, we would like to investigate whether the individuals with historic VACV Tiantan strain vaccination, even after more than 40 years, could still provide ELISA reactivity and neutralizing protection; and whether the unvaccinated individuals have no antibody reactivity against MPXV at all., Results: We established serologic ELISA to measure the serum anti-MPXV titer by using immunodominant MPXV surface proteins, A35R, B6R, A29L, and M1R. A small proportion of individuals (born before 1980) with historic VACV Tiantan strain vaccination exhibited serum ELISA cross-reactivity against these MPXV surface proteins. Consistently, these donors also showed ELISA seropositivity and serum neutralization against VACV Tiantan strain. However, surprisingly, some unvaccinated young adults (born after 1980) also showed potent serum ELISA activity against MPXV proteins, possibly due to their past infection by some self-limiting Orthopoxvirus (OPXV)., Conclusions: We report the serum ELISA cross-reactivity against MPXV surface protein in a small proportion of individuals both with and without VACV Tiantan strain vaccination history. Combined with our serum neutralization assay against VACV and the recent literature about mice vaccinated with VACV Tiantan strain, our study confirmed the anti-MPXV cross-reactivity and cross-neutralization of smallpox vaccine using VACV Tiantan strain. Therefore, it is necessary to restart the smallpox vaccination program in high risk populations., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objective: This article reviews the published data encompassing the development, pharmacology, efficacy, and safety of brincidofovir, a nucleotide analogue DNA polymerase inhibitor developed for the treatment of smallpox., Data Sources: A literature review was conducted in PubMed, MEDLINE, and Clinicaltrials.gov from inception up to December 2022, using terms Tembexa, brincidofovir, CMX001, smallpox treatment , and variola treatment ., Study Selection and Data Extraction: Data were limited to studies published in English language, which evaluated the efficacy and safety of brincidofovir., Data Synthesis: Two surrogate animal models were included in the Food and Drug Administration's (FDA) decision to approve brincidofovir: ectromelia virus in mice and rabbitpox in rabbits. Phases 2 and 3 studies established safety for approval. Brincidofovir biweekly for the treatment of disseminated adenovirus disease resulted in all-cause mortality, ranging from 13.8% to 29%. In a study for cytomegalovirus prophylaxis, patients with clinically significant cytomegalovirus infection through week 24 posttransplant was 51.2% with brincidofovir and 52.3% with placebo., Conclusions: Brincidofovir adds a second oral agent to treat smallpox, with a different mechanism of action than tecovirimat. In the event of a smallpox outbreak, prompt treatment will be necessary to contain its spread. Brincidofovir shows efficacy in surrogate animal models. In healthy volunteers and individuals treated, or used as prophylaxis, for cytomegalovirus or adenovirus, the primary adverse events were gastrointestinal in addition to transient hepatotoxicity. Additionally, excessive deaths were observed in hematopoietic cell transplant patients receiving it as cytomegalovirus prophylaxis, requiring a black box warning.

Monkeypox (MPOX) is a viral zoonosis endemic in West or Central African countries that is sporadically exported to another area. In May 2022, a global outbreak of MPOX smallpox began to occur in several countries in Europe and North America. Most of the reported cases are identified at the outpatient level and mainly affect men who have sex with men (MSM). Transmission is by close contact with lesions, body fluids, respiratory secretions or contaminated material from an infected person or animal. The clinical picture is similar to human smallpox, with less severity. Mild, self-limiting skin involvement predominates after 2-4 weeks. In MSM, atypical skin lesions appear due to the mode of infection. Severe forms or complications may appear in certain risk groups. The case fatality rate is 3%-6% depending on the clade responsible. The diagnosis of suspicion is confirmed by detection of the virus from exudates of lesions or scabs, with nucleic acid amplification techniques by conventional or real-time PCR. Clinical management in most cases is performed in primary care (PC), by monitoring the main symptoms. Between 5-10% require hospital management and there are some specific antiviral treatment options. Human smallpox vaccines protect against MPOX and are used as pre- and post-exposure prophylaxis for persons at risk. Measures to reduce exposure to the virus are the main MPOX prevention strategy. In addition, the role of the family physician is key to controlling the spread of MPOX through active surveillance and early diagnosis of the disease., (Copyright © 2023 The Authors. Publicado por Elsevier España, S.L.U. All rights reserved.)

In early 2022, a cluster of monkeypox virus (MPXV) infection (mpox) cases were identified within the UK with no prior travel history to MPXV-endemic regions. Subsequently, case numbers exceeding 80,000 were reported worldwide, primarily affecting gay, bisexual, and other men who have sex with men (GBMSM). Public health agencies worldwide have offered the IMVANEX Smallpox vaccination to these individuals at high-risk to provide protection and limit the spread of MPXV. We have developed a comprehensive array of ELISAs to study poxvirus-induced antibodies, utilising 24 MPXV and 3 Vaccinia virus (VACV) recombinant antigens. Panels of serum samples from individuals with differing Smallpox-vaccine doses and those with prior MPXV infection were tested on these assays, where we observed that one dose of Smallpox vaccination induces a low number of antibodies to a limited number of MPXV antigens but increasing with further vaccination doses. MPXV infection induced similar antibody responses to diverse poxvirus antigens observed in Smallpox-vaccinated individuals. We identify MPXV A27 as a serological marker of MPXV-infection, whilst MPXV M1 (VACV L1) is likely IMVANEX-specific. Here, we demonstrate analogous humoral antigen recognition between both MPXV-infected or Smallpox-vaccinated individuals, with binding to diverse yet core set of poxvirus antigens, providing opportunities for future vaccine (e.g., mRNA) and therapeutic (e.g., mAbs) design., (© 2023. Crown.)

The ongoing pandemic caused by mpox virus (MPXV) has become an international public health emergency that poses a significant threat to global health. The vaccinia virus Tiantan strain (VTT) was used to vaccinate against smallpox in China 42 years ago. It is urgent to assess the level of immunity to smallpox in individuals vaccinated 43 or more years ago and evaluate their immunological susceptibility to MPXV. Here, we recruited 294 volunteers and detected the level of residual humoral immunity, including the vaccinia-specific IgG level and neutralizing antibody titer, and the cross-antibodies of MPXV A29L, B6R, A35R, and M1R. Our results showed that the humoral immunity from the smallpox vaccine in the population still remains, and VTT-specific NAb levels wane with age. The majority of the population pre-1981 who should be immunized with VTT still maintains certain levels of MPXV-specific antibodies, in particular, targeting A35R and B6R antigens. Furthermore, we separately analyzed the correlations between the OD450 values of VTT-specific IgG and A35R-specific IgG, B6R-specific IgG, and A29L-specific IgG with plasma samples diluted 1:40, showing a linear correlation (p < 0.0001). Our findings suggest that most Chinese populations still maintain VTT-specific IgG antibodies for 42 or more years after smallpox vaccination and could provide some level of protection against MPXV., (© 2023. West China Hospital, Sichuan University.)

Although one member of the poxvirus family, variola virus, has caused one of the most devastating human infections worldwide, smallpox, the knowledge gained over the last 30 years on the molecular, virological and immunological mechanisms of these viruses has allowed the use of members of this family as vectors for the generation of recombinant vaccines against numerous pathogens. In this review, we cover different aspects of the history and biology of poxviruses with emphasis on their application as vaccines, from first- to fourth-generation, against smallpox, monkeypox, emerging viral diseases highlighted by the World Health Organization (COVID-19, Crimean-Congo haemorrhagic fever, Ebola and Marburg virus diseases, Lassa fever, Middle East respiratory syndrome and severe acute respiratory syndrome, Nipah and other henipaviral diseases, Rift Valley fever and Zika), as well as against one of the most concerning prevalent virus, the Human Immunodeficiency Virus, the causative agent of Acquired Immunodeficiency Syndrome. We discuss the implications in human health of the 2022 monkeypox epidemic affecting many countries, and the rapid prophylactic and therapeutic measures adopted to control virus dissemination within the human population. We also describe the preclinical and clinical evaluation of the Modified Vaccinia virus Ankara and New York vaccinia virus poxviral strains expressing heterologous antigens from the viral diseases listed above. Finally, we report different approaches to improve the immunogenicity and efficacy of poxvirus-based vaccine candidates, such as deletion of immunomodulatory genes, insertion of host-range genes and enhanced transcription of foreign genes through modified viral promoters. Some future prospects are also highlighted., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The management of the coronavirus pandemic required huge worldwide vaccination efforts. In this endeavour, healthcare workers faced the twofold challenge of reaching remote areas, and persuading people to take the vaccine. As it happens, this is nothing new in the history of medicine. Health workers may indeed continue to take inspiration from Francisco Xavier Balmis, a Spanish physician of the 19th century who realised the importance of Jenner's vaccine against smallpox, and led a successful expedition to administer the vaccines in the Spanish colonial possessions of the Western hemisphere and Asia. This article presents a biographical sketch of Balmis, focusing on his expedition.

Beijing and Shanghai, representative modern cities in China, witnessed the development of various urban infrastructures and quarantine systems in the 1920s and 1930s. Both cities established Health Demonstration Stations in the 1930s, as part of their implementation of modern health administration. This foundation played a pivotal role for making health administration more practical. Huang Zi-fang (1899-1940) and Hu Hung-ji (1894-1932), the inaugural directors of the health bureau in the respective cities, were both graduates of the Johns Hopkins University School of Public Health in the United States. They shared a similar view of public health. Active exchanges occurred between the heads of the health administration in the two cities who were the leading forces in the health reform, encompassing various health experiments including the Health Demonstration Station. During the 1930s in China, state medicine gained prominence as the most ideal medical model for constructing a modern state. As such, the quarantine activities they promoted were also considered the most ideal model. The public health care centered on Health Demonstration Stations in the 1920s and 1930s that developed in large Chinese cities such as Beijing and Shanghai pursued similar goals by strengthening quarantine administration through free medical treatment and modern spatial control. Nonetheless, each city exhibited differences in terms of the subjects and targets of quarantine, as well as the primary bases of quarantine, which were either Health Demonstration Stations or hospitals. Both municipal governments and the civilian sector led the sanitary infrastructure development. While Shanghai showed stronger development in terms of the number of vaccinations, Shanghai's dualized quarantine system did not necessarily create a better health environment than Beijing in terms of spatial control. In the 1940s, the Japanese occupation government implemented measures to inherit and further develop existing health administrations in Beijing and Shanghai. Existing international settlements were incorporated into the Japanese occupation government, and the occupation government pursued homogenization of urban space and tried to maintain the existing urban policy as much as possible to preserve the status quo. However, the intensification of the Anti-Japanese War and the Chinese Civil War brought an end to the health experiment centered around the Health Demonstration Station in China in the first half of the twentieth century.

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., Competing Interests: The authors declare no conflict of interest., (©2023 Pacini Editore SRL, Pisa, Italy.)

Vaccines against smallpox are known to have cross-protective activity against monkeypox, and smallpox and monkeypox infections are believed to generate permanent immunity. Nevertheless, there are scarce data about the possibility of reinfection or reactivation. Recently, a case of apparent monkeypox reinfection has been reported. We present a suspected case of second episode of monkeypox in a healthy and previously vaccinated man, with a confirmed primary monkeypox infection occurring three months before the second confirmed presentation.

A complex epidemiological situation marked the health system at the time of the establishment of the Czechoslovak Republic. Reducing the number of infectious diseases was an essential task of the State Administration of Health. It required new legislation and various steps directed at reducing infectious diseases. Serious infectious diseases, such as scarlet fever, diphtheria, typhoid, dysentery, smallpox, and malaria, were among the most significant health problems in Czechoslovakia. In 1920, Act No. 412 Coll. regarding compulsory smallpox vaccination was issued, as well as government Regulation No. 298, which describes vaccination obligations and stipulated proper isolation of patients with infectious diseases. Other steps that led to improvements included establishing the National Institute of Health and mobile disinfectant units. Conclusion: The systematic development of new legislation contributed to the new Republic's proficiency at the task and the gradual reduction in the number of infectious diseases.

Despite different lifestyles, humankind has suffered from osteoporosis for thousands of years. A literature review concerning the history of osteoporosis in the following databases: Index Medicus, Medline, PubMed, and PMC Citations was done. In the final analysis, 18 review articles and 31 original papers were included. The works were published during the period 1705-2020. Although there is evidence of the existence of osteoporosis for many centuries, it was first described as a disease at the beginning of the 18th century. It was first perceived as an unavoidable course of aging with no possibility to cure. This approach changed only in the 20th century thanks to sudden diagnostic and therapeutic progress. This paper presents the milestones and most important researchers in osteoporosis history. Rapid progress in diagnostic and therapeutic possibilities sheds new light on osteoporosis’ nature. A comprehensive outlook on its history may help find answers for the still unsolved problems of this disease.

Monkeypox is an emerging threat to humans since a new outbreak in May 2022. It is hypothesised that increasing the immunologically naive population after the cessation of the smallpox vaccination campaign in the 1980s is one of the leading causes of it. A literature search was conducted using different electronic databases including MEDLINE (through PubMed), SCOPUS, Web of Science, Cochrane library, and EMBASE for relevant studies. After duplication removal, abstract and title screening, and full-text screening were done, the data were extracted, tabulated, and analysed. The risk of bias was assessed following the Risk of Bias Assessment tool for Non-randomised Studies. We found a total of 1068 relevant articles and finally, we included 6 articles including 2083 participants. The studies suggested that smallpox is 80.7% efficacious to prevent human monkeypox and the immunity provided by prior smallpox vaccination is long-lasting. Moreover, the smallpox vaccination decreases the risk of human monkeypox by 5.2-folds. Two cross-sectional studies based on the Democratic Republic of the Congo (DRC) including a total of around 1800 monkeypox cases found that unvaccinated participants had 2.73 and 9.64-fold increased risk of monkeypox compared to the vaccinated participants. Other studies in USA and Spain also demonstrated that unvaccinated people were more prone to develop monkeypox than vaccinated people. Furthermore, monkeypox incidence has increased by 20 folds, 30 years after the cessation of the smallpox vaccination campaign in DRC. Evidence-based preventive and therapeutic agents are still not available for human monkeypox. Further study should be done to explore the role of the smallpox vaccine in preventing human monkeypox., (© 2023 The Authors. Reviews in Medical Virology published by John Wiley & Sons Ltd.)

The monkeypox virus (MPOX) is an uncommon zoonotic illness brought on by an orthopoxvirus (OPXV). MPOX can occur with symptoms similar to smallpox. Since April 25, 2023, 110 nations have reported 87,113 confirmed cases and 111 fatalities. Moreover, the outspread prevalence of MPOX in Africa and a current outbreak of MPOX in the U.S. have made it clear that naturally occurring zoonotic OPXV infections remain a public health concern. Existing vaccines, though they provide cross-protection to MPOX, are not specific for the causative virus, and their effectiveness in the light of the current multi-country outbreak is still to be verified. Furthermore, as a sequel of the eradication and cessation of smallpox vaccination for four decades, MPOX found a possibility to re-emerge, but with distinct characteristics. The World Health Organization (WHO) suggested that nations use affordable MPOX vaccines within a framework of coordinated clinical effectiveness and safety evaluations. Vaccines administered in the smallpox control program and conferred immunity against MPOX. Currently, vaccines approved by WHO for use against MPOX are replicating (ACAM2000), low replicating (LC16m8), and non-replicating (MVA-BN). Although vaccines are accessible, investigations have demonstrated that smallpox vaccination is approximately 85% efficient in inhibiting MPOX. In addition, developing new vaccine methods against MPOX can help prevent this infection. To recognize the most efficient vaccine, it is essential to assess effects, including reactogenicity, safety, cytotoxicity effect, and vaccine-associated side effects, especially for high-risk and vulnerable people. Recently, several orthopoxvirus vaccines have been produced and are being evaluated. Hence, this review aims to provide an overview of the efforts dedicated to several types of vaccine candidates with different strategies for MPOX, including inactivated, live-attenuated, virus-like particles (VLPs), recombinant protein, nucleic acid, and nanoparticle-based vaccines, which are being developed and launched., Competing Interests: Declaration of competing interest The authors declared no conflicts of interest regarding the research, authorship, and publication of this article., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Mpox virus (MPXV) caused a multi-country outbreak in non-endemic areas in 2022. Following historic success of smallpox vaccination with vaccinia virus (VACV)-based vaccines, the third generation modified vaccinia Ankara (MVA)-based vaccine was used as prophylaxis for MPXV, but its effectiveness remains poorly characterized. Here, we applied two assays to quantify neutralizing antibodies (NAbs) in sera from control, MPXV-infected, or MVA-vaccinated individuals. Various levels of MVA NAbs were detected after infection, historic smallpox, or recent MVA vaccination. MPXV was minimally sensitive to neutralization. However, addition of complement enhanced detection of responsive individuals and NAb levels. Anti-MVA and -MPXV NAbs were observed in 94% and 82% of infected individuals, respectively, and 92% and 56% of MVA vaccinees, respectively. NAb titers were higher in individuals born before 1980, highlighting the impact of historic smallpox vaccination on humoral immunity. Altogether, our results indicate that MPXV neutralization is complement dependent and uncover mechanisms underlying vaccine effectiveness., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Wellington Sun reports a relationship with Moderna Inc, Merck Sharp & Dohme UK Ltd, Takeda Vaccines, Apriori Bio, International AIDS Vaccine Initiative, Inovio Pharmaceuticals Inc, Appilli Therapeutics, Inc, Laronde, Inc, Altimmune Inc, Curative, Inc, Hookipa Biotech GmbH, Henry M Jackson Foundation for the Advancement of Military Medicine Inc, IgM Biosciences Inc, Meissa Vaccines, Inc, Parexel International Corporation, RRD International LLC, Teva Pharmaceuticals USA Inc, Seres Therapeutics that includes: consulting or advisory services, employment, and equity or stock options. Wellington Sun has patent Tetravalent live attenuated dengue vaccine issued to Assignee.

The Royal Philanthropic Vaccine Expedition is considered in the history of medicine as the first international health expedition aimed at the global elimination of a contagious disease: smallpox. However, the initiatives carried out in this way before the arrival of the Balmis Expedition, by surgeons from the Spanish Navy, are less well known. Thus, the main objective of this research work is to offer an overview of the different anti-variolic vaccination initiatives prior to the campaign financed by the Spanish crown from these health facilities. Using the heuristic and hermeneutic method, our article is based on primary sources contrasted with specialised literature. The results obtained are presented in a narrative style from each of the surgeons identified as decisive in the implementation of the vaccine, thus providing a divergent and unpublished historiographic approach. As the facts described show, before the arrival of Balmis the vaccine substance was introduced in those countries thanks to the initiative of various surgeons: in Puerto Rico by Francisco Oller; in Cartagena and Santa Marta in Colombia by Ángel Hidalgo; in Venezuela by Alonso Ruiz; in Cuba by Tomás Romay and Bernardo de Cózar; in the Viceroyalty of New Granada (Colombia) by Lorenzo Vergés; in Guatemala by Miguel José Monzón and José María Ledesma; in the Viceroyalty of New Spain by Alejandro García Arboleya and Antonio Serrano; in Peru by Pedro Belomo; in Río de la Plata by Cristóbal Martín de Montúfar; in the Chilean region of Coquimbo by José María Gómez; and in the Philippines by Cristóbal Regidor. Finally, it should be noted that these surgeons and the approach presented are part of a historiography based on the personal actions of professionals trained, for the most part, at the Medical-Surgical School of Cadiz.

Background: Although modified vaccinia Ankara-Bavarian Nordic (MVA-BN) vaccination is approved for smallpox and monkeypox prevention, immunological persistence and booster effects remain undescribed., Methods: Participants naive to smallpox vaccination were randomized to 1 dose MVA-BN (1×MVA, n = 181), 2 doses MVA-BN (2×MVA, n = 183), or placebo (n = 181). Participants with previous smallpox vaccination received 1 MVA-BN booster (HSPX, n = 200). Subsets of the formerly naive groups (approximately 75 each) received an MVA-BN booster 2 years later., Results: Neutralizing antibody (nAb) geometric mean titers (GMTs) increased from 1.1 (baseline, both naive groups) to 7.2 and 7.5 (week 4, 1×MVA and 2×MVA, respectively), and further to 45.6 (week 6, 2×MVA after second vaccination). In HSPX, nAb GMT rapidly increased from 21.6 (baseline) to 175.1 (week 2). At 2 years, GMTs for 1×MVA, 2×MVA, and HSPX were 1.1, 1.3, and 10.3, respectively. After boosting in the previously naive groups, nAb GMTs increased rapidly in 2 weeks to 80.7 (1×MVA) and 125.3 (2×MVA), higher than after primary vaccination and comparable to boosted HSPX subjects. Six months after boosting, GMTs were 25.6 (1×MVA) and 49.3 (2×MVA). No safety concerns were identified., Conclusions: Anamnestic responses to boosting without sustained high nAb titers support presence of durable immunological memory following primary MVA-BN immunization. Clinical Trials Registration. NCT00316524 and NCT00686582., Competing Interests: Potential conflicts of interest. H.I. is a former employee of Harrison Clinical Research Deutschland GmbH; N. S., D. R., D. S., J. D. P., T. P. H. M., G. S., R. N., H. W., and L. C. are current or former employees and stakeholders of Bavarian Nordic; L. d. M. is the company CMO and P. C. is the company CEO. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objectives: (1) Characterize the initial clinical characteristics and long-term outcomes of smallpox vaccine-associated hypersensitivity myocarditis and pericarditis (MP) in United States service members. (2) Describe the process of case identification and adjudication using the 2003 CDC nationally defined myocarditis/pericarditis epidemiologic case definitions to include consideration of case-specific diversity and evolving evidence., Background: Between 2002 and 2016, 2.546 million service members received a smallpox Vaccinia vaccine. Acute MP is associated with vaccinia, but the long-term outcomes have not been studied., Methods: Records of vaccinia-associated MP reported to the Vaccine Adverse Event Reporting System by vaccination date were adjudicated using the 2003 MP epidemiologic case definitions for inclusion in a retrospective observational cohort study. Descriptive statistics of clinical characteristics, presentation, cardiac complications, and time course of clinical and cardiac recovery were calculated with comparisons by gender, diagnosis and time to recovery., Results: Out of over 5000 adverse event reports, 348 MP cases who survived the acute illness, including 276 myocarditis (99.6% probable/confirmed) and 72 pericarditis (29.2% probable/confirmed), were adjudicated for inclusion in the long-term follow-up. Demographics included a median age of 24 years (IQR 21,30) and male predominance (96%). Compared to background military population, the myocarditis and pericarditis cohort had a higher percentage of white males by 8.2% (95% CI: 5.6, 10.0) and age <40 years by 4.2% (95% CI: 1.7,5.8). Long-term follow-up documented full recovery in 267/306 (87.3%) with 74.9% recovered in less than a year (median ~3 months). Among patients with myocarditis, the percentage who had a delayed time to recovery at time of last follow-up was 12.8% (95% CI: 2.1,24.7) higher in those with an acute left ventricular ejection fraction (EF) of ≤50% and 13.5% (95% CI: 2.4,25.7) higher in those with hypokinesis. Patient complications included 6 ventricular arrhythmias (2 received implanted defibrillators) and 14 with atrial arrhythmias (2 received radiofrequency ablation). Three of 6 patients (50%) diagnosed with cardiomyopathy had clinical recovery at their last follow-up date., Conclusions: Hypersensitivity myocarditis/pericarditis following the smallpox vaccine is associated with full clinical and functional ventricular recovery in over 87% of cases (74.9% <1 year). A minority of MP cases experienced prolonged or incomplete recovery beyond 1 year., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)