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

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

La vacunación: estrategia fundamental en la eliminación de la viruela en Cuba (1804-1923) / Vaccination: fundamental strategy in the elimination of smallpox in Cuba (1804-1923)

Las epidemias de viruela azotaron a Cuba desde 1522, produciendo elevada morbilidad y mortalidad. En 1804, se inició la estrategia de vacunación contra esta enfermedad que, con distintos avatares y fases en su desarrollo, tuvo como figura central a Tomas Romay. El objetivo del trabajo fue analizar los resultados de la estrategia de vacunación llevada a cabo en la eliminación de la viruela en Cuba y como se transformaron las instituciones en relación a los avances y producción de la vacuna en función del contexto científico, social y político del periodo estudiado. Las fuentes primarias utilizadas han sido diversas: fuentes de tipo epidemiológico y estadístico, documentos relacionados con los organismos puestos en marcha para la propagación y producción de la vacuna, informes institucionales y periodismo científico local. El trabajo reconstruye el papel jugado por la Junta Central de la Vacuna (1804), para planificar, ejecutar y expandir esta estrategia en el territorio, el Instituto de Vacunación Animal (1873) y el Centro General de la Vacuna (1883) en la producción de la misma. En el siglo XX, se convirtió en obligatoria por ley y junto a las estrictas medidas de aislamiento tomadas sobre los casos y los controles de focos, llevaron a la eliminación de la enfermedad a partir de 1923

The epidemics of smallpox lashed Cuba since 1522, producing high morbidity and mortality which with different ups and downs in its development, had as central figure Tomas Romay. The main aim of this paper is to analyze the results of the vaccination strategy performed in Cuba for the elimination of smallpox in Cuba and how the institutions were transformed in relation to the advances and production of the vaccine. The primary sources used have been diverse: epidemiological and statistical sources, documents related to organisms set up for to the spread and production of the vaccine, institutional reports and local scientific journalism. The work reconstructs the role played by the Central Vaccine Board (1804) emerged to plan, execute and expand this strategy in the territory, the Animal Vaccination Institute (1873) and the General Vaccine Center (1883) to produce it. In the twentieth century, it became mandatory by law and together with strict isolation measures taken on cases and spot checks, led to the elimination of the disease in 1923

Stopping live vaccines after disease eradication may increase mortality.

Several live vaccines may have beneficial non-specific effects (NSEs) reducing mortality more than can be explained by the prevention of the target infection, a phenomenon which has been linked to innate immune training. Most randomised controlled trials (RCTs) of oral polio vaccine (OPV) and measles vaccine (MV) have shown a large reduction in mortality that must have been at least partly nonspecific because it was much larger than the reduction explained by prevention of the target disease. Hence, stopping a live vaccine after disease-eradication could have negative health effects if the potential beneficial NSEs are not considered. We reviewed one eradicated disease, smallpox, and two infections likely to be eradicated in coming decades, polio and measles. No study was made of unintended effects of stopping smallpox vaccination when it happened in 1980. We have subsequently documented in both Guinea-Bissau and Denmark that smallpox-vaccinated individuals continued to have a survival advantage long after smallpox had been eradicated. The few studies which have examined the effect of OPV on survival all suggest strong beneficial NSEs; in RCTs, OPV compared with inactivated polio vaccine (IPV) has been associated with non-specific reductions in morbidity. RCTs, natural experiments and observational studies have found strong beneficial NSEs for MV. Hence, the imminent eradication of polio and the planned stop of OPV in 2024 and the subsequent eradication of measles infection and the possible stop to live MV could have negative effects for child survival. Before live vaccines are phased out, potential unintended effects of stopping these vaccines should be thoroughly studied.

La mortalidad causada por la viruela en Jerez de la Frontera (1880-1895) / Smallpox mortality in Jerez de la Frontera (1880-1895)

En este artículo se estudia la mortalidad causada por la viruela en Jerez de la Frontera (Cádiz, España), en un amplio periodo de tiempo (1880-1895), enfermedad endémica en la ciudad que afectó sobre todo en las primeras edades de la vida; asimismo se estudia la epidemia que causó esta enfermedad en la citada localidad en el año 1882, tanto en los aspectos de morbilidad como de mortalidad; epidemia que se produce en el contexto de una crisis social y económica que afectó a la ciudad. Se han utilizado diversas fuentes documentales procedentes principalmente del Archivo Municipal y de Bibliotecas Públicas de Jerez, destacando los libros de registro del Cementerio, así como informes o escritos de médicos como José María Escudero Franco y Manuel Ruiz de la Rabia, haciendo hincapié en las medidas preventivas propuestas y especialmente en el problema de las vacunaciones y revacunaciones, desde la década de los sesenta a la de los ochenta del siglo XIX

We have studied in this article the mortality caused by smallpox in Jerez de la Frontera (Cádiz, Spain), over a long period of time (1880-1895), an endemic disease in the city that especially affected in the first ages of life. The epidemic that caused this disease, in the aforementioned locality in 1882, has also been studied both in its morbidity and mortality aspects. The epidemic took place in the context of a social and economic crisis that hit the city. We have used various documentary sources, mainly from the Municipal Archive and from the Jerez Public Libraries, highlighting the Cemetery register log books, as well as reports or writings by doctors such as José María Escudero Franco and Manuel Ruiz de la Rabia, with special emphasis on proposals for preventive measures, especially in the problem of vaccinations and revaccinations, from the sixties to the eighties of the nineteenth century

Linear Epitopes in Vaccinia Virus A27 Are Targets of Protective Antibodies Induced by Vaccination against Smallpox.

UNLABELLED: Vaccinia virus (VACV) A27 is a target for viral neutralization and part of the Dryvax smallpox vaccine. A27 is one of the three glycosaminoglycan (GAG) adhesion molecules and binds to heparan sulfate. To understand the function of anti-A27 antibodies, especially their protective capacity and their interaction with A27, we generated and subsequently characterized 7 murine monoclonal antibodies (MAbs), which fell into 4 distinct epitope groups (groups I to IV). The MAbs in three groups (groups I, III, and IV) bound to linear peptides, while the MAbs in group II bound only to VACV lysate and recombinant A27, suggesting that they recognized a conformational and discontinuous epitope. Only group I antibodies neutralized the mature virion in a complement-dependent manner and protected against VACV challenge, while a group II MAb partially protected against VACV challenge but did not neutralize the mature virion. The epitope for group I MAbs was mapped to a region adjacent to the GAG binding site, a finding which suggests that group I MAbs could potentially interfere with the cellular adhesion of A27. We further determined the crystal structure of the neutralizing group I MAb 1G6, as well as the nonneutralizing group IV MAb 8E3, bound to the corresponding linear epitope-containing peptides. Both the light and the heavy chains of the antibodies are important in binding to their antigens. For both antibodies, the L1 loop seems to dominate the overall polar interactions with the antigen, while for MAb 8E3, the light chain generally appears to make more contacts with the antigen. IMPORTANCE: Vaccinia virus is a powerful model to study antibody responses upon vaccination, since its use as the smallpox vaccine led to the eradication of one of the world's greatest killers. The immunodominant antigens that elicit the protective antibodies are known, yet for many of these antigens, little information about their precise interaction with antibodies is available. In an attempt to better understand the interplay between the antibodies and their antigens, we generated and functionally characterized a panel of anti-A27 antibodies and studied their interaction with the epitope using X-ray crystallography. We identified one protective antibody that binds adjacent to the heparan sulfate binding site of A27, likely affecting ligand binding. Analysis of the antibody-antigen interaction supports a model in which antibodies that can interfere with the functional activity of the antigen are more likely to confer protection than those that bind at the extremities of the antigen.

[The American Almanac, smallpox in Santiago in 1872 and the isolations hospitals]. / El Almanaque Americano, la viruela en Santiago en 1872 y los lazaretos.

Due to the smallpox epidemic in Santiago in 1872, a Commission or Central Board of isolation hospitals was created. These institutions were endowed with the necessary personnel to receive and assist the sick, highlighting the work of medical students, interns at these hospitals. The total number of patients treated in the infirmaries of Santiago reached 6,782, with a fatality rate of 3,073 (45.3%).

[Lessons learnt from the German smallpox outbreaks after World War II]. / Pockenausbrüche nach dem zweiten Weltkrieg in Deutschland.

BACKGROUND: Even though smallpox was declared eradicated by WHO in 1980, it cannot be ruled out that the etiological variola virus could be used as a biological weapon. Undestroyed viruses from biowarfare programmes, virus strains left undetected in a freezer or dangerous recombinant poxvirus constructs could cause dangerous outbreaks in a relatively unprotected population. OBJECTIVES: Despite an abundance of studies performed during the eradication of smallpox, epidemiological data for preparedness planning and outbreak control in modern, industrialized countries are scarce. MATERIAL AND METHODS: Full-text hand search for the period from 1945 to 1975 in the main German public health journals. RESULTS: After World War II 12 smallpox outbreaks occurred in Germany. They were studied with the focus on the period of contagiousness, the protective effect of vaccination, booster-effect of revaccination and the place of infection. A total of 95 individuals contracted smallpox, including 10 fatalities. Despite having been previously vaccinated, 81 vaccinated persons came down with smallpox, yet 91% of them developed only mild symptoms. These patients presented a high risk for spreading the infection to contact persons due to misinterpretation of symptoms and the continuing social contacts. Basically, the risk of transmission in the first 2 to 3 days after onset of symptoms was low, thus facilitating antiepidemic measures. The importance of hospital preparedness is emphasized by the fact that most infections occurred in hospitals. CONCLUSION: The data analyzed provide valuable information for today's outbreak response planning and counter bioterrorism preparedness.

[Treatment and remedies against smallpox outbreaks in Ferrara in the late nineteenth century]. / Cure e rimedi contro le epidemie di vaiolo a Ferrara nella seconda metà del secolo XIX.

Health interventions against smallpox during the two epidemics in the second half of the 19th century are outlined. The 1871 hospital health report and the medical report on smallpox patients treated at the hospital and poorhouse of Ferrara between January 1891 and January 1892, drawn up by Alessandro Bennati, provide both interesting data and insights into the treatments and remedies of the time. The treatment of this illness was - and indeed could be - nothing other than symptomatic, there being no real means to halt the spread of the disease. Rather, other remedies were found by alleviating pain and regaining energy during the various stages of the disease. A close relationship between vaccination and the incidence and gravity of the illness is underlined. When the practice of vaccination started to be widely employed at the end of the century, there were almost no cases of death due to smallpox. The pharmacopoeias of the time, Antonio Campana's Farmacopea ferrarese in particular, proved an essential guide in the analysis of each document.

Effect of the deletion of genes encoding proteins of the extracellular virion form of vaccinia virus on vaccine immunogenicity and protective effectiveness in the mouse model.

Antibodies to both infectious forms of vaccinia virus, the mature virion (MV) and the enveloped virion (EV), as well as cell-mediated immune response appear to be important for protection against smallpox. EV virus particles, although more labile and less numerous than MV, are important for dissemination and spread of virus in infected hosts and thus important in virus pathogenesis. The importance of the EV A33 and B5 proteins for vaccine induced immunity and protection in a murine intranasal challenge model was evaluated by deletion of both the A33R and B5R genes in a vaccine-derived strain of vaccinia virus. Deletion of either A33R or B5R resulted in viruses with a small plaque phenotype and reduced virus yields, as reported previously, whereas deletion of both EV protein-encoding genes resulted in a virus that formed small infection foci that were detectable and quantifiable only by immunostaining and an even more dramatic decrease in total virus yield in cell culture. Deletion of B5R, either as a single gene knockout or in the double EV gene knockout virus, resulted in a loss of EV neutralizing activity, but all EV gene knockout viruses still induced a robust neutralizing activity against the vaccinia MV form of the virus. The effect of elimination of A33 and/or B5 on the protection afforded by vaccination was evaluated by intranasal challenge with a lethal dose of either vaccinia virus WR or IHD-J, a strain of vaccinia virus that produces relatively higher amounts of EV virus. The results from multiple experiments, using a range of vaccination doses and virus challenge doses, and using mortality, morbidity, and virus dissemination as endpoints, indicate that the absence of A33 and B5 have little effect on the ability of a vaccinia vaccine virus to provide protection against a lethal intranasal challenge in a mouse model.

El otoño de la muerte: la crisis demográfica de 1779 en la ciudad de México / The fall death: the demographic crisis of 1779 in Mexico City

Este artículo es un acercamiento histórico a la mortal epidemia de viruela de 1779 y las diversas manifestaciones que produjo tanto en el campo de la salud como en el de la demografía de la ciudad, aunque su objetivo principal es presentar la información estdística encontrada en el archivo. (AU)

Smallpox eradication in Bangladesh, 1972-1976.

Rahima Banu, the world's last endemic case of severe smallpox, Variola Major, developed rash on October 16, 1975 on Bhola Island, Bangladesh. Achieving eradication in a country destroyed by war challenged the achievement of smallpox eradication. Between January 1, 1972 and December 31, 1975, 225,000 smallpox cases and 45,000 smallpox deaths occurred. Adapting the global smallpox eradication strategies of surveillance, the detection of smallpox cases, and containment, the interruption of smallpox transmission, utilized progress toward three objectives to monitor performance: (1) surveillance - the percent of smallpox infected villages detected within 14 days of the first case of rash, (2) knowledge of the reward - public knowledge of the current amount of the reward for reporting smallpox, and (3) containment - the percent of infected villages interrupting smallpox transmission within 14 days of detection. Failures to achieve these objectives led to the identification and implementation of improved strategies that eventually achieved eradication. Essential to this success was a tripartite partnership of the citizens of Bangladesh, the Bangladesh Ministry of Health, its field staff, and staff and resources mobilized by the World Health Organization.

Remaining questions about clinical variola major.

After the recent summary of World Health Organization-authorized research on smallpox, several clinical issues remain. This policy review addresses whether early hemorrhagic smallpox is disseminated intravascular coagulation and speculates about the cause of the high mortality rate among pregnant women and whether ocular smallpox is partly the result of trachoma or vitamin A deficiency. The joint destruction common in children with smallpox might be prevented by antiviral drugs, but intraarticular infusion of antiviral drugs is unprecedented. Development of highly effective antiviral drugs against smallpox raises the issue of whether postexposure vaccination can be performed without interference by an antiviral drug. Clinicians should consider whether patients with smallpox should be admitted to general hospitals. Although an adequate supply of second-generation smallpox vaccine exists in the United States, its use is unclear. Finally, political and ethical forces suggest that destruction of the remaining stocks of live smallpox virus is now appropriate.

Smallpox and American Indians revisited.

Smallpox ravaged the people of Europe and the Americas in the early modern era. Why it was a catastrophic cause of death for American Indians that helped lead to severe depopulation, but a manageable cause among Europeans that allowed continued population growth, has puzzled scholars. Research on variola continued after smallpox eradication in 1977, prompted in part by the fear that aerosolized smallpox might be used in bioterrorism. That research updates factors that may have aggravated smallpox lethality in American Indians, giving new information about infectivity, the proportion of people who may have contracted smallpox, the burden on infants of mothers who had not had smallpox, and the toll for pregnant women. This essay reviews old and new hypotheses about why so many in the New World died from smallpox using recent smallpox research and older sources.

Smallpox virus plaque phenotypes: genetic, geographical and case fatality relationships.

Smallpox (infection with Orthopoxvirus variola) remains a feared illness more than 25 years after its eradication. Historically, case-fatality rates (CFRs) varied between outbreaks (<1 to approximately 40 %), the reasons for which are incompletely understood. The extracellular enveloped virus (EEV) form of orthopoxvirus progeny is hypothesized to disseminate infection. Investigations with the closely related Orthopoxvirus vaccinia have associated increased comet formation (EEV production) with increased mouse mortality (pathogenicity). Other vaccinia virus genetic manipulations which affect EEV production inconsistently support this association. However, antisera against vaccinia virus envelope protect mice from lethal challenge, further supporting a critical role for EEV in pathogenicity. Here, we show that the increased comet formation phenotypes of a diverse collection of variola viruses associate with strain phylogeny and geographical origin, but not with increased outbreak-related CFRs; within clades, there may be an association of plaque size with CFR. The mechanisms for variola virus pathogenicity probably involves multiple host and pathogen factors.

Short- and long-term immunogenicity and protection induced by non-replicating smallpox vaccine candidates in mice and comparison with the traditional 1st generation vaccine.

This study assessed three non-replicating smallpox vaccine candidates (modified vaccinia Ankara (MVA), NYVAC and HR) for their immunogenicity and ability to protect mice against an intranasal cowpox virus challenge and compared them with the traditional replicating vaccine. A single immunisation with the non-replicating vaccines induced a complete protection from death at short-term, but was not fully protective when mice were challenged 150 days post-vaccination with protection correlated with the specific neutralizing antibodies and CD4(+) T-cells responses. Prime-boost vaccination enabled effective long-term protection from death for mice vaccinated with MVA, but protection from disease and CD4(+) T-cell level were lower than the ones induced by the traditional vaccine over the long-term period. Further investigations are necessary with MVA to determine the optimal conditions of immunisation to induce at long-term immunogenicity and protection observed with the 1st generation smallpox vaccine.

Safety, immunogenicity and protective efficacy in mice of a new cell-cultured Lister smallpox vaccine candidate.

It is now difficult to manufacture the first-generation smallpox vaccine, as the process could not comply with current safety and manufacturing regulations. In this study, a candidate non-clonal second-generation smallpox vaccine developed by Sanofi-Pasteur from the Lister strain has been assessed using a cowpox virus challenge in mice. We have observed similar safety, immunogenicity and protection (from disease and death) after a short or long interval following vaccination, as well as similar virus clearance post-challenge, with the second-generation smallpox vaccine candidate as compared to the traditional vaccine used as a benchmark.

New insights about host response to smallpox using microarray data.

BACKGROUND: Smallpox is a lethal disease that was endemic in many parts of the world until eradicated by massive immunization. Due to its lethality, there are serious concerns about its use as a bioweapon. Here we analyze publicly available microarray data to further understand survival of smallpox infected macaques, using systems biology approaches. Our goal is to improve the knowledge about the progression of this disease. RESULTS: We used KEGG pathways annotations to define groups of genes (or modules), and subsequently compared them to macaque survival times. This technique provided additional insights about the host response to this disease, such as increased expression of the cytokines and ECM receptors in the individuals with higher survival times. These results could indicate that these gene groups could influence an effective response from the host to smallpox. CONCLUSION: Macaques with higher survival times clearly express some specific pathways previously unidentified using regular gene-by-gene approaches. Our work also shows how third party analysis of public datasets can be important to support new hypotheses to relevant biological problems.