Biology of Variola Virus.

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.

[Human poxvirus infections]. / Infections humaines à poxvirus.

Poxvirus (PXV) infections are a common cause of cutaneous signs. In France, certain forms of poxvirus are frequent and benign (molluscum contagiosum), while others are rare but potentially serious (cowpox virus [CPXV]). Whereas only smallpox and molluscum contagiosum viruses have a human reservoir and are transmitted between humans, most poxvirus infections are zoonoses having only animal reservoirs. Only a small number of poxviruses are responsible for infection in humans, but the increasing number of new pets, some of which are exotic, coupled with the rapid rise in international travel are creating a greater risk of transmission of zoonotic PXV to new vectors and of spread of these diseases to new regions throughout the world. In France, molluscum contagiosum, orf and milkers' nodule give rise to numerous consultations and are well known to dermatologists. However, dermatologists must also be able to identify other parapoxviruses of similar presentation to orf; thus, CPXV and monkeypox are considered potentially emergent viruses with a high risk of epidemic and spread due to increasing international transport and the loss of the maximum protection against smallpox. Finally, despite its declared eradication, smallpox is currently being monitored because of the potential risk of reintroduction, whether accidentally or deliberately through bioterrorism.

Detecting differential transmissibilities that affect the size of self-limited outbreaks.

Our ability to respond appropriately to infectious diseases is enhanced by identifying differences in the potential for transmitting infection between individuals. Here, we identify epidemiological traits of self-limited infections (i.e. infections with an effective reproduction number satisfying [0 < R eff < 1) that correlate with transmissibility. Our analysis is based on a branching process model that permits statistical comparison of both the strength and heterogeneity of transmission for two distinct types of cases. Our approach provides insight into a variety of scenarios, including the transmission of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in the Arabian peninsula, measles in North America, pre-eradication smallpox in Europe, and human monkeypox in the Democratic Republic of the Congo. When applied to chain size data for MERS-CoV transmission before 2014, our method indicates that despite an apparent trend towards improved control, there is not enough statistical evidence to indicate that R eff has declined with time. Meanwhile, chain size data for measles in the United States and Canada reveal statistically significant geographic variation in R eff, suggesting that the timing and coverage of national vaccination programs, as well as contact tracing procedures, may shape the size distribution of observed infection clusters. Infection source data for smallpox suggests that primary cases transmitted more than secondary cases, and provides a quantitative assessment of the effectiveness of control interventions. Human monkeypox, on the other hand, does not show evidence of differential transmission between animals in contact with humans, primary cases, or secondary cases, which assuages the concern that social mixing can amplify transmission by secondary cases. Lastly, we evaluate surveillance requirements for detecting a change in the human-to-human transmission of monkeypox since the cessation of cross-protective smallpox vaccination. Our studies lay the foundation for future investigations regarding how infection source, vaccination status or other putative transmissibility traits may affect self-limited transmission.

Smallpox Vaccination of Laboratory Workers at US Variola Testing Sites.

To evaluate the need to revaccinate laboratory workers against smallpox, we assessed regular revaccination at the US Laboratory Response Network's variola testing sites by examining barriers to revaccination and the potential for persistence of immunity. Our data do not provide evidence to suggest prolonging the recommended interval for revaccination.

The XIX century smallpox prevention in Naples and the risk of transmission of human blood-related pathogens.

Vaccines are the most successful strategy developed in Medicine to prevent and even eradicate the most dreadful epidemic infectious diseases. The history of smallpox vaccination in Naples is quite unique. Although Galbiati established the retro-vaccination (1803) and developed the "calf" lymph vaccine, recognized and implemented since 1864 as the optimal smallpox vaccine in the following hundred years, Naples general population was mainly vaccinated with "human" lymph from abandoned children until 1893. Mini-epidemics of syphilis and serum hepatitis were periodically reported as results of arm-to-arm procedure. The risk of transmission of blood-related pathogens was higher in Naples where >80% of abandoned children, used as repository of cowpox virus, were dying in their first year of life. Recent vaccinology standards finally eliminated the risk of adventitious contaminating pathogens. Implementation of hepatitis B vaccination since 1991 eventually contributed to current HBV prevalence in Campania region <1%, within the range of the European Countries.

Dynamics of Multi-stage Infections on Networks.

This paper investigates the dynamics of infectious diseases with a non-exponentially distributed infectious period. This is achieved by considering a multi-stage infection model on networks. Using pairwise approximation with a standard closure, a number of important characteristics of disease dynamics are derived analytically, including the final size of an epidemic and a threshold for epidemic outbreaks, and it is shown how these quantities depend on disease characteristics, as well as the number of disease stages. Stochastic simulations of dynamics on networks are performed and compared to output of pairwise models for several realistic examples of infectious diseases to illustrate the role played by the number of stages in the disease dynamics. These results show that a higher number of disease stages results in faster epidemic outbreaks with a higher peak prevalence and a larger final size of the epidemic. The agreement between the pairwise and simulation models is excellent in the cases we consider.

Poxvirus viability and signatures in historical relics.

Although it has been >30 years since the eradication of smallpox, the unearthing of well-preserved tissue material in which the virus may reside has called into question the viability of variola virus decades or centuries after its original occurrence. Experimental data to address the long-term stability and viability of the virus are limited. There are several instances of well-preserved corpses and tissues that have been examined for poxvirus viability and viral DNA. These historical specimens cause concern for potential exposures, and each situation should be approached cautiously and independently with the available information. Nevertheless, these specimens provide information on the history of a major disease and vaccination against it.

Improved estimation of the initial number of susceptible individuals in the general stochastic epidemic model using penalized likelihood.

The initial size of a completely susceptible population in a group of individuals plays a key role in drawing inferences for epidemic models. However, this can be difficult to obtain in practice because, in any population, there might be individuals who may not transmit the disease during the epidemic. This short note describes how to improve the maximum likelihood estimators of the infection rate and the initial number of susceptible individuals and provides their approximate Hessian matrix for the general stochastic epidemic model by using the concept of the penalized likelihood function. The simulations of major epidemics show significant improvements in performance in averages and coverage ratios for the suggested estimator of the initial number in comparison to existing methods. We applied the proposed method to the Abakaliki smallpox data.

Non-exponential tolerance to infection in epidemic systems--modeling, inference, and assessment.

The transmission dynamics of infectious diseases have been traditionally described through a time-inhomogeneous Poisson process, thus assuming exponentially distributed levels of disease tolerance following the Sellke construction. Here we focus on a generalization using Weibull individual tolerance thresholds under the susceptible-exposed-infectious-removed class of models which is widely employed in epidemics. Applications with experimental foot-and-mouth disease and historical smallpox data are discussed, and simulation results are presented. Inference is carried out using Markov chain Monte Carlo methods following a Bayesian approach. Model evaluation is performed, where the adequacy of the models is assessed using methodology based on the properties of Bayesian latent residuals, and comparison between 2 candidate models is also considered using a latent likelihood ratio-type test that avoids problems encountered with relevant methods based on Bayes factors.

Secondary and tertiary transmission of vaccinia virus after sexual contact with a smallpox vaccinee--San Diego, California, 2012.

On June 24, 2012, CDC notified Public Health Services, County of San Diego Health and Human Services Agency, of a suspected case of vaccinia virus infection transmitted by sexual contact. The case had been reported to CDC by an infectious disease specialist who had requested vaccinia immune globulin intravenous (VIGIV) (Cangene Corporation, Berwyn, Pennsylvania) for a patient with lesions suspicious for vaccinia. The patient reported two recent sexual contacts: one with a partner who recently had been vaccinated against smallpox and a later encounter with an unvaccinated partner. Infections resulting from secondary transmission of vaccinia virus from the smallpox vaccinee to the patient and subsequent tertiary transmission of the virus from the patient to the unvaccinated partner were confirmed by the County of San Diego Public Health Laboratory. The smallpox vaccine had been administered under the U.S. Department of Defense smallpox vaccination program. The vaccinee did not experience vaccine-associated complications; however, the secondary and tertiary patients were hospitalized and treated with VIGIV. No further transmission was known to have occurred. This report describes the epidemiology and clinical course of the secondary and tertiary cases and efforts to prevent further transmission to contacts.

[Highly contagious diseases with human-to-human transmission]. / Vysoce nebezpecne nakazy s mezilidskym prenosem.

Highly contagious diseases are caused by various biological agents that pose a risk to individuals and may have a potential for public health impact. They result in high mortality and morbidity rates, might cause public panic and therefore require special measures. The pathogens that can be easily disseminated or transmitted from person to person are the riskiest for clinicians (Ebola virus, Marburg virus, Lassa virus, Crimean-Congo hemorrhagic fever virus, Variola major, SARS virus and Yersinia pestis). Human-to-human transmission has not been confirmed for the other biological agents and therefore they pose a very low risk for population.

Countering the potential re-emergence of a deadly infectious disease-Information warfare, identifying strategic threats, launching countermeasures.

OBJECTIVES: Eradicated infectious diseases like smallpox can re-emerge through accident or the designs of bioterrorists, and cause heavy casualties. Presently, the populace is largely susceptible as only a small percentage is vaccinated, and their immunity is likely to have waned. And when the disease re-emerges, the susceptible individuals may be manipulated by disinformation on Social Media to refuse vaccines. Thus, a combination of countermeasures consisting of antiviral drugs and vaccines and a range of policies for their application need to be investigated. Opinions regarding whether to receive vaccines evolve over time through social exchanges via networks that overlap with but are not identical to the disease propagation networks. These couple the spread of the biological and information contagion and necessitate a joint investigation of the two. METHODS: We develop a computationally tractable metapopulation epidemiological model that captures the joint spatio-temporal evolution of an infectious disease (e.g., smallpox, COVID-19) and opinion dynamics. RESULTS: Considering smallpox, the computations based on the model show that opinion dynamics have a substantial impact on the fatality count. Towards understanding how perpetrators are likely to seed the infection, we identify a) the initial distribution of infected individuals that maximize the overall fatality count; and b) which habitation structures are more vulnerable to outbreaks. We assess the relative efficacy of different countermeasures and conclude that a combination of vaccines and drugs minimize the fatalities, and by itself, drugs reduce fatalities more than the vaccine. Accordingly, we assess the impact of increase in the supply of drugs and identify the most effective among a collection of policies for administering of drugs for various parameter combinations. Many of the observed patterns are stable to variations of a diverse set of parameters. CONCLUSIONS: Our findings provide a quantitative foundation for various important elements of public health discourse that have largely been conducted qualitatively.

Social contact networks and disease eradicability under voluntary vaccination.

Certain theories suggest that it should be difficult or impossible to eradicate a vaccine-preventable disease under voluntary vaccination: Herd immunity implies that the individual incentive to vaccinate disappears at high coverage levels. Historically, there have been examples of declining coverage for vaccines, such as MMR vaccine and whole-cell pertussis vaccine, that are consistent with this theory. On the other hand, smallpox was globally eradicated by 1980 despite voluntary vaccination policies in many jurisdictions. Previous modeling studies of the interplay between disease dynamics and individual vaccinating behavior have assumed that infection is transmitted in a homogeneously mixing population. By comparison, here we simulate transmission of a vaccine-preventable SEIR infection through a random, static contact network. Individuals choose whether to vaccinate based on infection risks from neighbors, and based on vaccine risks. When neighborhood size is small, rational vaccinating behavior results in rapid containment of the infection through voluntary ring vaccination. As neighborhood size increases (while the average force of infection is held constant), a threshold is reached beyond which the infection can break through partially vaccinated rings, percolating through the whole population and resulting in considerable epidemic final sizes and a large number vaccinated. The former outcome represents convergence between individually and socially optimal outcomes, whereas the latter represents their divergence, as observed in most models of individual vaccinating behavior that assume homogeneous mixing. Similar effects are observed in an extended model using smallpox-specific natural history and transmissibility assumptions. This work illustrates the significant qualitative differences between behavior-infection dynamics in discrete contact-structured populations versus continuous unstructured populations. This work also shows how disease eradicability in populations where voluntary vaccination is the primary control mechanism may depend partly on whether the disease is transmissible only to a few close social contacts or to a larger subset of the population.

Contingency planning for a deliberate release of smallpox in Great Britain--the role of geographical scale and contact structure.

BACKGROUND: In the event of a release of a pathogen such as smallpox, which is human-to-human transmissible and has high associated mortality, a key question is how best to deploy containment and control strategies. Given the general uncertainty surrounding this issue, mathematical modelling has played an important role in informing the likely optimal response, in particular defining the conditions under which mass-vaccination would be appropriate. In this paper, we consider two key questions currently unanswered in the literature: firstly, what is the optimal spatial scale for intervention; and secondly, how sensitive are results to the modelling assumptions made about the pattern of human contacts? METHODS: Here we develop a novel mathematical model for smallpox that incorporates both information on individual contact structure (which is important if the effects of contact tracing are to be captured accurately) and large-scale patterns of movement across a range of spatial scales in Great Britain. RESULTS: Analysis of this model confirms previous work suggesting that a locally targeted 'ring' vaccination strategy is optimal, and that this conclusion is actually quite robust for different socio-demographic and epidemiological assumptions. CONCLUSIONS: Our method allows for intuitive understanding of the reasons why national mass vaccination is typically predicted to be suboptimal. As such, we present a general framework for fast calculation of expected outcomes during the attempted control of diverse emerging infections; this is particularly important given that parameters would need to be interactively estimated and modelled in any release scenario.

Planning for smallpox outbreaks.

Mathematical models of viral transmission and control are important tools for assessing the threat posed by deliberate release of the smallpox virus and the best means of containing an outbreak. Models must balance biological realism against limitations of knowledge, and uncertainties need to be accurately communicated to policy-makers. Smallpox poses the particular challenge that key biological, social and spatial factors affecting disease spread in contemporary populations must be elucidated largely from historical studies undertaken before disease eradication in 1979. We review the use of models in smallpox planning within the broader epidemiological context set by recent outbreaks of both novel and re-emerging pathogens.

Modelling disease outbreaks in realistic urban social networks.

Most mathematical models for the spread of disease use differential equations based on uniform mixing assumptions or ad hoc models for the contact process. Here we explore the use of dynamic bipartite graphs to model the physical contact patterns that result from movements of individuals between specific locations. The graphs are generated by large-scale individual-based urban traffic simulations built on actual census, land-use and population-mobility data. We find that the contact network among people is a strongly connected small-world-like graph with a well-defined scale for the degree distribution. However, the locations graph is scale-free, which allows highly efficient outbreak detection by placing sensors in the hubs of the locations network. Within this large-scale simulation framework, we then analyse the relative merits of several proposed mitigation strategies for smallpox spread. Our results suggest that outbreaks can be contained by a strategy of targeted vaccination combined with early detection without resorting to mass vaccination of a population.

Micro-simulation of a smallpox outbreak using official register data.

To explore the efficacy of four vaccine-based policy strategies (ring vaccination, targeted vaccination, mass vaccination, and pre-vaccination of healthcare personnel combined with ring vaccination) for controlling smallpox outbreaks in Sweden, disease transmission on a spatially explicit social network was simulated. The mixing network was formed from high-coverage official register data of the entire Swedish population, building on the Swedish Total Population Register, the Swedish Employment Register, and the Geographic Database of Sweden. The largest reduction measured in the number of infections was achieved when combining ring vaccination with a pre-vaccination of healthcare personnel. In terms of per dose effectiveness, ring vaccination was by far the most effective strategy. The results can to some extent be adapted to other diseases and environments, including other countries, and the methods used can be analysed in their own right.

Military medicine and the ethics of war: British colonial warfare during the Seven Years War (1756-63).

This article examines 18th-century European warfare, tracing the first formal codifications of conventions of war, frequently introduced by military physicians and initially regarding the treatment of the sick and wounded. It outlines to what extent these conventions were followed in practice, particularly in the challenging environment of American irregular warfare, with a focus on the most well-known incident of "biological warfare" in the period: the deliberate spread of smallpox by British officers among Amerindians in 1763. More broadly, it demonstrates that the history of military medicine provides a fruitful method with which to uncover assumptions about the ethics of war.

Rethinking the History of Smallpox in the Early Twentieth Century: The SS Korea and Uncertainty Surrounding the Diagnosis of Smallpox.

This research explores the case of the 1903 smallpox outbreak on the SS Korea , a transpacific carrier making runs between Southeast Asia, East Asia, Hawaii, and the United States. These regions were connected to a degree that no one had ever imagined through the SS Korea . Honolulu, Hawaii, was one of the most important territories in US maritime history and served as a waypoint between Asia and San Francisco on the mainland. As increasing numbers of people traveled by sea, various microbes were communicated across the Pacific Ocean. International tourists traveling across the ocean to Hawaii and the United States were alerted to infectious diseases, smallpox being one of the most significant of such diseases. The story of the SS Korea serves as an important lens through which to explore the early twentieth century transpacific world connected through Honolulu. Focusing on the spread of smallpox via international travelers, this research studies aspects of the public health system that were developed to contain smallpox infection on international ships and the application of smallpox vaccination as a method for infectious disease control. More importantly, in bringing attention to the uncertainty surrounding the diagnosis of smallpox, this research argues for the necessity of historians to build a more comprehensive medical historical context for disease control systems that includes the limits of medical science in making diagnoses of infectious diseases, the uncertainties arising from a lack of this component, and the implementation of health policies and preventative medical technologies.