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- The evolution and evolutionary relationships between extant vaccinia virus strains. [JOURNAL ARTICLE]
- J Virol 2014 Nov 19.
Although vaccinia virus (VACV) was once used as a vaccine to eradicate smallpox on a worldwide scale, the biological origins of VACV are uncertain, as are the historical relationships between the different strains once used as smallpox vaccines. Here, we sequenced additional VACV strains that represent either relatively pristine examples of old vaccines (e.g. Dryvax, Lister, and Tashkent) or which have been subjected to additional laboratory passage (e.g. IHD-W and WR). These genome sequences were compared with those previously reported for other VACV as well as other orthopoxviruses. These extant VACV do not always cluster in simple phylogenetic trees that are aligned with the known historical relationships between these strains. Rather, the pattern of deletions suggests that all existing strains likely come from a complex stock of viruses that has been passaged, distributed, and randomly sampled over time, thus obscuring simple historical or geographic links. We examined surviving non-clonal vaccine stocks, like Dryvax, which continue to harbor larger and now rare variants including one we have designated "clone DPP25". DPP25 encodes genes not found in most VACV strains including an ankyrin-F-box protein, a homolog of the variola virus (Bangladesh) B18R gene, which we show can be deleted without affecting virulence in mice. We propose a simple common mechanism by which recombination of a larger and hypothetical DPP25-like ancestral strain, combined with selection for retention of critically important genes near the terminal inverted repeat boundaries (vaccinia growth factor gene and an interferon α/β receptor homolog), could produce all known VACV variants.Smallpox was eradicated using a combination of intensive disease surveillance and vaccination using vaccinia virus (VACV). Interestingly, little is known about the historical relationships between different strains of vaccinia virus (VACV) and how these viruses may have evolved from a common ancestral strain. To understand these relationships additional strains were sequenced and compared to existing strains of VACV as well as other Orthopoxviruses using whole genome sequence alignments. Extant strains of VACV didn't always cluster in simple phylogenetic trees based on known historical relationships between these strains. Based on these findings it is possible that all existing strains of VACV could derive from a single complex stock of viruses that has been passaged, distributed, and sampled over time.
- Ebola Virus Disease: Preparedness in Japan. [JOURNAL ARTICLE]
- Disaster Med Public Health Prep 2014 Nov 17.:1-5.
ABSTRACT The current outbreak of Ebola virus disease (EVD) is due to a lack of resources, untrained medical personnel, and the specific contact-mediated type of infection of this virus. In Japan's history, education and mass vaccination of the native Ainu people successfully eradicated epidemics of smallpox. Even though a zoonotic virus is hard to control, appropriate precautions and personal protection, as well as anti-symptomatic treatment, will control the outbreak of EVD. Ebola virus utilizes the antibody-dependent enhancement of infection to seed the cells of various organs. The pathogenesis of EVD is due to the cytokine storm of pro-inflammatory cytokines and the lack of antiviral interferon-α2. Matricellular proteins of galectin-9 and osteopontin might also be involved in the edema and abnormality of the coagulation system in EVD. Anti-fibrinolytic treatment will be effective. In the era of globalization, interviews of travelers with fever within 3 weeks of departure from the affected areas will be necessary. Not only the hospitals designated for specific biohazards but every hospital should be aware of the biology of biohazards and establish measures to protect both patients and the community. (Disaster Med Public Health Preparedness. 2014;0:1-5).
- Discovery of forgotten variola specimens at the National Institutes of Health in the USA. [Journal Article]
- Expert Rev Anti Infect Ther 2014 Dec; 12(12):1419-21.
In early July 2014, the National Institutes of Health in the USA discovered a few vials containing smallpox virus in their Bethesda, Maryland facility. The subsequent investigation, performed by US CDC, documented viable virus in two of the discovered vials that were subjected to tissue culture testing.
- Multiplexed Analysis of Genes and of Metal Ions Using Enzyme/DNAzyme Amplification Machineries. [Journal Article]
- Anal Chem 2014 Nov 18; 86(22):11326-33.
The progressive development of amplified DNA sensors using nucleic acid-based machineries, involving the isothermal autonomous synthesis of the Mg(2+)-dependent DNAzyme, is used for the amplified, multiplexed analysis of genes (Smallpox, TP53) and metal ions (Ag(+), Hg(2+)). The DNA sensing machineries are based on the assembly of two sensing modules consisting of two nucleic acid scaffolds that include recognition sites for the two genes and replication tracks that yield the nicking domains for Nt.BbvCI and two different Mg(2+)-dependent DNAzyme sequences. In the presence of any of the genes or the genes together, their binding to the respective recognition sequences triggers the nicking/polymerization machineries, leading to the synthesis of two different Mg(2+)-dependent DNAzyme sequences. The cleavage of two different fluorophore/quencher-modified substrates by the respective DNAzymes leads to the fluorescence of F1 and/or F2 as readout signals for the detection of the genes. The detection limits for analyzing the Smallpox and TP53 genes correspond to 0.1 nM. Similarly, two different nucleic acid scaffolds that include Ag(+)-ions or Hg(2+)-ions recognition sequences and the replication tracks that yield the Nt.BbvCI nicking domains and the respective Mg(2+)-dependent DNAzyme sequences are implemented as nicking/replication machineries for the amplified, multiplexed analysis of the two ions, with detection limits corresponding to 1 nM. The ions sensing modules reveal selectivities dominated by the respective recognition sequences associated with the scaffolds.
- Being Prepared: Bioterrorism and Mass Prophylaxis: Part II. [Journal Article]
- Adv Emerg Nurs J 2014 Oct-Dec; 36(4):307-17.
Although several biological agents have been recognized as presenting a significant threat to public health if used in a bioterrorist attack, those that are of greatest importance are known as the Category A agents: Bacillus anthracis (anthrax); variola major (smallpox); Yersinia pestis (plague); Francisella tularensis (tularemia); ribonucleic acid viruses (hemorrhagic fevers); and Clostridium botulinum (botulism toxin). In the previous issue, Part I of this review focused on the clinical presentation and treatment of anthrax, plague, and tularemia. In this second part of this 2-part review of these agents, the focus is on the clinical presentation and treatment of smallpox, viral hemorrhagic fevers, and botulism toxin. The utilization of mass prophylaxis to limit the morbidity and mortality associated with all these agents is also discussed along with the role emergency care personnel play in its implementation.
- Detecting differential transmissibilities that affect the size of self-limited outbreaks. [Journal Article]
- PLoS Pathog 2014 Oct; 10(10):e1004452.
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 [Formula: see text]) 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 [Formula: see text] has declined with time. Meanwhile, chain size data for measles in the United States and Canada reveal statistically significant geographic variation in [Formula: see text], 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.
- CD4+ T cell help is dispensable for protective CD8+ T cell memory against mousepox following vaccinia virus immunization. [JOURNAL ARTICLE]
- J Virol 2014 Oct 29.
It has been shown in various infection models that CD4(+) T cell help (TH) is necessary for the conditioning, maintenance and/or recall responses of memory CD8(+) T cells (CD8M). Yet, in the case of vaccinia virus (VACV), which constitutes the vaccine used to eradicate smallpox and is a candidate vector for other infectious diseases, the issue is controversial because different groups have shown either TH dependence or independence of CD8M conditioning, maintenance and or recall response. In agreement with some of these groups, we show that TH plays a role but is not essential for the maintenance, proliferation and effector differentiation of polyclonal memory CD8(+) T cells after infection with wild type VACV WR. More important, we show that un-helped and helped anti-VACV memory CD8(+) T cells are similarly efficient at protecting susceptible mice from lethal mousepox, the mouse equivalent of human smallpox. Thus, TH is not essential for the conditioning and maintenance of memory CD8(+) T cells capable of mounting a recall response strong enough to protect from a lethal natural pathogen. Our results may partly explain why the VACV vaccine is so effective.We used vaccinia virus (VACV) -a gold standard vaccine - as the immunogen, and ectromelia virus (ECTV) as the pathogen to demonstrate that the conditioning and maintenance of anti-VACV memory CD8(+) T cells and their ability to protect against an Orthopoxvirus (OPV) infection in its natural host can develop in the absence of CD4(+) T cell help. Our results provide important insight to our basic knowledge of the immune system. Further, because VACV is used as a vaccine in humans, our results may help us understand how this vaccine induces protective immunity in this species. In addition, this work may partly explain why VACV is so effective as a vaccine.
- 'Forgotten' NIH smallpox virus languishes on death row. [News]
- Nature 2014 Oct 30; 514(7524):544.
- TLR3 and TLR9 Agonists Improve Postexposure Vaccination Efficacy of Live Smallpox Vaccines. [Journal Article]
- PLoS One 2014; 9(10):e110545.
Eradication of smallpox and discontinuation of the vaccination campaign resulted in an increase in the percentage of unvaccinated individuals, highlighting the need for postexposure efficient countermeasures in case of accidental or deliberate viral release. Intranasal infection of mice with ectromelia virus (ECTV), a model for human smallpox, is curable by vaccination with a high vaccine dose given up to 3 days postexposure. To further extend this protective window and to reduce morbidity, mice were vaccinated postexposure with Vaccinia-Lister, the conventional smallpox vaccine or Modified Vaccinia Ankara, a highly attenuated vaccine in conjunction with TLR3 or TLR9 agonists. We show that co-administration of the TLR3 agonist poly(I:C) even 5 days postexposure conferred protection, avoiding the need to increase the vaccination dose. Efficacious treatments prevented death, ameliorated disease symptoms, reduced viral load and maintained tissue integrity of target organs. Protection was associated with significant elevation of serum IFNα and anti-vaccinia IgM antibodies, modulation of IFNγ response, and balanced activation of NK and T cells. TLR9 agonists (CpG ODNs) were less protective than the TLR3 agonist poly(I:C). We show that activation of type 1 IFN by poly(I:C) and protection is achievable even without co-vaccination, requiring sufficient amount of the viral antigens of the infective agent or the vaccine. This study demonstrated the therapeutic potential of postexposure immune modulation by TLR activation, allowing to alleviate the disease symptoms and to further extend the protective window of postexposure vaccination.
- Vaccination and the politics of medical knowledge in nineteenth-century Japan. [Historical Article, Journal Article, Research Support, Non-U.S. Gov't]
- Bull Hist Med 2014; 88(3):431-56.
The adoption of the cowpox vaccine in nineteenth-century Japan has often been seen as a more straightforward development than its introduction to other non-Western countries. However, the research leading to this conclusion has been based primarily on sources written by Japanese practitioners of Westernstylemedicine (ranpoˉ), while the perspectives of Chinese-style (kanpoˉ) practitioners,who were more numerous than ranpoˉ practitioners but less likely to have shown immediate enthusiasm for vaccination, have been largely neglected. Kanpoˉdoctors typically learned about vaccination from Chinese rather than European sources and often held an ambivalent attitude toward the vaccine’s foreign origins.This article develops an analysis of kanpoˉ writings on vaccination and suggests that skepticism about the vaccine remained widespread for at least a decade after its initial arrival in Japan, providing new insights into both the initial opposition and the subsequent acceptance of the technique.