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- 'Poisonous, Filthy, Loathsome, Damnable Stuff': The Rhetorical Ecology of Vaccination Concern. [REVIEW]
- Yale J Biol Med 2014 Dec; 87(4):403-416.
In this article, we analyze newspaper articles and advertisements mentioning vaccination from 1915 to 1922 and refer to historical studies of vaccination practices and attitudes in the early 20th century in order to assess historical continuities and discontinuities in vaccination concern. In the Progressive Era period, there were a number of themes or features that resonated with contemporary issues and circumstances: 1) fears of vaccine contamination; 2) distrust of medical professionals; 3) resistance to compulsory vaccination; and 4) the local nature of vaccination concern. Such observations help scholars and practitioners understand vaccine skepticism as longstanding, locally situated, and linked to the sociocultural contexts in which vaccination occurs and is mandated for particular segments of the population. A rhetorical approach offers a way to understand how discourses are engaged and mobilized for particular purposes in historical contexts. Historically situating vaccine hesitancy and addressing its articulation with a particular rhetorical ecology offers scholars and practitioners a robust understanding of vaccination concerns that can, and should, influence current approaches to vaccination skepticism.
- John Haygarth's 18th-century 'rules of prevention' for eradicating smallpox. [Journal Article]
- J R Soc Med 2014 Dec; 107(12):494-9.
- A Negative Feedback Modulator of Antigen Processing Evolved from a Frameshift in the Cowpox Virus Genome. [JOURNAL ARTICLE]
- PLoS Pathog 2014 Dec; 10(12):e1004554.
Coevolution of viruses and their hosts represents a dynamic molecular battle between the immune system and viral factors that mediate immune evasion. After the abandonment of smallpox vaccination, cowpox virus infections are an emerging zoonotic health threat, especially for immunocompromised patients. Here we delineate the mechanistic basis of how cowpox viral CPXV012 interferes with MHC class I antigen processing. This type II membrane protein inhibits the coreTAP complex at the step after peptide binding and peptide-induced conformational change, in blocking ATP binding and hydrolysis. Distinct from other immune evasion mechanisms, TAP inhibition is mediated by a short ER-lumenal fragment of CPXV012, which results from a frameshift in the cowpox virus genome. Tethered to the ER membrane, this fragment mimics a high ER-lumenal peptide concentration, thus provoking a trans-inhibition of antigen translocation as supply for MHC I loading. These findings illuminate the evolution of viral immune modulators and the basis of a fine-balanced regulation of antigen processing.
- Development of Eczema Vaccinatum in Atopic Mouse Models and Efficacy of MVA Vaccination against Lethal Poxviral Infection. [Journal Article]
- PLoS One 2014; 9(12):e114374.
Smallpox vaccine based on live, replicating vaccinia virus (VACV) is associated with several potentially serious and deadly complications. Consequently, a new generation of vaccine based on non-replicating Modified vaccinia virus Ankara (MVA) has been under clinical development. MVA seems to induce good immune responses in blood tests, but it is impossible to test its efficacy in vivo in human. One of the serious complications of the replicating vaccine is eczema vaccinatum (EV) occurring in individuals with atopic dermatitis (AD), thus excluding them from all preventive vaccination schemes. In this study, we first characterized and compared development of eczema vaccinatum in different mouse strains. Nc/Nga, Balb/c and C57Bl/6J mice were epicutaneously sensitized with ovalbumin (OVA) or saline control to induce signs of atopic dermatitis and subsequently trans-dermally (t.d.) immunized with VACV strain Western Reserve (WR). Large primary lesions occurred in both mock- and OVA-sensitized Nc/Nga mice, while they remained small in Balb/c and C57Bl/6J mice. Satellite lesions developed in both mock- and OVA-sensitized Nc/Nga and in OVA-sensitized Balb/c mice with the rate 40-50%. Presence of mastocytes and eosinophils was the highest in Nc/Nga mice. Consequently, we have chosen Nc/Nga mice as a model of AD/EV and tested efficacy of MVA and Dryvax vaccinations against a lethal intra-nasal (i.n.) challenge with WR, the surrogate of smallpox. Inoculation of MVA intra-muscularly (i.m.) or t.d. resulted in no lesions, while inoculation of Dryvax t.d. yielded large primary and many satellite lesions similar to WR. Eighty three and 92% of mice vaccinated with a single dose of MVA i.m. or t.d., respectively, survived a lethal i.n. challenge with WR without any serious illness, while all Dryvax-vaccinated animals survived. This is the first formal prove of protective immunity against a lethal poxvirus challenge induced by vaccination with MVA in an atopic organism.
- Modeling the Effect of Herd Immunity and Contagiousness in Mitigating a Smallpox Outbreak. [JOURNAL ARTICLE]
- Med Decis Making 2014 Dec 5.
The smallpox antiviral tecovirimat (Arestvyr) has recently been purchased by the U.S. Strategic National Stockpile. Given significant uncertainty regarding both the contagiousness of smallpox in a contemporary outbreak and the efficiency of a mass vaccination campaign, vaccine prophylaxis alone may be unable to control a smallpox outbreak following a bioterror attack. Here, we present the results of a compartmental epidemiological model that identifies conditions under which tecovirimat is required to curtail the epidemic by exploring how the interaction between contagiousness and prophylaxis coverage of the affected population affects the ability of the public health response to control a large-scale smallpox outbreak. Each parameter value in the model is based on published empirical data. We describe contagiousness parametrically using a novel method of distributing an assumed R-value over the disease course based on the relative rates of daily viral shedding from human and animal studies of cognate orthopoxvirus infections. Our results suggest that vaccination prophylaxis is sufficient to control the outbreak when caused either by a minimally contagious virus or when a very high percentage of the population receives prophylaxis. As vaccination coverage of the affected population decreases below 70%, vaccine prophylaxis alone is progressively less capable of controlling outbreaks, even those caused by a less contagious virus (R0 less than 4). In these scenarios, tecovirimat treatment is required to control the outbreak (total number of cases under an order of magnitude more than the number of initial infections). The first study to determine the relative importance of smallpox prophylaxis and treatment under a range of highly uncertain epidemiological parameters, this work provides public health decision-makers with an evidence-based guide for responding to a large-scale smallpox outbreak.
- Intraepithelial T-cell cytotoxicity, induced bronchus-associated lymphoid tissue, and proliferation of pneumocytes in experimental mouse models of influenza. [Journal Article]
- Viral Immunol 2014 Dec; 27(10):484-96.
Abstract Immunopathologic examination of the lungs of mice with experimental influenza virus infection reveals three prominent findings. (i) There is rapidly developing perivasuclar (arterial) and peribronchial infiltration with T-cells and invasion of T-cells into the bronchiolar epithelium, separation of epithelial cells from each other and from the basement membrane, leading to defoliation of the bronchial epithelium. This reaction is analogous to a viral exanthema of the skin, such as measles and smallpox. This previously described but unappreciated reaction most likely is an effective way to eliminate virus-infected cells, but may contribute to acute toxicity and mortality. (ii) After this, there is formation of dense collections of lymphocytes adjacent to bronchi consisting mainly of B-cells, with a scattering of T-cells and macrophages. This is known as induced bronchial-associated lymphoid tissue (iBALT) and correlates with increased interleukin (IL)-17 in the lung. iBALT provides sites for a local immune reaction in the lung to both the original infection and related viral infections (heterologous immunity). (iii) Within the first 2-3 weeks, there is proliferation of type II pneumocytes and/or terminal bronchial epithelial cells extending from the terminal bronchioles into the adjacent alveoli, eventually leading to large zones of the lung filled with tumor-like epithelial cells with squamous metaplasia. The proliferation correlates with IL-17 and IL-22 expression, and the extent of this reaction appears to be determined by the availability of T-regulatory cells.
- Comparative live bioluminescence imaging of monkeypox virus dissemination in a wild-derived inbred mouse (Mus musculus castaneus) and outbred African dormouse (Graphiurus kelleni). [JOURNAL ARTICLE]
- Virology 2014 Dec 2.:150-158.
Monkeypox virus belongs to the orthopoxvirus genus, infects rodents and monkeys in Africa, produces a smallpox-like zoonotic disease in humans, and has the potential for global spread and exploitation for bioterrorism. Several small animal models for studying monkeypox virus pathogenesis have been investigated. The African dormouse is a candidate natural host but is outbred and no immunological reagents exist. Although not a natural host, the CAST/EiJ mouse is inbred and animals and reagents are commercially available. We compared the dissemination of monkeypox virus by bioluminescence imaging in CAST/EiJ mice and dormice. In CAST/EiJ mice, intense replication occurred at the intranasal site of inoculation and virus spread rapidly to lungs and abdominal organs, which had a lower virus burden. Compared to CAST/EiJ mice, dormice exhibited a greater variation of virus spread, a slower time course, less replication in the head and chest, and more replication in abdominal organs prior to death.
- Attenuation of monkeypox virus by deletion of genomic regions. [JOURNAL ARTICLE]
- Virology 2014 Dec 1.:129-138.
Monkeypox virus (MPXV) is an emerging pathogen from Africa that causes disease similar to smallpox. Two clades with different geographic distributions and virulence have been described. Here, we utilized bioinformatic tools to identify genomic regions in MPXV containing multiple virulence genes and explored their roles in pathogenicity; two selected regions were then deleted singularly or in combination. In vitro and in vivo studies indicated that these regions play a significant role in MPXV replication, tissue spread, and mortality in mice. Interestingly, while deletion of either region led to decreased virulence in mice, one region had no effect on in vitro replication. Deletion of both regions simultaneously also reduced cell culture replication and significantly increased the attenuation in vivo over either single deletion. Attenuated MPXV with genomic deletions present a safe and efficacious tool in the study of MPX pathogenesis and in the identification of genetic factors associated with virulence.
- Design of inhibitors of thymidylate kinase from Variola virus as new selective drugs against smallpox. [JOURNAL ARTICLE]
- Eur J Med Chem 2014 Oct 13.
Recently we constructed a homology model of the enzyme thymidylate kinase from Variola virus (VarTMPK) and proposed it as a new target to the drug design against smallpox. In the present work, we used the antivirals cidofovir and acyclovir as reference compounds to choose eleven compounds as leads to the drug design of inhibitors for VarTMPK. Docking and molecular dynamics (MD) studies of the interactions of these compounds inside VarTMPK and human TMPK (HssTMPK) suggest that they compete for the binding region of the substrate and were used to propose the structures of ten new inhibitors for VarTMPK. Further docking and MD simulations of these compounds, inside VarTMPK and HssTMPK, suggest that nine among ten are potential selective inhibitors of VarTMPK.
- Real-time PCR assay for specific detection of cowpox virus. [Journal Article]
- J Virol Methods 2015 Jan.:8-11.
The species cowpox virus (CPXV), genus Orthopoxvirus (OPV), consists of isolates highly variable in their biological properties and their genotypes. A TaqMan PCR assay for the specific detection of CPXV DNA based on sequences of the ORF D11L has been developed recently. (Gavrilova et al., 2010; Shchelkunov et al., 2011); however, a rather limited panel of CPXV stains has been used. When a much larger panel of 47 CPXV DNAs has been tested, three strains could not be amplified at all because of large deletions in their respective ORF D11L. In addition, a deletion of 23bp led to low-efficiency detection of five other CPXV strains. To solve this problem a new primer/probe combinations was selected based on sequences of ORF D8L, and a new real-time PCR method for (i) a genus-specific detection of OPVs and (ii) a simultaneous CPXV-specific differentiation is described in this study. The specificity and sensitivity were assessed by analyzing DNA of 67 strains belonging to human-pathogenic OPV species, including variola virus, as well as specimens of CPXV-infected mice.