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- Rapid expansion of CD8+ T cells in wildtype and type I interferon receptor deficient mice correlates with protection after low-dose emergency immunization with Modified Vaccinia virus Ankara. [JOURNAL ARTICLE]
- J Virol 2014 Jul 9.
Immunization with Modified Vaccinia virus Ankara (MVA) can rapidly protect mice against lethal ectromelia virus (ECTV) infection, serving as an experimental model for severe systemic infections. Importantly, this early protective capacity of MVA vaccination completely depends on virus-specific cytotoxic CD8+ T cell responses. We used MVA vaccination in the mousepox challenge model using ECTV infection to investigate the previously unknown factors required to elicit rapid protective T cell immunity in normal C57BL/6 mice and in mice lacking the interferon alpha/beta receptor (IFNAR-/-). We found a minimal dose of 10(5) plaque-forming units of MVA vaccine fully sufficient to allow robust protection against lethal mousepox, as assessed by the absence of disease symptoms and failure to detect ECTV in organs from vaccinated animals. Moreover, MVA immunization at low dosage also protected IFNAR-/- mice, indicating efficient activation of cellular immunity even in the absence of type I interferon signaling. When monitoring for virus specific CD8+T cell responses in mice vaccinated with the minimal protective dose of MVA, we found significantly enhanced levels of antigen specific T cells in animals that were MVA vaccinated and ECTV challenged compared to mice that were only vaccinated. The initial priming of naïve CD8+ T cells by MVA immunization appears highly efficient, and even at low doses, mediates a rapid in vivo burst of pathogen-specific T cells upon challenge. Our findings define striking requirements for protective emergency immunization against severe systemic infections with orthopoxviruses.We demonstrate that single-shot low dose immunizations with vaccinia virus MVA can rapidly induce T cell mediated protective immunity against lethal orthopoxvirus infections. Our data provides new evidence for an efficient protective capacity of vaccination with replication deficient MVA. These data are of important practical relevance for public health as the effectiveness of a safety-tested next-generation smallpox vaccine based on MVA is still debated. Furthermore, producing sufficient amounts of vaccine is considered a major challenge should an outbreak occur. Moreover, prevention of other infections may require rapidly protective immunization, hence MVA could be an extremely useful vaccine for delivering heterologous T cell antigens, particularly for infectious diseases that fit a scenario of emergency vaccination.
- The genome sequence of ectromelia virus Naval and Cornell isolates from outbreaks in North America. [JOURNAL ARTICLE]
- Virology 2014 Jul 3.:218-226.
Ectromelia virus (ECTV) is the causative agent of mousepox, a disease of laboratory mouse colonies and an excellent model for human smallpox. We report the genome sequence of two isolates from outbreaks in laboratory mouse colonies in the USA in 1995 and 1999: ECTV-Naval and ECTV-Cornell, respectively. The genome of ECTV-Naval and ECTV-Cornell was sequenced by the 454-Roche technology. The ECTV-Naval genome was also sequenced by the Sanger and Illumina technologies in order to evaluate these technologies for poxvirus genome sequencing. Genomic comparisons revealed that ECTV-Naval and ECTV-Cornell correspond to the same virus isolated from independent outbreaks. Both ECTV-Naval and ECTV-Cornell are extremely virulent in susceptible BALB/c mice, similar to ECTV-Moscow. This is consistent with the ECTV-Naval genome sharing 98.2% DNA sequence identity with that of ECTV-Moscow, and indicates that the genetic differences with ECTV-Moscow do not affect the virulence of ECTV-Naval in the mousepox model of footpad infection.
- Interspecific and locational differences in metal levels in edible fish tissue from Saudi Arabia. [JOURNAL ARTICLE]
- Environ Monit Assess 2014 Jul 6.
Metal levels in fish have been extensively studied, but little data currently exists for the Middle East. We examined the levels of metals and metalloids (aluminum, arsenic, copper, manganese, selenium, zinc, and mercury) in the flesh of 13 fish species collected from three fishing sites and a local fish market in Jeddah, Saudi Arabia. We tested the following null hypotheses: (1) there are no interspecific differences in metal levels, (2) there are no differences in metal levels in fishes between market and fishing sites, (3) there are no size-related differences in metal levels, and (4) there are no differences in selenium:mercury molar ratio among different fish species. There were significant interspecific differences in concentrations for all metals. There was an order of magnitude difference in the levels of aluminum, arsenic, mercury, manganese, and selenium, indicating wide variation in potential effects on the fish themselves and on their predators. Fishes from Area II, close to a large commercial port, had the highest levels of arsenic, mercury, and selenium, followed by market fishes. Mercury was positively correlated with body size in 6 of the 13 fish species examined. Mercury was correlated positively with arsenic and selenium, but negatively with aluminum, cobalt, copper, manganese, and zinc. Selenium:mercury molar ratios varied significantly among species, with Carangoides bajad, Cephalopholis argus, Variola louti, and Ephinephelus tauvina having ratios below 10:1. These findings can be used in risk assessments, design of mercury reduction plans, development of fish advisories to protect public health, and future management decision-making.
- Safety of attenuated smallpox vaccine LC16m8 in immunodeficient mice. [JOURNAL ARTICLE]
- Clin Vaccine Immunol 2014 Jul 2.
Freeze-dried live attenuated smallpox vaccine LC16m8 prepared in cell culture has been the sole smallpox vaccine licensed in Japan since 1975 and was recently recommended as a WHO stockpile vaccine. We evaluated the safety of recently re-manufactured lots of LC16m8 using a series of immunodeficient mouse models. These models included suckling mice, severe combined immunodeficiency disease (SCID) mice, and wild-type mice treated with cyclosporine A. LC16m8 showed extremely low virulence in each of the three mouse models when compared with its parental strains, Lister and LC16mO. These results provide further evidence that LC16m8 is one of the safest replication-competent smallpox vaccines in the world, and may be considered for use in immunodeficient patients.
- Type I IFN mimetics bypass vaccinia virus decoy receptor virulence factor for protection of mice against lethal infection. [JOURNAL ARTICLE]
- Clin Vaccine Immunol 2014 Jun 25.
The canonical model of interferon (IFN) signaling focuses solely on the activation of STAT transcription factors which, according to the model, is initiated by the singular event of cross-linkage of receptor extracellular domain by the IFN. The IFN has no further function beyond this. The model thus provides no approach to circumventing poxviruses decoy receptors which compete with the IFN receptors for the IFNs. This simple event has allowed smallpox virus to decimate human populations throughout the ages. We have developed a non-canonical model of IFN signaling that has resulted in the development of small peptide mimetics to both types I and II IFNs. In this report, we focus on a type I IFN mimetic, IFNα1(152-189), that corresponds to the C-terminus of human IFNα1. The mimetic functions intracellularly and is thus not recognized by the B18R vaccinia virus decoy receptor. Mimetic synthesized with an attached palmitate (lipo-) for cell penetration protects mice from a lethal dose of vaccinia virus, while the parent IFNα1 is ineffective. Unlike IFNα1, the mimetic does not bind to B18R decoy receptor. It further differs from the parent IFN in that it lacks toxicity of weight loss and bone marrow suppression in mice while at the same time possessing strong adjuvant effect on the immune system. The mimetic is thus an innate and adaptive immune regulator which is evidence of the dynamical nature of the non-canonical model of IFN signaling in stark contrast to the canonical or classical model of signaling.
- The ontology of genetic susceptibility factors (OGSF) and its application in modeling genetic susceptibility to vaccine adverse events. [Journal Article]
- J Biomed Semantics 2014.:19.
Due to human variations in genetic susceptibility, vaccination often triggers adverse events in a small population of vaccinees. Based on our previous work on ontological modeling of genetic susceptibility to disease, we developed an Ontology of Genetic Susceptibility Factors (OGSF), a biomedical ontology in the domain of genetic susceptibility and genetic susceptibility factors. The OGSF framework was then applied in the area of vaccine adverse events (VAEs).OGSF aligns with the Basic Formal Ontology (BFO). OGSF defines 'genetic susceptibility' as a subclass of BFO:disposition and has a material basis 'genetic susceptibility factor'. The 'genetic susceptibility to pathological bodily process' is a subclasses of 'genetic susceptibility'. A VAE is a type of pathological bodily process. OGSF represents different types of genetic susceptibility factors including various susceptibility alleles (e.g., SNP and gene). A general OGSF design pattern was developed to represent genetic susceptibility to VAE and associated genetic susceptibility factors using experimental results in genetic association studies. To test and validate the design pattern, two case studies were populated in OGSF. In the first case study, human gene allele DBR*15:01 is susceptible to influenza vaccine Pandemrix-induced Multiple Sclerosis. The second case study reports genetic susceptibility polymorphisms associated with systemic smallpox VAEs. After the data of the Case Study 2 were represented using OGSF-based axioms, SPARQL was successfully developed to retrieve the susceptibility factors stored in the populated OGSF. A network of data from the Case Study 2 was constructed by using ontology terms and individuals as nodes and ontology relations as edges. Different social network analys is (SNA) methods were then applied to verify core OGSF terms. Interestingly, a SNA hub analysis verified all susceptibility alleles of SNPs and a SNA closeness analysis verified the susceptibility genes in Case Study 2. These results validated the proper OGSF structure identified different ontology aspects with SNA methods.OGSF provides a verified and robust framework for representing various genetic susceptibility types and genetic susceptibility factors annotated from experimental VAE genetic association studies. The RDF/OWL formulated ontology data can be queried using SPARQL and analyzed using centrality-based network analysis methods.
- IN VITRO EFFICACY OF BRINCIDOFOVIR AGAINST VARIOLA VIRUS. [JOURNAL ARTICLE]
- Antimicrob Agents Chemother 2014 Jun 23.
Brincidofovir (CMX001), a lipid conjugate of the acyclic nucleotide phosphonate cidofovir, is under development for smallpox treatment using "the Animal Rule," established by FDA in 2002. Brincidofovir reduces mortality caused by orthopoxvirus infection in animal models. Compared to cidofovir, brincidofovir has increased potency, oral administration, and no evidence of nephrotoxicity. Here we report the brincidofovir EC50 against five variola virus strains in vitro averaged 0.11 μM, nearly 100-fold more potent than cidofovir.