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1.  Protection of Non-Human Primates against Rabies with an Adenovirus Recombinant Vaccine 
Virology  2014;0:243-249.
Rabies remains a major neglected global zoonosis. New vaccine strategies are needed for human rabies prophylaxis. A single intramuscular immunization with a moderate dose of an experimental chimpanzee adenovirus (Ad) vector serotype SAd-V24, also termed AdC68, expressing the rabies virus glycoprotein, resulted in sustained titers of rabies virus neutralizing antibodies and protection against a lethal rabies virus challenge infection in a non-human primate model. Taken together, these data demonstrate the safety, immunogenicity, and efficacy of the recombinant Ad-rabies vector for further consideration in human clinical trials.
doi:10.1016/j.virol.2013.12.029
PMCID: PMC4038128  PMID: 24503087
adenoviral vaccine; NHP; rabies virus; VNA
2.  Case Definitions, Diagnostic Algorithms, and Priorities in Encephalitis: Consensus Statement of the International Encephalitis Consortium 
We present a consensus document that proposes a standardized case definition and diagnostic guidelines for evaluation of adults and children with suspected encephalitis. In addition, areas of research priority, including host genetics and selected emerging infections, are discussed.
Background. Encephalitis continues to result in substantial morbidity and mortality worldwide. Advances in diagnosis and management have been limited, in part, by a lack of consensus on case definitions, standardized diagnostic approaches, and priorities for research.
Methods. In March 2012, the International Encephalitis Consortium, a committee begun in 2010 with members worldwide, held a meeting in Atlanta to discuss recent advances in encephalitis and to set priorities for future study.
Results. We present a consensus document that proposes a standardized case definition and diagnostic guidelines for evaluation of adults and children with suspected encephalitis. In addition, areas of research priority, including host genetics and selected emerging infections, are discussed.
Conclusions. We anticipate that this document, representing a synthesis of our discussions and supported by literature, will serve as a practical aid to clinicians evaluating patients with suspected encephalitis and will identify key areas and approaches to advance our knowledge of encephalitis.
doi:10.1093/cid/cit458
PMCID: PMC3783060  PMID: 23861361
encephalitis; guidelines; viral; autoimmune; host genetics
3.  Host immunity to repeated rabies virus infection in big brown bats 
The Journal of General Virology  2010;91(Pt 9):2360-2366.
Bats are natural reservoirs for the majority of lyssaviruses globally, and are unique among mammals in having exceptional sociality and longevity. Given these facets, and the recognized status of bats as reservoirs for rabies viruses (RABVs) in the Americas, individual bats may experience repeated exposure to RABV during their lifetime. Nevertheless, little information exists with regard to within-host infection dynamics and the role of immunological memory that may result from abortive RABV infection in bats. In this study, a cohort of big brown bats (Eptesicus fuscus) was infected intramuscularly in the left and right masseter muscles with varying doses [10−0.1–104.9 median mouse intracerebral lethal doses (MICLD50)] of an E. fuscus RABV variant isolated from a naturally infected big brown bat. Surviving bats were infected a second time at 175 days post-(primary) infection with a dose (103.9–104.9 MICLD50) of the same RABV variant. Surviving bats were infected a third time at either 175 or 305 days post-(secondary) infection with a dose (104.9 MICLD50) of the same RABV variant. When correcting for dose, similar mortality was observed following primary and secondary infection, but reduced mortality was observed following the third and last RABV challenge, despite infection with a high viral dose. Inducible RABV-neutralizing antibody titres post-infection were ephemeral among infected individuals, and dropped below levels of detection in several bats between subsequent infections. These results suggest that long-term repeated infection of bats may confer significant immunological memory and reduced susceptibility to RABV infection.
doi:10.1099/vir.0.020073-0
PMCID: PMC3052523  PMID: 20519458
4.  Molecular epidemiology identifies only a single rabies virus variant circulating in complex carnivore communities of the Serengeti 
Understanding the transmission dynamics of generalist pathogens that infect multiple host species is essential for their effective control. Only by identifying those host populations that are critical to the permanent maintenance of the pathogen, as opposed to populations in which outbreaks are the result of ‘spillover’ infections, can control measures be appropriately directed. Rabies virus is capable of infecting a wide range of host species, but in many ecosystems, particular variants circulate among only a limited range of potential host populations. The Serengeti ecosystem (in northwestern Tanzania) supports a complex community of wild carnivores that are threatened by generalist pathogens that also circulate in domestic dog populations surrounding the park boundaries. While the combined assemblage of host species appears capable of permanently maintaining rabies in the ecosystem, little is known about the patterns of circulation within and between these host populations. Here we use molecular phylogenetics to test whether distinct virus–host associations occur in this species-rich carnivore community. Our analysis identifies a single major variant belonging to the group of southern Africa canid-associated viruses (Africa 1b) to be circulating within this ecosystem, and no evidence for species-specific grouping. A statistical parsimony analysis of nucleoprotein and glycoprotein gene sequence data is consistent with both within- and between-species transmission events. While likely differential sampling effort between host species precludes a definitive inference, the results are most consistent with dogs comprising the reservoir of rabies and emphasize the importance of applying control efforts in dog populations.
doi:10.1098/rspb.2007.0664
PMCID: PMC2279181  PMID: 17609187
rabies; evolution; statistical parsimony; Serengeti
5.  PATRIC: The VBI PathoSystems Resource Integration Center 
Nucleic Acids Research  2006;35(Database issue):D401-D406.
The PathoSystems Resource Integration Center (PATRIC) is one of eight Bioinformatics Resource Centers (BRCs) funded by the National Institute of Allergy and Infection Diseases (NIAID) to create a data and analysis resource for selected NIAID priority pathogens, specifically proteobacteria of the genera Brucella, Rickettsia and Coxiella, and corona-, calici- and lyssaviruses and viruses associated with hepatitis A and E. The goal of the project is to provide a comprehensive bioinformatics resource for these pathogens, including consistently annotated genome, proteome and metabolic pathway data to facilitate research into counter-measures, including drugs, vaccines and diagnostics. The project's curation strategy has three prongs: ‘breadth first’ beginning with whole-genome and proteome curation using standardized protocols, a ‘targeted’ approach addressing the specific needs of researchers and an integrative strategy to leverage high-throughput experimental data (e.g. microarrays, proteomics) and literature. The PATRIC infrastructure consists of a relational database, analytical pipelines and a website which supports browsing, querying, data visualization and the ability to download raw and curated data in standard formats. At present, the site warehouses complete sequences for 17 bacterial and 332 viral genomes. The PATRIC website () will continually grow with the addition of data, analysis and functionality over the course of the project.
doi:10.1093/nar/gkl858
PMCID: PMC1669763  PMID: 17142235
6.  Evaluation of a TaqMan PCR Assay To Detect Rabies Virus RNA: Influence of Sequence Variation and Application to Quantification of Viral Loads 
Journal of Clinical Microbiology  2004;42(1):299-306.
Published assays that use TaqMan PCR are consistently sensitive, rapid, and readily transferable. Here we describe a TaqMan PCR-based method for the detection of rabies virus (RV) RNA in tissue samples. We show that the method has an acceptable linear range, is both sensitive and specific, and, importantly, correlates with the concentration of infectious virus. In addition, the levels of RV-specific amplification are adjustable according to the levels of an endogenous control (β-actin mRNA), allowing the calculation of comparable quantities. We tested the capacity of this assay to cope with target sequence variations. The number of sequence mismatches between gene-specific oligonucleotides and the target sequence significantly affects amplification (P < 0.001), and point mutations at the center of the probe can result in false-negative results through the prevention of probe binding and subsequent fluorescence. This study demonstrates that the genetic heterogeneity of RVs may prove a serious obstacle in the development of a diagnostic assay based on TaqMan PCR; however, the quantification of RV levels may prove to be a valuable application of this assay.
doi:10.1128/JCM.42.1.299-306.2004
PMCID: PMC321704  PMID: 14715769
7.  The prevalence of interstitial nephritis and leptospirosis in 283 raccoons (Procyon lotor) from 5 different sites in the United States. 
The Canadian Veterinary Journal  2001;42(11):869-871.
A retrospective histopathological study was carried out on tissues of 283 raccoons from 5 different geographical locations for presence of interstitial nephritis and renal leptospirosis. Results of this study indicate that although interstitial nephritis was common in raccoons from all locations, the presence of renal leptospiral spirochetes was not.
PMCID: PMC1476672  PMID: 11708206
8.  Human rabies in Israel. 
Emerging Infectious Diseases  1999;5(2):306-308.
PMCID: PMC2640707  PMID: 10221893
9.  The cost of rabies postexposure prophylaxis: one state's experience. 
Public Health Reports  1998;113(3):247-251.
OBJECTIVE: This study was undertaken to evaluate trends in the use of rabies postexposure prophylaxis (PEP) before, during, and following an epidemic of raccoon rabies in Massachusetts. METHODS: The authors reviewed initiation of PEP as reported to the Massachusetts Department of Public Health (MDPH) from August 1994 to December 1995 and surveyed hospital pharmacies to determine the number of vials of Human Rabies Immune Globulin (HRIG) dispensed from 1991 through 1995 and charges to patients per vial. RESULTS: PEP use increased dramatically, from 1.7 per 100,000 population in 1991 (pre-epidemic) to 45 per 100,000 in 1995 (after the first stages of the epidemic). The median costs per patient for biologics was $1646 (range: $632-$3435). Including physician and emergency room charges, per-patient median costs were $2376 (range: $1038-$4447). Total health care charges for PEP in Massachusetts in 1995 were estimated at $2.4 million to $6.4 million. CONCLUSIONS: Given the rapid increase in use of PEP, further studies should be undertaken to determine the appropriateness of use, and other alternatives, such as oral wildlife vaccines, should be considered.
PMCID: PMC1308677  PMID: 9633871
10.  Current issues in rabies prevention in the United States health dilemmas. Public coffers, private interests. 
Public Health Reports  1996;111(5):400-407.
OVER THE LAST 100 years, rabies in the United States has changed dramatically. More than 90% of all animal rabies cases reported annually to the CDC now occur in wildlife, whereas before 1960 the majority were in domestic animals. The principal rabies hosts today are wild carnivores and bats infected with several viral variants. Annual human deaths have fallen from more than a hundred at the turn of the century to one to two per year despite major outbreaks of animal rabies in several geographic areas. Modern day prophylaxis has proven nearly 100% successful; most human fatalities now occur in people who fail to seek medical treatment, usually because they do not recognize a risk in the animal contact leading to the infection. Although these human rabies deaths are rare, the estimated public health costs associated with disease detection, prevention, and control have risen, exceeding millions of dollars each year. Cost considerations must be weighed along with other factors in addressing issues such as the appropriate handling of nontraditional and exotic pets, future guidelines for rabies prophylaxis, and novel methods of disease prevention.
PMCID: PMC1381782  PMID: 8837628
12.  The ascension of wildlife rabies: a cause for public health concern or intervention? 
Emerging Infectious Diseases  1995;1(4):107-114.
The epidemiology of rabies in the United States has changed substantially during the last half century, as the source of the disease has changed from domesticated animals to wildlife, principally raccoons, skunks, foxes, and bats. Moreover, the changes observed among affected wildlife populations have not occurred without human influence. Rather, human attraction to the recreational and economic resources provided by wildlife has contributed to the reemergence of rabies as a major zoonosis. Although human deaths caused by rabies have declined recently to an average of one or two per year, the estimated costs associated with the decrease in deaths amount to hundreds of millions of dollars annually. In future efforts to control rabies harbored by free-ranging animal reservoirs, public health professionals will have to apply imaginative, safe, and cost-effective solutions to this age-old malady in addition to using traditional measures.
PMCID: PMC2626887  PMID: 8903179
13.  Biological characterization of human monoclonal antibodies to rabies virus. 
Journal of Virology  1990;64(6):3087-3090.
Rabies virus antigen-specific human monoclonal antibodies (MAbs) that recognized either viral glycoprotein, ribonucleoprotein, or matrix proteins were generated. Only glycoprotein-specific MAb neutralized a variety of rabies viruses and protected laboratory rodents against lethal rabies virus infection. The determinant recognized by this MAb does not appear to reside in previously defined antigenic sites of the viral glycoprotein.
Images
PMCID: PMC249498  PMID: 2335829
14.  Use of mouse anti-rabies monoclonal antibodies in postexposure treatment of rabies. 
Journal of Clinical Investigation  1989;84(3):971-975.
Immunization of mice and hamsters with a cocktail of mouse MAbs specific for rabies virus nucleocapsid protein and glycoprotein protected animals not only when challenged with a lethal dose of rabies virus after immunization, but also in post-exposure situations. Hamsters treated with the MAb cocktail 3 h after virus inoculation were completely protected from lethal rabies virus infection, and 80% of the animals survived when the MAb cocktail was given 36 h after virus challenge. The potential usefulness of this MAb cocktail for the postexposure treatment of human rabies is discussed.
PMCID: PMC329743  PMID: 2760222

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