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Viruses Nov 2020As countries with endemic canine rabies progress towards elimination by 2030, it will become necessary to employ techniques to help plan, monitor, and confirm canine...
As countries with endemic canine rabies progress towards elimination by 2030, it will become necessary to employ techniques to help plan, monitor, and confirm canine rabies elimination. Sequencing can provide critical information to inform control and vaccination strategies by identifying genetically distinct virus variants that may have different host reservoir species or geographic distributions. However, many rabies testing laboratories lack the resources or expertise for sequencing, especially in remote or rural areas where human rabies deaths are highest. We developed a low-cost, high throughput rabies virus sequencing method using the Oxford Nanopore MinION portable sequencer. A total of 259 sequences were generated from diverse rabies virus isolates in public health laboratories lacking rabies virus sequencing capacity in Guatemala, India, Kenya, and Vietnam. Phylogenetic analysis provided valuable insight into rabies virus diversity and distribution in these countries and identified a new rabies virus lineage in Kenya, the first published canine rabies virus sequence from Guatemala, evidence of rabies spread across an international border in Vietnam, and importation of a rabid dog into a state working to become rabies-free in India. Taken together, our evaluation highlights the MinION's potential for low-cost, high volume sequencing of pathogens in locations with limited resources.
Topics: Animals; Diagnostic Equipment; Dog Diseases; Dogs; Endemic Diseases; Guatemala; Humans; India; Kenya; Nanopores; Phylogeny; Public Health; Rabies; Rabies virus; Sequence Analysis, DNA; Vietnam
PubMed: 33158200
DOI: 10.3390/v12111255 -
Epidemiology and Infection Mar 2021Rabies post-exposure prophylaxis (R-PEP) including wound treatment, vaccination and application of rabies immunoglobulin (RIG) is essential in preventing rabies...
Rabies post-exposure prophylaxis (R-PEP) including wound treatment, vaccination and application of rabies immunoglobulin (RIG) is essential in preventing rabies mortality. Today, Germany is officially declared free from terrestrial rabies and rabies is only found in bats. However, physicians in A&E Departments are frequently consulted on the need for R-PEP. We retrospectively analysed patients who received R-PEP at the A&E Department of the University Hospital Bonn between 01.01.2013 and 30.06.2019. Demographic data, travel history, clinical and laboratory findings, previous rabies vaccinations and R-PEP vaccination regimen were recorded. During the study period, 90 patients received R-PEP at the University Hospital Bonn, in 10 cases without indication for R-PEP. Altogether, we found deviations from R-PEP guidelines in 51% (n = 41/80). Infiltration of RIG was missed in 12 patients and incorrectly administrated in 24 patients. Furthermore, vaccination scheme was incorrect in 11 patients. Correct wound washing and documentation of tetanus status was missing in 14% and 63% of patients, respectively. Despite rabies elimination in Germany patients frequently seek advice for R-PEP, the majority returning from foreign travel. Our data show that there is a high need for education on indication for R-PEP before and after travel and for implementation of precise R-PEP guidelines in daily clinical practice.
Topics: Adolescent; Adult; Animals; Bites and Stings; Child; Female; Germany; Hospitals, University; Humans; Immunoglobulins; Male; Middle Aged; Post-Exposure Prophylaxis; Rabies; Rabies Vaccines; Rabies virus; Retrospective Studies; Tetanus Toxoid; Travel; Young Adult
PubMed: 33734061
DOI: 10.1017/S0950268821000601 -
PLoS Neglected Tropical Diseases May 2021Rabies is a fatal yet vaccine-preventable disease. In the last two decades, domestic dog populations have been shown to constitute the predominant reservoir of rabies in... (Review)
Review
BACKGROUND
Rabies is a fatal yet vaccine-preventable disease. In the last two decades, domestic dog populations have been shown to constitute the predominant reservoir of rabies in developing countries, causing 99% of human rabies cases. Despite substantial control efforts, dog rabies is still widely endemic and is spreading across previously rabies-free areas. Developing a detailed understanding of dog rabies dynamics and the impact of vaccination is essential to optimize existing control strategies and developing new ones. In this scoping review, we aimed at disentangling the respective contributions of mathematical models and phylodynamic approaches to advancing the understanding of rabies dynamics and control in domestic dog populations. We also addressed the methodological limitations of both approaches and the remaining issues related to studying rabies spread and how this could be applied to rabies control.
METHODOLOGY/PRINCIPAL FINDINGS
We reviewed how mathematical modelling of disease dynamics and phylodynamics have been developed and used to characterize dog rabies dynamics and control. Through a detailed search of the PubMed, Web of Science, and Scopus databases, we identified a total of n = 59 relevant studies using mathematical models (n = 30), phylodynamic inference (n = 22) and interdisciplinary approaches (n = 7). We found that despite often relying on scarce rabies epidemiological data, mathematical models investigated multiple aspects of rabies dynamics and control. These models confirmed the overwhelming efficacy of massive dog vaccination campaigns in all settings and unraveled the role of dog population structure and frequent introductions in dog rabies maintenance. Phylodynamic approaches successfully disentangled the evolutionary and environmental determinants of rabies dispersal and consistently reported support for the role of reintroduction events and human-mediated transportation over long distances in the maintenance of rabies in endemic areas. Potential biases in data collection still need to be properly accounted for in most of these analyses. Finally, interdisciplinary studies were determined to provide the most comprehensive assessments through hypothesis generation and testing. They also represent new avenues, especially concerning the reconstruction of local transmission chains or clusters through data integration.
CONCLUSIONS/SIGNIFICANCE
Despite advances in rabies knowledge, substantial uncertainty remains regarding the mechanisms of local spread, the role of wildlife in dog rabies maintenance, and the impact of community behavior on the efficacy of control strategies including vaccination of dogs. Future integrative approaches that use phylodynamic analyses and mechanistic models within a single framework could take full advantage of not only viral sequences but also additional epidemiological information as well as dog ecology data to refine our understanding of rabies spread and control. This would represent a significant improvement on past studies and a promising opportunity for canine rabies research in the frame of the One Health concept that aims to achieve better public health outcomes through cross-sector collaboration.
Topics: Animals; Animals, Wild; Disease Reservoirs; Dog Diseases; Dogs; Models, Theoretical; Phylogeography; Rabies; Rabies Vaccines; Rabies virus; Vaccination
PubMed: 34043640
DOI: 10.1371/journal.pntd.0009449 -
Frontiers in Cellular and Infection... 2023Macrophages are amongst the first immune cells that encounter rabies virus (RABV) at virus entry sites. Activation of macrophages is essential for the onset of a potent...
Macrophages are amongst the first immune cells that encounter rabies virus (RABV) at virus entry sites. Activation of macrophages is essential for the onset of a potent immune response, but insights into the effects of RABV on macrophage activation are scarce. In this study we performed high-throughput sequencing on RNA extracted from macrophages that were exposed to RABV for 48 hours, and compared their transcriptional profiles to that of non-polarized macrophages (M0), and macrophages polarized towards the canonical M1, M2a and M2c phenotypes. Our analysis revealed that RABV-stimulated macrophages show high expression of several M1, M2a and M2c signature genes. Apart from their partial resemblance to these phenotypes, unbiased clustering analysis revealed that RABV induces a unique and distinct polarization program. Closer examination revealed that RABV induced multiple pathways related to the interferon- and antiviral response, which were not induced under other classical polarization strategies. Surprisingly, our data show that RABV induces an activated rather than a fully suppressed macrophage phenotype, triggering virus-induced activation and polarization. This includes multiple genes with known antiviral (e.g. APOBEC3A, IFIT/OAS/TRIM genes), which may play a role in anti-RABV immunity.
Topics: Humans; Rabies virus; Transcriptome; Rabies; Macrophages; Antiviral Agents
PubMed: 36798087
DOI: 10.3389/fcimb.2023.1013842 -
Metabolic Brain Disease Aug 2021Infection with the deadly rabies virus (RABV) leads to alteration of cellular gene expression. The RABV, similar to other neurodegenerative diseases may be implicated in...
Infection with the deadly rabies virus (RABV) leads to alteration of cellular gene expression. The RABV, similar to other neurodegenerative diseases may be implicated in neuronal death due to an imbalance in Ca homeostasis. Parvalbumin (PV) and Secretagogin (Scgn), two members of the Calcium-Binding Proteins (CBPs) are useful neuronal markers responsible for calcium regulation and buffering with possible protective roles against infections. This study investigated whether infection with rabies virus causes variance in expression levels of PV and Scgn using the Challenge virus standard (CVS) and Nigerian Street Rabies virus (SRV) strains. Forty-eight, 4-week-old BALB/c mice strains were divided into two test groups and challenged with Rabies virus (RABV) infection and one control group. The presence of RABV antigen was verified by direct fluorescent antibody test (DFAT) and real-time quantitative PCR (qRT-PCR) was used to assess PV and Scgn gene expression. Infection with both virus strains resulted in significant (p < 0.05) increases in expression during early infection. Mid-infection phase caused reduced expression for both genes. However, as infection progressed to the terminal phase, a lower increase in expression was measured. Gene expression and viral load correlation indicated no positive relationship. Neurons with these CBPs may have a greater capacity to buffer calcium and be more resistant to degenerative changes caused by RABV. This implies that, when PV and Scgn expression levels are kept adequately high, the integrity of neurons may be maintained and degeneration caused by RABV infection may be prevented or stopped, hence, these are possible constituents of effective rabies therapy.
Topics: Animals; Brain; Female; Gene Expression Regulation; Mice; Mice, Inbred BALB C; Parvalbumins; Rabies; Rabies virus; Secretagogins; Viral Load
PubMed: 33783673
DOI: 10.1007/s11011-021-00717-4 -
Emerging Microbes & Infections Dec 2023The persistence and clinical consequences of rabies virus (RABV) infection have prompted global efforts to develop a safe and effective vaccines against rabies. mRNA...
The persistence and clinical consequences of rabies virus (RABV) infection have prompted global efforts to develop a safe and effective vaccines against rabies. mRNA vaccines represent a promising option against emerging and re-emerging infectious diseases, gaining particular interest since the outbreak of COVID-19. Herein, we report the development of a highly efficacious rabies mRNA vaccine composed of sequence-modified mRNA encoding RABV glycoprotein (RABV-G) packaged in core-shell structured lipopolyplex (LPP) nanoparticles, named LPP-mRNA-G. The bilayer structure of LPP improves protection and delivery of RABV-G mRNA and allows gradual release of mRNA molecules as the polymer degrades. The unique core-shell structured nanoparticle of LPP-mRNA-G facilitates vaccine uptake and demonstrates a desirable biodistribution pattern with low liver targeting upon intramuscular immunization. Single administration of low-dose LPP-mRNA-G in mice elicited potent humoral immune response and provided complete protection against intracerebral challenge with lethal RABV. Similarly, single immunization of low-dose LPP-mRNA-G induced high levels of virus-neutralizing antibody titers in dogs. Collectively, our data demonstrate the potential of LPP-mRNA-G as a promising next-generation rabies vaccine used in human and companion animals.
Topics: Dogs; Animals; Mice; Humans; Rabies; Rabies Vaccines; Immunity, Humoral; Tissue Distribution; Antibodies, Viral; mRNA Vaccines; Rabies virus; Immunization; RNA, Messenger
PubMed: 37819147
DOI: 10.1080/22221751.2023.2270081 -
Journal of Neuroscience Methods Dec 2020Connectomic studies have become 'viral', as viral pathogens have been turned into irreplaceable neuroscience research tools. Highly sensitive viral transneuronal tracing... (Review)
Review
Connectomic studies have become 'viral', as viral pathogens have been turned into irreplaceable neuroscience research tools. Highly sensitive viral transneuronal tracing technologies are available, based on the use of alpha-herpesviruses and a rhabdovirus (rabies virus), which function as self-amplifying markers by replicating in recipient neurons. These viruses highly differ with regard to host range, cellular receptors, peripheral uptake, replication, transport direction and specificity. Their characteristics, that make them useful for different purposes, will be highlighted and contrasted. Only transneuronal tracing with rabies virus is entirely specific. The neuroscientist toolbox currently include wild-type alpha-herpesviruses and rabies virus strains enabling polysynaptic tracing of neuronal networks across multiple synapses, as well as genetically modified viral tracers for dual transneuronal tracing, and complementary viral tools including defective and chimeric recombinants that function as single step or monosynaptically restricted tracers, or serve for monitoring and manipulating neuronal activity and gene expression. Methodological issues that are crucial for appropriate use of these technologies will be summarized. Among wild-type and genetically engineered viral tools, rabies virus and chimeric recombinants based on rabies virus as virus backbone are the most powerful, because of the ability of rabies virus to propagate exclusively among connected neurons unidirectionally (retrogradely), without affecting neuronal function. Understanding in depth viral properties is essential for neuroscientists who intend to exploit alpha-herpesviruses, rhabdoviruses or derived recombinants as research tools. Key knowledge will be summarized regarding their cellular receptors, intracellular trafficking and strategies to contrast host defense that explain their different pathophysiology and properties as research tools.
Topics: Connectome; Neurons; Neurosciences; Rabies virus; Viruses
PubMed: 32835704
DOI: 10.1016/j.jneumeth.2020.108917 -
Biomedical and Environmental Sciences :... Sep 2022Preliminary assessment of rabies virus neutralizing activity, safety and immunogenicity of a recombinant human rabies antibody (NM57) compared with human rabies... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Preliminary assessment of rabies virus neutralizing activity, safety and immunogenicity of a recombinant human rabies antibody (NM57) compared with human rabies immunoglobulin (HRIG) in Chinese healthy adults.
METHODS
Subjects were randomly (1:1:1) allocated to Groups A (20 IU/kg NM57), B (40 IU/kg NM57), or C (20 IU/kg HRIG). One injection was given on the day of enrollment. Blood samples were collected on days -7 to 0 (pre-injection), 3, 7, 14, 28, and 42. Adverse events (AEs) and serious AEs (SAEs) were recorded over a period of 42 days after injection.
RESULTS
All 60 subjects developed detectable rabies virus neutralizing antibodies (RVNAs) (> 0.05 IU/mL) on days 3, 7, 14, 28, and 42. The RVNA levels peaked on day 3 in all three groups, with a geometric mean concentration (GMC) of 0.2139 IU/mL in Group A, 0.3660 IU/mL in Group B, and 0.1994 IU/mL in Group C. At each follow-up point, the GMC in Group B was significantly higher than that in Groups A and C. The areas under the antibody concentration curve over 0-14 days and 0-42 days in Group B were significantly larger than those in Groups A and C. Fifteen AEs were reported. Except for one grade 2 myalgia in Group C, the other 14 were all grade 1. No SAEs were observed.
CONCLUSION
The rabies virus neutralizing activity of 40 IU/kg NM57 was superior to that of 20 IU/kg NM57 and 20 IU/kg HRIG, and the rabies virus neutralizing activity of 20 IU/kg NM57 and 20 IU/kg HRIG were similar. Safety was comparable between NM57 and HRIG.
Topics: Adult; Antibodies, Neutralizing; Antibodies, Viral; Data Collection; Humans; Rabies; Rabies Vaccines; Rabies virus
PubMed: 36189993
DOI: 10.3967/bes2022.103 -
One Health (Amsterdam, Netherlands) Dec 2023Rabies is an acute zoonotic infectious disease caused by rabies virus. In 2015, the World Health Organization proposed the goal of eliminating dog-induced human rabies...
Rabies is an acute zoonotic infectious disease caused by rabies virus. In 2015, the World Health Organization proposed the goal of eliminating dog-induced human rabies by 2030. In response to this goal positively, China has been dedicated to the control and elimination of rabies mainly caused by dogs, for nearly 10 years. By applying infectious disease dynamics, in this paper, we establish a dog-human rabies transmission model to forecast future epidemic trends of rabies, assess whether the goal of eliminating dog-induced human rabies cases in China can be achieved in 2030, and further evaluate and suggest the follow-up sustained preventive measures after the elimination of human rabies. By analyzing and simulating above dynamic model, it is concluded that rabies has been well controlled in China in recent years, but dog-induced human rabies cannot be eliminated by 2030 according to current situation. In addition, we propose to improve rabies control efforts by increasing the immunization coverage rate of rural domestic dogs, controlling the number of stray dogs and preventing the import of rabies virus in wild animals. Immunization coverage rate of rural domestic dogs which is currently less than 10% is far from requirement, and it needs to reach 50%-60% to meet the goal of 2030. Since it is difficult to immunize stray dogs, we suggest to control the number of stray dogs below 15.27 million to achieve the goal. If the goal of eliminating human rabies is reached in 2030, the essential immunization coverage needs to be maintained for 18 years to reduce the number of canine rabies cases to zero. Lastly, to prevent transmission of rabies virus from wild animals to dogs, the thresholds of the number of dogs and the immunization coverage rate of dogs after eliminating canine rabies cases are also discussed.
PubMed: 37638210
DOI: 10.1016/j.onehlt.2023.100615 -
MMWR. Morbidity and Mortality Weekly... May 2022On June 16, 2021, rabies virus infection was confirmed in a dog included in a shipment of rescue animals imported into the United States from Azerbaijan. A multistate...
On June 16, 2021, rabies virus infection was confirmed in a dog included in a shipment of rescue animals imported into the United States from Azerbaijan. A multistate investigation was conducted to prevent secondary rabies cases, avoid reintroduction of a dog-maintained rabies virus variant (DMRVV), identify persons who might have been exposed and would be recommended to receive rabies postexposure prophylaxis, and investigate the cause of importation control failures. Results of a prospective serologic monitoring (PSM) protocol suggested that seven of 32 (22%) animals from the same shipment as the dog with confirmed rabies virus infection and who had available titer results after rabies vaccine booster had not been adequately vaccinated against rabies before importation. A requirement for rabies vaccination certificates alone will not adequately identify improper vaccination practices or fraudulent paperwork and are insufficient as a stand-alone rabies importation prevention measure. Serologic titers before importation would mitigate the risk for importing DMRVV.
Topics: Animals; Azerbaijan; Dog Diseases; Dogs; Humans; Pennsylvania; Prospective Studies; Rabies; Rabies Vaccines; Rabies virus; United States; Vaccination
PubMed: 35587914
DOI: 10.15585/mmwr.mm7120a3