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1.
PLoS Negl Trop Dis ; 16(9): e0010318, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36067231

RESUMO

OBJECTIVES: Dog vaccination can eliminate rabies in dogs, but annual delivery strategies do not sustain vaccination coverage between campaigns. We describe the development of a community-based continuous mass dog vaccination (CBC-MDV) approach designed to improve and maintain vaccination coverage in Tanzania and examine the feasibility of delivering this approach as well as lessons for its optimization. METHODS: We developed three delivery strategies of CBC-MDV and tested them against the current annual vaccination strategy following the UK Medical Research Council's guidance: i) developing an evidence-based theoretical framework of intervention pathways and ii) piloting to test feasibility and inform optimization. For our process evaluation of CBC-MDV we collected data using non-participant observations, meeting reports and implementation audits and in-depth interviews, as well as household surveys of vaccination coverage to assess potential effectiveness. We analyzed qualitative data thematically and quantitative data descriptively. RESULTS: The final design included delivery by veterinary teams supported by village-level one health champions. In terms of feasibility, we found that less than half of CBC-MDV's components were implemented as planned. Fidelity of delivery was influenced by the strategy design, implementer availability and appreciation of value intervention components, and local environmental and socioeconomic events (e.g. elections, funerals, school cycles). CBC-MDV activities decreased sharply after initial campaigns, partly due to lack of supervision. Community engagement and involvement was not strong. Nonetheless, the CBC-MDV approaches achieved vaccination coverage above the critical threshold (40%) all-year-round. CBC-MDV components such as identifying vaccinated dogs, which village members work as one health champions and how provision of continuous vaccination is implemented need further optimization prior to scale up. INTERPRETATION: CBC-MDV is feasible to deliver and can achieve good vaccination coverage. Community involvement in the development of CBC-MDV, to better tailor components to contextual situations, and improved supervision of activities are likely to improve vaccination coverage in future.


Assuntos
Doenças do Cão , Vacinas Antirrábicas , Raiva , Animais , Doenças do Cão/prevenção & controle , Cães , Estudos de Viabilidade , Vacinação em Massa/veterinária , Raiva/prevenção & controle , Raiva/veterinária , Vacinação/veterinária
2.
Proc Biol Sci ; 289(1982): 20220860, 2022 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-36069012

RESUMO

The pathogen transmission dynamics in bat reservoirs underpin efforts to reduce risks to human health and enhance bat conservation, but are notoriously challenging to resolve. For vampire bat rabies, the geographical scale of enzootic cycles, whether environmental factors modulate baseline risk, and how within-host processes affect population-level dynamics remain unresolved. We studied patterns of rabies exposure using an 11-year, spatially replicated sero-survey of 3709 Peruvian vampire bats and co-occurring outbreaks in livestock. Seroprevalence was correlated among nearby sites but fluctuated asynchronously at larger distances. A generalized additive mixed model confirmed spatially compartmentalized transmission cycles, but no effects of bat demography or environmental context on seroprevalence. Among 427 recaptured bats, we observed long-term survival following rabies exposure and antibody waning, supporting hypotheses that immunological mechanisms influence viral maintenance. Finally, seroprevalence in bats was only weakly correlated with outbreaks in livestock, reinforcing the challenge of spillover prediction even with extensive data. Together our results suggest that rabies maintenance requires transmission among multiple, nearby bat colonies which may be facilitated by waning of protective immunity. However, the likelihood of incursions and dynamics of transmission within bat colonies appear largely independent of bat ecology. The implications of these results for spillover anticipation and controlling transmission at the source are discussed.


Assuntos
Quirópteros , Vírus da Raiva , Raiva , Animais , Humanos , Gado , Raiva/epidemiologia , Raiva/veterinária , Estudos Soroepidemiológicos
3.
Biol Lett ; 18(9): 20220298, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36069068

RESUMO

Rabies virus (RABV) transmitted by the common vampire bat (Desmodus rotundus) poses a threat to agricultural development and public health throughout the Neotropics. The ecology and evolution of rabies host-pathogen dynamics are influenced by two infection-induced behavioural changes. RABV-infected hosts often exhibit increased aggression which facilitates transmission, and rabies also leads to reduced activity and paralysis prior to death. Although several studies document rabies-induced behavioural changes in rodents and other dead-end hosts, surprisingly few studies have measured these changes in vampire bats, the key natural reservoir throughout Latin America. Taking advantage of an experiment designed to test an oral rabies vaccine in captive male vampire bats, we quantify for the first time, to our knowledge, how rabies affects allogrooming and aggressive behaviours in this species. Compared to non-rabid vampire bats, rabid individuals reduced their allogrooming prior to death, but we did not detect increases in aggression among bats. To put our results in context, we review what is known and what remains unclear about behavioural changes of rabid vampire bats (resumen en español, electronic supplementary material, S1).


Assuntos
Quirópteros , Vacinas Antirrábicas , Vírus da Raiva , Raiva , Animais , Masculino , Raiva/prevenção & controle , Raiva/veterinária
4.
Elife ; 112022 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-36040301

RESUMO

To understand the function of neuronal circuits, it is crucial to disentangle the connectivity patterns within the network. However, most tools currently used to explore connectivity have low throughput, low selectivity, or limited accessibility. Here, we report the development of an improved packaging system for the production of the highly neurotropic RVdGenvA-CVS-N2c rabies viral vectors, yielding titers orders of magnitude higher with no background contamination, at a fraction of the production time, while preserving the efficiency of transsynaptic labeling. Along with the production pipeline, we developed suites of 'starter' AAV and bicistronic RVdG-CVS-N2c vectors, enabling retrograde labeling from a wide range of neuronal populations, tailored for diverse experimental requirements. We demonstrate the power and flexibility of the new system by uncovering hidden local and distal inhibitory connections in the mouse hippocampal formation and by imaging the functional properties of a cortical microcircuit across weeks. Our novel production pipeline provides a convenient approach to generate new rabies vectors, while our toolkit flexibly and efficiently expands the current capacity to label, manipulate and image the neuronal activity of interconnected neuronal circuits in vitro and in vivo.


Assuntos
Vírus da Raiva , Raiva , Animais , Vetores Genéticos , Camundongos , Neurônios , Vírus da Raiva/genética
5.
Virulence ; 13(1): 1446-1454, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35999776

RESUMO

Rabies is an important zoonotic disease caused by the rabies virus (RABV). Currently, no effective treatment is available for this condition. The prevention and control of rabies mainly depend on effective vaccination. Therefore, it is crucial to enhance the immune responses induced by the rabies vaccine. Virus neutralizing antibodies (VNA) induced by rabies vaccines are important for the clearance of RABV. Interleukin-25 (IL-25) has been demonstrated to activate T helper type 2 cells that contribute to humoral immune responses. The IL-25 gene was inserted into the genome of RABV, and the immunogenicity of recombinant RABV with IL-25 gene was investigated to develop more efficient rabies vaccines. Here, we found that the expression of IL-25 did not affect RABV production in vitro and pathogenicity in vivo. However, recombinant RABV expression of IL-25 induced a better VNA level than the parental virus in mice. In addition, expression of IL-25 enhanced the IgG1 level induced by RABV. Furthermore, mice immunized with recombinant RABV showed a higher survival rate and milder clinical signs than those immunized with the parent strain after challenge with CVS-11. Thus, these results showed that IL-25 could enhance the humoral immune responses induced by RABV, suggesting that IL-25 can be used as a viral vaccine adjuvant.


Assuntos
Vacinas Antirrábicas , Vírus da Raiva , Raiva , Animais , Anticorpos Antivirais , Imunidade Humoral , Interleucina-17/genética , Camundongos , Raiva/prevenção & controle , Vacinas Antirrábicas/genética , Vírus da Raiva/genética
6.
MMWR Morb Mortal Wkly Rep ; 71(34): 1081-1084, 2022 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-36006831

RESUMO

Dog-maintained rabies virus variant (DMRVV) was eliminated in the United States in 2007. During 2015­2019, three dogs with rabies were imported into the United States from Egypt, where DMRVV is endemic. CDC developed a risk mitigation strategy, in consultation with a diverse group of subject matter experts, that permitted 296 dogs to be imported from Egypt during May 10, 2019­December 31, 2020, minimizing the risk for future rabid dog importations. The broadly vetted risk mitigation strategy, which included serologic testing for rabies antibody titer, improved CDC's ability to ensure that imported dogs from Egypt posed no public health risk in the United States. This strategy could be used to guide future policy decisions regarding dog importations.


Assuntos
Doenças do Cão , Vacinas Antirrábicas , Vírus da Raiva , Raiva , Animais , Centers for Disease Control and Prevention, U.S. , Doenças do Cão/epidemiologia , Cães , Egito , Humanos , Saúde Pública , Raiva/epidemiologia , Raiva/prevenção & controle , Raiva/veterinária , Estados Unidos/epidemiologia
7.
Cell Host Microbe ; 30(9): 1219-1230.e7, 2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-35985336

RESUMO

Rabies virus (RABV) causes lethal encephalitis and is responsible for approximately 60,000 deaths per year. As the sole virion-surface protein, the rabies virus glycoprotein (RABV-G) mediates host-cell entry. RABV-G's pre-fusion trimeric conformation displays epitopes bound by protective neutralizing antibodies that can be induced by vaccination or passively administered for post-exposure prophylaxis. We report a 2.8-Å structure of a RABV-G trimer in the pre-fusion conformation, in complex with two neutralizing and protective monoclonal antibodies, 17C7 and 1112-1, that recognize distinct epitopes. One of these antibodies is a licensed prophylactic (17C7, Rabishield), which we show locks the protein in pre-fusion conformation. Targeted mutations can similarly stabilize RABV-G in the pre-fusion conformation, a key step toward structure-guided vaccine design. These data reveal the higher-order architecture of a key therapeutic target and the structural basis of neutralization by antibodies binding two key antigenic sites, and this will facilitate the development of improved vaccines and prophylactic antibodies.


Assuntos
Vacinas Antirrábicas , Vírus da Raiva , Raiva , Anticorpos Monoclonais , Anticorpos Neutralizantes/uso terapêutico , Anticorpos Antivirais , Epitopos , Glicoproteínas/genética , Humanos , Proteínas de Membrana , Raiva/tratamento farmacológico , Raiva/prevenção & controle , Vacinas Antirrábicas/genética
8.
PLoS Negl Trop Dis ; 16(8): e0010422, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35994498

RESUMO

Dog-mediated rabies is responsible for tens of thousands of human deaths annually, and in resource-constrained settings, vaccinating dogs to control the disease at source remains challenging. Currently, rabies elimination efforts rely on mass dog vaccination by the parenteral route. To increase the herd immunity, free-roaming and stray dogs need to be specifically addressed in the vaccination campaigns, with oral rabies vaccination (ORV) of dogs being a possible solution. Using a third-generation vaccine and a standardized egg-flavoured bait, bait uptake and vaccination was assessed under field conditions in Namibia. During this trial, both veterinary staff as well as dog owners expressed their appreciation to this approach of vaccination. Of 1,115 dogs offered a bait, 90% (n = 1,006, 95%CI:91-94) consumed the bait and 72.9% (n = 813, 95%CI:70.2-75.4) of dogs were assessed as being vaccinated by direct observation, while for 11.7% (n = 130, 95%CI:9.9-17.7) the status was recorded as "unkown" and 15.4% (n = 172, 95%CI: 13.4-17.7) were considered as being not vaccinated. Smaller dogs and dogs offered a bait with multiple other dogs had significantly higher vaccination rates, while other factors, e.g. sex, confinement status and time had no influence. The favorable results of this first large-scale field trial further support the strategic integration of ORV into dog rabies control programmes. Given the acceptance of the egg-flavored bait under various settings worldwide, ORV of dogs could become a game-changer in countries, where control strategies using parenteral vaccination alone failed to reach sufficient vaccination coverage in the dog population.


Assuntos
Doenças do Cão , Vacinas Antirrábicas , Raiva , Administração Oral , Animais , Doenças do Cão/epidemiologia , Doenças do Cão/prevenção & controle , Cães , Humanos , Namíbia , Raiva/epidemiologia , Raiva/prevenção & controle , Raiva/veterinária , Vacinação/métodos , Vacinação/veterinária
9.
PLoS Negl Trop Dis ; 16(8): e0010699, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36026522

RESUMO

Vampire bat transmitted rabies (VBR) is a continuing burden to public health and agricultural sectors in Latin America, despite decades-long efforts to control the disease by culling bat populations. Culling has been shown to disperse bats, leading to an increased spread of rabies. Thus, non-lethal strategies to control VBR, such as vaccination, are desired. Here, we evaluated the safety and efficacy of a viral-vectored recombinant mosaic glycoprotein rabies vaccine candidate (RCN-MoG) in vampire bats (Desmodus rotundus) of unknown history of rabies exposure captured in México and transported to the United States. Vaccination with RCN-MoG was demonstrated to be safe, even in pregnant females, as no evidence of lesions or adverse effects were observed. We detected rabies neutralizing antibodies in 28% (8/29) of seronegative bats post-vaccination. Survival proportions of adult bats after rabies virus (RABV) challenge ranged from 55-100% and were not significantly different among treatments, pre- or post-vaccination serostatus, and route of vaccination, while eight pups (1-2.5 months of age) used as naïve controls all succumbed to challenge (P<0.0001). Importantly, we found that vaccination with RCN-MoG appeared to block viral shedding, even when infection proved lethal. Using real-time PCR, we did not detect RABV nucleic acid in the saliva samples of 9/10 vaccinated bats that succumbed to rabies after challenge (one was inconclusive). In contrast, RABV nucleic acid was detected in saliva samples from 71% of unvaccinated bats (10/14 sampled, plus one inconclusive) that died of the disease, including pups. Low seroconversion rates post-vaccination and high survival of non-vaccinated bats, perhaps due to earlier natural exposure, limited our conclusions regarding vaccine efficacy. However, our findings suggest a potential transmission-blocking effect of vaccination with RCN-MoG that could provide a promising strategy for controlling VBR in Latin America beyond longstanding culling programs.


Assuntos
Quirópteros , Ácidos Nucleicos , Vacinas Antirrábicas , Vírus da Raiva , Raiva , Animais , Feminino , Raiva/prevenção & controle , Raiva/veterinária , Vírus da Raiva/genética , Vacinas Sintéticas/genética , Eliminação de Partículas Virais
10.
J Virol ; 96(17): e0105022, 2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36005758

RESUMO

Infection with laboratory-attenuated rabies virus (RABV), but not wild-type (wt) RABV, can enhance the permeability of the blood-brain barrier (BBB), which is considered a key determinant for RABV pathogenicity. A previous study showed that the enhancement of BBB permeability is directly due not to RABV infection but to virus-induced inflammatory molecules. In this study, the effect of the matrix metallopeptidase (MMP) family on the permeability of the BBB during RABV infection was evaluated. We found that the expression level of MMP8 was upregulated in mice infected with lab-attenuated RABV but not with wt RABV. Lab-attenuated RABV rather than wt RABV activates inflammatory signaling pathways mediated by the nuclear factor κB (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. Activated NF-κB (p65) and AP-1 (c-Fos) bind to the MMP8 promoter, resulting in upregulation of its transcription. Analysis of mouse brains infected with the recombinant RABV expressing MMP8 indicated that MMP8 enhanced BBB permeability, leading to infiltration of inflammatory cells into the central nervous system (CNS). In brain-derived endothelial cells, treatment with MMP8 recombinant protein caused the degradation of tight junction (TJ) proteins, and the application of an MMP8 inhibitor inhibited the degradation of TJ proteins after RABV infection. Furthermore, an in vivo experiment using an MMP8 inhibitor during RABV infection demonstrated that BBB opening was diminished. In summary, our data suggest that the infection of lab-attenuated RABV enhances the BBB opening by upregulating MMP8. IMPORTANCE The ability to change BBB permeability was associated with the pathogenicity of RABV. BBB permeability was enhanced by infection with lab-attenuated RABV instead of wt RABV, allowing immune cells to infiltrate into the CNS. We found that MMP8 plays an important role in enhancing BBB permeability by degradation of TJ proteins during RABV infection. Using an MMP8 selective inhibitor restores the reduction of TJ proteins. We reveal that MMP8 is upregulated via the MAPK and NF-κB inflammatory pathways, activated by lab-attenuated RABV infection but not wt RABV. Our findings suggest that MMP8 has a critical role in modulating the opening of the BBB during RABV infection, which provides fresh insight into developing effective therapeutics for rabies and infection with other neurotropic viruses.


Assuntos
Vírus da Raiva , Raiva , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo , Células Endoteliais/metabolismo , Metaloproteinase 8 da Matriz/genética , Metaloproteinase 8 da Matriz/metabolismo , Metaloproteinase 8 da Matriz/farmacologia , Camundongos , NF-kappa B/metabolismo
11.
Ciudad de Buenos Aires; GCBA. Gerencia Operativa de Epidemiología; 19 ago. 2022. f:18 l:22 p. tab, graf.(Boletín Epidemiológico Semanal: Ciudad Autónoma de Buenos Aires, 7, 313).
Monografia em Espanhol | LILACS, InstitutionalDB, BINACIS, UNISALUD | ID: biblio-1392542

RESUMO

Informe con datos de vigilancia de rabia animal, y de otras enfermedades zoonóticas de notificación obligatoria, en la Ciudad de Buenos Aires: observación de animales mordedores, detección de virus rábico en muestras de laboratorio, vigilancia de reservorios de enfermedades zoonóticas, y vacunación antirrábica de animales, durante junio de 2022.


Assuntos
Raiva/diagnóstico , Raiva/transmissão , Raiva/epidemiologia , Zoonoses/prevenção & controle , Zoonoses/epidemiologia , Notificação de Doenças/estatística & dados numéricos , Epidemiologia , Monitoramento Epidemiológico
12.
PLoS Negl Trop Dis ; 16(8): e0010614, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35921319

RESUMO

Rabies is an endemic, highly fatal, and vaccine-preventable disease with severe socio-economic implications. Most (99%) human rabies cases are transmitted through dog bites. Children under 15 years account for 40% of all dog bite victims and 35-50% of all rabies deaths. Rabies awareness among this vulnerable group is critical to rabies prevention. However, there is a paucity of data on rabies awareness among pupils under 15. Hence, this study assessed the awareness and attitude of pupils under 15 years towards canine rabies in Kwara state in Nigeria. The study was conducted as a cross-sectional survey of 1,388 pupils across the state using a structured questionnaire that was administered as a one-on-one interview using the Open Data Kit on Android phones in December 2019. Of the 1388 pupils included in this study, only 21.7% (n = 301) of them were aware of rabies. The mean rabies score was 1.7±0.8 and only 29.2% (n = 88/301) of the pupils had adequate knowledge of canine rabies. The dog ownership rate was 18.7% (n = 259) with an average of 1.93 dogs per household. Approximately 5% (n = 66) of the pupils have been previously bitten by a dog. One-third of the dog bite victims (35%, n = 23/66) were managed and treated at home and only 12% (n = 8/66) were treated in a health facility. The result of the multivariable logistic regression showed that students aged between 13-15 years were more likely (OR: 1.93; 95% CI: 0.72-3.01; p < 0.001) to have adequate knowledge of rabies than the younger pupils. Similarly, pupils that have dogs in their households (OR: 2.09; 95%CI: 1.49-2.75; p < 0.001) and those that reside in Kwara South (OR:1.78 95% CI:1.29, 2.44; p < 0.001) were more likely to be aware and have adequate knowledge of canine rabies respectively. Finally, Pupils from non-dog-owning households were more likely (OR:2.2; 95% CI: 1.45, 4.42; p < 0.001) to have been bitten by dogs than those from dog-owning households. The awareness and attitude of pupils under 15 to canine rabies was poor. We advocate the introduction of rabies lessons into the school curriculum in Kwara State to reduce the incidence of dog bites and prevent dog-mediated human rabies.


Assuntos
Mordeduras e Picadas , Doenças do Cão , Vacinas Antirrábicas , Raiva , Adolescente , Animais , Mordeduras e Picadas/epidemiologia , Criança , Estudos Transversais , Doenças do Cão/epidemiologia , Doenças do Cão/prevenção & controle , Cães , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Nigéria/epidemiologia , Percepção , Raiva/epidemiologia , Raiva/prevenção & controle , Raiva/veterinária , Inquéritos e Questionários
13.
PLoS Negl Trop Dis ; 16(8): e0010634, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35944018

RESUMO

Rabies is one of the most lethal infectious diseases, with those living in Asia and Africa having the highest risk of dying from rabies. We conducted a knowledge, attitudes and practices survey in urban and peri-urban areas of Bangladesh to describe canine bite rates, rabies knowledge, and healthcare seeking behaviors and barriers to human and dog vaccination. A bite risk assessment score (BRAS) and healthcare-seeking behavior score (HSBS) was calculated for each bite victim. Respondents were given two hypothetical situations to assess potential behaviors after a bite and willingness to pay for rabies vaccine and immunoglobulin. In total, 2,447 households participated in the survey and 85 bite victims were identified. The BRAS identified that 31% of bites posed no risk of rabies transmission. Multivariate analyses showed that living in Chittagong (ß = 1.4; 95% CI: 0.1, 2.7) was associated with a higher HSBS. Findings presented here provide useful information regarding bite occurrences, healthcare-seeking behaviors, and a need for strategies to increase rabies awareness.


Assuntos
Mordeduras e Picadas , Doenças do Cão , Vacinas Antirrábicas , Raiva , Animais , Bangladesh/epidemiologia , Doenças do Cão/prevenção & controle , Cães , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Raiva/epidemiologia , Raiva/prevenção & controle , Inquéritos e Questionários , População Urbana
14.
Vaccine ; 40(36): 5347-5355, 2022 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-35933278

RESUMO

Shorter rabies pre-exposure prophylaxis (PrEP) regimens may offer improved convenience and feasibility over classic 3-week regimens, for example in regions with poor access to vaccines or for travelers to rabies-endemic regions. In this multicenter, open-label, controlled trial, 570 healthy participants aged 2-64 years were randomized to receive: 1-week PrEP (vaccination days [D]0 and 7; Group 1) or classic 3-week PrEP regimen (D0, D7, and D21; Group 2) with one 1.0 mL intramuscular [IM] dose of human diploid cell culture rabies vaccine (HDCV) at each visit; 1-week PrEP with two 0.1 mL intradermal (ID) HDCV doses at each visit (Group 3); or 1-week PrEP with one 0.5 mL IM dose (Group 4) or two 0.1 mL ID doses (Group 5) of Vero cell rabies vaccine (PVRV) at each visit. Participants received simulated post-exposure prophylactic (PEP) vaccination (two IM or ID doses of HDCV or PVRV three days apart) one year later. Rabies virus neutralizing antibody titers and seroconversion (titers ≥ 0.5 IU/mL) rates were assessed 14 days and up to 1 year post-PrEP, and pre- and post-PEP. Safety was assessed throughout the study. Seroconversion rates were high 14 days post-last PrEP injection (ranging from 96.7 % to 97.2 % across groups 1, 3-5; 1-week PrEP) and reached 100 % in Group 2 (3-week PrEP). Non-inferiority of Group 1 versus Group 2 in terms of seroconversion rates 14 days post-last PrEP injection (primary objective) was not demonstrated. After simulated PEP, all groups showed rapid and robust immune responses, with all but one participant achieving seroconversion (titers ≥ 0.5 IU/mL). There were no safety concerns, and the tolerability profiles of the vaccines were similar across the groups. A 1-week, IM or ID PrEP regimen with HDCV or PVRV provided efficacious priming, enabling rapid robust anamnestic responses to simulated PEP 1 year later across age groups. ClinicalTrials.gov number: NCT03700242. WHO Universal Trial Number (UTN): U1111-1183-5743.


Assuntos
Profilaxia Pré-Exposição , Vacinas Antirrábicas , Vírus da Raiva , Raiva , Animais , Anticorpos Antivirais , Chlorocebus aethiops , Diploide , Humanos , Injeções Intradérmicas , Profilaxia Pós-Exposição , Raiva/prevenção & controle , Vacinação , Células Vero
15.
Viruses ; 14(8)2022 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-36016320

RESUMO

Canine rabies is responsible for an estimated 59,000 human deaths every year. In an attempt to reach the ZeroBy30 goal, robust disease surveillance coupled with improved diagnostics play a paramount role in ensuring reliable data and gradually attesting rabies control advancements. In this context, proficiency testing is organized to harmonize rabies diagnostic capacities. In most exercises, rabies-positive samples consist of brains collected from intracerebrally inoculated mice. This procedure causes distress and severe suffering to animals, raising important ethical concerns that can no longer be ignored. In the last decades, the 3Rs tenet (Replace, Reduce, Refine) has been successfully implemented in several scientific areas, and we strongly support its application in the framework of rabies proficiency testing. Here, we discuss cell-based technologies as innovative sustainable in vitro candidate systems to replace in vivo experiments for the production of proficiency testing samples. The application of these alternative methods can allow completely in vitro or ex vivo production of rabies proficiency testing panels, which would represent an important replacement or reduction/refinement for current in vivo procedures.


Assuntos
Vacinas Antirrábicas , Raiva , Animais , Cães , Humanos , Ensaio de Proficiência Laboratorial , Camundongos , Raiva/diagnóstico
16.
Vaccine ; 40(33): 4780-4787, 2022 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-35778281

RESUMO

A serum-free, highly purified Vero cell rabies vaccine (PVRV-NG) is under development. We previously demonstrated that pre-exposure prophylaxis (PrEP) with PVRV-NG had a satisfactory safety profile and was immunogenically non-inferior to the licensed purified Vero cell rabies vaccine in adults. Here, we evaluated the safety and immunogenic non-inferiority of PrEP with PVRV-NG compared to the licensed human diploid cell vaccine (HDCV) in healthy adults (NCT01784874). Participants received three vaccinations (days 0, 7, and 28) as PrEP with or without a booster injection after 12 months. Rabies virus neutralising antibodies (RVNA) were evaluated on days 0, 28 (subgroup only), and 42, and Months 6, 12, and 12 + 14 days (booster group only). Non-inferiority (first primary objective) was based on the proportion of participants with RVNA titres ≥ 0.5 IU/mL (World Health Organization criteria for seroconversion) on day 42, expected to be ≥ 99% (second primary objective). Safety was evaluated after each dose and monitored throughout the study. At day 42, PVRV-NG was non-inferior to HDCV and the first primary objective was met; seroconversion was observed for 98.3% of PVRV-NG recipients and 99.1% of HDCV recipients. As < 99% of participants in the PVRV-NG group had RVNA titres ≥ 0.5 IU/mL, the second primary objective was not met. Booster vaccination produced a strong increase in RVNA titres for all groups, primed with PVRV-NG or HDCV. RVNA geometric mean titres tended to be higher for HDCV than PVRV-NG primary vaccine recipients. In a complementary evaluation using alternative criteria for seroconversion (complete virus neutralization at 1:5 serum dilution), 99.6% and 100% of participants in the PVRV-NG and HDCV groups, respectively, achieved seroconversion across the vaccine groups. No major safety concerns were observed during the study. PVRV-NG was well tolerated, with a similar safety profile to HDCV in terms of incidence, duration, and severity of adverse events after primary and booster vaccinations. ClinicalTrials.gov number: NCT01784874.


Assuntos
Vacinas Antirrábicas , Raiva , Adulto , Anticorpos Antivirais , Humanos , Profilaxia Pré-Exposição , Raiva/prevenção & controle , Vacinas Antirrábicas/efeitos adversos , Vacinas Antirrábicas/imunologia , Vírus da Raiva
17.
Vet Clin North Am Equine Pract ; 38(2): 323-338, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35811198

RESUMO

Several viruses transmitted by biological vectors or through direct contact, air, or ingestion cause neurologic disease in equids. Of interest are viruses of the Togaviridae, Flaviviridae, Rhabdoviridae, Herpesviridae, Bornaviridae, and Bunyaviridae families. Variable degree of inflammation is present with these viruses but lack of an inflammatory response does not rule out their presence. The goal of this article is to provide an overview on pathophysiologic and clinical aspects of nonarboviral equine encephalitides, specifically on lyssaviruses (rabies) and bornaviruses (Borna disease).


Assuntos
Doenças dos Cavalos , Raiva , Animais , Cavalos , Raiva/veterinária
18.
PLoS Negl Trop Dis ; 16(7): e0010595, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35852994

RESUMO

Rabies remains a public health problem in the Philippines despite the widespread provision of rabies vaccines and rabies immunoglobulin (RIG) as post-exposure prophylaxis (PEP). Detailed descriptions of recent human rabies cases in the Philippines are scarce. This study aimed to describe the clinical, epidemiological, and spatial features of human rabies cases between January 1, 2006, and December 31, 2015. We conducted a retrospective hospital-based case record review of all patients admitted to one referral hospital in Manila who received a clinical diagnosis of rabies. During the 10-year study period there were 575 patients (average 57.5 cases per year, range 57 to 119) with a final diagnosis of rabies. Most patients were male (n = 404, 70.3%) and aged ≥ 20 years (n = 433, 75.3%). Patients mostly came from the National Capital Region (n = 160, 28.0%) and the adjacent Regions III (n = 197, 34.4%) and IV-A (n = 168, 29.4%). Case mapping and heatmaps showed that human rabies cases were continuously observed in similar areas throughout the study period. Most patients had hydrophobia (n = 444, 95.5%) and/or aerophobia (n = 432, 93.3%). The leading causative animals were dogs (n = 421, 96.3%) and cats (n = 16, 3.7%). Among 437 patients with animal exposure history, only 42 (9.6%) had been administered at least one rabies vaccine. Two patients (0.5%), young children bitten on their face, had received and a full course of rabies vaccine. Human rabies patients were continuously admitted to the hospital, with no notable decline over the study period. The geographical area in which human rabies cases commonly occurred also did not change. Few patients received PEP and there were two suspected cases of PEP failure. The retrospective design of this study was a limitation; thus, prospective studies are required.


Assuntos
Mordeduras e Picadas , Vacinas Antirrábicas , Raiva , Animais , Mordeduras e Picadas/tratamento farmacológico , Criança , Pré-Escolar , Cães , Feminino , Humanos , Masculino , Filipinas/epidemiologia , Transtornos Fóbicos , Profilaxia Pós-Exposição , Raiva/tratamento farmacológico , Raiva/epidemiologia , Raiva/prevenção & controle , Estudos Retrospectivos
19.
Lancet Microbe ; 3(9): e663-e671, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35907430

RESUMO

BACKGROUND: Rabies kills around 60 000 people each year. ChAdOx2 RabG, a simian adenovirus-vectored rabies vaccine candidate, might have potential to provide low-cost single-dose pre-exposure rabies prophylaxis. This first-in-human study aimed to evaluate its safety and immunogenicity in healthy adults. METHODS: We did a single-centre phase 1 study of ChAdOx2 RabG, administered as a single intramuscular dose, with non-randomised open-label dose escalation at the Centre for Clinical Vaccinology and Tropical Medicine, Oxford, UK. Healthy adults were sequentially allocated to groups receiving low (5 × 109 viral particles), middle (2·5 × 1010 viral particles), and high doses (5 x 1010 viral particles) of ChAdOx2 RabG and were followed up to day 56 after vaccination. The primary objective was to assess safety. The secondary objective was to assess immunogenicity with the internationally standardised rabies virus neutralising antibody assay. In an optional follow-up phase 1 year after enrolment, we measured antibody maintenance then administered a licensed rabies vaccine (to simulate post-exposure prophylaxis) and measured recall responses. The trial is registered with ClinicalTrials.gov, NCT04162600, and is now closed to new participants. FINDINGS: Between Jan 2 and Oct 28, 2020, 12 adults received low (n=3), middle (n=3), and high doses (n=6) of ChAdOx2 RabG. Participants reported predominantly mild-to-moderate reactogenicity. There were no serious adverse events. Virus neutralising antibody concentrations exceeded the recognised correlate of protection (0·5 IU/mL) in three middle-dose recipients and six high-dose recipients within 56 days of vaccination (median 18·0 IU/mL). The median peak virus neutralising antibody concentrations within 56 days were 0·7 IU/mL (range 0·0-54·0 IU/mL) for the low-dose group, 18·0 IU/mL (0·7-18·0 IU/mL) for the middle-dose group, and 18·0 IU/mL (6·0-486·0 IU/mL) for the high-dose group. Nine participants returned for the additional follow-up after 1 year. Of these nine participants, virus neutralising antibody titres of more than 0·5 IU/mL were maintained in six of seven who had received middle-dose or high-dose ChAdOx2 RabG. Within 7 days of administration of the first dose of a licensed rabies vaccine, nine participants had virus neutralising antibody titres of more than 0·5 IU/mL. INTERPRETATION: In this study, ChAdOx2 RabG showed an acceptable safety and tolerability profile and encouraging immunogenicity, supporting further clinical evaluation. FUNDING: UK Medical Research Council and Engineering and Physical Sciences Research Council.


Assuntos
Adenovirus dos Símios , Vacinas Antirrábicas , Raiva , Adenovirus dos Símios/genética , Adulto , Anticorpos Neutralizantes , Anticorpos Antivirais , Humanos , Raiva/prevenção & controle , Vacinas Antirrábicas/efeitos adversos
20.
Biologicals ; 78: 10-16, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35786353

RESUMO

We have obtained an attenuated rabies virus CTN181-3. In this paper, we make a comprehensive studies on CTN181-3. CTN181-3 showed no pathogenicity by i. c. or o. i. inoculation in 3-week-old mice, lower pathogenic in 2-week-old mice, and no virulence by o. i. inoculation in 8-week-old golden hamsters. CTN181-3 showed high immunogenicity, which produced high level neutralizing antibodies, 100% sero-conversation and >5.0 IU/ml GMT by one dose i. m. or o. i. vaccination in mice and golden hamsters. Cellular immune response by one dose i. m. or o. i. inoculation was detected. Especially in PEP, reduced dose of vaccination resulted in 50% (one dose) and 100% (2 doses) protections in golden hamsters. Molecular basis of the attenuation indicated that eight substitutions compared to its parental virus strain CTN-1, among them the two substitutions at the G276 (Leu→Val) and L1496 (Met→Trp) were the critical attenuated site. The phenotypic and genotypic characteristics of CTN181-3 were highly stable, no reversion was occurred when the virus was multiple passaged in suckling mice brains, guinea pig submandibular glands or BSR/Vero cell cultures. The gene homology compared to the Chinese rabies isolates showed much higher than rabies vaccine strains used in China, suggesting CTN181-3 is a promising and suitable oral rabies vaccine candidate strain.


Assuntos
Vacinas Antirrábicas , Vírus da Raiva , Raiva , Animais , Anticorpos Antivirais , Chlorocebus aethiops , Cricetinae , Cobaias , Mesocricetus , Camundongos , Raiva/prevenção & controle , Vírus da Raiva/genética , Células Vero
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