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Vaccine Aug 2019Rabies virus remains an important burden of disease claiming an estimated 60,000 lives each year, mainly children, and having a huge economical and societal cost.... (Review)
Review
Rabies virus remains an important burden of disease claiming an estimated 60,000 lives each year, mainly children, and having a huge economical and societal cost. Post-exposure prophylaxis (PEP) is highly effective, however in patients that present with neurological symptoms the case-fatality ratio is extremely high (>99%). During the last decades several attempts to identify potent and effective antivirals were made. Only a few of these demonstrated improvement in clinical signs in animal studies and none of the trials in humans showed significant efficacy. Here we explore novel opportunities to identify more potent anti-rabies molecules. In particular important progress has been made on antivirals against other Mononegavirales (paramyxoviruses, filoviruses) which should be an impetus to test and optimize these molecules towards anti-rabies virus therapies. Effective rabies antivirals for therapeutic use need to be molecules that can be dosed into the cerebrospinal fluid and that rapidly and potently block ongoing virus replication and as such stop the further spread of the virus. Antivirals for prophylactic use can also be envisaged and these should be able to prevent infection of peripheral nerve cells and should have the potential to replace the current anti-rabies immunoglobulins that are used in PEP.
Topics: Adenine; Adenosine; Adenosine Monophosphate; Alanine; Amides; Antiviral Agents; Drug Repositioning; Humans; Post-Exposure Prophylaxis; Pyrazines; Pyrrolidines; Rabies; Rabies virus
PubMed: 29279280
DOI: 10.1016/j.vaccine.2017.12.051 -
Journal of the Neurological Sciences May 2021Several Lyssaviruses are known to be a causative agent of rabies and rabies like syndrome. There are no proven effective treatment strategies for symptomatic rabies...
Several Lyssaviruses are known to be a causative agent of rabies and rabies like syndrome. There are no proven effective treatment strategies for symptomatic rabies patient. Risk of infection from dog variant of rabies virus is highest with deep bite reaching muscular layer and much higher when compared to scratch. Failure of viral eradication at the central nervous system (CNS) is partly due to inadequate immune response. Favipiravir selectively inhibit viral RNA polymerase and has been shown to reduce rabies replication in neuronal cell and mouse model system. Endocannabinoid system has emerged as an important regulator for CNS integrity, cell fate and may serve as an important novel neuroprotective agent. Cannabinoid may be able to regulate the impaired homeostasis induced by rabies virus by promoting infected cell survival and promote complete autophagy in infected cell.
Topics: Animals; Case Management; Central Nervous System; Dogs; Humans; Lyssavirus; Mice; Rabies; Rabies virus
PubMed: 33812240
DOI: 10.1016/j.jns.2021.117413 -
Current Opinion in Virology Oct 2020Appropriate choice of vaccine vector is crucial for effective vaccine development. Rhabdoviral vectors, such as rabies virus and vesicular stomatitis virus, have been... (Review)
Review
Appropriate choice of vaccine vector is crucial for effective vaccine development. Rhabdoviral vectors, such as rabies virus and vesicular stomatitis virus, have been used in a variety of vaccine strategies. These viruses have small, easily manipulated genomes that can stably express foreign glycoproteins due to a well-established reverse genetics system for virus recovery. Both viruses have well-described safety profiles and have been demonstrated to be effective vaccine vectors. This review will describe how these Rhabdoviruses can be manipulated for use as vectors, their various applications as vaccines or therapeutics, and the advantages and disadvantages of their use.
Topics: Animals; Genetic Vectors; Glycoproteins; Humans; Mice; Rabies virus; Reverse Genetics; Rhabdoviridae; Vaccines, Synthetic; Vesiculovirus; Viral Vaccines; Virus Diseases
PubMed: 33130500
DOI: 10.1016/j.coviro.2020.09.003 -
The Veterinary Record Oct 2022
Topics: Animals; RNA, Viral; Rabies; Rabies virus; Real-Time Polymerase Chain Reaction
PubMed: 36205939
DOI: 10.1002/vetr.2286 -
ELife Nov 2023Transsynaptic viral vectors provide means to gain genetic access to neurons based on synaptic connectivity and are essential tools for the dissection of neural circuit...
Transsynaptic viral vectors provide means to gain genetic access to neurons based on synaptic connectivity and are essential tools for the dissection of neural circuit function. Among them, the retrograde monosynaptic ΔG-Rabies has been widely used in neuroscience research. A recently developed engineered version of the ΔG-Rabies, the non-toxic self-inactivating (SiR) virus, allows the long term genetic manipulation of neural circuits. However, the high mutational rate of the rabies virus poses a risk that mutations targeting the key genetic regulatory element in the SiR genome could emerge and revert it to a canonical ΔG-Rabies. Such revertant mutations have recently been identified in a SiR batch. To address the origin, incidence and relevance of these mutations, we investigated the genomic stability of SiR in vitro and in vivo. We found that "revertant" mutations are rare and accumulate only when SiR is extensively amplified in vitro, particularly in suboptimal production cell lines that have insufficient levels of TEV protease activity. Moreover, we confirmed that SiR-CRE, unlike canonical ΔG-Rab-CRE or revertant-SiR-CRE, is non-toxic and that revertant mutations do not emerge in vivo during long-term experiments.
Topics: Humans; Rabies; Rabies virus; Mutation; Cell Line; Genomic Instability
PubMed: 37921437
DOI: 10.7554/eLife.83459 -
Advances in Virus Research 2022Rabies infects all mammals; however, transmission cycles are only maintained in certain bat and carnivore species. The high incidence of rabies in Greater Kudu...
Rabies infects all mammals; however, transmission cycles are only maintained in certain bat and carnivore species. The high incidence of rabies in Greater Kudu (Tragelaphus strepsiceros) observed in Namibia for over 40 years has led to postulation that independent virus transmission is occurring within this antelope population. We have analysed extensive experimental, epidemiological, phylogeographic and deep sequence data, which collectively refute maintenance of an independent rabies cycle in kudu. As rabies in kudu continues to have a negative impact on the Namibian agricultural sector, measures to protect kudu have been investigated, including the use of a third-generation oral rabies vaccine. Initial results show protection of kudu from rabies infection via the oral route, with an appropriate bait design, different application schedules and vaccination doses further enhancing the immune response. Rabies in kudu is a complex interplay at the wildlife-livestock interface and requires a concerted approach to successfully control.
Topics: Animals; Animals, Wild; Antelopes; Rabies; Rabies Vaccines; Rabies virus
PubMed: 35840180
DOI: 10.1016/bs.aivir.2022.04.001 -
Viral Immunology Oct 2021Rabies is an almost invariably fatal disease. According to the World Health Organization (WHO), rabies virus neutralizing antibody (RVNA) titers of ≥0.5 IU/mL are... (Review)
Review
Rabies is an almost invariably fatal disease. According to the World Health Organization (WHO), rabies virus neutralizing antibody (RVNA) titers of ≥0.5 IU/mL are considered adequate for rabies protection. Therefore, detection and quantification of RABV antibodies are important. Many methods have been developed for detecting RABV antibodies. In the present study, we reviewed several methods of detecting RABV antibodies in human and animal samples and evaluated and compared their performance. Of 34 methods, 5 demonstrated unsatisfactory sensitivity or specificity. The others exhibited sensitivity and specificity of ≥75%. The correlation coefficient for five of eight methods was >0.8. The Bland-Altman mean bias of five of five methods was <±2.0. The kappa values of 25 of 28 methods were higher than 0.4, demonstrating at least moderate agreement. Analysis of the performance of these methods emphasized that any new technology should be considered carefully and objectively before being used as an appropriate and applicable alternative.
Topics: Animals; Antibodies, Neutralizing; Antibodies, Viral; Neutralization Tests; Rabies; Rabies virus
PubMed: 34550784
DOI: 10.1089/vim.2020.0317 -
International Journal of Medical... 2023Rabies continues to be a huge threat to public health. The rabies virus envelope glycoprotein (RABV G) is a major rabies virus antigen and contains neutralizing...
Rabies continues to be a huge threat to public health. The rabies virus envelope glycoprotein (RABV G) is a major rabies virus antigen and contains neutralizing epitopes, which are primary candidates for subunit vaccines and diagnostic antigens. However, the production and purification of rRABV G while retaining its antigenic and immunogenic remains to be a challenge. Here, we aimed to establish a platform for rRABV G production and purification, and determine the immunogenicity and antigenicity of rRABV G. The cDNA fragment encoding the soluble form of RABV G was synthesized and cloned into a lentiviral expressing vector. Recombinant lentiviral vector LV-CMV-RABV G-eGFP was packaged, titered, and then transduced into HEK 293T cells. The cell culture supernatant was purified using nickel affinity chromatography and subsequently confirmed through Western Blot analysis and indirect enzyme-linked immunosorbent assay (ELISA). The ELISA utilized human sera obtained from individuals who had been vaccinated with the human commercial Purified Vero Cells Rabies Vaccine (PVRV). Notably, we observed a neutralizing antibody response in immunized pigs rather than in mice. This discrepancy could potentially be attributed to factors such as the instability of the rRABV G protein, variations in host responses, and variances in the adjuvant used. Taking all these findings into account, the rRABV G protein generated in this study exhibits promise as a potential vaccine candidate for the prevention of rabies.
Topics: Chlorocebus aethiops; Humans; Animals; Mice; Swine; Rabies virus; Rabies; HEK293 Cells; Vero Cells; Antibodies, Viral; Glycoproteins; Rabies Vaccines; Viral Envelope Proteins; Recombinant Proteins
PubMed: 37786447
DOI: 10.7150/ijms.87134 -
Vaccine Nov 2023Rabies is a preventable zoonotic disease caused by rabies virus (RABV) with high mortality. Messenger RNA (mRNA) vaccines have opened up new avenues for vaccine...
Rabies is a preventable zoonotic disease caused by rabies virus (RABV) with high mortality. Messenger RNA (mRNA) vaccines have opened up new avenues for vaccine development and pandemic preparedness with potent scalability, which may overcome the only licensed rabies inactived vaccine' shortcoming of time and cost wasting. Here, we designed an RABV mRNA vaccines expressed RABV G protein and capsulated with lipid nanoparticle (LNP) and different nucleic acid immunostimulator (CPG 1018, CPG 2395 and Poly I:C) and then assessed the immunogenicity and protective capacity in mice. While RABV mRNA capsulated with LNP and CPG 1018 could induce more potent humoral response with highest and durable RABV-G specific IgG titers and virus neutralizing titers, but also induced stronger RABV G-specific cell-mediated immunity (CMI) responses, including the highest proportions of interferon-γ (IFN-γ) and tumor necrosis factor alpha (TNFα)- producing CD4+/CD8 + T cells according to a flow cytometry assay in mice. In addition, in the pre- and post-exposure challenge assays, LNP + CPG 1018 capsulated RABV G mRNA induced 100 % protection against 25 LD50 of RABV infection with highest inhibition efficacy of viral replication with the decreased virus genome detected by qRT-PCR. These results showed that RABV G mRNA capsulated with LNP immune-stimulating nucleic acids CPG 1018 showed promise as a safe and economical rabies vaccine candidate.
Topics: Animals; Mice; Rabies; Rabies virus; Antibodies, Viral; Rabies Vaccines; RNA, Messenger
PubMed: 37866995
DOI: 10.1016/j.vaccine.2023.10.019 -
Journal of Neuroscience Methods Sep 2019An understanding of how the brain processes information requires knowledge of its underlying wiring diagrams, as well as insights into the relationship between circuit... (Review)
Review
An understanding of how the brain processes information requires knowledge of its underlying wiring diagrams, as well as insights into the relationship between circuit architecture and physiological function. Notably, rabies virus based single-cell genetic manipulations that can facilitate an experimental link between physiology and genetics have recently advanced the field of systems neuroscience. It allows capturing the synaptic and the anatomical receptive fields of individual neurons. Recently, the methodological portfolio has been upgraded by two novel approaches, single cell electroporation with genetically encoded Ca sensors allowing for functionalized transsynaptic tracing and single cell targeted virus stamping. Especially the development of virus stamping provides a versatile solution for targeted single-cell infection of diverse cell types with different viruses at once, both in vitro and in vivo. Here we will summarize the latest developments in this rapidly moving field and provide a perspective for automated, quantitative analysis of single cell initiated connectomes.
Topics: Animals; Nerve Net; Neuroanatomical Tract-Tracing Techniques; Neurons; Neurosciences; Rabies virus
PubMed: 31330160
DOI: 10.1016/j.jneumeth.2019.108365