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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 -
Frontiers in Immunology 2023Rabies is a serious public health problem worldwide for which an effective treatment method is lacking but can be prevented by vaccines. Current vaccines are produced in...
INTRODUCTION
Rabies is a serious public health problem worldwide for which an effective treatment method is lacking but can be prevented by vaccines. Current vaccines are produced in cell or egg cultures, which are both costly and time consuming.
METHODS
Here, a non-replicating mRNA vaccine (RV021) encoding the rabies virus glycoprotein was developed , and its immunogenicity and protective efficacy against live virus was evaluated in mice.
RESULTS
A two-dose vaccination with 1 μg of RV021 at 7-day intervals induced a protective level of neutralizing antibody that was maintained for at least 260 days. RV021 induced a robust cellular immune response that was significantly superior to that of an inactivated vaccine. Two doses of 1 μg RV021 provided full protection against challenge with CVS of 30~60-fold lethal dose, 50%. Vaccine potency testing (according to the National Institutes of Health) revealed that the potency of RV021 at 15 μg/dose was 7.5 IU/dose, which is substantially higher than the standard for lot release of rabies vaccines for current human use.
CONCLUSION
The mRNA vaccine RV021 induces a strong protective immune response in mice, providing a new and promising strategy for human rabies prevention and control.
Topics: United States; Animals; Humans; Mice; Rabies; Rabies Vaccines; Antibodies, Viral; Antibodies, Neutralizing; Rabies virus
PubMed: 37954577
DOI: 10.3389/fimmu.2023.1288879 -
The Journal of General Virology Dec 2023The zoonotic rabies virus (RABV) is a non-segmented negative-sense RNA virus classified within the family , and is the most common aetiological agent responsible for...
The zoonotic rabies virus (RABV) is a non-segmented negative-sense RNA virus classified within the family , and is the most common aetiological agent responsible for fatal rabies disease. The RABV glycoprotein (G) forms trimeric spikes that protrude from RABV virions and mediate virus attachment, entry and spread, and is a major determinant of RABV pathogenesis. A range of RABV strains exist that are highly pathogenic in part due to their ability to evade host immune detection. However, some strains are disease-attenuated and can be cleared by host defences. A detailed molecular understanding of how strain variation relates to pathogenesis is currently lacking. Here, we reveal key differences in the trafficking profiles of RABV-G proteins from the challenge virus standard strain (CVS-11) and a highly attenuated vaccine strain SAD-B19 (SAD). We show that CVS-G traffics to the cell surface and undergoes rapid internalization through both clathrin- and cholesterol-dependent endocytic pathways. In contrast, SAD-G remains resident at the plasma membrane and internalizes at a significantly slower rate. Through engineering hybrids of CVS-G and SAD-G, we show that the cytoplasmic tail of CVS-G is the key determinant of these different internalization profiles. Alanine scanning further revealed that mutation of Y497 in CVS-G (H497 in SAD-G) could reduce the rate of internalization to SAD-G levels. Together, these data reveal new phenotypic differences between CVS-G and SAD-G proteins that may contribute to altered pathogenicity.
Topics: Humans; Rabies virus; Virus Internalization; Rabies; Rabies Vaccines; Glycoproteins; GTP-Binding Proteins
PubMed: 38063294
DOI: 10.1099/jgv.0.001935 -
Viruses Jul 2023Rabies kills approximately 60,000 humans each year, with deaths mostly occurring in developing countries, where rabies lyssavirus (RABV) variants are maintained in dog...
Rabies kills approximately 60,000 humans each year, with deaths mostly occurring in developing countries, where rabies lyssavirus (RABV) variants are maintained in dog populations [...].
Topics: Humans; Animals; Dogs; Rabies; Lyssavirus; Rabies virus; Dog Diseases
PubMed: 37515243
DOI: 10.3390/v15071557 -
The Indian Journal of Medical Research Jan 2024Rabies is a lethal viral disease transmitted through the bite of rabid animals. India has a high burden of rabies, contributing to a significant proportion of the global... (Review)
Review
Rabies is a lethal viral disease transmitted through the bite of rabid animals. India has a high burden of rabies, contributing to a significant proportion of the global deaths. However, under-reporting of the disease is prevalent due to lack of laboratory confirmation. Laboratory diagnosis of rabies plays a crucial role in differentiating the disease from clinical mimics, initiation of appropriate care, implementing infection control measures and informing disease surveillance. This review provides an overview of the recent advancements in laboratory diagnosis of rabies, aimed at updating physicians involved in diagnosis and management of rabies cases in India.
Topics: Animals; Rabies; Rabies virus; Laboratories; India; Clinical Laboratory Techniques; Bites and Stings
PubMed: 38376376
DOI: 10.4103/ijmr.ijmr_131_23 -
Vaccines Nov 2023Nipah virus (NiV) causes severe, lethal encephalitis in humans and pigs. However, there is no licensed vaccine available to prevent NiV infection. In this study, we used...
Nipah virus (NiV) causes severe, lethal encephalitis in humans and pigs. However, there is no licensed vaccine available to prevent NiV infection. In this study, we used the reverse genetic system based on the attenuated rabies virus strain SRV9 to construct two recombinant viruses, rSRV9-NiV-F and rSRV9-NiV-G, which displayed the NiV envelope glycoproteins F and G, respectively. Following three immunizations in BALB/c mice, the inactivated rSRV9-NiV-F and rSRV9-NiV-G alone or in combination, mixed with the adjuvants ISA 201 VG and poly (I:C), were able to induce the antigen-specific cellular and Th1-biased humoral immune responses. The specific antibodies against rSRV9-NiV-F and rSRV9-NiV-G had reactivity with two constructed bacterial-like particles displaying the F and G antigens of NiV. These data demonstrate that rSRV9-NiV-F or rSRV9-NiV-G has the potential to be developed into a promising vaccine candidate against NiV infection.
PubMed: 38140162
DOI: 10.3390/vaccines11121758 -
Current Biology : CB Sep 2023Remote memories play an important role in how we perceive the world, and they are rooted throughout the brain in "engrams": ensembles of cells that are formed during...
Remote memories play an important role in how we perceive the world, and they are rooted throughout the brain in "engrams": ensembles of cells that are formed during acquisition. Upon their reactivation, a specific memory can be recalled. Many studies have focused on the ensembles in CA1 of the hippocampus and the anterior cingulate cortex (ACC). However, the evolution of these components during systems' consolidation has not yet been comprehensively addressed. By applying transgenic approaches for ensemble identification, CLARITY, retro-AAV, and pseudo-rabies virus for circuit mapping, and chemogenetics for functional interrogation, we addressed the dynamics of recent and remote CA1 ensembles. We expected both stability (as they represent the same memory) and maturation (over time). Indeed, we found that CA1 engrams remain stable between recent and remote recalls, and the inhibition of engrams for recent recall during remote recall functionally impairs memory. We also found that new cells in the remote recall engram in the CA1 are not added randomly during maturation but differ according to their connections. First, we show in two ways that the anterograde CA1 → ACC engram cell projection grows larger. Finally, in the retrograde projections, the ACC reduces input to CA1 engram cells, whereas input from the entorhinal cortex and paraventricular nucleus of the thalamus increases. Our results shine fresh light on systems' consolidation by providing a deeper understanding of engram stability and maturation in the transition from recent to remote memory.
Topics: Hippocampus; Memory, Long-Term; Mental Recall; Entorhinal Cortex; Gyrus Cinguli
PubMed: 37586373
DOI: 10.1016/j.cub.2023.07.042 -
EFSA Journal. European Food Safety... Dec 2023This report by the European Food Safety Authority and the European Centre for Disease Prevention and Control presents the results of the zoonoses monitoring and...
This report by the European Food Safety Authority and the European Centre for Disease Prevention and Control presents the results of the zoonoses monitoring and surveillance activities carried out in 2022 in 27 Member States (MSs), the United Kingdom (Northern Ireland) and 11 non-MSs. Key statistics on zoonoses and zoonotic agents in humans, food, animals and feed are provided and interpreted historically. In 2022, the first and second most reported zoonoses in humans were campylobacteriosis and salmonellosis, respectively. The number of cases of campylobacteriosis and salmonellosis remained stable in comparison with 2021. Nineteen MSs and the United Kingdom (Northern Ireland) achieved all the established targets in poultry populations for the reduction of prevalence for the relevant serovars. samples from carcases of various animal species, and samples for quantification from broiler carcases, were more frequently positive when performed by the competent authorities than when own checks were conducted. Yersiniosis was the third most reported zoonosis in humans, followed by Shiga toxin-producing (STEC) and infections. and West Nile virus infections were the most severe zoonotic diseases, with the most hospitalisations and highest case fatality rates. In 2022, reporting showed an increase of more than 600% compared with 2021 in locally acquired cases of human West Nile virus infection, which is a mosquito-borne disease. In the EU, the number of reported foodborne outbreaks and cases, hospitalisations and deaths was higher in 2022 than in 2021. The number of deaths from outbreaks was the highest ever reported in the EU in the last 10 years, mainly caused by and to a lesser degree by . and in particular Enteritidis remained the most frequently reported causative agent for foodborne outbreaks. Norovirus (and other calicivirus) was the agent associated with the highest number of outbreak human cases. This report also provides updates on brucellosis, (Q fever), echinococcosis, rabies, toxoplasmosis, trichinellosis, infection with complex (focusing on and ) and tularaemia.
PubMed: 38089471
DOI: 10.2903/j.efsa.2023.8442 -
BioRxiv : the Preprint Server For... Nov 2023Mapping the connectivity of diverse neuronal types provides the foundation for understanding the structure and function of neural circuits. High-throughput and low-cost...
Mapping the connectivity of diverse neuronal types provides the foundation for understanding the structure and function of neural circuits. High-throughput and low-cost neuroanatomical techniques based on RNA barcode sequencing have the potential to map circuits at cellular resolution and a brain-wide scale, but existing Sindbis virus-based techniques can only map long-range projections using anterograde tracing approaches. Rabies virus can complement anterograde tracing approaches by enabling either retrograde labeling of projection neurons or monosynaptic tracing of direct inputs to genetically targeted postsynaptic neurons. However, barcoded rabies virus has so far been only used to map non-neuronal cellular interactions and synaptic connectivity of cultured neurons. Here we combine barcoded rabies virus with single-cell and sequencing to perform retrograde labeling and transsynaptic labeling in the mouse brain. We sequenced 96 retrogradely labeled cells and 295 transsynaptically labeled cells using single-cell RNA-seq, and 4,130 retrogradely labeled cells and 2,914 transsynaptically labeled cells . We found that the transcriptomic identities of rabies virus-infected cells can be robustly identified using both single-cell RNA-seq and sequencing. By associating gene expression with connectivity inferred from barcode sequencing, we distinguished long-range projecting cortical cell types from multiple cortical areas and identified cell types with converging or diverging synaptic connectivity. Combining sequencing with barcoded rabies virus complements existing sequencing-based neuroanatomical techniques and provides a potential path for mapping synaptic connectivity of neuronal types at scale.
PubMed: 36993334
DOI: 10.1101/2023.03.16.532873 -
Microorganisms Mar 2024Viruses are minuscule infectious agents that reproduce exclusively within the living cells of an organism and are present in almost every ecosystem. Their continuous... (Review)
Review
Viruses are minuscule infectious agents that reproduce exclusively within the living cells of an organism and are present in almost every ecosystem. Their continuous interaction with humans poses a significant threat to the survival and well-being of everyone. Apart from the common cold or seasonal influenza, viruses are also responsible for several important diseases such as polio, rabies, smallpox, and most recently COVID-19. Besides the loss of life and long-term health-related issues, clinical viral infections have significant economic and social impacts. Viral enzymes, especially proteases which are essential for viral multiplication, represent attractive drug targets. As a result, screening of viral protease inhibitors has gained a lot of interest in the development of anti-viral drugs. Despite the availability of anti-viral therapeutics, there is a clear need to develop novel curative agents that can be used against a given virus or group of related viruses. This review highlights the importance of yeasts as an in vivo model for screening viral enzyme inhibitors. We also discuss the advantages of yeast-based screening platforms over traditional assays. Therefore, in the present article, we discuss why yeast is emerging as a model of choice for in vivo screening of anti-viral molecules and why yeast-based screening will become more relevant in the future for screening anti-viral and other molecules of clinical importance.
PubMed: 38543629
DOI: 10.3390/microorganisms12030578