Generation of Arctic-like Rabies Viruses Containing Chimeric Glycoproteins Enables Serological Potency Studies

ABSTRACTRabies viruses have the highest case fatality rate of any known virus and are responsible for an estimated 60,000 deaths each year. This is despite the fact that there are highly efficacious vaccines and postexposure prophylaxis available. However, while it is assumed these biologics provide protection against all rabies virus isolates, there are certain subdivisions of RABV lineages, such as within the Arctic-like RABV (AL rabies virus lineage, where data is limited and thus the potency of existing biologics has not been thoroughly assessed. By fusing the Arctic-like rabies virus envelope glycoprotein ecto- and transmembrane domains with the vesicular stomatitis virus cytoplasmic domain, a high titre (7.7 x 105− 6.1 x 106RLU/ml) pseudotyped virus was generated that was subsequently used in a pseudotyped virus neutralisation assay. These results showed that Arctic-like rabies viruses are neutralised to human, canine and feline vaccines and human post-exposure prophylaxis and this was not influenced by the swapping of the cytoplasmic domains (CVS-11 vs CVS-11etmVSVc;r= 0.99,p< 0.0001). This study supports the concept that rabies virus vaccines and newly identified mAbs are able to neutralise rabies virus variants that cluster in a monophyletic clade, referred to as phylogroup I lyssaviruses.

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Eradicate Rabies with Mass Parental Vaccination, Human Post-Exposure Prophylaxis, and Gene Therapy: A Systematic Review

10.20944/preprints201805.0103.v1 ◽

2018 ◽

Author(s):

Martin L. Nelwan

Keyword(s):

Gene Therapy ◽

Human Resource Development ◽

Rabies Virus ◽

Neglected Tropical Diseases ◽

Clinical Signs ◽

Post Exposure Prophylaxis ◽

Post Exposure ◽

Pubmed Database ◽

Exposure Prophylaxis

Rabies is one of the neglected tropical diseases, almost 100% fatal, but preventable. Rabies virus causes the disease and causes about 59000 human deaths annually. The author searched the Pubmed Database at NCBI for articles on rabies disease published between 2007 and 2018. All articles are open access, free for redistribution and in English. To examine rabies virus, Seller’s test was used. In this article, references written by the author were included and relevant publications were also included. The author reviewed a rabies dog case kept at Nelwan Institution for Human Resource Development. The dog showed clinical signs such as aggressive behavior, in-appetence, and soaking in water. Currently, there are no drugs to treat rabies. Vaccination is the best way to prevent the disease. To eradicate rabies, mass vaccination in dogs, post-exposure prophylaxis, and gene therapy can be used. To prevent rabies disease, minimum 70% of the dog population should receive vaccination. Humans with category II exposure should receive rabies vaccine and rabies immunoglobulin. For treatment, in vivo experiment showed that gene therapy can eliminate rabies from the infected neurons by using rAAV-N796. To fight rabies virus, induced pluripotent cells in combination with CRISPR/Cas9 system can also be beneficial. Furthermore, it needs US$ 8.6 billion to fight rabies annually.

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Human exposure to potential rabies virus transmitters in Olinda, State of Pernambuco, between 2002 and 2006

Revista da Sociedade Brasileira de Medicina Tropical ◽

10.1590/s0037-86822007000600003 ◽

2007 ◽

Vol 40 (6) ◽

pp. 617-621 ◽

Cited By ~ 4

Author(s):

Filipe Dantas-Torres ◽

Edmilson Ferreira de Oliveira-Filho

Keyword(s):

Rabies Virus ◽

Human Exposure ◽

Nonhuman Primates ◽

Prophylactic Treatment ◽

Human Rabies ◽

Post Exposure Prophylaxis ◽

Wild Animals ◽

Health Unit ◽

Multifaceted Approach ◽

Exposure Prophylaxis

The aim of the present study was to evaluate the data on human exposure to potential rabies virus transmitters in Olinda, State of Pernambuco, Brazil. Data from 7,062 patients who underwent antirabies prophylactic treatment in Olinda between 2002 and 2006 were analyzed. As expected, dogs and cats were involved in most of the cases; i.e. 82.3 and 16.3%, respectively. Attacks by nonhuman primates, bats and other species (unspecified) were also reported. Among the 7,062 patients who underwent antirabies treatment, 582 patients abandoned the treatment, either by indication from the health unit (195) or by their own decision (387). In conclusion, this study has indicated that prophylaxis for human rabies in this urban area will require a multifaceted approach, including health education, post-exposure prophylaxis, systematic vaccination for dogs and cats, and possibly selective control over wild animals such as hematophagous bats.

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Molecular epidemiological study of Arctic rabies virus isolates from Greenland and comparison with isolates from throughout the Arctic and Baltic regions

Virus Research ◽

10.1016/j.virusres.2005.08.007 ◽

2006 ◽

Vol 116 (1-2) ◽

pp. 1-10 ◽

Cited By ~ 30

Author(s):

K.L. Mansfield ◽

V. Racloz ◽

L.M. McElhinney ◽

D.A. Marston ◽

N. Johnson ◽

...

Keyword(s):

Epidemiological Study ◽

Rabies Virus ◽

The Arctic ◽

Molecular Epidemiological Study ◽

Virus Isolates

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Clofazimine: A Promising Inhibitor of Rabies Virus

Frontiers in Pharmacology ◽

10.3389/fphar.2021.598241 ◽

2021 ◽

Vol 12 ◽

Author(s):

Jiajing Wu ◽

Shouchun Cao ◽

Shan Lei ◽

Qiang Liu ◽

Yinghong Li ◽

...

Keyword(s):

Rabies Virus ◽

High Throughput Screening ◽

Survival Rates ◽

Positive Control ◽

Post Exposure Prophylaxis ◽

Antiviral Therapies ◽

Clinical Drugs ◽

Underlying Mechanisms ◽

Exposure Prophylaxis

With an almost 100% mortality rate, rabies virus (RABV) infection is a global concern. Limited post-exposure prophylaxis and lack of an effective treatment necessitate novel antiviral therapies against RABV. Here, using a high-throughput screening (HTS) method developed in our lab, 11 candidates with anti-RABV activity were identified from a library of 767 clinical drugs. Clofazimine (CFZ), an anti-leprosy drug, displayed an EC50 of 2.28 μM, and SI over 967 against RABV. Investigations into the underlying mechanisms revealed that CFZ targeted viral membrane fusion at the early stages of virus replication. Moreover, CFZ and Clofazimine salicylates (CFZS) exhibited elevated survival rates in vivo, compared with the positive control T-705. Thus, this study revealed CFZ as a promising drug against RABV infection.

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Assessing clinicians’ Post-Exposure Prophylaxis recommendations for rabies virus exposures in Hunan Province, China

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0009564 ◽

2021 ◽

Vol 15 (7) ◽

pp. e0009564

Author(s):

Yu Li ◽

Jeanette J. Rainey ◽

Hao Yang ◽

Cuc H. Tran ◽

Yang Huai ◽

...

Keyword(s):

High Risk ◽

Patient Care ◽

Rabies Virus ◽

Hunan Province ◽

Human Rabies ◽

P Value ◽

Post Exposure Prophylaxis ◽

National Guidelines ◽

Clinic Staff ◽

Exposure Prophylaxis

Background Timely and appropriate administration of post-exposure prophylaxis (PEP) is an essential component of human rabies prevention programs. We evaluated patient care at rabies clinics in a high-risk county in Hunan Province, China to inform strategies needed to achieve dog-mediated human rabies elimination by 2030. Methods We collected information on PEP, staff capacity, and service availability at the 17 rabies clinics in the high-risk county during onsite visits and key staff interviews. Additionally, we conducted observational assessments at five of these clinics, identified through purposive sampling to capture real-time information on patient care during a four-week period. Wound categories assigned by trained observers were considered accurate per national guidelines for comparison purposes. We used the kappa statistic and an alpha level of 0.05 to assess agreement between observers and clinic staff. Results In 2015, the 17 clinics provided PEP to 5,261 patients. Although rabies vaccines were available at all 17 clinics, rabies immune globulin (RIG) was only available at the single urban clinic in the county. During the assessment period in 2016, 196 patients sought care for possible rabies virus exposures. According to observers, 88 (44%) patients had category III wounds, 104 (53%) had category II wounds and 4 (2%) had category I wounds. Observers and PEP clinic staff agreed on approximately half of the assigned wound categories (kappa = 0.55, p-value< 0.001). Agreement for the urban county-level CDC clinic (kappa = 0.93, p-value<0.001) was higher than that of the rural township clinics (kappa = 0.16, p-value = 0.007). Using observer assigned wound categories, 142 (73%) patients received rabies vaccinations and RIG as outlined in the national guidelines. Conclusion Rabies PEP services were available at each town of the project county; however, gaps between clinical practice of PEP and recommendations of national rabies guidelines were identified. We used these findings to develop and implement a training to rabies clinic staff on wound categorization, wound care, and appropriate use of PEP. Additional risk-based approaches for evaluating human rabies virus exposures may be needed as China progresses towards elimination.

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Experimental utility of rabies virus-neutralizing human monoclonal antibodies in post-exposure prophylaxis

Vaccine ◽

10.1016/s0264-410x(01)00135-9 ◽

2001 ◽

Vol 19 (28-29) ◽

pp. 3834-3842 ◽

Cited By ~ 51

Author(s):

C.A Hanlon ◽

C.A DeMattos ◽

C.C DeMattos ◽

M Niezgoda ◽

D.C Hooper ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Rabies Virus ◽

Post Exposure Prophylaxis ◽

Human Monoclonal Antibodies ◽

Post Exposure ◽

Exposure Prophylaxis

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Purified Vero Cell Rabies Vaccine (PVRV, Verorab®): A Systematic Review of Intradermal Use Between 1985 and 2019

Tropical Medicine and Infectious Disease ◽

10.3390/tropicalmed5010040 ◽

2020 ◽

Vol 5 (1) ◽

pp. 40 ◽

Cited By ~ 1

Author(s):

Thomas Moulenat ◽

Céline Petit ◽

Valérie Bosch Castells ◽

Guy Houillon

Keyword(s):

Systematic Review ◽

Vero Cell ◽

Rabies Virus ◽

Neutralizing Antibodies ◽

Rabies Vaccine ◽

Post Exposure Prophylaxis ◽

Post Exposure ◽

Exposure Prophylaxis ◽

Rabies Prevention ◽

Rabies Vaccination

The purified Vero cell rabies vaccine (PVRV; Verorab®, Sanofi Pasteur) has been used in rabies prevention since 1985. Evolving rabies vaccination trends, including shorter intradermal (ID) regimens with reduced volume, along with WHO recommendation for ID administration has driven recent ID PVRV regimen assessments. Thus, a consolidated review comparing immunogenicity of PVRV ID regimens during pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP) is timely and beneficial in identifying gaps in current research. A search of seven databases for studies published from 1985 to November 2019 identified 35 studies. PrEP was assessed in 10 studies (n = 926) with 1–3-site, 1–3-visit regimens of up to 3-months duration. Seroconversion (rabies virus neutralizing antibodies [RVNA] ≥ 0.5 IU/mL) rates of 90–100% were reported within weeks, irrespective of regimen, with robust booster responses at 1 year (100% seroconversion rates by day 14 post-booster). However, data are lacking for the current WHO-recommended, 2-site, 1-week ID PrEP regimen. PEP was assessed in 25 studies (n = 2136) across regimens of 1-week to 90-day duration. All ID PEP regimens assessed induced ≥ 99% seroconversion rates (except in HIV participants) by day 14–28. This review confirms ID PVRV suitability for rabies prophylaxis and highlights the heterogeneity of use in the field.

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The Urtica Dioica Agglutinin Prevents Rabies Virus Infection in a Muscle Explant Model

10.1101/2021.05.21.441744 ◽

2021 ◽

Author(s):

Xinyu Wang ◽

Lisanne Terrie ◽

Guanghui Wu ◽

Els Van Damme ◽

Lieven Thorrez ◽

...

Keyword(s):

Rabies Virus ◽

Virus Production ◽

Urtica Dioica ◽

Cold Chain ◽

Infection Model ◽

Post Exposure Prophylaxis ◽

Rabies Virus Infection ◽

Muscle Infection ◽

Exposure Prophylaxis ◽

Urtica Dioica Agglutinin

Infection with the rabies virus (RABV) causes fatal encephalitis and paralysis in humans and animals. Post-exposure prophylaxis (PEP) consists of vaccination and the injection of anti-rabies immunoglobulins (RIGs) around the (bite) wound. This is 100% effective in preventing disease if administered in a timely manner. However, the costs, the required cold chain for storage and transport and the limited availability of RIGs makes the treatment challenging. Cheaper and easier to produce alternatives are urgently needed. To aid in the discovery and development of such alternative therapeutics, we developed a physiological relevant infection model. Strips of freshly dissected swine skeletal muscle were placed under tension in culture medium and infected with RABV. Viral antigens were produced in the muscle explants and the virus production increased significantly over time, indicating that RABV infects and replicates in the muscle explants. Subsequently, in a search for inhibitors of RABV entry in muscle cells, we first screened a panel of 34 different lectins in a RABV / BHK-21J cell assay. The Urtica Dioica (stinging nettle) Agglutinin (UDA; a N-acetyl-D-glucosamine specific agglutinin) was found to be able to completely inhibit infection of cells with the RABV (EC50 8.2 μg/mL) by preventing binding of the virus to the host cell. When the infection of the muscle strips was carried out in the presence of UDA, infection of the tissue was completely prevented. We thus developed a physiological relevant RABV muscle infection model and identified an easy to produce component that (i) may serve as a reference for further studies and (ii) holds promise as an alternative for RIGs in PEP.

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