Genetically modified rabies virus ERA strain is safe and induces long-lasting protective immune response in dogs after oral vaccination

Shuai, Lei; Feng, Na; Wang, Xijun; Ge, Jinying; Wen, Zhiyuan; Chen, Weiye; Qin, Lide; Xia, Xianzhu; Bu, Zhigao

doi:10.1016/j.antiviral.2015.06.011

Cited by 39 publications

(27 citation statements)

References 36 publications

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“…The ERA and ERAGS strains grew at similar rates in NG108-15 cells and reached over 10 7.5 FAID 50 /mL at 96-hour post-inoculation. The growth property of the ERAGS strain seems to be similar to those of other recombinant RABVs, such as the rERAG 333E and Ni-CE (G333Glu) strains [ 15 24 26 ].…”

Section: Discussionmentioning

confidence: 92%

“…Thus, because safer candidates are necessary, several recombinant RABVs constructed using reverse genetic systems have been developed under names such as the rERAG 333E , rERAG3G, SPBNGA, Ni-CE (G333Glu), and ERAG333 strains [ 15 24 25 26 27 ]. These recombinant RABVs are based on the concept that the Arg at position 333 of the G protein of RABV is responsible for virulence.…”

Section: Discussionmentioning

confidence: 99%

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Safety and immunogenicity of recombinant rabies virus (ERAGS) in mice and raccoon dogs

Yang

Kim

Choi

et al. 2016

Clin Exp Vaccine Res

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PurposeThe development of a genetically modified live rabies vaccine applicable to wild raccoon dogs is necessary for the eradication of rabies in Korea. Thus, we constructed a recombinant rabies virus (RABV) called the ERAGS strain, using a reverse genetic system and evaluated its safety and efficacy in mice and its safety and immunogenicity in raccoon dogs.Materials and MethodsERAGS, which has Asn194Ser and Arg333Glu substitutions in the glycoprotein, was constructed using site-directed mutagenesis. Mice were inoculated with the ERAGS strain (either 105.0 or 107.0 FAID50/mL) via intramuscular (IM) or intracranial injections and then challenged with a virulent RABV. Raccoon dogs were administered the ERAGS strain (108.0 FAID50/mL) either orally or via the IM route and the immunogenicity of the strain was evaluated using fluorescent antibody virus neutralization tests.ResultsThe ERAGS strain inoculated into murine neuroblastoma cells reached 107.8 FAID50/mL at 96-hour post-inoculation. The virus was not pathogenic and induced complete protection from virulent RABV in immunized 4- and 6-week-old mice. Korean raccoon dogs immunized with the ERAGS strain via IM or oral route were also safe from the virus and developed high titer levels (26.4-32.8 IU/mL) of virus-neutralizing antibody (VNA) at 4 weeks post-inoculation.ConclusionThe ERAGS RABV strain was effectively protective against rabies in mice and produced a high VNA titer in raccoon dogs.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Safety and immunogenicity of recombinant rabies virus (ERAGS) in mice and raccoon dogs

Yang

Kim

Choi

et al. 2016

Clin Exp Vaccine Res

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“…However, safety concerns remain. There are indirect indications that live attenuated vaccines such as the ERA strain should be replaced; the ERA strain is pathogenic in adult mice [ 18 ]. Therefore, we constructed the ERAGS strain with multiple mutations in the glycoprotein gene and evaluated safety and immunogenicity in mice, raccoon dogs, and pigs [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

A genetically modified rabies vaccine (ERAGS) induces protective immunity in dogs and cattle

Yang

Kim

Lee

et al. 2017

Clin Exp Vaccine Res

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PurposeThe current live attenuated rabies vaccine must be replaced with a safer vaccine based on the ERAGS strain to prevent rabies in South Korea. We evaluated the safety and immunogenicity of a new strain in dogs and cattle.Materials and MethodsThe ERAGS strain, featuring two mutations altering two amino acids in a glycoprotein of rabies virus, was propagated in NG108-15 cells. We lyophilized the virus in the presence of two different stabilizers to evaluate the utilities of such preparations as novel rabies vaccines for animals. To explore safety and immunogenicity, dogs and cattle were inoculated with the vaccine at various doses via different routes and observed daily for 8 weeks post-inoculation (WPI). Immunogenicity was evaluated using a fluorescent antibody virus neutralization test or enzyme-linked immunosorbent assay.ResultsThe two different stabilizers did not differ greatly in terms of maintenance of virus viability in accelerated stability testing. No clinical signs of rabies developed in dogs or cattle inoculated with the vaccines (107.0 FAID50/mL). Dogs and cattle inoculated intramuscularly with 105.0 FAID50/mL exhibited virus neutralization assay titers of 4.6 IU/mL and 1.5 to 0.87 IU/mL at 4 WPI, respectively. All control animals remained rabies virus–seronegative throughout, confirming that no contact transmission occurred between vaccinated and control animals.ConclusionOur findings indicate that the new rabies vaccine is safe and immunogenic in dogs and cattle.

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“…The RABV ERA strain was propagated, titrated, and maintained in our laboratory [11]. ERA-mCherry is a recombinant ERA that has the mCherry gene inserted between the ERA M and G genes as an additional transcription unit.…”

Section: Cells and Virusmentioning

confidence: 99%

The Serine/Threonine Kinase AP2-Associated Kinase 1 Plays an Important Role in Rabies Virus Entry

Wang

Shuai

et al. 2019

Viruses

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Rabies virus (RABV) invades the central nervous system and nearly always causes fatal disease in humans. RABV enters cells via clathrin-mediated endocytosis upon receptor binding. The detailed mechanism of this process and how it is regulated are not fully understood. Here, we carried out a high-through-put RNAi analysis and identified AP2-associated kinase 1 (AAK1), a serine/threonine kinase, as an important cellular component in regulating the entry of RABV. AAK1 knock-down greatly inhibits RABV infection of cells, and AAK1-induced phosphorylation of threonine 156 of the μ subunit of adaptor protein 2 (AP2M1) is found to be required for RABV entry. Inhibition of AAK1 kinase activity by sunitinib blocked AP2M1 phosphorylation, significantly inhibiting RABV infection and preventing RABV from entering early endosomes. In vivo studies revealed that sunitinib prolongs the survival of mice challenged with RABV street virus. Our findings indicate that AAK1 is a potential drug target for postexposure prophylaxis against rabies.

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Genetically modified rabies virus ERA strain is safe and induces long-lasting protective immune response in dogs after oral vaccination

Cited by 39 publications

References 36 publications

Safety and immunogenicity of recombinant rabies virus (ERAGS) in mice and raccoon dogs

Safety and immunogenicity of recombinant rabies virus (ERAGS) in mice and raccoon dogs

A genetically modified rabies vaccine (ERAGS) induces protective immunity in dogs and cattle

The Serine/Threonine Kinase AP2-Associated Kinase 1 Plays an Important Role in Rabies Virus Entry

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