Nonclinical safety assessment of repeated administration and biodistribution of a novel rabies self-amplifying mRNA vaccine in rats

Stokes, Alan H.; Pion, Johanne; Binazon, Ornella; Laffont, Benoit; Bigras, Maude; Dubois, Guillaume; Blouin, Karine; Young, Jamie; Ringenberg, Michael A.; Abdeljelil, Nawel Ben; Haruna, Julius; Rodriguez, Luis-Alexander

doi:10.1016/j.yrtph.2020.104648

Cited by 54 publications

(50 citation statements)

References 26 publications

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“…In the pre-clinical safety evaluation of vaccine products, a single animal species should be used to study the toxicity of repeated administration ( CDE, 2008 ). The Sprague Dawley rats used in this study are the most commonly used rodents in vaccines general toxicity studies ( Mancebo et al, 2012 ; Sifontes-Rodríguez et al, 2009 ; Stokes et al, 2020 ). The background information of this family of animals is abundant, and the supply of animals is sufficient.…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 inactivated vaccine (Vero cells) shows good safety in repeated administration toxicity test of Sprague Dawley rats

Huang

Jiang

Wang

et al. 2021

Food and Chemical Toxicology

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Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 inactivated vaccine (Vero cells) shows good safety in repeated administration toxicity test of Sprague Dawley rats

Huang

Jiang

Wang

et al. 2021

Food and Chemical Toxicology

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“…Rabies, another infectious disease with a licensed vaccine, has recently been the focus of GSK's vaccinology program (RG-SAM GSK3903133A) which boasts the only clinical trial for a synthetic saRNA to date (NCT04062669). Preclinical evaluations of CNE formulated saRNA encoding the glycoprotein G antigen, showed that the vaccine was well tolerated following multiple IM injections in rats [92]. The saRNA-derived rabies RNA was detected up to 2 months after a single injection, emphasizing the durability of the approach.…”

Section: Animal-transmitted Virusmentioning

confidence: 95%

Self-amplifying RNA vaccines for infectious diseases

2020

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Vaccinology is shifting toward synthetic RNA platforms which allow for rapid, scalable, and cell-free manufacturing of prophylactic and therapeutic vaccines. The simple development pipeline is based on in vitro transcription of antigenencoding sequences or immunotherapies as synthetic RNA transcripts, which are then formulated for delivery. This approach may enable a quicker response to emerging disease outbreaks, as is evident from the swift pursuit of RNA vaccine candidates for the global SARS-CoV-2 pandemic. Both conventional and self-amplifying RNAs have shown protective immunization in preclinical studies against multiple infectious diseases including influenza, RSV, Rabies, Ebola, and HIV-1. Self-amplifying RNAs have shown enhanced antigen expression at lower doses compared to conventional mRNA, suggesting this technology may improve immunization. This review will explore how self-amplifying RNAs are emerging as important vaccine candidates for infectious diseases, the advantages of synthetic manufacturing approaches, and their potential for preventing and treating chronic infections.

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“…Besides the COVID-19 mRNA vaccines, many other mRNA vaccines have shown protective immunization in previous preclinical studies against multiple infectious diseases including influenza [ 150 , 164 , 165 ], dengue virus (DENV) [ 166 , 167 ], herpes simplex virus type 2 (HSV-2) [ 168 , 169 ], Rabies [170] , Zika virus (ZIKV) [ 112 , 167 ] and HIV-1 [ 171 , 172 ] ( Table 1 ). Feldman et al confirmed the safety and immunogenicity of the first mRNA vaccines against pandemic avian H10N8 and H7N9 influenza viruses, which consisted of chemically m 1 Ψ-modified mRNAs encoding the full-length hemagglutinin [150] .…”

Section: Therapeutic Applicationsmentioning

confidence: 99%

“…Based on the LNP encapsulation strategy, an m 1 Ψ-modified anti-ZIKV mRNA vaccine encoding the premembrane and envelope (prM-E) glycoproteins was tested for its immunogenicity and protection in mice, and the vaccine elicited rapid and durable protective immunity [ 112 , 167 ]. Recently, an m 1 Ψ-modified HIV-1 mRNA vaccine encoding the HIV-1 envelope protein was investigated in mice, and an antigen-specific IgG response was observed [ 171 , 172 ]. There are many other ongoing clinical and preclinical trials for mRNA vaccines at present, most of which harness chemically modified mRNA.…”

Section: Therapeutic Applicationsmentioning

confidence: 99%

Synthetic modified messenger RNA for therapeutic applications

et al. 2021

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Synthetic modified messenger RNA (mRNA) has manifested great potentials for therapeutic applications such as vaccines and gene therapies, with the recent mRNA vaccines for global pandemic COVID-19 (corona virus disease 2019) attracting the tremendous attention. The chemical modifications and delivery vehicles of synthetic mRNAs are the two key factors for their in vivo therapeutic applications. Chemical modifications like nucleoside methylation endow the synthetic mRNAs with high stability and reduced stimulation of innate immunity. The development of scalable production of synthetic mRNA and efficient mRNA formulation and delivery strategies in recent years have remarkably advanced the field. It is worth noticing that we had limited knowledge on the roles of mRNA modifications in the past. However, the last decade has witnessed not only new discoveries of several naturally occurring mRNA modifications but also substantial advances in understanding their roles on regulating gene expression. It is highly necessary to reconsider the therapeutic system made by synthetic modified mRNAs and delivery vectors. In this review, we will mainly discuss the roles of various chemical modifications on synthetic mRNAs, briefly summarize the progresses of mRNA delivery strategies, and highlight some latest mRNA therapeutics applications including infectious disease vaccines, cancer immunotherapy, mRNA-based genetic reprogramming and protein replacement, mRNA-based gene editing.

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Nonclinical safety assessment of repeated administration and biodistribution of a novel rabies self-amplifying mRNA vaccine in rats

Cited by 54 publications

References 26 publications

SARS-CoV-2 inactivated vaccine (Vero cells) shows good safety in repeated administration toxicity test of Sprague Dawley rats

SARS-CoV-2 inactivated vaccine (Vero cells) shows good safety in repeated administration toxicity test of Sprague Dawley rats

Self-amplifying RNA vaccines for infectious diseases

Synthetic modified messenger RNA for therapeutic applications

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