Vetnuus | September 2024 23 produced strong neutralizing antibodies, as well as CD8+ and CD4+T cell responses. In non-human primates, two doses of 100 μg CV7202 with a 28 d interval were well tolerated, producing antibody titers 20 times higher than commercially available rabies vaccines.95 The phase I results showed that two doses of 1 μg produced high titer, strong adaptive immune responses, good tolerance, and significant improvement compared to CV7201 with a protamine delivery system.94 In 2023, many reports related to mRNA rabies vaccines were published. Numerous preclinical studies on mRNA rabies vaccines have shown that, regardless of the delivery system used, whether self-amplifying or non-amplifying, mRNA can cause animals to produce strong neutralizing antibodies. SYS6008 has been studied in mice and non-human primates, and the results showed that SYS6008 can generate a good immune response in crab-eating monkeys and maintain effective RVNA levels in the medium to long term. LVRNA001 has been studied in mouse and dog models. It can induce sustained neutralizing antibodies and strong Th1 cell immune responses in mice and maintain high antibody levels for at least 6 months after immunization. Immunization in dogs showed that the survival rate after the two doses of LVRNA001 was 100%, whereas the survival rate of the inactivated vaccine control group at 3 months was only 33.33%. Although there are many studies on mRNA rabies vaccines, most of the animal models used in these studies were mice or rats. Gene vaccines are generally considered less effective in large animals than in rodents.96 Therefore, Yu et al.82 conducted a study in a larger species with closer proximity to the human genome (cynomolgus macaques) and evaluated the immunogenicity of the SYS6008 rabies vaccine. Cynomolgus macaques, non-human primates, are the best animal models for human vaccine development, and their vaccine immunization dose used is equivalent to the vaccine immunization dose used in humans. The results showed that all cynomolgus macaques had neutralizing antibody titers above the protective level of 0.5 IU/ mL on day 7 after the first immunization, and the RVNA titers remained above 0.5 IU/mL on day 152, suggesting that it is important to conduct immunogenicity and immunoprotection studies in large animals before launching a clinical study of a new gene vaccine. Moreover, the immunization effect in small animal models needs to be further validated in larger animal models. Most current human rabies vaccines are inactivated vaccines, and the immunization procedure is mostly four or five doses by intramuscular injection, with a long immunization cycle and a high number of visits. The rabies mRNA vaccines discussed in this review mostly use a two-dose immunization procedure, requiring only two doses of immunization, with a short visit cycle and a low number of visits, which can considerably reduce the cost of immunization in rabies PEP. Although mRNA vaccines are a promising new platform with high versatility, effectiveness, simplicity, scalability, affordability, and cold chain-free potential, two phase I clinical trials targeting mRNA rabies vaccines have shown that, although they had overall good tolerance and immunogenicity, the response was weaker than expected based on animal results. Therefore, it is necessary to better understand the mechanism of action of mRNA vaccines to understand the impact of innate immune responses generated by mRNA and delivery systems, as well as the different immune responses to mRNA vaccines in different species, to accelerate the development of mRNA vaccines. v PEP Post-exposure prophylaxis NTV Nerve tissue vaccine CCV Cell culture vaccines UTR Untranslated region RABV-G Rabies virus glycoprotein PHK Primary hamster kidney DEV Duck embryo vaccine HEP Flury high egg passage vaccine HDCV Human diploid cell vaccine NLU No longer used PCECV Primary chick embryo cell vaccine PDEV Purified duck embryo vaccine PHKCV Primary hamster kidney cell vaccine PVRV Purified Vero rabies vaccine RVA Rhesus cell rabies vaccine PrEP Pre-exposure prophylaxis VLPs Virus-like particle vaccines RABV Rabies virus TLR Toll-like receptors RVNA Rabies virus neutralizing antibody SaRNA Self-amplifying RNA ORF Open reading frame NSP Non-structural proteins SGP Subgenomic promoter VEEV Venezuelan equine encephalitis virus SINV Sindbis virus SFV Semliki Forest virus SGP Subgenomic promoter GOI Gene of interest PRRs Pattern recognition receptors IFN Interferon LNPs Lipid nanoparticles PEG Polyethylene glycol CNE Cationic nanoemulsion Abbreviations References available on request. Development of mRNA rabies vaccines <<<22
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