Vetnews | September 2024 16 « BACK TO CONTENTS ABSTRACT Rabies, primarily transmitted to humans by dogs (accounting for 99% of cases). Once rabies occurs, its mortality rate is approximately 100%. Post-exposure prophylaxis (PEP) is critical for preventing the onset of rabies after exposure to rabid animals, and vaccination is a pivotal element of PEP. However, high costs and complex immunization protocols have led to poor adherence to rabies vaccinations. Consequently, there is an urgent need to develop new rabies vaccines that are safe, highly immunogenic, and cost-effective to improve compliance and effectively prevent rabies. In recent years, mRNA vaccines have made significant progress in the structural modification and optimization of delivery systems. Various mRNA vaccines are currently undergoing clinical trials, positioning them as viable alternatives to the traditional rabies vaccines. In this article, we discuss a novel mRNA rabies vaccine currently undergoing clinical and preclinical testing, and evaluate its potential to replace existing vaccines. Introduction Rabies is an acute infectious disease caused by the rabies virus (RABV) and is a zoonotic neurological disease. The most common way for humans to contract rabies is through bites, scratching, licking, or mucosal damage by dogs, cats, wild carnivores, as well as carnivorous and vampire bats infected with the RABV. It is estimated that approximately 59,000 people1 worldwide die from rabies each year, of which 97% of cases occur in Asia and Africa. Rabies remains a serious public health concern. Rabies can be broadly categorized into two types: furious and paralytic. Furious rabies is characterized by classical symptoms, including severe agitation and hydrophobia. By contrast, paralytic rabies predominantly presents with weakness and flaccid paralysis. Once clinical symptoms appear, the mortality rate of patients with rabies is almost 100%. Timely, standardized, and complete post-exposure prophylaxis (PEP) can provide effective preventive protection for individuals exposed to rabies.2 Injection of the rabies vaccine is a key step in PEP. Vaccine immunization can produce neutralizing antibodies against the RABV in the body, which can effectively kill the virus before it enters the central nervous system. However, in the real world, implementing correct PEP for severe bites, scratches, and other injuries close to the nerve centre, such as the head and face, often makes it difficult to prevent rabies in all cases. The rate at which vaccines produce effective protective neutralizing antibodies is the underlying reason for PEP failure. Currently, commercially available rabies vaccines are mainly inactivated cell tissue culture vaccines, commonly administered via intramuscular injections following the Essen regimen (1-1-1-1-1), 4-dose Essen regimen (1-1-1-10), or Zagreb regimen (2-0-1-0-1). Compliance issues caused by frequent visits and long visit cycles hinder the implementation of the complete PEP. Therefore, the development of vaccines with faster neutralizing antibodies, better compliance, and stronger protection while ensuring safety is an important direction in the field of rabies vaccine development. With the continuous development and progress of science and technology, the revolutionary mRNA biotechnology is sparking a revolution in the vaccine field. mRNA vaccines have broad prospects for the prevention and treatment of infectious diseases, owing to their low risk of insertion mutations, high efficacy, fast development cycles, and low production costs.3 Recently, several mRNA vaccines have entered clinical trials and are expected to combat new and recurrent infectious diseases,4–6 Recently, the successful application of the COVID-19 mRNA vaccine further verified the advantages of this platform and opened the door for the use of mRNA vaccines in infectious disease prevention.7–10 This review summarizes recent research on the development of mRNA vaccines for rabies, with a brief review of mRNA rabies vaccine-related studies that have shown to be effective in preclinical animal models or clinical trials, and describes the current research status of mRNA rabies vaccines. In addition, most preclinical animal models for rabies mRNA vaccines in this review have used small animals, but some research organizations have conducted immunogenicity studies in non-human primates, such as cynomolgus macaques, and have obtained favourable immunity results. Rabies vaccines Typically, vaccines are administered before exposure to an infectious agent and are not particularly useful after exposure. Historically, rabies has been an exception to most other vaccinepreventable infectious diseases because immunization proceeds as a critical intervention not only before but also after exposure to the virus. Although Louis Pasteur invented the rabies vaccine in 188511 and effective rabies vaccines have been accessible for a considerable period, existing vaccination regimens require multiple doses to attain elevated neutralizing titers. These vaccination regimens are associated with high costs and pose challenges to developing countries where rabies mortality is high. Conventional rabies vaccines Over the past century, various substrates such as whole-animal tissues, primary cell cultures, diploid cells, and continuous cell lines have been widely used for virus propagation. Based on the different culture media, the development of traditional rabies vaccines has gone through three stages: animal nerve tissue vaccines (NTV), avian embryo vaccines, and cell culture vaccines (CCV). Table 1 summarizes the history of rabies vaccine development and lists the major currently available CCV. Many laboratory-fixed RABV strains have been used to prepare rabies vaccines over the past century.12 The early rabies vaccines were modified versions of the Pasteur vaccine. They were produced in nerve tissues and inactivated with phenol. For PEP, 14–21 daily doses were required to induce adequate antibody titers. The potency of Semple vaccines was highly variable; these vaccines contained residual nerve tissue, and neurological complications such as neuropathy, Guillain–Barré syndrome, meningitis or encephalitis were common.13 NTVs are no longer recommended by the WHO, which endorses the use of vaccines grown in cell culture or embryonated eggs.14 Duck embryo vaccines (DEV) were prepared from a virus propagated in embryonated duck eggs. Although it reduced the number and severity of post-vaccine reactions, DEV was less immunogenic than the brain tissue vaccines.15 For DEV vaccines, 14–23 daily inoculations were recommended, but even this “heroic” dosage did not always protect against rabies after severe exposure. Problems, such as high adverse reaction rates and low immunization protection rates, have led to the widespread use of embryo avian vaccines. Thus, there has long been a pressing need for a highly immunogenic rabies vaccine that can be safely and effectively used at low doses for primary immunization and prevention after rabies exposure.16 Development of mRNA rabies vaccines Zixin Fang, Pengcheng Yu , and Wuyang Zhu National Institute for Viral Disease Control and Prevention, China CDC, Key Laboratory of Biosafety, National Health Commission, Beijing, People’s Republic of China
RkJQdWJsaXNoZXIy OTc5MDU=