Reverse genetics of rabies virus: new strategies to attenuate virus virulence for vaccine development

Abstract

Rabies is an ancient neurological disease that is almost invariably fatal once the clinical symptoms develop. Currently, prompt wound cleansing after exposing to a potentially rabid animal and vaccination using rabies vaccine combined with administration of rabies immune globulin are the only effective methods for post-exposure prophylaxis against rabies. Reverse genetic technique is a novel approach to investigate the function of a specific gene by analyzing the phenotypic effects through directly manipulating the gene sequences. It has revolutionized and provided a powerful tool to study the molecular biology of RNA viruses and has been widely used in rabies virus research. The attenuation of rabies virus virulence is the prerequisite for rabies vaccine development. Given the current challenge that sufficient and affordable high-quality vaccines are limited and lacking for global rabies prevention and control, highly cell-adapted, stable, and attenuated rabies viruses with broad cross-reactivity against different viral variants are ideal candidates for consideration to meet the need for human rabies control in the future. A number of approaches have been pursued to reduce the virulence of the virus and improve the safety of rabies vaccines. The application of reverse genetic technique has greatly advanced the engineering of rabies virus and paves the avenue for utilizing rabies virus for vaccine against rabies, viral vectors for exogenous antigen expression, and gene therapy in the future.

Research Advances on the Interactions between Rabies Virus Structural Proteins and Host Target Cells: Accrued Knowledge from the Application of Reverse Genetics Systems

“…progress in reverse genetics systems to better understand viral pathogenic mechanisms and to develop novel biologics [6][7][8][9][10].…”

“…These five structural proteins work together to regulate viral replication, transcription, infection, and evasion of the host immune response. The aim of this study is to summarize the interactions between RABV structural proteins and host cells and to review the progress in reverse genetics systems to better understand viral pathogenic mechanisms and to develop novel biologics [6][7][8][9][10].…”

Rabies Control and Treatment: From Prophylaxis to Strategies with Curative Potential

“…To further increase immunogenicity and address the safety issues associated with a live-attenuated RABV-based vaccine, several strategies have been employed, such as the construction of a replication-deficient virus, targeting specific viral genes, and the insertion of proinflammatory cytokines/chemokines into the viral backbone, using reverse genetic techniques to engineer the RABV genome. These strategies are briefly summarized in Table 2 [9]. …”

“…While a number of excellent reviews have been written focusing on reverse genetics of negative-strand RNA viruses, the biology of RABV, rabies vaccines, and the pathology and prophylaxis of rabies [6,7,8,9,10], this review rectifies the lack of focus on current strategies that have been evaluated for prevention or as PEP of rabies. This review places particular emphasis on the most promising approaches using live-attenuated and/or recombinant vaccine platforms for preventive vaccinations.…”

Expressão do ectodomínio da glicoproteína do vírus da raiva em células de inseto (>i<Drosophila melanogaster>/i< Schneider 2)

“…Apesar de todo conhecimento acumulado e todos os avanços em torno da tentativa de contenção da doença, muito ainda precisa ser feito, visto que o contágio pelo lissavírus da raiva (RABV) atinge desde mamíferos silvestres e domésticos até humanos (60.000 mortes humanas/ano no mundo) (FAO, 2018;WALLACE et al, 2017;GENZ et al, 2012;ERTL, 2009). Embora as vacinas clássicas contra a raiva sejam eficientes ainda existe o interesse em se desenvolver novas tecnologias para obtenção de vacinas mais imunogênicas, aperfeiçoando o processo de produção e visando o desenvolvimento tecnológico com justificativa em fatores como biossegurança e eficiência vacinal (ZHU et al, 2015;SAKAMOTO et al, 1999).…”