Live bacterial vaccine vector and delivery strategies of heterologous antigen: A review
Introduction
An ideal vaccine vector should not only enable trigger potent innate but also adaptive immune responses in inoculated host. Using live bacterial as vector to deliver heterologous antigen is an effective and original alternative for developing a new vaccine. The immunostimulatory capacity of live microorganisms makes it extremely efficient system for induction of long-term and specific immune responses against heterologous antigens. Besides expression and delivery of target antigens, the natural properties of these live microorganisms enable them to act as effective immune adjuvants. For example, the characteristic about intracellular transmission of Listeria monocytogenes (Lm) make this microorganism uniquely suitable for processing as a live bacterial vaccine vector to induce cellular immunologic response against infectious diseases and cancer [1]; the intestinal adhesion of lactic acid bacteria (LAB) play a key role in producing bioactive metabolites to maintain gastrointestinal ecological balance [2].
Although there are many advantages involved in viewing live bacterial as an alternative system for the delivery of heterologous molecules applications, certain problems must also be resolved before the use of these live microorganisms can be applied in the field. There are many safe issues regarding the use of live bacterial and their potential release for human consumption, such the risk of genetically modified organisms (GMOs) persistence in the host and environment. However, preclinical results supporting potential risks of live bacterial vaccine are predictable, and current strategies to delivery heterologous antigen are diversified, such as bacterial surface display system, bacterial secretion system and balanced lethal vector system. The form of immunogen expression and delivery has a crucial impact on the quality and level of the immune response of the inoculated host. Hence, we should select suitable bacterial vaccine vector and corresponding heterologous antigen delivery system according to different diseases. This review attempts to compare the development of representative live bacterial vectors, and summarize the main characterizations of the various delivery strategies of heterologous antigen in live bacterial vector. Because our review had to be brief, we apologize for not being able to provide a more detailed analysis for all live bacterial vaccine vectors.
Section snippets
Attenuated bacteria as live vaccine vector
William Coley first found that tumor was regressed after the injection of killed bacteria directly in 1893 [[3], [4]]. With the development of immunology, both of cellular and humoral immune response could be stimulated by inoculation of attenuated bacteria to protect host against challenge of corresponding wild pathogens. Further, live-attenuated bacteria, carrying heterologous antigens, are also promising combination vaccine vectors to induce effective immune-mediated protection against other
Lactic acid bacteria (LAB) as mucosal delivery vehicles
Although live-attenuated bacterial is a powerful adjuvant, the certain limitations, such as risk of reversion, and imbalance between immunogenicity and side effects, must also be taken into account. LAB are non-pathogenic, they can overcome some of the limitations of live-attenuated bacteria vaccine vector and are attractive alternative to attenuated bacteria. Moreover, LAB are good candidates for the development of oral vaccines and satisfy the requirements of delivery systems for mucosal
Delivery strategies of heterologous antigen in live bacterial
The form of heterologous antigen expression has a crucial impact on the type and efficiency of immune response of live bacterial vaccine. In most experiments, heterologous antigens are fused into bacterial host by plasmid. However, heterologous proteins expressed from genome site-specific integration are more stable than those expressed by plasmids. Most recombinant plasmids display stability in vitro under antibiotic selective pressure, the plasmid-bearing vaccine strain often degenerates
Conclusions and future directions
Over the past two decades, the research of live bacterial vaccines has shown inspiring progress. A number of live bacterial vectors are proved to be effective tools for application in the field of biotherapy, some of which are currently evaluated in clinical trials. New bacterial vectors, expression strategies of heterologous antigen and immunization routes have significantly raised the feasibility of vaccines based on live bacterial vector platform. In parallel with the development of live
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Conflict of interest
The authors declare that they have no conflict of interest.
Acknowledgments
This study was supported by grants from the Natural Science Foundation of China (NO. 31371776), the Agricultural Science Promotion Plan of Shanghai (2017, NO. 4-4) and the Science and Technology Innovation Plan of Shanghai: Yangtze River Delta Joint Research (NO. 15395810900).
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