Abstract
Tuberculosis (TB) is one of the deadliest infectious diseases worldwide and is caused by Mycobacterium tuberculosis (Mtb). An effective vaccine to prevent TB is considered the most cost-effective measure for controlling this disease. Many different vaccine antigen (Ag) candidates, including well-known and newly identified Ags, have been evaluated in clinical and preclinical studies. In this study, we took advantage of a plant system of protein expression using Nicotiana benthamiana to produce N-glycosylated antigen 85A (G-Ag85A), which is one of the most well-characterized vaccine Ag candidates in the field of TB vaccines, and compared its immunogenicity and vaccine efficacy with those of nonglycosylated Ag85A (NG-Ag85A) produced with an Escherichia coli system. Notably, G-Ag85A induced a more robust IFN-γ response than NG-Ag85A, which indicated that G-Ag85A is well recognized by the host immune system during Mtb infection. We subsequently compared the vaccine potential of G-Ag85A and NG-Ag85A by evaluating their immunological features and substantial protection efficacies. Interestingly, G-Ag85A yielded moderately enhanced long-term protective efficacy, as measured in terms of bacterial burden and lung inflammation. Strikingly, G-Ag85A-immunized mice showed a more balanced proportion of multifunctional Th1-biased immune responses with sustained IFN-γ response than did NG-Ag85A-immunized mice. Collectively, plant-derived G-Ag85A could induce protective and balanced Th1 responses and confer long-term protection against a hypervirulent Mtb Beijing strain infection, which indicated that plant-produced G-Ag85A might provide an excellent example for the production of an Mtb subunit vaccine Ag and could be an effective platform for the development of anti-TB vaccines.
Highlights
Tuberculosis (TB), which is caused by Mycobacterium tuberculosis (Mtb), remains a major infectious threat with high morbidity and mortality worldwide [1], and as a result, researchers continually aim to develop effective vaccines against TB
We decided to use N. benthamiana as the host for the production of Ag85A in plants, and we compared the Ag85A produced in N. benthamiana with that expressed in E. coli
An helical linker (HL) was introduced between CBM3 and the enterokinase cleavage site to facilitate the access of enterokinase to the target site
Summary
Tuberculosis (TB), which is caused by Mycobacterium tuberculosis (Mtb), remains a major infectious threat with high morbidity and mortality worldwide [1], and as a result, researchers continually aim to develop effective vaccines against TB. Antigen (Ag) targets and vaccine platforms have been developed to improve the Mtb vaccine [3,4] These efforts have yielded many results, some of which include optimistic outcomes in the clinical phase, but more diverse and dynamic pipelines are needed [5]. In 2018, two multi-Ag subunit vaccines against TB that induce Ag-specific multifunctional CD4+ T cell responses demonstrated promising results in clinical efficacy trials [6,7]. These vaccine candidates contain highly immunogenic Ags, such as PPE18 and Ag85B [6,7]. The yeast expression system is safe but produces a low yield [9]
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