Abstract
Tuberculosis (TB), induced by Mycobacterium tuberculosis (Mtb) infection, remains a top killer among infectious diseases. While Bacillus Calmette-Guerin (BCG) is the sole TB vaccine, the clumped-clustered features of BCG in intradermal immunization appear to limit both the BCG protection efficacy and the BCG vaccination safety. We hypothesize that engineering of clumped-clustered BCG into nanoscale particles would improve safety and also facilitate the antigen-presenting-cell (APC)’s uptake and the following processing/presentation for better anti-TB protective immunity. Here, we engineered BCG protoplasts into nanoscale membraned BCG particles, termed as “BCG-Nanocage” to enhance the anti-TB vaccination efficiency and safety. BCG-Nanocage could readily be ingested/taken by APC macrophages selectively; BCG-Nanocage-ingested macrophages exhibited better viability and developed similar antimicrobial responses with BCG-infected macrophages. BCG-Nanocage, like live BCG bacilli, exhibited the robust capability to activate and expand innate-like T effector cell populations of Vγ2+ T, CD4+ T and CD8+ T cells of rhesus macaques in the ex vivo PBMC culture. BCG-Nanocage immunization of rhesus macaques elicited similar or stronger memory-like immune responses of Vγ2Vδ2 T cells, as well as Vγ2Vδ2 T and CD4+/CD8+ T effectors compared to live BCG vaccination. BCG-Nanocage- immunized macaques developed rapidly-sustained pulmonary responses of Vγ2Vδ2 T cells upon Mtb challenge. Furthermore, BCG- and BCG-Nanocage- immunized macaques, but not saline controls, exhibited undetectable Mtb infection loads or TB lesions in the Mtb-challenged lung lobe and hilar lymph node at endpoint after challenge. Thus, the current study well justifies a large pre-clinical investigation to assess BCG-Nanocage for safe and efficacious anti-TB vaccination, which is expected to further develop novel vaccines or adjuvants.Graphical
Highlights
Tuberculosis (TB), induced by Mycobacterium tuberculosis (Mtb) infection, remains one of the top killers among infectious diseases world widely with 1.5 million deaths in 2020 as reported by the global tuberculosis report 2021
Development and characterization of nanoparticle‐like Bacillus Calmette-Guerin (BCG)‐Nanocage from microscale Bacillus Calmette‐Guerin (BCG) Presumably Nano-sized biomaterials are more readily ingested by antigen-presenting cells (APC) (e.g. Dentric cell (DC) and macrophages (MΦ)) than micro-sized biomaterials or clumped aggregates, and more effectively activate/differentiate T cells for robust effector functions and protection [36, 37]
To generate BCG-Nanocage, the outer membrane of BCG was deleted by treatment with EDTA and β-mercaptoethanol for lipopolysaccharide removal and disulfide bond destruction of membrane proteins, which would improve the sensitivity of BCG against lysozyme lysis (Fig. 1A)
Summary
Tuberculosis (TB), induced by Mycobacterium tuberculosis (Mtb) infection, remains one of the top killers among infectious diseases world widely with 1.5 million deaths in 2020 as reported by the global tuberculosis report 2021. Despite global efforts to halt the spread of TB, the lack of an effective vaccine, limited cure rates for drugresistant Mtb (MDR-TB), and HIV/AIDS co-infection make TB remain a leading global public health threat [1]. Bacille Calmette-Guerin (BCG), a live attenuated form of Mycobacterium bovis, is widely used as the only vaccine against TB in newborn babies in most of countries [2]. There are several hypotheses to explain the limitation or failure of BCG vaccinations to mount more effective protection against pulmonary TB [6], the exact mechanisms underlying this insufficient protection efficacy of BCG vaccination remain largely unclear
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
