A lipidated peptide of Mycobacterium tuberculosis resuscitates the protective efficacy of BCG vaccine by evoking memory T cell immunity

• Published in: Journal of translational medicine Vol. 15; no. 1; p. 201
• Main Authors: Rai, Pradeep K, Chodisetti, Sathi Babu, Zeng, Weiguang, Nadeem, Sajid, Maurya, Sudeep K, Pahari, Susanta, Janmeja, Ashok K, Jackson, David C, Agrewala, Javed N
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 06-10-2017; BioMed Central; BMC
• Subjects: Animals; Antigen-Presenting Cells - metabolism; Antigens; Apoptosis; Bacillus; Bacillus Calmette-Guerin vaccine; BCG; BCG Vaccine - immunology; Causes of; CD4 antigen; Cell culture; Cell Proliferation - drug effects; Cytokines; Enzyme-linked immunosorbent assay; Exhaustion; Female; Growth factors; Helper cells; Hemagglutinins; Humans; Immune response; Immunity; Immunity - drug effects; Immunologic Memory - drug effects; Immunological memory; Infections; Influenza; Interferon; L91; Lipids - chemistry; Long term memory; Lungs; Lymphocyte Activation - drug effects; Lymphocytes; Lymphocytes T; Memory cells; Mice; Mice, Inbred BALB C; Mtb; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - immunology; NF-kappa B - metabolism; Nitric Oxide Synthase Type II - metabolism; PD-1 protein; Peptides; Peptides - pharmacology; Phenotype; Protective Agents - pharmacology; Receptors, Chemokine - metabolism; Studies; Surface markers; T cells; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; Th1; Th1 Cells - drug effects; Th1 Cells - immunology; Th17 Cells - drug effects; Th17 Cells - immunology; Tuberculosis; Tuberculosis - immunology; Tuberculosis - microbiology; Tumor necrosis factor; Vaccination; Vaccine; Vaccines; Viruses; L91; BCG; Memory T cells; Mtb; Vaccine; Th1; Th17; TB
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-017-1301-x

The current BCG vaccine induces only short-term protection against Mycobacterium tuberculosis (Mtb), suggesting its failure to generate long-lasting memory T cells. Previously, we have demonstrated that a self-adjuvanting peptide of Mtb (L91), successfully generated enduring memory Th1 cells. Consequently, we investigated if L91 was able to recuperate BCG potency in perpetuating the generation of memory T cells and protection against Mtb infected mice.
In the present study, we evaluated the potency of a self adjuvanting Mtb peptide vaccine L91 in invigorating BCG immune response against Mtb in mice. Female BALB/c mice were immunized with BCG. Later, they were boosted twice with L91 or an antigenically irrelevant lipidated influenza virus hemagglutinin peptide (LH). Further, PBMCs obtained from BCG vaccinated healthy subjects were cultured in vitro with L91. T cell responses were determined by surface markers and intracellular cytokine staining. Secretion of cytokines was estimated in the culture supernatants (SNs) by ELISA.
Compared to the BCG-vaccinated controls, L91 booster significantly enhanced the percentage of memory Th1 cells and Th17 cells and reduced the mycobacterial burden in BCG primed and L91-boosted (BCG-L91) group, even after 229 days of BCG vaccination. Further, substantial augmentation in the central (CD44
CD62L
CD127
) and effector memory (CD44
CD62L
CD127
) CD4 T cells was detected. Furthermore, greater frequency of polyfunctional Th1 cells (IFN-γ
TNF-α
) and Th17 cells (IFN-γ
IL-17A
) was observed. Importantly, BCG-L91 successfully prevented CD4 T cells from exhaustion by decreasing the expression of PD-1 and Tim-3. Additionally, augmentation in the frequency of Th1 cells, Th17 cells and memory CD4 T cells was observed in the PBMCs of the BCG-vaccinated healthy individuals following in vitro stimulation with L91.
Our study demonstrated that L91 robustly reinvigorate BCG potency to invoke enduring protection against Mtb. This novel vaccination stratagem involving BCG-priming followed by L91-boosting can be a future prophylactic measure to control TB.