Back to Search
Start Over
Novel lipopeptides of ESAT-6 induce strong protective immunity against Mycobacterium tuberculosis: Routes of immunization and TLR agonists critically impact vaccine's efficacy.
- Source :
-
Vaccine [Vaccine] 2016 Nov 04; Vol. 34 (46), pp. 5677-5688. Date of Electronic Publication: 2016 Sep 29. - Publication Year :
- 2016
-
Abstract
- Mycobacterium tuberculosis (Mtb), the bacterial cause of tuberculosis, is a leading infectious agent worldwide. The development of a new vaccine against Mtb is essential to control global spread of tuberculosis, since the current vaccine BCG is not very effective and antibiotic resistance is a serious, burgeoning problem. ESAT-6 is a secreted protein of Mtb, which is absent in BCG but has been implicated in inducing protective immunity against Mtb. Peptide based subunit vaccines are attractive due to their safety and high specificity in eliciting immune responses, but small synthetic peptides are usually not very immunogenic. We have designed a novel subunit vaccine for Mtb by using simple lipid (palmitic acid) modified derivatives of peptides from ESAT-6 protein corresponding to dominant human T cell epitopes and examined their ability to stimulate protective immunity against Mtb by intranasal and subcutaneous immunization in mice. We also investigated how individual TLR agonists as adjuvants (PolyI:C, MPL and GDQ) contribute to enhancing the induced immune responses and resulting protective efficacy of our vaccine. We observed that single C-terminal palmitoyl-lysine modified lipopeptides derived from ESAT-6 induce significant cellular immune responses on their own upon mucosal and subcutaneous immunizations. Intriguingly, a combination of immunogenic lipopeptides of ESAT-6 antigen exhibited local (pulmonary) and systemic immune responses along with efficient protective efficacy when administered intranasally or subcutaneously. Surprisingly, combination of ESAT-6 derived lipopeptides with a TLR-4 agonist (MPL) enhanced protection, whereas TLR-3 (Poly I:C) and TLR-7/8 agonists (gardiquimod, GDQ) led to reduced protection associated with specific local and systemic immune modulation. Our studies demonstrate the potential of ESAT-6 derived lipopeptides as a promising vaccine candidate against Mtb, and emphasize that selection of adjuvant is critical for the success of vaccines. These findings demonstrate the promise of synthetic lipopeptides as the basis of a subunit vaccine for TB.<br /> (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Subjects :
- Adjuvants, Immunologic
Administration, Intranasal
Animals
Antigens, Bacterial chemistry
Bacterial Proteins chemistry
Cytokines biosynthesis
Epitopes, T-Lymphocyte chemistry
Immunity, Cellular
Immunization methods
Lipopeptides administration & dosage
Lipopeptides chemical synthesis
Lipopeptides immunology
Lipoylation
Mice
Palmitic Acid chemistry
Palmitic Acid metabolism
Tuberculosis prevention & control
Tuberculosis Vaccines administration & dosage
Tuberculosis Vaccines adverse effects
Tuberculosis Vaccines chemistry
Vaccines, Subunit administration & dosage
Vaccines, Subunit adverse effects
Vaccines, Subunit chemistry
Vaccines, Subunit immunology
Antigens, Bacterial immunology
Bacterial Proteins immunology
Lipopeptides chemistry
Mycobacterium tuberculosis immunology
Toll-Like Receptors agonists
Tuberculosis Vaccines immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1873-2518
- Volume :
- 34
- Issue :
- 46
- Database :
- MEDLINE
- Journal :
- Vaccine
- Publication Type :
- Academic Journal
- Accession number :
- 27693020
- Full Text :
- https://doi.org/10.1016/j.vaccine.2016.08.075