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- Title
Intranasal multivalent adenoviral-vectored vaccine protects against replicating and dormant M.tb in conventional and humanized mice.
- Authors
Afkhami, Sam; D'Agostino, Michael R.; Vaseghi-Shanjani, Maryam; Lepard, Madeleine; Yang, Jack X.; Lai, Rocky; Choi, Margaret Wa Yan; Chacon, Alexis; Zganiacz, Anna; Franken, Kees L. M. C.; Ertl, Hildegund C.; Ottenhoff, Tom H. M.; Jeyanathan, Mangalakumari; Gillgrass, Amy; Xing, Zhou
- Abstract
Viral-vectored vaccines are highly amenable for respiratory mucosal delivery as a means of inducing much-needed mucosal immunity at the point of pathogen entry. Unfortunately, current monovalent viral-vectored tuberculosis (TB) vaccine candidates have failed to demonstrate satisfactory clinical protective efficacy. As such, there is a need to develop next-generation viral-vectored TB vaccine strategies which incorporate both vaccine antigen design and delivery route. In this study, we have developed a trivalent chimpanzee adenoviral-vectored vaccine to provide protective immunity against pulmonary TB through targeting antigens linked to the three different growth phases (acute/chronic/dormancy) of Mycobacterium tuberculosis (M.tb) by expressing an acute replication-associated antigen, Ag85A, a chronically expressed virulence-associated antigen, TB10.4, and a dormancy/resuscitation-associated antigen, RpfB. Single-dose respiratory mucosal immunization with our trivalent vaccine induced robust, sustained tissue-resident multifunctional CD4+ and CD8+ T-cell responses within the lung tissues and airways, which were further quantitatively and qualitatively improved following boosting of subcutaneously BCG-primed hosts. Prophylactic and therapeutic immunization with this multivalent trivalent vaccine in conventional BALB/c mice provided significant protection against not only actively replicating M.tb bacilli but also dormant, non-replicating persisters. Importantly, when used as a booster, it also provided marked protection in the highly susceptible C3HeB/FeJ mice, and a single respiratory mucosal inoculation was capable of significant protection in a humanized mouse model. Our findings indicate the great potential of this next-generation TB vaccine strategy and support its further clinical development for both prophylactic and therapeutic applications.
- Subjects
MICE; COMBINED vaccines; MYCOBACTERIUM tuberculosis; VACCINES; VACCINATION; TUBERCULOSIS; IMMUNOGLOBULINS
- Publication
NPJ Vaccines, 2023, Vol 8, Issue 1, p1
- ISSN
2059-0105
- Publication type
Article
- DOI
10.1038/s41541-023-00623-z