Intranasal multivalent adenoviral-vectored vaccine protects against replicating and dormant M.tb in conventional and humanized mice

Afkhami, S.; D'Agostino, M.R.; Vaseghi-Shanjani, M.; Lepard, M.; Yang, J.X.; Lai, R.; ... ; Xing, Z. (2023)

Article / Letter to editor

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.

• All authors: Afkhami, S.; D'Agostino, M.R.; Vaseghi-Shanjani, M.; Lepard, M.; Yang, J.X.; Lai, R.; Choi, M.W.Y.; Chacon, A.; Zganiacz, A.; Franken, K.L.M.C.; Ertl, H.C.; Ottenhoff, T.H.M.; Jeyanathan, M.; Gillgrass, A.; Xing, Z.
• Date: 2023-02-23
• Journal: npj Vaccines
• Volume: 8
• Issue: 1
• DOI: doi:10.1038/s41541-023-00623-z