Immunization of Mice with a Recombinant Adenovirus Vaccine Inhibits the Early Growth of Mycobacterium tuberculosis After Infection

Abstract

BackgroundIn pulmonary Mycobacterium tuberculosis (Mtb) infection, immune responses are delayed compared to other respiratory infections, so that antigen-specific cells are not detected in the lungs earlier than day 14. Even after parenteral immunization with Bacille Calmette Guerin (BCG) or a subunit vaccine, the immune response after Mtb challenge is only slightly accelerated and the kinetics of pulmonary Mtb growth do not differ between naïve and immunized animals up to day 14.Methods and FindingsMice were immunized intranasally with a recombinant adenovirus expressing mycobacterial antigen 85A (Ad85A), challenged by aerosol with Mtb and the kinetics of Mtb growth in the lungs measured. Intranasal immunization with Ad85A inhibits Mtb growth in the early phase of infection, up to day 8. Protection is sustained for at least 7 months and correlates with the presence of antigen-specific activated effector CD8 T cells in the lungs. Antigen 85A-specific T cells respond to antigen presenting cells from the lungs of mice immunized with Ad85A 23 weeks previously, demonstrating the persistence of antigen in the lungs.Conclusions/SignificanceIntranasal immunization with Ad85A can inhibit early growth of Mtb because it establishes a lung antigen depot and maintains an activated lung-resident lymphocyte population. We propose that an optimal immunization strategy for tuberculosis should aim to induce both lung and systemic immunity, targeting the early and late phases of Mtb growth.

CXCR6 Is a Marker for Protective Antigen-Specific Cells in the Lungs after Intranasal Immunization against Mycobacterium tuberculosis

“…immunization with Ad85A. BALB/c mice immunized with Ad85A i.n., but not i.d., showed a statistically significant reduction in mycobacterial load following pulmonary M. tuberculosis challenge (Table 1) (26,40). Since microarray analysis of CD8 T cells isolated from the lungs of mice immunized with Ad85A i.n.…”

“…Mice were immunized with a recombinant replication-deficient adenovirus of serotype 5 containing the 85A antigen of M. tuberculosis (Ad85A) (40). For i.d.…”

“…We and others have shown that this is the case (13,40,52). When BALB/c mice are immunized intranasally (i.n.)…”

“…When BALB/c mice are immunized intranasally (i.n.) with a replication-deficient recombinant adenovirus expressing antigen 85A of M. tuberculosis (Ad85A), a large population of lung-resident antigen-specific CD8 T cells is established, and when these mice are challenged with M. tuberculosis, mycobacterial growth is inhibited during the first 7 days after infection (40). The lung-resident antigen-specific cells are highly activated, and many are within the bronchoalveolar lavage (BAL)-recoverable compartment (20).…”

“…or intramuscularly (i.m.) does not protect against pulmonary challenge with M. tuberculosis, despite inducing a large population of splenic antigen-specific CD8 T cells, as well as the entry of T cells into lung tissues, but not the BAL-recoverable population (40,42). To identify differences between lung CD8 T cells induced by protective (i.n.)…”