Single Mucosal, but Not Parenteral, Immunization with Recombinant Adenoviral-Based Vaccine Provides Potent Protection from Pulmonary Tuberculosis

Abstract

Bacillus Calmette-Guérin (BCG) vaccine has failed to control the global tuberculosis (TB) epidemic, and there is a lack of safe and effective mucosal vaccines capable of potent protection against pulmonary TB. A recombinant replication-deficient adenoviral-based vaccine expressing an immunogenic Mycobacterium tuberculosis Ag Ag85A (AdAg85A) was engineered and evaluated for its potential to be used as a respiratory mucosal TB vaccine in a murine model of pulmonary TB. A single intranasal, but not i.m., immunization with AdAg85A provided potent protection against airway Mycobacterium tuberculosis challenge at an improved level over that by cutaneous BCG vaccination. Systemic priming with an Ag85A DNA vaccine and mucosal boosting with AdAg85A conferred a further enhanced immune protection which was remarkably better than BCG vaccination. Such superior protection triggered by AdAg85 mucosal immunization was correlated with much greater retention of Ag-specific T cells, particularly CD4 T cells, in the lung and was shown to be mediated by both CD4 and CD8 T cells. Thus, adenoviral TB vaccine represents a promising novel vaccine platform capable of potent mucosal immune protection against TB. Our study also lends strong evidence that respiratory mucosal vaccination is critically advantageous over systemic routes of vaccination against TB.

Vaccine against tuberculosis: what’s new?

“…AdAg85a is a recombinant strain of replication-deficient adenoviral vector expressing the Mtb Ag85A [33] (Table 1). …”

“…Experimental data showed that it provided potent protection against pulmonary TB infection in mice when administered intranasally, either as priming and as booster vaccine for BCG [33,34]. Intranasal administration enhanced a better protection than intramuscular in both settings [33,34].…”

“…Intranasal administration enhanced a better protection than intramuscular in both settings [33,34]. In guinea pigs, both intranasal and intramuscular vaccination were protective against pulmonary TB infection.…”

Pulmonary Mycobacterial Granuloma

“…1,48,49 Thus, in relation to pulmonary mycobacterial infection, it would be important to examine the immune responses both in the airway lumen, ie, the site of initial infection, and the granuloma, ie, the focal point of bacterial control and a site to which the majority of mycobacteria home. 12,50 The granuloma is composed of a nucleus of infected macrophages along with recruited monocytes, T cells, neutrophils, and NK cells, and it is formed within the lung parenchymal tissue around the vessel and bronchi.…”

Chimeric flagellin expressed by Salmonella typhimurium induces an ESAT-6-specific Th1-type immune response and CTL effects following intranasal immunization

“…immunization with either live BCG or killed-BCG formulated in an adjuvant or recombinant adenovirus-based vaccines has been shown to provide protection against MTB. 8 In addition, i.n. immunization of mice with an adenoviral-based vaccine expressing Ag85A 9 or microparticles encapsulated with ESAT-6 elicited antigen-specific CD4 1 and CD8 1 T cells capable of interferon (IFN)-c production and cytotoxic activity in the airways, lungs and mediastinal lymph nodes.…”