Intrapulmonary (i.pulmon.) Pull Immunization With the Tuberculosis Subunit Vaccine Candidate H56/CAF01 After Intramuscular (i.m.) Priming Elicits a Distinct Innate Myeloid Response and Activation of Antigen-Presenting Cells Than i.m. or i.pulmon. Prime Immunization Alone

Abstract

Understanding the in vivo fate of vaccine antigens and adjuvants and their safety is crucial for the rational design of mucosal subunit vaccines. Prime and pull vaccination using the T helper 17-inducing adjuvant CAF01 administered parenterally and mucosally, respectively, has previously been suggested as a promising strategy to redirect immunity to mucosal tissues. Recently, we reported a promising tuberculosis (TB) vaccination strategy comprising of parenteral priming followed by intrapulmonary (i.pulmon.) mucosal pull immunization with the TB subunit vaccine candidate H56/CAF01, which resulted in the induction of lung-localized, H56-specific T cells and systemic as well as lung mucosal IgA responses. Here, we investigate the uptake of H56/CAF01 by mucosal and systemic innate myeloid cells, antigen-presenting cells (APCs), lung epithelial cells and endothelial cells in mice after parenteral prime combined with i.pulmon. pull immunization, and after parenteral or i.pulmon. prime immunization alone. We find that i.pulmon. pull immunization of mice with H56/CAF01, which are parenterally primed with H56/CAF01, substantially enhances vaccine uptake and presentation by pulmonary and splenic APCs, pulmonary endothelial cells and type I epithelial cells and induces stronger activation of dendritic cells in the lung-draining lymph nodes, compared with parenteral immunization alone, which suggests activation of both innate and memory responses. Using mass spectrometry imaging of lipid biomarkers, we further show that (i) airway mucosal immunization with H56/CAF01 neither induces apparent local tissue damage nor inflammation in the lungs, and (ii) the presence of CAF01 is accompanied by evidence of an altered phagocytic activity in alveolar macrophages, evident from

An Overview of the Development of New Vaccines for Tuberculosis

“…It is a combination of Ag85B, ESAT-6, and Rv660c. In a recent preclinical trial, the vaccine H56: CAF01 has shown activation of both innate and adaptive immunity in mice [ 48 ]. This study and others showed hope for new subunit delivery strategies [ 49 ].…”

Intrapulmonary vaccination with delta-inulin adjuvant stimulates non-polarised chemotactic signalling and diverse cellular interaction

“…2). The sustained presence of adjuvant following delivery has also been previously characterised for spray-dried H56/CAF01, which is present within the lungs 14 days following pulmonary vaccination, 30 and Alum-adjuvanted vaccines which have detectable aluminium in tissue up to 9 months following subcutaneous or intramuscular delivery. 31 Given the delicate nature of the respiratory mucosa, the persistence of adjuvant may be concerning in its potential to induce prolonged local inflammation.…”

“…17 While the dynamics of leucocyte responses to parenteral adjuvant administration have been characterised, there are few detailed analyses of innate immune cell recruitment, uptake and activation induced by pulmonary adjuvant candidates and greater understanding in this area is still required. [18][19][20] In the present study, fluorescein-conjugated Advax was administered intratracheally (i.t.) either alone or with the CysVac2 fusion protein, a TB vaccine candidate that is highly immunogenic and protective in pre-clinical studies and generates enhanced protection when administered as a pulmonary vaccine.…”

Advancing Adjuvants for Mycobacterium tuberculosis Therapeutics

“…Naturally-derived carbohydrate particles such as delta inulin (Advax), chitosan, and Bacillus subtilis spores have all been utilised as mucosal adjuvants in TB vaccine candidates, all producing a Th 1 /Th 17 phenotype alongside increased pulmonary IgA (37,(114)(115)(116). CAF01 has been tested intranasally and has also been spray-dried for intrapulmonary administration (107). Th 17 immunity is often achieved via mode of administration, as it has been observed across multiple vaccine platforms that mucosal vaccination, particularly intranasal, favours Th 17 differentiation (117,118).…”

“…These important innate immune effector cells can be uniquely targeted via intranasal and/or intrapulmonary vaccination. Several groups have explored a “prime-pull” strategy which takes advantage of both parenteral vaccine (prime) and mucosal vaccine boost (pull) to direct antigen-specific T RM to the lungs ( 107 , 108 ).…”