Intranasal Vaccination with Mannosylated Chitosan Formulated DNA Vaccine Enables Robust IgA and Cellular Response Induction in the Lungs of Mice and Improves Protection against Pulmonary Mycobacterial Challenge

Abstract

Induction of specific humoral and cellular immunity in the lung airways is proposed to be critical for vaccine protection against Mycobacterium tuberculosis (M. tb). To facilitate airway delivery and antigen targeting to the antigen presenting cells in the alveoli, we employed mannosylated chitosan (MCS) to formulate a multi-T-epitope DNA vaccine, pPES, as an intranasal TB vaccine. MCS-DNA nanoparticles appeared spherical with the average particle sizes as 400 nm. HSP65-specific bronchoalveolar lavage fluid SIgA level was significantly elevated by 4 doses of MCS-pPES intranasal immunization as compared to chitosan (CS)-DNA and BCG vaccine. I.n. immunization with MCS-DNA induced a modest peptide-specific Th1(IFN-γ, TNF-α, and IL-2) response in the spleen, while a potent poly-functional CD4+ T response that largely produced TNF-α and IFN-γ, as well as IL-2 in the lung, qualitatively better than that induced by CS-DNA and BCG vaccination. Such response by i.n. immunization with MCS-DNA provided improved protection in the lung against airway Mycobacterial bovis BCG challenge over i.n. CS-DNA and DNA, that is comparable to protection achieved by s.c. BCG vaccination. This enhanced protection was correlated with much greater accessibility of DNA particles to the alveolar macrophages in the lung mediated by man-chitosan. Thus, man-chitosan TB vaccine represents a promising vaccine platform capable of eliciting robust multi-functional T response in the lung mucus and achieving enhanced mucosal immune protection against pulmonary TB.

Dual-Isotope SPECT/CT Imaging of the Tuberculosis Subunit Vaccine H56/CAF01: Induction of Strong Systemic and Mucosal IgA and T-Cell Responses in Mice Upon Subcutaneous Prime and Intrapulmonary Boost Immunization

“…In line with this, passive protection by mucosally administered human IgA antibodies against Mtb infection in the lungs of mice has been reported ( 81 , 82 ). Recently, vaccine-induced pulmonary secretory IgA has been associated with immunological protection against TB in mice ( 17 , 83 ). Given the fact that antibodies are protective against many intracellular infections, further studies are required to verify the functional differences in antibodies to Mtb and the precise role of mucosal antibodies in the immunological protection against TB ( 84 ).…”

Nanoparticle-Based Vaccines Against Respiratory Viruses

“…This observation correlated closely with the reduced lung pathology and the substantial clearance of the virus from the animal lungs. Other polymeric nanoparticles, such as chitosan, a natural polymer composed of randomly distributed β-(1-4)-linked d-glucosamine and N-acetyl-d-glucosamine, and N-(2-hydroxypropyl)methacrylamide/N-isopropylacrylamide (HPMA/NIPAM), were also investigated as intranasal vaccines against respiratory viruses (85)(86)(87)(88)(89)(90)(115)(116)(117)(118)(119)(120)(121). Overall, polymeric nanoparticles have many advantages, including biocompatibility (122), antigen encapsulation and stabilization (123,124), controlled release of antigens and intracellular persistence in APCs (125,126), pathogen-like characteristics, and suitability for intranasal administration (126,127).…”

Engineered Nanodelivery Systems to Improve DNA Vaccine Technologies

“…The surface of DCs and macrophages express large quantities of mannose receptors and are thus easily targeted by decorating the surface of NPs with mannose structures [43]. In one study, a multi-T epitope DNA vaccine against Mycobacterium tuberculosis was developed using mannosylated chitosan NPs as the delivery vector [44]. The results indicated effective targeting of macrophages, which aligned with the potent induction of antigen-specific T-cell responses, as shown in Figure 4.…”

“…***p < 0.001. Reprinted from[44], which is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/).…”