Mucosal delivery of a multistage subunit vaccine promotes development of lung-resident memory T cells and affords interleukin-17-dependent protection against pulmonary tuberculosis

Counoupas, Claudio; Ferrell, Kia C.; Ashhurst, Anneliese S.; Bhattacharyya, Nayan D.; Nagalingam, Gayathri; Stewart, Erica L.; Feng, Carl G.; Petrovsky, Nikolai; Britton, Warwick J.; Triccas, James A.

doi:10.1038/s41541-020-00255-7

Cited by 57 publications

(88 citation statements)

References 46 publications

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“…Despite these differences, the level of protection conferred was equal across the different delivery methods ( 51 ). In a recent study, protection conferred by intra-tracheal administration of the fusion protein TB vaccine candidate, CysVac2, was associated with the induction of higher levels of antigen-specific CD4 + lung T RM , expressing IL-17, and RORγT ( 52 ).…”

Section: Adaptive Pulmonary Immunitymentioning

confidence: 99%

Local Pulmonary Immunological Biomarkers in Tuberculosis

Morrison

McShane

2021

Front. Immunol.

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Regardless of the eventual site of disease, the point of entry for Mycobacterium tuberculosis (M.tb) is via the respiratory tract and tuberculosis (TB) remains primarily a disease of the lungs. Immunological biomarkers detected from the respiratory compartment may be of particular interest in understanding the complex immune response to M.tb infection and may more accurately reflect disease activity than those seen in peripheral samples. Studies in humans and a variety of animal models have shown that biomarkers detected in response to mycobacterial challenge are highly localized, with signals seen in respiratory samples that are absent from the peripheral blood. Increased understanding of the role of pulmonary specific biomarkers may prove particularly valuable in the field of TB vaccines. Here, development of vaccine candidates is hampered by the lack of defined correlates of protection (COPs). Assessing vaccine immunogenicity in humans has primarily focussed on detecting these potential markers of protection in peripheral blood. However, further understanding of the importance of local pulmonary immune responses suggests alternative approaches may be necessary. For example, non-circulating tissue resident memory T cells (TRM) play a key role in host mycobacterial defenses and detecting their associated biomarkers can only be achieved by interrogating respiratory samples such as bronchoalveolar lavage fluid or tissue biopsies. Here, we review what is known about pulmonary specific immunological biomarkers and discuss potential applications and further research needs.

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Section: Adaptive Pulmonary Immunitymentioning

confidence: 99%

Local Pulmonary Immunological Biomarkers in Tuberculosis

Morrison

McShane

2021

Front. Immunol.

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“…14,15 In recent pre-clinical studies, it has been demonstrated that Advax as a mucosal adjuvant generates systemic and mucosal antibody responses and enhances T cell mediated responses. 13,16 There is increasing interest in delineating the exact mechanism of adjuvants in clinical use, for example by studying innate immune cell interactions with fluorescently-conjugated adjuvants. 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.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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There is an urgent need for novel vaccination strategies to combat respiratory pathogens. Mucosal vaccine delivery is an attractive option as it directly targets the site of infection; however, preclinical development has been hindered by a lack of suitable mucosal adjuvants and a limited understanding of their immune effects in the lung environment. Herein, we define the early immune events following the intrapulmonary delivery of a vaccine incorporating the adjuvant delta-inulin. Analysis of the early inflammatory response showed vaccine-induced innate cell recruitment to lungs and local lymph nodes (LN) was transient and non-polarised, correlating with an increase in pulmonary chemotactic factors. Use of fluorescently labelled adjuvant revealed widespread tissue dissemination of adjuvant particles, coupled with broad cellular uptake and transit to the lung-draining LN by a range of innate immune cells. Mass cytometric analysis revealed extensive phenotypic changes in innate and adaptive cell subsets induced by vaccination; this included identification of unconventional lymphocytes such as γδ-T cells and MAIT cells that increased following vaccination and displayed an activated phenotype. This study details a comprehensive view of the immune response to intrapulmonary adjuvant administration and provides pre-clinical evidence to support delta-inulin as a suitable adjuvant for pulmonary vaccines.

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“…Advax is based on plant-derived inulin, a polysaccharide that when formulated into delta inulin particles and co-administered with subunit antigens, induces Ag-specific Th1, Th2 and Th17 T cell responses (10)(11)(12). Amongst its immunological effects, Advax TM induces a strong chemotactic effect, resulting in the recruitment of leukocytes to the site of vaccination, and engenders vaccine-induced protection against viral and bacterial pathogens (10)(11)(12)(13)(14)(15)(16)(17)(18). Advax has not been previously investigated in fungal vaccines.…”

Section: Introductionmentioning

confidence: 99%

“…Formulating Advax with TLR agonists enables additional modulation of T cell phenotypes, that may further enhance protective immunity. For example, formulation of the recombinant fusion protein, CysVac containing Ag85B and CysD, with Advax and the TLR9 agonist, CpG, drove an Ag-specific Th1 and Th17 cell response and provided superior protection against aerosol Mycobacterium tuberculosis infection(13).…”

Section: Introductionmentioning

confidence: 99%

Combination adjuvants enhance recombinant protein vaccine protection against fungal infection

Wuethrich

Dobson²,

Taira³

et al. 2021

Preprint

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The development of effective vaccines against fungal infections requires the induction of protective, pathogen-specific cell mediated immune responses. Here, we asked whether combination adjuvants based on delta inulin (Advax) formulated with TLR agonists could improve vaccine protection mediated by a fungal recombinant protein, Bl-Eng2, which itself harbors an immunodominant antigen and Dectin-2 agonist/adjuvant. We found that Bl-Eng2 formulated with Advax3 containing TLR9 agonist or Advax8, containing TLR4 agonist, provided the best protection against pulmonary infection with Blastomyces dermatitidis, being more effective than Freunds complete adjuvant or Adjuplex. Advax3 was most efficient in inducing IFN-γ and IL-17 producing antigen-specific T cells that migrated to the lung upon Blastomyces dermatitidis infection. Mechanistic studies revealed Bl-Eng2/Advax3 protection was tempered by neutralization of IL-17 and particularly IFN-γ. Likewise, greater numbers of lung-resident T cells producing IFN-γ, IL-17, or IFN-γ and IL-17+ correlated with fewer fungi recovered from lung. Protection was maintained after depletion of CD4+ T cells, partially reduced by depletion of CD8+ T cells, and completely eliminated after depletion of both CD4+ and CD8+ T cells. We conclude that Bl-Eng2 formulated with Advax3 is promising for eliciting vaccine-induced antifungal immunity, through a previously uncharacterized mechanism involving CD8+ and also CD4+ T cells producing IFN-γ and/or IIL-17. Although no licensed vaccine exists as yet against any fungal disease, these findings indicate the importance of adjuvant selection for the development of effective fungal vaccines.

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Mucosal delivery of a multistage subunit vaccine promotes development of lung-resident memory T cells and affords interleukin-17-dependent protection against pulmonary tuberculosis

Cited by 57 publications

References 46 publications

Local Pulmonary Immunological Biomarkers in Tuberculosis

Local Pulmonary Immunological Biomarkers in Tuberculosis

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

Combination adjuvants enhance recombinant protein vaccine protection against fungal infection

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