Pulmonary BCG induces lung-resident macrophage activation and confers long-term protection against tuberculosis

Mata, Elena; Tarancón, Raquel; Guerrero, C.; Moreo, Eduardo; Moreau, Flavie; Uranga, Santiago; Gómez, Alberto Gómez; Marinova, Dessislava; Domenech, Mirian; González-Camacho, Fernando; Monzón, Marta; Badiola, Juan José; Domínguez‐Andrés, Jorge; Yuste, José; Anel, Alberto; Peixoto, António; Martı́n, Carlos; Aguiló, Nacho

doi:10.1126/sciimmunol.abc2934

Cited by 36 publications

(40 citation statements)

References 41 publications

(68 reference statements)

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“…The respiratory tract is the natural route of Mtb infection. Therefore, when compared with traditional parenteral routes of vaccination, there is general agreement that mucosal vaccination induces superior protection against Mtb challenge (Goonetilleke et al, 2003;Chen et al, 2004;Wang et al, 2004;Santosuosso et al, 2005;Perdomo et al, 2016;Mata et al, 2021;Ning et al, 2021). The successful formulation and manufacture of the prophylactic TB vaccine (ID93) co-lyophilized with the GLA-SE oil-in-water emulsion adjuvant produced a thermostable, single-vial candidate product that is being evaluated in an ongoing clinical trial as a reconstituted IM vaccine (Kramer et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Development and Testing of a Spray-Dried Tuberculosis Vaccine Candidate in a Mouse Model

et al. 2022

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Converting a vaccine into a thermostable dry powder is advantageous as it reduces the resource burden linked with the cold chain and provides flexibility in dosage and administration through different routes. Such a dry powder presentation may be especially useful in the development of a vaccine towards the respiratory infectious disease tuberculosis (TB). This study assesses the immunogenicity and protective efficacy of spray-dried ID93+GLA-SE, a promising TB vaccine candidate, against Mycobacterium tuberculosis (Mtb) in a murine model when administered via different routes. Four administration routes for the spray-dried ID93+GLA-SE were evaluated along with relevant controls—1) reconstitution and intramuscular injection, 2) reconstitution and intranasal delivery, 3) nasal dry powder delivery via inhalation, and 4) pulmonary dry powder delivery via inhalation. Dry powder intranasal and pulmonary delivery was achieved using a custom nose-only inhalation device, and optimization using representative vaccine-free powder demonstrated that approximately 10 and 44% of the maximum possible delivered dose would be delivered for intranasal delivery and pulmonary delivery, respectively. Spray-dried powder was engineered according to the different administration routes including maintaining approximately equivalent delivered doses of ID93 and GLA. Vaccine properties of the different spray-dried lots were assessed for quality control in terms of nanoemulsion droplet diameter, polydispersity index, adjuvant content, and antigen content. Our results using the Mtb mouse challenge model show that both intranasal reconstituted vaccine delivery as well as pulmonary dry powder vaccine delivery resulted in Mtb control in infected mice comparable to traditional intramuscular delivery. Improved protection in these two vaccinated groups over their respective control groups coincided with the presence of cytokine-producing T cell responses. In summary, our results provide novel vaccine formulations and delivery routes that can be harnessed to provide protection against Mtb infection.

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Section: Discussionmentioning

confidence: 99%

Development and Testing of a Spray-Dried Tuberculosis Vaccine Candidate in a Mouse Model

et al. 2022

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“…In addition to enhancement of Mtb-specific adaptive responses, based on shared antigens, BCG vaccination also leads to changes in hematopoiesis and epigenetic reprogramming of myeloid cells in the bone marrow 7 , early monocyte recruitment and Mtb dissemination 18 , and innate activation of dendritic cells critical for T cell priming 19 . Intranasal BCG vaccination protects against Streptococcus pneumoniae and induces long term activation of AMs 20 . BCG vaccination is also associated with trained immunity effects in humans 21, 22, 23 , including well-described reductions in all-cause neonatal mortality and protection against bladder cancer 3, 24 .…”

Section: Introductionmentioning

confidence: 99%

Exposure tomycobacteriumremodels alveolar macrophages and the early innate response toMycobacterium tuberculosisinfection

Mai¹,

Jahn²,

Murray³

et al. 2022

Preprint

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As innate sentinels in the lung, alveolar macrophages (AMs) play a critical role during Mycobacterium tuberculosis (Mtb) infection as the first cells to encounter bacteria. We previously showed that AMs initially respond to Mtb infection in vivo by mounting a cell-protective, rather than pro-inflammatory response, yet whether the AM response could be modified by environmental factors was unknown. Here, we characterize how previous exposure to mycobacteria, either through subcutaneous vaccination with Mycobacterium bovis (scBCG) or through a contained Mtb infection (coMtb), impacts the initial response by AMs and early innate response in the lung. We find that both scBCG and coMtb accelerate early innate cell activation and recruitment and generate a stronger pro-inflammatory AM response to Mtb in vivo. AMs from scBCG vaccinated mice mount a robust interferon response, while AMs from coMtb mice produce a broader and more diverse inflammatory response. Using single-cell RNA-sequencing, we identify exposure-induced changes to airway-resident cells, with scBCG and coMtb enriching for different AM subpopulations. Ex vivo stimulation assays reveal that AMs from scBCG and coMtb mice switch on an interferon-dependent response, which is absent in AMs from unexposed mice. Overall, our studies reveal significant, durable, and cell-intrinsic modifications to AMs following exposure to mycobacterium, and comparison of scBCG and coMtb models reveals that AMs can be reprogrammed into more than one state. These findings highlight the plasticity of innate responses in the airway and underscore the unexplored potential of targeting AMs through vaccination or host-directed therapy to augment host responses.

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“…BCG administration provides enhanced protection in mice and guinea pigs compared to subcutaneous delivery ( 389 – 391 ). Both the adaptive ( 392 ) and, most recently, trained innate immune responses ( 393 ) have been independently characterized for pulmonary BCG delivery-induced protection. Heat-killed MTBVAC delivered intranasally induces mucosal IgA, IgM, and IgG responses in both mouse and NHP models ( 315 ).…”

Section: Review Of Clinical Stage Vaccine Candidates and Strategiesmentioning

confidence: 99%

It Takes a Village: The Multifaceted Immune Response to Mycobacterium tuberculosis Infection and Vaccine-Induced Immunity

Larsen

Williams²,

Rais³

et al. 2022

Front. Immunol.

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Despite co-evolving with humans for centuries and being intensely studied for decades, the immune correlates of protection against Mycobacterium tuberculosis (Mtb) have yet to be fully defined. This lapse in understanding is a major lag in the pipeline for evaluating and advancing efficacious vaccine candidates. While CD4+ T helper 1 (TH1) pro-inflammatory responses have a significant role in controlling Mtb infection, the historically narrow focus on this cell population may have eclipsed the characterization of other requisite arms of the immune system. Over the last decade, the tuberculosis (TB) research community has intentionally and intensely increased the breadth of investigation of other immune players. Here, we review mechanistic preclinical studies as well as clinical anecdotes that suggest the degree to which different cell types, such as NK cells, CD8+ T cells, γ δ T cells, and B cells, influence infection or disease prevention. Additionally, we categorically outline the observed role each major cell type plays in vaccine-induced immunity, including Mycobacterium bovis bacillus Calmette-Guérin (BCG). Novel vaccine candidates advancing through either the preclinical or clinical pipeline leverage different platforms (e.g., protein + adjuvant, vector-based, nucleic acid-based) to purposefully elicit complex immune responses, and we review those design rationales and results to date. The better we as a community understand the essential composition, magnitude, timing, and trafficking of immune responses against Mtb, the closer we are to reducing the severe disease burden and toll on human health inflicted by TB globally.

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Pulmonary BCG induces lung-resident macrophage activation and confers long-term protection against tuberculosis

Abstract: Pulmonary BCG administration induces protection against tuberculosis infection via lung macrophage activation.

Cited by 36 publications

References 41 publications

Development and Testing of a Spray-Dried Tuberculosis Vaccine Candidate in a Mouse Model

Development and Testing of a Spray-Dried Tuberculosis Vaccine Candidate in a Mouse Model

Exposure tomycobacteriumremodels alveolar macrophages and the early innate response toMycobacterium tuberculosisinfection

It Takes a Village: The Multifaceted Immune Response to Mycobacterium tuberculosis Infection and Vaccine-Induced Immunity

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