Subunit Vaccine ESAT-6:c-di-AMP Delivered by Intranasal Route Elicits Immune Responses and Protects Against Mycobacterium tuberculosis Infection

Ning, Huanhuan; Zhang, Wei; Kang, Jian; Ding, Tao; Liang, Xuan; Lu, Yanzhi; Guo, Chengxuan; Sun, Wenjie; Wang, Huapeng; Bai, Yang; Shen, Liuhong

doi:10.3389/fcimb.2021.647220

Cited by 20 publications

(21 citation statements)

References 58 publications

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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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“…c-di-AMP could induce innate immune responses and enhance antigen-induced Th1/Th2/Th17 responses as an adjuvant ( Ebensen et al, 2011 ; Devaux et al, 2018 ; Ning et al, 2021 ). It has been revealed that M. tuberculosis Δ cnpB could trigger host innate immune responses, which could promote the clearance of bacteria ( Yang et al, 2014 ; Dey et al, 2017 ).…”

Section: Resultsmentioning

confidence: 99%

“…Now, c-di-AMP has been considered a key mycobacterial pathogen-associated molecular pattern (PAMP) inducing host innate immune responses, including type I IFN response and autophagy ( Woodward et al, 2010 ; Dey et al, 2015 ; Devaux et al, 2018 ; Ning et al, 2019 ; Singh et al, 2022 ). Additionally, c-di-AMP as an adjuvant enhanced antigen-induced Th1/Th2/Th17 pattern responses ( Ebensen et al, 2011 ; Ning et al, 2021 ). It has been noted that cnpB -deleted strain of M. tuberculosis triggered a potent type I IFN response, showing the reduction of bacillary burden in the mouse model, implying virulence attenuation in M. tuberculosis ( Yang et al, 2014 ; Dey et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

c-di-AMP Accumulation Regulates Growth, Metabolism, and Immunogenicity of Mycobacterium smegmatis

et al. 2022

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Cyclic dimeric adenosine monophosphate (c-di-AMP) is a ubiquitous second messenger of bacteria involved in diverse physiological processes as well as host immune responses. MSMEG_2630 is a c-di-AMP phosphodiesterase (cnpB) of Mycobacterium smegmatis, which is homologous to Mycobacterium tuberculosis Rv2837c. In this study, cnpB-deleted (ΔcnpB), -complemented (ΔcnpB::C), and -overexpressed (ΔcnpB::O) strains of M. smegmatis were constructed to investigate the role of c-di-AMP in regulating mycobacterial physiology and immunogenicity. This study provides more precise evidence that elevated c-di-AMP level resulted in smaller colonies, shorter bacteria length, impaired growth, and inhibition of potassium transporter in M. smegmatis. This is the first study to report that elevated c-di-AMP level could inhibit biofilm formation and induce porphyrin accumulation in M. smegmatis by regulating associated gene expressions, which may have effects on drug resistance and virulence of mycobacterium. Moreover, the cnpB-deleted strain with an elevated c-di-AMP level could induce enhanced Th1 immune responses after M. tuberculosis infection. Further, the pathological changes and the bacteria burden in ΔcnpB group were comparable with the wild-type M. smegmatis group against M. tuberculosis venous infection in the mouse model. Our findings enhanced the understanding of the physiological role of c-di-AMP in mycobacterium, and M. smegmatis cnpB-deleted strain with elevated c-di-AMP level showed the potential for a vaccine against tuberculosis.

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“…ESAT-6 has been shown to inhibit autophagic flux by impeding autophagosome-lysosome fusion in ex vivo cell culture, which assists in Mtb immune escape from macrophages (220)(221)(222). Preclinical studies in Balb/c mice show that vaccination with ESAT-6 and c-di-AMP regulate macrophage autophagy, resulting in the inhibition of Mtb growth in macrophages during early infection (223).…”

Section: Monocytes/macrophagesmentioning

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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Subunit Vaccine ESAT-6:c-di-AMP Delivered by Intranasal Route Elicits Immune Responses and Protects Against Mycobacterium tuberculosis Infection

Cited by 20 publications

References 58 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

c-di-AMP Accumulation Regulates Growth, Metabolism, and Immunogenicity of Mycobacterium smegmatis

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

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