Trained immunity induction by the inactivated mucosal vaccine MV130 protects against experimental viral respiratory infections

Brandi, Paola; Conejero, Laura; Cueto, Francisco J.; Martínez-Cano, Sarai; Dunphy, Gillian; Gómez, Manuel J.; Relaño, Carlos; Saz-Leal, Paula; Enamorado, Michel; Quintas, Ana; Dopazo, Ana; Amores, J.; Fresno, Carlos del; Ardavı́n, Carlos; Nieto, Antonio; Casanovas, Miguel; Subiza, José Luis; Sancho, David

doi:10.1016/j.celrep.2021.110184

Cited by 44 publications

(53 citation statements)

References 68 publications

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“…In this context, prior vaccination with V132 as a trained immunity inducer may be useful to potentiate MV140, a sublingual vaccine indicated for the prevention of recurrent urinary tract infections (41). It should be noted that mucosal tissues are excellent targets for inducing trained immunity by whole cell microorganisms (62,63), supporting the approach we describe here. On the other hand, vaccination through the sublingual route induces strong immune responses in local and peripheral lymphoid organs as well as in distant mucosa such as the genitourinary tract (64-66).…”

Section: Discussionsupporting

confidence: 78%

Candida albicans V132 induces trained immunity and enhances the responses triggered by the polybacterial vaccine MV140 for genitourinary tract infections

Martín-Cruz

Angelina²,

Baydemir³

et al. 2022

Front. Immunol.

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IntroductionRecurrent urinary tract infections (RUTIs) and recurrent vulvovaginal candidiasis (RVVCs) represent major healthcare problems all over the world. Antibiotics and antifungals are widely used for such infectious diseases, which is linked with microbial resistances and microbiota deleterious effects. The development of novel approaches for genitourinary tract infections (GUTIs) such as trained immunity-based vaccines (TIbV) is therefore highly required. MV140 is a sublingual whole-cell heat-inactivated polybacterial preparation with demonstrated clinical efficacy for RUTIs. The sublingual heat-inactivated Candida albicans vaccine V132 has been developed for RVVCs. We previously showed that the combination of MV140 and V132 promotes potent Th1/Th17 and regulatory T-cell responses against antigens contained in the formulation and unrelated antigens. The specific contribution of each preparation to such effects and the underlying molecular mechanisms remain incompletely understood.MethodsPBMC and monocytes were isolated from healthy donors and in vitro stimulated with V132, MV140 or MV140/V132. After 6 days of resting, cells were reestimulated with LPS and MV140. Analysis of cytokine production by ELISA, Seahorse assays for functional metabolic experiments and chromatin immunoprecipitation assays were performed. BALB/c mice were intraperitoneally and sublingually immunized with V132.ResultsWe uncover that V132 induces trained immunity in human PBMCs and purified monocytes, significantly increasing the responses triggered by subsequent stimulation with MV140. Mechanistically, V132 drives metabolic rewiring towards increased glycolysis and oxidative phosphorylation and induces epigenetic reprogramming that enhances the transcription of the pro-inflammatory genes IL6 and TNFA. Splenocytes and peritoneal cells from V132-immunize mice show increased responses upon in vitro stimulation with MV140. Remarkably, splenocytes from sublingually V132-immunized and MV140 in vivo treatment mice show stronger Th17 responses than mice exposed to excipients upon in vitro stimulation with MV140.ConclusionOverall, we provide novel mechanistic insights into how V132-induced trained immunity enhances both innate and adaptive immune responses triggered by MV140, which might open the door for new interventions for GUTIs with important clinical implications.

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Section: Discussionsupporting

confidence: 78%

Candida albicans V132 induces trained immunity and enhances the responses triggered by the polybacterial vaccine MV140 for genitourinary tract infections

Martín-Cruz

Angelina²,

Baydemir³

et al. 2022

Front. Immunol.

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“…Trained immunity is characterized by epigenetic reprogramming in innate immune cells such as monocytes ( 9 , 10 ) and NK cells ( 11 ) after infection or vaccination. The live-attenuated bacillus Calmette–Guérin (BCG) vaccine ( 9 , 12 ), influenza vaccine ( 13 , 14 ), and inactivated mucosal vaccine ( 15 ) induce epigenetic changes in monocytes, exerting protective effects against viral infections. Despite these findings, it is still unclear whether SARS-CoV-2 mRNA vaccines induce a similar alteration.…”

Section: Introductionmentioning

confidence: 99%

Consecutive BNT162b2 mRNA vaccination induces short-term epigenetic memory in innate immune cells

Yamaguchi¹,

Kato²,

Edahiro³

et al. 2022

JCI Insight

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Consecutive mRNA vaccinations against SARS-CoV-2 reinforced both innate and adaptive immune responses. However, it remains unclear whether the enhanced innate immune responses are mediated by epigenetic regulation and, if so, whether these effects persist. Using mass cytometry, RNA-seq, and ATAC-seq, we show that BNT162b2 mRNA vaccination upregulated antiviral and IFN-stimulated gene expression in monocytes with greater effects after the second vaccination than those after the first vaccination. Transcription factor-binding motif analysis also revealed enriched IFN regulatory factors and PU.1 motifs in accessible chromatin regions. Importantly, although consecutive BNT162b2 mRNA vaccinations boosted innate immune responses and caused epigenetic changes in isolated monocytes, we showed that these effects occur only transiently and disappear 4 weeks after the second vaccination. Furthermore, single-cell RNA sequencing analysis revealed that a similar gene signature was impaired in the monocytes of unvaccinated COVID-19 patients with acute respiratory distress syndrome. These results reinforce the importance of the innate immune response in the determination of COVID-19 severity but indicate that, unlike adaptive immunity, innate immunity is not unexpectedly sustained even after consecutive vaccination. This study, which focuses on innate immmune memory, may provide novel insights into the vaccine development against infectious diseases.

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“…It is also believed that bacterial lysates via trained immunity provide a broad-spectrum crossprotection against various pathogens (heterologous protection) [45,46]. Trained immunity can be understood as a non-specific memory (duration of several weeks to months) of the innate immune system, where a stimulus from various agents [45][46][47] like pathogens, live vaccines, microbial extracts, β-glucan and lipopolysaccharide modifies the immune system in such a way that a robust immune response is obtained towards future challenges. Interestingly, trained immunity provides protection against not only the initial mediator, but also other unrelated agents/pathogens including bacteria, fungi, viruses and parasites (heterologous immunity).…”

Section: How Do Microbial Lysates Work In Preventing and Alleviating ...mentioning

confidence: 99%

Conformationally modulated immunogenic proteins in homeopathic medicines: Does protein-based mucosal immunotherapy have the potential to treat diverse diseases?

Sen¹

2022

Preprint

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The absence of any drug in the ultra-diluted homeopathic medicines coupled with unfavourable clinical trial results has painted homeopathic remedies as placebos. Different mechanisms have been forwarded to explain the anomalies but with little success. Here it is proposed that homeopathy is a form of protein-based immunotherapy and the immunogenic proteins exist in the microbial lysates, which are present in the homeopathic medicines. The microbial lysates are formed in the homeopathic medicines during their preparation, when microbes from the surrounding environment are unwittingly incorporated into the homeopathic medicines and the microbial cell lysis is induced by alcohol, a component of the drug vehicle (water-alcohol mixture), and augmented by powerful shaking. The drugs in the homeopathic medicines modulate the conformations and, in essence, the immunogenicity of the proteins present in the medicines. The modulated proteins act as immunostimulants and help in boosting and tuning both innate and adaptive immunity. In addition, bystander T cell activation and trained immunity are expected to play important roles in the therapeutic and prophylactic actions of the homeopathic medicines. The importance of dilution in homeopathy vis-à-vis the ‘law of infinitesimals’ can be appreciated by considering the effect of dilution on protein folding and the immunogenicity of proteins. In the case of ultra-diluted homeopathic medicines devoid of any drug molecule, it has been suggested that in the absence of drug-protein interaction, protein-protein interaction leads to the conformational modulation of protein molecules, where allosteric communication and synchronization of vibrating of the protein molecules play key roles. The dictum ‘like cures like’ can be understood by considering the mimicry between the antigens present on the invading pathogen and the antigens present on the proteins in the selected homeopathic medicine. The discrepancies in the clinical trial results of homeopathic medicines arising from the heterogeneities inherent in immunotherapy as well as from a strong placebo response in the clinical trials in some diseases may partly be mitigated by conducting modified clinical trials.

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Trained immunity induction by the inactivated mucosal vaccine MV130 protects against experimental viral respiratory infections

Cited by 44 publications

References 68 publications

Candida albicans V132 induces trained immunity and enhances the responses triggered by the polybacterial vaccine MV140 for genitourinary tract infections

Candida albicans V132 induces trained immunity and enhances the responses triggered by the polybacterial vaccine MV140 for genitourinary tract infections

Consecutive BNT162b2 mRNA vaccination induces short-term epigenetic memory in innate immune cells

Conformationally modulated immunogenic proteins in homeopathic medicines: Does protein-based mucosal immunotherapy have the potential to treat diverse diseases?

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