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Abstract: Respivax (BulBio-NCIPD Ltd.) is an oral polybacterial immunomodulator intended for treatment and prevention of non-specific respiratory tract infections. We studied for the first time its effects on the inductive mechanisms of innate immunity, in the course of 3-month immunoprophylaxis of 25 patients with recurrent and chronic respiratory infections. The expression of pattern-recognition receptors on peripheral blood (PB) monocytes and plymorphonuclear cells (PMNs), the antigen-presenting and co-stimulatory potential of peripheral blood monocytes and dendritic cells; and the stimulated Th1/Th2 cytokine production were determined by flow cytometry. As compared to healthy controls, patients were characterized with down-regulation of TLR2 and TLR4/CD14 complex on PB monocytes (p <0.01), decreased share of CD14+CD16+ DCs precursors (p <0.01), decreased CD86 expression on PB DCs (p <0.05) and a Th2 shift of cytokine profile. Respivax modulated differentially the surface expression of pattern-recognition receptors on PB monocytes, increasing TLR2 and CD14 without affecting TLR4 expression. Further on, Respivax enhanced the differentiation of mature CD86high dendritic cells (DCs). Importantly, Respivax promoted a Th1 shift of cytokine profile and restored the Th1/Th2 cytokine balance without pro-inflammatory effects. Noteworthy, Th1/Th2 ratios in the patient''s group correlated positively with the levels of TLR2 (R =0.5, p <0.001) and CD14 expression (R =0.4, p <0.05). We conclude that Respivax treatment restores the inductive function of innate immunity at three key levels: antigen recognition and presentation, co-stimulation of naïve T cells, and Th1/Th2 balance. This results, at least in part, from a differential modulation effect on the expression of pathogen-recognition receptors. [Copyright &y& Elsevier]

MV130 is an inactivated polybacterial mucosal vaccine that confers protection to patients against recurrent respiratory infections, including those of viral etiology. However, its mechanism of action remains poorly understood. Here, we find that intranasal prophylaxis with MV130 modulates the lung immune landscape and provides long-term heterologous protection against viral respiratory infections in mice. Intranasal administration of MV130 provides protection against systemic candidiasis in wild-type and Rag1 -deficient mice lacking functional lymphocytes, indicative of innate immune-mediated protection. Moreover, pharmacological inhibition of trained immunity with metformin abrogates the protection conferred by MV130 against influenza A virus respiratory infection. MV130 induces reprogramming of both mouse bone marrow progenitor cells and in vitro human monocytes, promoting an enhanced cytokine production that relies on a metabolic shift. Our results unveil that the mucosal administration of a fully inactivated bacterial vaccine provides protection against viral infections by a mechanism associated with the induction of trained immunity. [Display omitted] • MV130 reduces morbi-mortality in mouse models of viral respiratory infection • MV130 modulates mouse immunity complying with key features of trained immunity • MV130 promotes reprogramming of mouse bone marrow progenitors • MV130 induces trained immunity in human monocytes Brandi et al. investigate the mechanism of action of an inactivated polybacterial mucosal immunomodulator, MV130, which confers protection in patients suffering from recurrent respiratory infections. They show that MV130 induces trained immunity both in mouse bone marrow progenitors, resulting in protection from viral infection, and in human monocytes in vitro. [ABSTRACT FROM AUTHOR]

Abstract: The oral polybacterial immunomodulator Dentavax (D), composed of killed cells from Klebsiella pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, Candida albicans and Lactobacillus acidophilus and their lysates was created for immunoprophylaxis and therapy of oral mucosa and parodont inflammations. The stimulating effect of the preparation was evaluated in twelve volunteers immunized for 10 consecutive days. On days 7, 14, 21, 28 and 49 after the last immunization peripheral blood (PB) lymphocyte subsets, T lymphocyte activation and PB phagocytic activity, were studied by flow cytometry. PB lymphocyte proliferative responses to PHA, rIL-2, LPS and D were evaluated radiometrically. The production of TNF-alpha in supernatants of in vitro stimulated lymphocytes and specific IgA, IgM and IgG antibodies in serum and saliva was determined by ELISA. Ultrastructural morphologic changes in T and B lymphocyte populations were also investigated. Although no significant changes in the levels of basic lymphocyte subsets were detected, the early/late (CD57+/CD57−) CD8 T effectors ratio was increased at the end of the studied period, as were the percentage of PHA-responding (CD69+) T cells and PB phagocytizing cells. The most prominent lymphoprolipherative responses were measured upon costimulation with LPS+D and PHA+D on day 21. Electron-microscopic studies demonstrated a significant effect of D on both T and B cell activity. TNF-alpha concentration increased progressively from day 7 till the end of the investigation. Maximal concentrations were observed after stimulation with D and LPS. An increased level of specific salivary and serum antibodies against the components of D was found, with highest levels between days 7 and 21. Specific secretory IgA predominated in saliva as compared to IgM and IgG. Our results demonstrate the stimulating effect of Dentavax on PB lymphocyte functional activity and the specific humoral systemic and mucosal immunity. [Copyright &y& Elsevier]