A Combination of Polybacterial MV140 and Candida albicans V132 as a Potential Novel Trained Immunity-Based Vaccine for Genitourinary Tract Infections

Abstract

Recurrent urinary tract infections (RUTIs) and recurrent vulvovaginal candidiasis (RVVCs) represent major healthcare problems with high socio-economic impact worldwide. Antibiotic and antifungal prophylaxis remain the gold standard treatments for RUTIs and RVVCs, contributing to the massive rise of antimicrobial resistance, microbiota alterations and co-infections. Therefore, the development of novel vaccine strategies for these infections are sorely needed. The sublingual heat-inactivated polyvalent bacterial vaccine MV140 shows clinical efficacy for the prevention of RUTIs and promotes Th1/Th17 and IL-10 immune responses. V132 is a sublingual preparation of heat-inactivated Candida albicans developed against RVVCs. A vaccine formulation combining both MV140 and V132 might well represent a suitable approach for concomitant genitourinary tract infections (GUTIs), but detailed mechanistic preclinical studies are still needed. Herein, we showed that the combination of MV140 and V132 imprints human dendritic cells (DCs) with the capacity to polarize potent IFN-γ– and IL-17A–producing T cells and FOXP3+ regulatory T (Treg) cells. MV140/V132 activates mitogen-activated protein kinases (MAPK)-, nuclear factor-κB (NF-κB)- and mammalian target of rapamycin (mTOR)-mediated signaling pathways in human DCs. MV140/V132 also promotes metabolic and epigenetic reprogramming in human DCs, which are key molecular mechanisms involved in the induction of innate trained immunity. Splenocytes from mice sublingually immunized with MV140/V132 display enhanced proliferative responses of CD4+ T cells not only upon in vitro stimulation with the related antigens contained in the vaccine formulation but also upon stimulation with phytohaemagglutinin. Additionally, in vivo sublingual immunization with MV140/V132 induces the generation of IgG and IgA antibodies against all the components contained in the vaccine formulation. We uncover immunological mechanisms underlying the potential mode of action of a combination of MV140 and V132 as a novel promising trained immunity-based vaccine (TIbV) for GUTIs.

Sublingual Bacterial Vaccination Reduces Recurrent Infections in Patients With Autoimmune Diseases Under Immunosuppressant Treatment

“…In the case of MV130, this immune response has been also observed against unrelated stimuli (27). In addition, a role for both bacterial formulations triggering trained immunity has been also assessed (Brandi et al, submitted) (29). A possible detrimental role for trained immunity triggering or enhancing autoimmune and autoinflammatory diseases has previously been speculated (30); however, this was not the case in our study.…”

Cannabinoid WIN55212‐2 impairs peanut‐allergic sensitization and promotes the generation of allergen‐specific regulatory T cells

“…In this study, we initially sought to assess the potential capacity of the synthetic cannabinoid WIN55212‐2 to interfere with the polarizing effects imprinted by CPE on human DCs. For that, we employed a well‐defined co‐culture experimental model of hmoDCs and allogeneic naïve CD4 + T cells, which allowed us to study how human DCs condition T‐cell polarization in a non‐antigen‐specific manner 33–35 …”

“…the synthetic cannabinoid WIN55212-2 to interfere with the polarizing effects imprinted by CPE on human DCs. For that, we employed a well-defined co-culture experimental model of hmoDCs and allogeneic naïve CD4 + T cells, which allowed us to study how human DCs condition T-cell polarization in a non-antigen-specific manner [33][34][35]. WIN55212-2 significantly impairs the expression of costimulatory molecules and proinflammatory cytokines induced by CPE-stimulated hmoDCs.…”

Vaccines against candidiasis: Status, challenges and emerging opportunity

“…Interestingly, the total cellular proteins extracted by β-mercaptoethanol treatment and their subsequent subcutaneous immunization to mice increased survivability (75%) with a decreased fungal burden than in the control groups ( Thomas et al., 2006 ). A combined vaccine formulation of MV140 and V132 has been tested to prevent both bacterial as well as fungal genitourinary tract infections (GUTIs) ( Martin-Cruz et al., 2020 ). The heat-inactivated polyvalent bacterial vaccine MV140 prevents RUTIs by eliciting Th1/Th17 and IL-10 immune responses, while the V132 is a heat-inactivated vaccine candidate developed against RVVCs.…”