Toscana Life Sciences

Background4CMenB (MenB-4C, GSK) has been licensed in the US since 2015 for individuals aged 10–25 years. This study assessed its safety and immunogenicity in US infants when administered concomitantly with PCV13 (Pfizer) and other US-recommended RIVs.MethodsThis phase 3B, observer-blind, randomized, placebo-controlled, multicenter study (NCT03621670) randomized (2:1 ratio) 1195 healthy US infants aged 6–12 weeks to receive, at approx. 2, 4, 6, and 12 months of age, either 4CMenB administered concomitantly with PCV13 and other RIVs (N=786; 4CMenB+RIVs) or placebo with PCV13 and other RIVs (N=409; Placebo+RIVs). Primary objectives were to assess vaccine safety, demonstrate sufficiency of immune responses to 4CMenB by human serum bactericidal assay (hSBA) against each of 4 serogroup B (MenB) indicator strains and all strains combined (composite), and non-inferiority of pneumococcal serotype-specific geometric mean antibody concentrations (GMCs).ResultsPre-specified sufficiency criteria 1 month post-dose 3 (based on lower limit [LL] of 99.2% confidence interval [CI] for hSBA titers ≥lower limit of quantitation [LLOQ]) and post-dose 4 (based on LL of 95.8% CI for hSBA titers ≥8/16) were met for fHbp, NadA, and PorA strains, but not for NHBA and the composite response. For NHBA, the CI LL for percentage of participants with hSBA titers ≥8 post-dose 4 was 72.5% (sufficiency criterion: ≥75%). Percentages of participants with hSBA titers ≥LLOQ against each MenB indicator strain post-dose 4 were 86.1%–99.6% (75.7%, composite) in the 4CMenB+RIVs group vs 0.0%–2.8% (0.0%, composite) in the Placebo+RIVs group. The success criterion for immunological non-inferiority of PCV13 (4CMenB+RIVs) vs PCV13 (Placebo+RIVs) was met for each PCV13 antigen (see table). 4CMenB was well tolerated, with no major between-group differences in unsolicited adverse events and no safety concerns identified.Conclusion4CMenB was well tolerated and immunogenic in US infants, with no clinically significant interference against concomitantly administered RIV. Comparison against the 4CMenB-naïve group shows MenB immune responses in the 4CMenB+RIVs group were elicited solely by 4CMenB.Acknowledgements: Enovalife Medical Communication Service Center, on behalf of GSK (writer: J. Knowles).Funding: GSK.DisclosuresAll Authors: No reported disclosures

ABSTRACT HIV persists in long-lived CD4⁺ T cell reservoirs despite antiretroviral therapy (ART) 1 . Elite controllers suppress viraemia without ART 2 , yet reservoir reactivation emerges with immune ageing 3 . Here we show that transient reprogramming of patient-derived CD4⁺ T cells restores their ability to eliminate HIV-infected reservoirs, excising integrated proviral DNA. A defined compound, or physiological induction, drove rapid reprogramming ex vivo, enabling clearance of HIV DNA within hours to days of treatment, independently of ART. Single-cell RNA sequencing revealed activation of an antiviral telomere transfer programme 4 that exceeds elite-like control. In humanised mice, adoptive transfer of reprogrammed patient CD4⁺ T cells, or in vivo reprogramming of murine T cells, eliminated HIV DNA across reservoirs, with undetectable viral genomes persisting for months. Modelling predicted that residual proviral reactivation would be governed by rare stochastic events, rendering viral rebound unlikely within a human lifespan. These findings identify a previously unrecognised form of intracellular immunity and establish a defined route to a functional HIV cure arising from the CD4⁺ T cell itself.

Rett Syndrome (RTT) is a rare neurodevelopmental disorder, primarily affecting girls (1:10,000 live births), largely caused by mutations in the X-linked gene MECP2, an epigenetic regulator encoding for the methyl-CpG binding protein 2 (MeCP2). Recent evidence links ferroptosis, an iron-dependent cell death characterized by lipid peroxide accumulation, to neurodegenerative and neurodevelopmental disorders like autism. Several RTT hallmarks, including redox imbalance, excess labile iron, increased lipid peroxidation, and impaired antioxidant enzyme activity, align with ferroptosis characteristics. Therefore, we investigated ferroptosis's role in RTT using human primary fibroblasts from healthy and RTT subjects, treating them with ferroptosis inducers: erastin and RSL3. Our findings show RTT cells are highly susceptible to ferroptosis, marked by elevated lipid peroxidation and mitochondrial reactive oxygen species (mtROS) production, crucial for ferroptotic cell death. We also observed altered iron metabolism and dysregulated ferritinophagy. RTT fibroblasts exhibited an imbalanced antioxidant defense, particularly after ferroptotic stimuli, and ferroptosis inducers worsened redox imbalance compared to controls. Importantly, a ferroptosis inhibitor (Ferrostatin-1) and a SOD mimetic (mito-TEMPO) prevented these effects and normalized the altered basal conditions of RTT cells. In conclusion, our results reveal a general dysregulation in RTT cells contributing to increased ferroptosis sensitivity. This suggests a significant role for ferroptosis in RTT pathophysiology and progression, potentially opening new therapeutic avenues for this condition.

In the version of the article initially published, in the "Early-life serological profiles" section, the text "two or more antigens of greater than 0.5 log10 RLU ml -1 " should have read "two or more antigens or greater than 0.5 log10 RLU ml -1 ".Additionally, in the "M/emm type-specific IgG measurement in a multiplex assay" section of the Methods, the sentence "Microspheres were conjugated to streptavidin-coupled MagPlex beads" has been corrected to "Biotinylated peptides were conjugated to streptavidin-coupled MagPlex beads".These corrections have been made to the HTML and PDF versions of the article.

Shigellosis significantly impacts global health, particularly affecting vulnerable populations in low- and middle-income countries, with over 270 million annual infections. It also causes morbidity in specific high-risk groups in high-income countries. Antibiotic treatment is increasingly compromised by multidrug-resistant strains, highlighting the urgent need for a Shigella vaccine. We developed a four-component O-antigen-based vaccine candidate targeting Shigella sonnei and Shigella flexneri 1b, 2a, and 3a serotypes, named altSonflex1-2-3, to provide broad protection against most globally prevalent Shigella strains. Here, we characterized the O-antigen structural features of a panel of S. flexneri drug-resistant clinical isolates and verified that they did not significantly differ from the O-antigen in the vaccine. Preclinical sera elicited by altSonflex1-2–3 were bactericidal against most strains, confirming the ability of anti-O-antigen antibodies to recognize and kill in vitro different clinical isolates. Importantly, our results suggest that altSonflex1-2–3 could offer protection against antimicrobial-resistant Shigella strains, addressing a critical public health issue.

Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders characterized by impairments in social communication, restricted interests, and repetitive behaviors. Although its etiology remains incompletely understood, increasing evidence suggests a multifactorial origin involving genetic alterations, immune dysregulation, and environmental exposures. The aim of this study was to investigate the redox-sensitive Nrf2 signaling pathway in primary dermal fibroblasts isolated from ASD patients. Our results revealed constitutive activation of Nrf2, accompanied by reduced expression of its downstream target heme oxygenase-1 (HO1) and marked nuclear accumulation of the transcriptional repressor BACH1 in ASD cells. Moreover, ASD fibroblasts failed to increase Nrf2 nuclear translocation upon sulforaphane (SFN) stimulation, a response consistent with elevated basal levels of Keap1, a negative regulator that sequesters Nrf2 in the cytoplasm. Notably, treatment with hemin, known to induce nuclear export and degradation of BACH1, successfully restored HO1 gene and protein expression and ameliorated impaired mitochondrial function in ASD fibroblasts, as suggested by the decrease of mtROS levels and the restored mitochondrial membrane potential. Collectively, these results identify a dysregulation of the Nrf2-Keap1-BACH1 axis in ASD and suggest that pharmacological targeting of this pathway may offer therapeutic potential to correct the redox imbalance associated with the disorder.