Journal of Infectious Diseases最新文献

Traditional vaccine clinical trials sample blood from all participants. In contrast, the test-negative immune correlates design only samples blood from participants who develop symptoms. We compared traditional to test-negative immune correlates methods in the mRNA-1273 SARS-CoV-2 vaccine efficacy clinical trial. Using a neutralizing antibody assay, hazard ratios were 0.48 (95% CI: 0.29, 0.73) and 0.55 (95% CI: 0.28, 1.06) respectively for traditional and test-negative methods. Analogous ratios for binding antibody assay were 0.69 (95% CI: 0.52, 0.94) and 0.78 (95% CI 0.50, 1.20. The results support use of the logistically simpler test-negative immune correlates design.

Background: A COVID-19 subunit vaccine developed with the Molecular Clamp platform was among the first to enter clinical trials in 2020. While the vaccine was well suited to large-scale manufacture and demonstrated a favourable safety and immunogenicity profile, it did not progress into further clinical testing due to the HIV-derived sequence in the Molecular Clamp interfering with certain point-of-care HIV diagnostic tests.A second-generation Molecular Clamp (MC2) has since been developed. Here, we describe a Phase I clinical trial of a MC2 stabilised SARS-CoV-2 Spike subunit vaccine, UQSC2.

Methods: A Phase I, double-blind, active comparator-controlled trial was conducted in Australia (ClinicalTrials.gov NCT05775887; ). Healthy adults (18-50 years), who had previously received three or more doses of approved mRNA SARS-CoV-2 vaccines, received a single booster dose of either UQSC2 or approved comparator NVX-CoV2373 (NuvaxovidTM; Novavax) (n=70; 35 per group). Safety, humoral immunogenicity (including against virus variants), and cellular immunogenicity were assessed to Day 183. Cases of confirmed COVID-19 infection during the study were also examined.

Results: Both vaccines were equally well tolerated and elicited comparable increases in neutralising humoral responses against vaccine matched prototypic, Wuhan strain of SARS-CoV-2.

Findings: UQSC2 was equally well tolerated to the authorised comparator vaccine and produced an equally robust boost in neutralising immune response. These findings support the effectiveness of the MC2 platform in producing vaccines against newly emerging variants of SARS-CoV-2, and other respiratory viruses, as well as the platform's potential use in emergency response to novel viruses.

Background: Tuberculosis (TB) is the leading single bacterial cause of death worldwide. In 2023, approximately 400 000 people developed multidrug- and rifampicin-resistant TB (MDR/RR-TB), which complicates treatment. TB preventive treatment (TPT) is a critical strategy to prevent the progression from TB infection to TB disease among those at risk. In February 2024, based on data from 2 randomized controlled trials, levofloxacin was strongly recommended by the World Health Organization (WHO) as a TPT option in people of all ages exposed to MDR/RR-TB. There are uncertainties about the optimal dosing of levofloxacin in children and adolescents when using dispersible and solid formulations. We used pharmacokinetic modeling and simulations to determine the best dosing strategy in people aged up to 19 years for both formulations of levofloxacin.

Methods: A previously developed population pharmacokinetic model of levofloxacin in children (0.2-16.8 years) was used and applied to new WHO harmonized weight bands. Simulations were conducted using demographic data from countries with the highest incidence of RR- or MDR-TB. Two currently available levofloxacin formulations (100 mg pediatric, dispersible tablets and 250 mg solid tablets) were considered.

Results: A dosing regimen by weight band was developed for levofloxacin when used as TPT in people aged 0-19 years exposed to MDR/RR-TB. Doses correspond to 8-33 mg/kg for the 100 mg dispersible tablets and 10-42 mg/kg for 250 mg solid tablets. These doses achieve adequate adult target exposure levels.

Conclusions: Pragmatic, weight-band dosing strategies help simplify the administration of MDR/RR-TB TPT and have been included in WHO guidance.

Background: The bacterial genotoxins cytolethal distending toxin (CDT) and colibactin cause severe DNA damage in host cells and impair the DNA-damage response, leading to genomic instability. Some phenotypes induced by these genotoxins (actin cytoskeleton remodeling, stress fibers accumulation, disturbance of focal adhesion, cell-cell junctions' disassembly, increased ploidy and genome instability, and endoreplication) are known to involve the Hippo signaling pathway, suggesting a link between some effects induced by these toxins and Hippo pathway.

Methods: We investigated the Hippo signaling pathway in normal and cancer-derived epithelial intestinal and hepatic cell lines following intoxication with CDT/CdtB and colibactin.

Results: We have shown that the active CdtB subunit of CDT modulates the expression of transcripts and proteins of the Hippo downstream central transcriptional coactivators YAP/TAZ. CdtB exposure drove increased TEAD-mediated transcription, confirmed by the upregulation of direct TEAD target genes. Inhibition of the YAP/TAZ binding to TEADs (verteporfin and K-975) dampened the effects of CdtB, particularly DNA damage and repair, and increased ploidy. These findings suggest that YAP/TAZ-TEAD signaling is involved in increased ploidy in cells surviving the DNA damage induced by CDT/CdtB. In addition, exposure to colibactin, a genotoxic metabolite produced by Escherichia coli, induced similar effects.

Conclusions: Overall, these data show that infection with genotoxin-producing bacteria involves the YAP/TAZ-TEAD signaling pathway to control ploidy following DNA damage in epithelial cells.

The detection and quantification of cryptococcal capsular PS antigen in body fluids is useful for the diagnosis of cryptococcosis. We compared the sensitivity of four assays for measuring amount of cryptococcal PS and two clinical assays (lateral flow assay (LFA) (IMMY) and the cryptococcal latex agglutination assay (CLAA) (Remel)) using the PS of four single motif repeat expressing Cryptococcus strains. These showed relatively consistent laboratory assay inter-strain sensitivity with significant inter-strain variation with the more sensitive clinical assays showing variation consistent with antigenic differences. Analysis of LFA false-negative isolates reveals cryptococcal PS motif expression is not recognized by the antibodies used in the assay. These results suggest that strain variation in PS structure affects the sensitivity of the various quantification tests while antigen-antibody matching is essential to avoid false negative results in cryptococcal antigen testing of bodily fluids. Including antibodies with more specificities in clinical assays could reduce false-negative results.