EBioMedicine最新文献

Background: Crohn's Disease (CD) is a chronic, debilitating condition hypothesised to be associated with Mycobacterium avium ssp paratuberculosis (MAP) infection. It is the causative pathogen of the granulomatous inflammatory enteritis in ruminants, Johne's Disease. A developing treatment approach is utilising heterologous prime-boost viral vectored vaccines. We report a Phase 1b dose-escalation trial to determine the safety, tolerability and immunogenicity of candidate recombinant ChAdOx2 and MVA vectored vaccines against MAP in patients with CD.

Methods: 28 patients with mild to moderate CD, aged 18-50, were randomly allocated into 5 groups. Group 1 and 2 were vaccinated with ChAdOx2 HAV, Groups 3 and 4 with MVA HAV and Group 5 with both vaccines in a prime-boost regimen. A 112-day follow-up period assessed safety and tolerability by recording adverse events (AEs) and serious adverse events (SAEs). Secondary objectives of immunogenicity were assessed by ELISpot (enzyme-linked immunosorbent spot) and clinical response by Crohn's Disease Activity Index (CDAI) and Simple Endoscopic Score for Crohn's Disease (SES-CD).

Findings: 28 participants received either a single dose of ChAdOx2 HAV (n = 12), a single dose of MVA HAV (n = 6) or a prime dose of ChAdOx2 HAV (n = 10) followed by an MVA HAV (n = 9) boost. Solicited AEs were 196 in all participants, one AE was graded as severe but resolved within 24 h. The majority of solicited AEs were graded as mild (149/196; 76%, 95% CI 69%-82%) or moderate (45/196; 23%, 95% CI 17%-29%). ELISpot responses increased in Groups 1 and 2 and significantly more after boosting with MVA HAV.

Interpretation: Candidate vaccines ChAdOx2 HAV and MVA HAV were safe, well-tolerated and immunogenic in patients with active CD. A heterologous prime-boost schedule induces a T cell-mediated immune response. Further studies are required to determine the efficacy and optimal regime of the vaccines.

Funding: HAV Vaccines Limited funded the trial and acted as trial sponsor. The Sponsor was involved in protocol development, trial conduct, including data monitoring and analysis, and the preparation of this manuscript in line with the Medicines for Human Use (Clinical Trials) Regulations 2004 and amendments.

Background: Multimorbidity, the presence of two or more conditions in one person, is common but studies are often limited to observational data and single datasets. We address this gap by integrating large-scale primary-care and genetic data from multiple studies to interrogate multimorbidity patterns and producing digital resources to support future research.

Methods: We defined chronic, common, and heritable conditions in individuals aged ≥65 years, using two large primary-care databases [CPRD (UK) N = 2,425,014 and SIDIAP (Spain) N = 1,053,640], and estimated heritability using the same definitions in UK Biobank (N = 451,197). We used logistic regression to estimate the co-occurrence of pairs of conditions in the primary care data. Linkage disequilibrium score regression was used to estimate genetic similarity between pairs of conditions. Meta-analyses were conducted across databases, and up to three sources of genetic data, for each pair of conditions. We classified pairs of conditions as across or within-domain based on the international classification of disease.

Findings: We identified 72 chronic conditions, with 43.6% of 2546 pairs showing higher co-occurrence than chance in primary care and evidence of shared genetics. Many across-domain pairs exhibited substantial shared genetics (e.g., iron deficiency anaemia and peripheral arterial disease: genetic correlation R_g = 0.45 [95% Confidence Intervals 0.27:0.64]). 33 pairs displayed negative genetic correlations, such as skin cancer and rheumatoid arthritis (R_g = -0.14 [-0.21:-0.06]), due to potential adverse drug effects. Discordance between genetic and primary care data was also observed, e.g., abdominal aortic aneurysm and bladder cancer co-occurred in primary care but were not genetically correlated (Odds-Ratio = 2.23 [2.09:2.37], R_g = 0.04 [-0.20:0.28]) and schizophrenia and fibromyalgia were less likely to co-occur together in primary care but were positively genetically correlated (OR = 0.84 [0.75:0.94], R_g = 0.20 [0.11:0.29]).

Interpretation: Most pairs of chronic conditions show evidence of shared genetics, and co-occurrence in primary care, suggesting shared mechanisms. The identified patterns of shared genetics, negative correlations and discordance between genetic and observational data provide a foundation for future multimorbidity research.

Funding: UK Medical Research Council [MR/W014548/1].

Background: How cardiovascular diseases (CVD) predispose to a higher risk of fragility fractures is not well understood. Both contribute to significant components of disease burden and health expenditure. Poor bone quality, central obesity, sarcopenia, falls, and low grip strength are independent risk factors for hip and other fragility fractures and also for CVD and early death.

Methods: We used proteomics and a cohort design combined with Mendelian randomisation analysis to understand shared mechanisms for developing CVD and fragility fractures, two significant sources of disease burden and health expenditure. We primarily aimed to discover and replicate the association of 274 cardio-metabolic-related proteins with future rates of hip and any fracture in two separate population-based cohorts, with a total of 12,314 women and men.

Findings: The average age at baseline was 68 years in the discovery cohort of women and 74 years in the mixed-sex replication cohort. During 100,619 person-years of follow-up, 2168 had any fracture, and 538 had a hip fracture. Our analysis resulted in 24 cardiometabolic proteins associated with fracture risk: 20 with hip fracture, 9 with any fracture, and 5 with both. The associations remained even if protein concentrations were measured from specimens taken during preclinical stages of cardio-metabolic diseases, and 19 associations remained after adjustment for bone mineral density. Twenty-two of the proteins were associated with total body fat mass or lean body mass. Mendelian randomisation (MR) analysis supported causality since genetically predicted levels of SOST (Sclerostin), CCDC80 (Coiled-coil domain-containing protein 80), NT-proBNP (N-terminal prohormone brain natriuretic peptide), and BNP (Brain natriuretic peptide) were associated with risk of hip fracture. MR analysis also revealed a possible negative impact on bone mineral density (BMD) by genetically predicted higher levels of SOST, CCDC80, and TIMP4 (Metalloproteinase inhibitor 4). The MR association with BMD was positive for PTX3 (Pentraxin-related protein) and SPP1 (Osteopontin). Genetically predicted higher concentrations of SOST and lower concentrations of SPP1 also conferred a higher risk of falls and lowered grip strength. The genetically determined concentration of nine proteins influenced fat mass, and one influenced lean body mass.

Interpretation: These data reveal biological links between cardiovascular diseases and fragility fractures. The proteins should be further evaluated as shared targets for developing pharmacological interventions to prevent fractures and cardiovascular disease.

Funding: The study was supported by funding from the Swedish Research Council (https://www.vr.se; grants No. 2015-03257, 2017-00644, 2017-06100, and 2019-01291 to Karl Michaëlsson) and funding from Olle Engkvist Byggmästares stiftelse (SOEB).

Background: Many studies have investigated early predictors for Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). However, evidence is sparse regarding specific and common predictors for these diseases. We aimed to identify medication use, health conditions, and blood biomarkers that might be associated with the risk of AD, PD, and ALS ten years later.

Methods: We conducted population-based nested case-control studies of AD, PD, and ALS using electronic medical records in Europe (France, the UK, and Sweden) and Australia. We retrieved data on medication use, diagnosed health conditions, and measured blood biomarkers from electronic medical records or biomedical cohorts. Conditional logistic regression models and meta-analysis were applied to assess the associations between these factors and the risk of receiving a diagnosis of AD, PD, or ALS.

Findings: We included a total of 149,642 AD cases (mean age: 79.1-81.2 years), 252,696 PD cases (73.2-75.9 years), and 27,533 ALS cases (64.4-69.6 years). The prescription of psychoanaleptics and nasal preparations was consistently associated with an increased risk of AD, PD, and ALS 5-10 years later. Constipation and use of related medications were associated with an increased risk of AD and PD, while diabetes and use of antidiabetics were associated with a reduced risk of ALS. A higher level of triglycerides was associated with a lower risk of AD, whereas a higher level of Apolipoprotein B was associated with a lower risk of PD, 5-10 years later.

Interpretation: Psychoanaleptics and nasal preparations may serve as common predictors for diagnosis of AD, PD, and ALS 5-10 years later. Conversely, the increased prevalence of constipation is specific to AD and PD, while the decreased prevalence of diabetes and use of antidiabetics is specific to ALS.

Funding: EU Joint Programme-Neurodegenerative Disease Research.

Background: Major depressive disorder (MDD) is a leading cause of disability, with a twofold increase in prevalence in women compared to men. Over the last few years, identifying molecular biomarkers of MDD has proven challenging, reflecting interactions among multiple environmental and genetic factors. Recently, epigenetic processes have been proposed as mediators of such interactions, with the potential for biomarker development.

Methods: We characterised gene expression and two mechanisms of epigenomic regulation, DNA methylation (DNAm) and microRNAs (miRNAs), in blood samples from a cohort of individuals with MDD and healthy controls (n = 169). Case-control comparisons were conducted for each omic layer. We also defined gene coexpression networks, followed by step-by-step annotations across omic layers. Third, we implemented an advanced multiomic integration strategy, with covariate correction and feature selection embedded in a cross-validation procedure. Performance of MDD prediction was systematically compared across 6 methods for dimensionality reduction, and for every combination of 1, 2 or 3 types of molecular data. Feature stability was further assessed by bootstrapping.

Findings: Results showed that molecular and coexpression changes associated with MDD were highly sex-specific and that the performance of MDD prediction was greater when the female and male cohorts were analysed separately, rather than combined. Importantly, they also demonstrated that performance progressively increased with the number of molecular datasets considered.

Interpretation: Informational gain from multiomic integration had already been documented in other medical fields. Our results pave the way toward similar advances in molecular psychiatry, and have practical implications for developing clinically useful MDD biomarkers.

Funding: This work was supported by the Centre National de la Recherche Scientifique (contract UPR3212), the University of Strasbourg, the Université Sorbonne Paris Nord, the Université Paris Cité, the Fondation de France (FdF N° Engt:00081244 and 00148126; ECI, IY, RB, PEL), the French National Research Agency (ANR-18-CE37-0002, BE, CMC, ADD, PEL, ECI; ANR-18-CE17-0009, ADD; ANR-19-CE37-0010, PEL; ANR-21-RHUS-009, ADD, BE, CMC, CCB; ANR-22-PESN-0013, ADD), the Fondation pour la Recherche sur le Cerveau (FRC 2019, PEL), Fondation de France (2018, BE, CMC, ADD) and American Foundation for Suicide Prevention (AFSP YIG-1-102-19; PEL).

Background: Individuals with primary and secondary immunodeficiencies, being more susceptible to infections, are a priority for vaccination. Here, we determined and compared in a longitudinal study the immune response elicited by SARS-CoV-2 vaccination across different groups of individuals who are immunocompromised.

Methods: In the PatoVac_COV longitudinal prospective single-centre study, the spike-specific B cell and antibody responses to SARS-CoV-2 mRNA vaccination were compared across 5 different groups of individuals with haematological malignancies, hematopoietic stem cell (HCT) or solid organ transplantation (SOT), undergoing haemodialysis, and people living with HIV (PLWH), for a total of 585 participants. Data from participants who were immunocompromised were compared to a group of 123 participants who were immunocompetent. Blood samples were collected before and after each vaccine administration, up to 2 years.

Findings: A different immune responsiveness was observed after the first two vaccine doses, with haematological, haemodialysis, and SOT participants showing reduced responsiveness compared to HCT and PLWH, and relative to the comparison group. Spike-specific B cell response was both slower and lower in all groups except in PLWH when compared to participants who were immunocompetent. However, the first booster dose enhanced both the B and the antibody responses in all groups, that persisted up to 2 years after the first vaccine administration. The administration of Omicron-adapted booster vaccines promoted a primary BA.2 RBD-specific B cell response, especially in participants who were immunocompromised. Despite repeated vaccinations, a subset of persistent low-responders, especially among SOT, was identified.

Interpretation: Our study highlights the heterogeneous immune response across individuals with different pathologies, the pivotal role of the first booster dose, the primary activation of Omicron-specific B cells elicited by updated variant-adapted vaccines and the persistence of low-responders despite multiple vaccine administrations. These aspects have a clinical relevance for planning vaccination schedules tailored for individuals with different immunocompromising conditions.

Funding: This work was supported by funds from the Department of Medical Biotechnologies of the University of Siena, and from EU within the NextGenerationEU-MUR PNRR Tuscany Health Ecosystem (Project no ECS00000017-THE).

Background: The use of cannabis during pregnancy is rising following its widespread legalization. Cannabidiol (CBD) is gaining popularity due to the public perception that it is safer than the psychoactive cannabis component Δ9-tetrahydrocannabinol (THC). However, while evidence underpins the harm of THC and cannabis smoke on fetal development, there is minimal research on the safety of CBD and oral cannabis. The current study aims to decipher the safety of oral CBD and THC use during pregnancy.

Methods: Using a mouse model, we directly compared the effects of oral CBD and THC oil exposure (20 mg/kg body weight) from early to mid-gestation on implantation site remodelling and fetal growth. We examined offspring behaviour and metabolic activity using both traditional and automated cage systems. Lastly, using human and mouse immune cells we assessed how CBD and THC influence angiogenic factor production.

Findings: We observed impaired maternal spiral artery remodelling in cannabis exposed mice and found that CBD and THC disrupt immune cell angiogenic factor production. Oral consumption of THC or CBD oil also resulted in significant fetal growth impairment and led to long-lasting sex-dependent consequences as male offspring exhibited altered aggression and metabolic activity while females had impaired spatial learning.

Interpretation: Our results show that oral consumption of either CBD or THC oil during pregnancy in mice results in harm to the developing fetus and causes behavioural changes after birth.

Funding: The Michael G. DeGroote Centre for Medicinal Cancer Research, the Canadian Institutes of Health Research, and the Canadian Foundation for Innovation.

Background: We report findings from an experimental medicine study of rationally designed prefusion stabilised native-like HIV envelope glycoprotein (Env) immunogens, representative of global circulating strains, delivered by sequential intramuscular injection.

Methods: Healthy adult volunteers were enrolled into one of five groups (A to E) each receiving a different schedule of one of two consensus Env immunogens (ConM SOSIP, ConS UFO, either unmodified or stabilised by chemical cross-linking, followed by a boost with two mosaic Env immunogens (Mos3.1 and Mos3.2). All immunogens were co-formulated with liposomal Monophosphoryl-Lipid A (MPLA) adjuvant, and volunteers were followed up for 28 days post final Mosaic booster injection. Participants gave written informed consent to join the study. The study is registered on ClinicalTrials.gov ID NCT03816137.

Findings: Fifty-one participants (men n = 23 and women n = 28) aged 18-55 were enrolled. The seroconversion rate against Env was 100% with all participants having measurable anti-Env IgG antibodies after their second injection and throughout the study. Neutralisation was detected against the ConM pseudovirus in sera of those who had received both ConM and ConS immunogens. However, this activity was limited in breadth and was neither boosted nor broadened in those receiving the Mos3.1 and Mos3.2 immunogens. Neutralising antibody function correlated with binding to V1/V3 and V5 epitopes and peaked after the third injection.

Interpretation: Rationally designed prefusion-stabilised native-like Env trimers are robustly immunogenic in a prime-boost schedule. When given alone they are insufficient to induce neutralising antibody titres of significant breadth, but they represent potentially valuable polishing immunogens after germline-targeting.

Funding: European Aids Vaccine initiative (EAVI2020) received funding from EU Horizon 2020, grant number 681137. Structural studies were supported by the Bill and Melinda Gates Foundation (INV-002916).