RESUMO
Recently updated COVID-19 mRNA vaccines encode the spike protein of the omicron subvariant XBB.1.5 and are recommended for patients with inflammatory bowel disease (IBD) on immunosuppressive treatment. Nonetheless, their immunogenicity in patients with IBD against rapidly expanding virus variants remains unknown. This prospective multicenter cohort study is the first study to investigate the immunogenicity of XBB.1.5-adapted vaccines in patients with IBD. Systemic and mucosal antibodies targeting the receptor-binding domains (RBDs) of the omicron subvariants XBB.1.5, EG.5.1, and BA.2.86, as well as their neutralization were quantified before and two to four weeks after vaccination with monovalent XBB.1.5-adapted mRNA vaccines. Vaccination increased levels of serum anti-RBD IgG targeting XBB.1.5, EG.5.1, and BA.2.86 (1.9-fold, 1.8-fold, and 2.6-fold, respectively) and enhanced corresponding neutralization responses (2.3-fold, 3.1-fold, and 3.5-fold, respectively). Following vaccination, anti-TNF-treated patients had reduced virus neutralization compared to patients on treatments with other cellular targets. 11.1% and 16.7% of patients lacked EG.5.1 and BA.2.86 neutralization, respectively; all these patients received anti-TNF treatment. At mucosal sites, vaccination induced variant-specific anti-RBD IgG but failed to induce RBD-targeting IgA. Our findings provide a basis for future vaccine recommendations while highlighting the importance of frequent booster vaccine adaptation and the need for mucosal vaccination strategies in patients with IBD.
RESUMO
BACKGROUND: Vaccine-elicited immune responses are impaired in patients with inflammatory bowel disease (IBD) treated with anti-TNF biologics. AIMS: To assess vaccination efficacy against the novel omicron sublineages BQ.1.1 and XBB.1.5 in immunosuppressed patients with IBD. METHODS: This prospective multicentre case-control study included 98 biologic-treated patients with IBD and 48 healthy controls. Anti-spike IgG concentrations and surrogate neutralisation against SARS-CoV-2 wild-type, BA.1, BA.5, BQ.1.1, and XBB.1.5 were measured at two different time points (2-16 weeks and 22-40 weeks) following third dose vaccination. Surrogate neutralisation was based on antibody-mediated blockage of ACE2-spike protein-protein interaction. Primary outcome was surrogate neutralisation against tested SARS-CoV-2 sublineages. Secondary outcomes were proportions of participants with insufficient surrogate neutralisation, impact of breakthrough infection, and correlation of surrogate neutralisation with anti-spike IgG concentration. RESULTS: Surrogate neutralisation against all tested sublineages was reduced in patients with IBD who were treated with anti-TNF biologics compared to patients treated with non-anti-TNF biologics and healthy controls (each p ≤ 0.001) at visit 1. Anti-TNF therapy (odds ratio 0.29 [95% CI 0.19-0.46]) and time since vaccination (0.85 [0.72-1.00]) were associated with low, and mRNA-1273 vaccination (1.86 [1.12-3.08]) with high wild-type surrogate neutralisation in a ß-regression model. Accordingly, higher proportions of patients treated with anti-TNF biologics had insufficient surrogate neutralisation against omicron sublineages at visit 1 compared to patients treated with non-anti-TNF biologics and healthy controls (each p ≤ 0.015). Surrogate neutralisation against all tested sublineages decreased over time but was increased by breakthrough infection. Anti-spike IgG concentrations correlated with surrogate neutralisation. CONCLUSIONS: Patients with IBD who are treated with anti-TNF biologics show impaired neutralisation against novel omicron sublineages BQ.1.1 and XBB.1.5 and may benefit from prioritisation for future variant-adapted vaccines.
Assuntos
COVID-19 , Doenças Inflamatórias Intestinais , Humanos , Vacinas contra COVID-19/uso terapêutico , SARS-CoV-2 , Estudos de Casos e Controles , Estudos Prospectivos , COVID-19/prevenção & controle , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infecções Irruptivas , Imunoglobulina G , Anticorpos AntiviraisRESUMO
BACKGROUND: Immunosuppressed patients with inflammatory bowel disease (IBD) experience increased risk of vaccine-preventable diseases such as COVID-19. AIMS: To assess humoral and cellular immune responses following SARS-CoV-2 booster vaccination in immunosuppressed IBD patients and healthy controls. METHODS: In this prospective, multicentre, case-control study, 139 IBD patients treated with biologics and 110 healthy controls were recruited. Serum anti-SARS-CoV-2 spike IgG concentrations were measured 2-16 weeks after receiving a third mRNA vaccine dose. The primary outcome was to determine if humoral immune responses towards booster vaccines differ in IBD patients under anti-TNF versus non-anti-TNF therapy and healthy controls. Secondary outcomes were antibody decline, impact of previous infection and SARS-CoV-2-targeted T cell responses. RESULTS: Anti-TNF-treated IBD patients showed reduced anti-spike IgG concentrations (geometric mean 2357.4 BAU/ml [geometric SD 3.3]) when compared to non-anti-TNF-treated patients (5935.7 BAU/ml [3.9]; p < 0.0001) and healthy controls (5481.7 BAU/ml [2.4]; p < 0.0001), respectively. In multivariable modelling, prior infection (geometric mean ratio 2.00 [95% CI 1.34-2.90]) and vaccination with mRNA-1273 (1.53 [1.01-2.27]) increased antibody concentrations, while anti-TNF treatment (0.39 [0.28-0.54]) and prolonged time between vaccination and antibody measurement (0.72 [0.58-0.90]) decreased anti-SARS-CoV-2 spike antibodies. Antibody decline was comparable in IBD patients independent of anti-TNF treatment and antibody concentrations could not predict breakthrough infections. Cellular and humoral immune responses were uncoupled, and more anti-TNF-treated patients than healthy controls developed inadequate T cell responses (15/73 [20.5%] vs 2/100 [2.0%]; p = 0.00031). CONCLUSIONS: Anti-TNF-treated IBD patients have impaired humoral and cellular immunogenicity following SARS-CoV-2 booster vaccination. Fourth dose administration may be beneficial for these patients.
Assuntos
Produtos Biológicos , COVID-19 , Doenças Inflamatórias Intestinais , Humanos , Produtos Biológicos/uso terapêutico , SARS-CoV-2 , Vacinas contra COVID-19 , Linfócitos T , Estudos de Casos e Controles , Estudos Prospectivos , COVID-19/prevenção & controle , Inflamação , Doenças Inflamatórias Intestinais/tratamento farmacológico , Anticorpos Antivirais , Vacinas de mRNA , Imunoglobulina GRESUMO
BACKGROUND: NOD2 variants are the strongest genetic predictors for susceptibility to Crohn's disease (CD). However, the clinical value of NOD2 on an individual patient level remains controversial. We aimed to define the predictive power of the major NOD2 mutations regarding complicated CD in a large single center cohort. METHODS: 1076 CD patients were prospectively genotyped for the three common CD-associated NOD2 mutations rs2066844, rs2066845, and rs2066847, followed by detailed genotype-phenotype analyses. RESULTS: Overall, 434 CD patients (40.3%) carried at least one of the three main NOD2 mutations. A significantly higher minor allele frequency (15.6%) of the NOD2 frameshift mutation p.Leu1007fsX1008 (rs2066847) was seen in patients with aggressive disease compared to 8.2% in patients with mild disease (p = 2.6 x 10-5). Moreover, a total of 54 CD patients (5.0%) were homozygous for this NOD2 frameshift mutation. 100% of these patients had ileal disease compared to 82% of NOD2 wild-type carriers (p<0.0001). In homozygous carriers of the NOD2 frameshift mutation, 87% presented with ileal stenosis, 68.5% had fistulas, and 72.2% required CD-related surgery despite immunosuppressive therapy in 87% of these patients. All homozygous carriers of the 1007fs mutation who were active smokers had ileal stenosis and required CD-related surgery. CONCLUSION: Homozygosity for Leu1007fsX1008 is an excellent biomarker for predicting complicated CD on an individual patient level. Active smoking and homozygosity for this mutation is associated with a 100% risk for developing ileal stenosis requiring CD-related surgery. In these patients, smoking cessation and early initiation of immunosuppressive strategies may be beneficial.
Assuntos
Doença de Crohn/genética , Doença de Crohn/patologia , Doenças do Íleo/cirurgia , Obstrução Intestinal/etiologia , Obstrução Intestinal/cirurgia , Mutação/genética , Proteína Adaptadora de Sinalização NOD2/genética , Fumar/efeitos adversos , Adolescente , Adulto , Estudos de Coortes , Doença de Crohn/complicações , Feminino , Dosagem de Genes , Frequência do Gene/genética , Marcadores Genéticos , Predisposição Genética para Doença , Heterozigoto , Homozigoto , Humanos , Doenças do Íleo/etiologia , Modelos Logísticos , Masculino , Fenótipo , Fatores de Risco , Índice de Gravidade de Doença , Adulto JovemRESUMO
BACKGROUND: The influence of high blood alcohol level (BAL) on the outcome of severely injured patients and the corresponding pathophysiological changes is a controversial issue. OBJECTIVE: To carry out a prognostic study to compare the physiological values and short-term outcome of severely injured patients depending on their serum alcohol level. METHODS: A total of 383 severely injured patients with an Injury Severity Score (ISS) ≥17 were admitted to the trauma division between October 2008 and December 2009 and enrolled into this study. Patients were grouped according to their BAL (>0.5,'BAL positive' vs <0.5,'BAL negative'). Trauma mechanism, pattern of injury and its treatment, and a course of intensive care treatment, physiological parameters and outcome with respect to mortality were analysed. RESULTS: Both groups had similar ISS. In comparison with the BAL-negative group, patients in the BAL-positive group had a significantly lower Glasgow Coma Scale score (9.64 vs 12 points; p=0.005) and, although not significant, a trend towards higher values of the Abbreviated Injury Score for the head (3.29 vs 2.81 points; p=0.146). Furthermore, significantly higher lactate (3.11â mmol/L vs 2.02â mmol/L; p<0.001) levels and lower median arterial pressure values (87.9â mmâ Hg vs 99.4â mmâ Hg; p=0.006) were seen in the BAL-positive group at day of admission. However, the overall in-hospital mortality was comparable to that in BAL-negative patients (19.6% vs 21.5%). Similarly, hospital stay (15.29 vs 17.55â days) and duration of intensive care unit treatment (8.53 vs 8.36â days) were not significantly affected by a high BAL upon admission. CONCLUSIONS: Severely injured patients with a raised BAL have a higher incidence of severe traumatic brain injury and worse initial physiological parameters. However, the survival rate and in-hospital stay is not influenced. This supports the theory of a neuroprotective role of alcohol.