Humoral and T-cell response 12 months after the first BNT162b2 vaccination in solid organ transplant recipients and controls: Kinetics, associated factors, and role of SARS-CoV-2 infection.

Introduction: We investigated humoral and T-cell responses within 12 months after first BNT162b2 vaccine in solid organ transplant (SOT) recipients and controls who had received at least three vaccine doses. Furthermore, we compared the immune response in participants with and without previous SARS-CoV-2 infection. Methods: We included adult liver, lung, and kidney transplant recipients, and controls were selected from a parallel cohort of healthcare workers. Results: At 12th-month, the IgG geometric mean concentrations (GMCs) (P<0.001), IgA GMCs (P=0.003), and median IFN-γ (P<0.001) were lower in SOT recipients than in controls. However, in SOT recipients and controls with previous infection, the neutralizing index was 99%, and the IgG, and IgA responses were comparable. After adjustment, female-sex (aOR: 3.6, P<0.009), kidney (aOR: 7.0, P= 0.008) or lung transplantation (aOR: 7.5, P= 0.014), and use of mycophenolate (aOR: 5.2, P=0.03) were associated with low IgG non response. Age (OR:1.4, P=0.038), time from transplantation to first vaccine (OR: 0.45, P<0.035), and previous SARS-CoV-2 infection (OR: 0.14, P<0.001), were associated with low IgA non response. Diabetes (OR:2.4, P=0.044) was associated with T-cell non response. Conclusion: In conclusion, humoral and T-cell responses were inferior in SOT recipients without previous SARS-CoV-2 infection but comparable to controls in SOT recipients with previous infection.

Waning humoral and cellular immunity after COVID-19 vaccination in patients with psoriasis treated with methotrexate and biologics: a cohort study.

BACKGROUND: mRNA-based COVID-19 vaccines have short and long-term efficacy in healthy individuals, but their efficacy in patients with psoriasis receiving immunomodulatory therapy is less studied. OBJECTIVE: To investigate long-term immunity after COVID-19 vaccination in patients with psoriasis receiving immunomodulatory therapy. METHODS: A prospective cohort study including patients (n = 123) with psoriasis receiving methotrexate (MTX) or biologics and controls (n = 226). Only mRNA-based COVID-19 vaccines administered with standard intervals between doses were investigated. Markers of immunity included SARS-CoV-2 spike-glycoprotein specific IgG and IgA, neutralizing capacity, and interferon-gamma release from T-cells stimulated with peptides of the SARS-CoV-2 spike-glycoprotein. RESULTS: The proportion of IgG responders was lower 6 months after vaccination in patients receiving anti-TNF compared to controls. Anti-TNF treatment was associated with lower IgG levels (ß=-0.82, 95% CI -1.38 to -0.25: P = 0.001). The median neutralizing index was lower in the anti-TNF group, 50% inhibition (IQR 37-89) compared to controls, 98% inhibition (IQR 96-99), P < 0.001. Cellular responses were numerically lowest in anti-TNF group. CONCLUSIONS: Treatment with anti-TNF has an impact on the immunity elicited by mRNA-based COVID-19 vaccination in patients with psoriasis, resulting in a faster waning of humoral and cellular markers of immunity, however, the clinical implications are unknown.

Persistent Symptoms and Sequelae After Severe Acute Respiratory Syndrome Coronavirus 2 Infection Not Requiring Hospitalization: Results From Testing Denmark, a Danish Cross-sectional Survey.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with persistent symptoms ("long COVID"). We assessed the burden of long COVID among nonhospitalized adults with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection. Methods: In the fall of 2020, a cross-sectional survey was performed in the adult Danish general population. This included a self-administered point-of-care test for SARS-CoV-2 antibodies, the Short Form Health Survey (SF-12), and coronavirus disease 2019 (COVID-19)-associated symptom questions. Nonhospitalized respondents with a positive SARS-CoV-2 PCR test ≥12 weeks before the survey (cases) were matched (1:10) to seronegative controls on age, sex, and body mass index. Propensity score-weighted odds ratios (ORs) and ORs for risk factors were estimated for each health outcome. Results: In total, 742 cases and 7420 controls were included. The attributable risk of at least 1 long-COVID symptom was 25.0 per 100 cases (95% confidence interval [CI], 22.2-27.4). Compared to controls, cases reported worse general health (OR, 5.9 [95% CI, 5.0-7.0]) and had higher odds for a broad range of symptoms, particularly loss of taste (OR, 11.8 [95% CI, 9.5-14.6]) and smell (OR, 11.2 [95% CI, 9.1-13.9]). Physical and Mental Component Summary scores were also significantly reduced with differences of -2.5 (95% CI, -3.1 to -1.8) and -2.0 (95% CI, -2.7 to -1.2), respectively. Female sex and severity of initial infection were major risk factors for long COVID. Conclusions: Nonhospitalized SARS-CoV-2 PCR-positive individuals had significantly reduced physical and mental health, and 1 in 4 reported persistence of at least 1 long-COVID symptom.

Short- and Long-Term Self-Reported Symptoms in Adolescents Aged 12-19 Years after Vaccination against SARS-CoV-2 Compared to Adolescents Not Vaccinated-A Danish Retrospective Cohort Study.

This study investigated self-reported short- and long-term symptoms among adolescents receiving the BNT162b2 (Pfizer/BioNTech) vaccine against SARS-CoV-2 and those who did not. A retrospective cohort study based on Danish national survey (collected between 20 July and 15 September 2021) and register data was conducted. Differences in short-term (<14 days) and long-term (>two months) symptoms were explored using logistic regression adjusted for confounders. A total of 747 vaccinated (first dose n = 326; second dose n = 421) and 6300 unvaccinated adolescents were included in analyses of short-term symptoms and 32 vaccinated and 704 unvaccinated adolescents in long-term symptom analyses. In the first 14 days after the first and second vaccine dose the most reported symptoms included headache and muscle or joint symptoms. In both vaccinated and unvaccinated adolescents, the 15-19-year-olds reported significantly higher proportions of all symptoms compared to the 12-14-year-olds. After the second vaccine dose vaccinated 12-14-year-olds reported significantly more headache in adjusted analyses (OR 2.20 (95% CI 1.24; 3.90)). Among the 15-19-year-olds, significantly more vaccinated adolescents reported gastrointestinal symptoms (1.38 (1.06; 1.81)), headache (1.66 (1.24; 2.22)), and tiredness (1.44 (1.08; 1.93)). No differences were found in long-term symptoms. Vaccinated adolescents reported significantly more short-term symptoms including headache, tiredness, and gastrointestinal symptoms after the second vaccine dose than unvaccinated adolescents. Long-term symptom results should be interpreted with caution due to limited sample size.

Early stimulated immune responses predict clinical disease severity in hospitalized COVID-19 patients.

Background: The immune pathogenesis underlying the diverse clinical course of COVID-19 is poorly understood. Currently, there is an unmet need in daily clinical practice for early biomarkers and improved risk stratification tools to help identify and monitor COVID-19 patients at risk of severe disease. Methods: We performed longitudinal assessment of stimulated immune responses in 30 patients hospitalized with COVID-19. We used the TruCulture whole-blood ligand-stimulation assay applying standardized stimuli to activate distinct immune pathways, allowing quantification of cytokine responses. We further characterized immune cell subsets by flow cytometry and used this deep immunophenotyping data to map the course of clinical disease within and between patients. Results: Here we demonstrate impairments in innate immune response pathways at time of COVID-19 hospitalization that are associated with the development of severe disease. We show that these impairments are transient in those discharged from hospital, as illustrated by functional and cellular immune reconstitution. Specifically, we identify lower levels of LPS-stimulated IL-1ß, and R848-stimulated IL-12 and IL-17A, at hospital admission to be significantly associated with increasing COVID-19 disease severity during hospitalization. Furthermore, we propose a stimulated immune response signature for predicting risk of developing severe or critical COVID-19 disease at time of hospitalization, to validate in larger cohorts. Conclusions: We identify early impairments in innate immune responses that are associated with subsequent COVID-19 disease severity. Our findings provide basis for early identification of patients at risk of severe disease which may have significant implications for the early management of patients hospitalized with COVID-19.

Antibody responses and risk factors associated with impaired immunological outcomes following two doses of BNT162b2 COVID-19 vaccination in patients with chronic pulmonary diseases.

INTRODUCTION: Responses to COVID-19 vaccination in patients with chronic pulmonary diseases are poorly characterised. We aimed to describe humoral responses following two doses of BNT162b2 mRNA COVID-19 vaccine and identify risk factors for impaired responses. METHODS: Prospective cohort study including adults with chronic pulmonary diseases and healthcare personnel as controls (1:1). Blood was sampled at inclusion, 3 weeks, 2 and 6 months after first vaccination. We reported antibody concentrations as geometric means with 95% CI of receptor binding domain (RBD)-IgG and neutralising antibody index of inhibition of ACE-2/RBD interaction (%). A low responder was defined as neutralising index in the lowest quartile (primary outcome) or RBD-IgG <225 AU/mL plus neutralising index <25% (secondary outcome), measured at 2 months. We tested associations using Poisson regression. RESULTS: We included 593 patients and 593 controls, 75% of all had neutralising index ≥97% at 2 months. For the primary outcome, 34.7% of patients (n=157/453) and 12.9% of controls (n=46/359) were low responders (p<0.0001). For the secondary outcome, 8.6% of patients (n=39/453) and 1.4% of controls (n=5/359) were low responders (p<0.001). Risk factors associated with low responder included increasing age (per decade, adjusted risk ratio (aRR) 1.17, 95% CI 1.03 to 1.32), Charlson Comorbidity Index (per point) (aRR 1.15, 95% CI 1.05 to 1.26), use of prednisolone (aRR 2.08, 95% CI 1.55 to 2.77) and other immunosuppressives (aRR 2.21, 95% CI 1.65 to 2.97). DISCUSSION: Patients with chronic pulmonary diseases established functional humoral responses to vaccination, however lower than controls. Age, comorbidities and immunosuppression were associated with poor immunological responses.

Long COVID symptoms in SARS-CoV-2-positive children aged 0-14 years and matched controls in Denmark (LongCOVIDKidsDK): a national, cross-sectional study.

BACKGROUND: After the acute phase of SARS-CoV-2 infection, children can develop long COVID symptoms. We aimed to investigate the prevalence of long-lasting symptoms, the duration and intensity of symptoms, quality of life, number of sick days and absences from daycare or school, and psychological and social outcomes in children aged 0-14 years who had been infected with SARS-CoV-2 relative to controls with no history of SARS-CoV-2 infection. METHODS: A nationwide cross-sectional study was conducted including children with a confirmed SARS-CoV-2-positive PCR test (cases) and matched controls from Danish national registers. A survey was sent to mothers (proxy reporting) of children aged 0-14 years who had had a positive SARS-CoV-2 test between Jan 1, 2020, and July 12, 2021, and a control group matched (1:4) by age and sex. The survey included the Pediatric Quality of Life Inventory (PedsQL) and the Children's Somatic Symptoms Inventory-24 (CSSI-24) to capture current overall health and wellbeing, and ancillary questions about the 23 most common long COVID symptoms. Descriptive statistics and logistic regression analysis were used. Clinically relevant differences were defined as those with a Hedges'g score greater than 0·2. This study is registered at ClinicalTrials.gov (NCT04786353). FINDINGS: Responses to the survey were received from 10 997 (28·8%) of 38 152 cases and 33 016 (22·4%) of 147 212 controls between July 20, 2021, and Sept 15, 2021. Median age was 10·2 years (IQR 6·6-12·8) in cases and 10·6 years (6·9-12·9) in controls. 5267 (48·2%) cases and 15 777 (48·3%) controls were female, and 5658 (51·8%) cases and 16 870 (51·7%) controls were male. Cases had higher odds of reporting at least one symptom lasting more than 2 months than did controls in the 0-3 years age group (478 [40·0%] of 1194 vs 1049 [27·2%] of 3855; OR 1·78 [95% CI 1·55-2·04], p<0·0001), 4-11 years age group (1912 [38·1%] of 5023 vs 6189 [33·7%] of 18 372; 1·23 [1·15-1·31], p<0·0001), and 12-14 years age group (1313 [46·0%] of 2857 vs 4454 [41·3%] of 10 789; 1·21 [1·11-1·32], p<0·0001). Differences in CSSI-24 symptom scores between cases and controls were statistically significant but not clinically relevant. Small clinically relevant differences in PedsQL quality-of-life scores related to emotional functioning were found in favour of cases in the children aged 4-11 years (median score 80·0 [IQR 65·0-95·0]) in cases vs 75·0 [60·0-85·0] in controls; p<0·0001) and 12-14 years (90·0 [70·0-100·0] vs (85·0 [65·0-95·0], p<0·0001). PedsQL social functioning scores were also higher in cases (100·0 [90·0-100·0] than controls (95·0 [80·0-100·0]) in the 12-14 years age group (p<0·0001; Hedges g>0·2). INTERPRETATION: Compared with controls, children aged 0-14 years who had a SARS-CoV-2 infection had more prevalent long-lasting symptoms. There was a tendency towards better quality-of-life scores related to emotional and social functioning in cases than in controls in older children. The burden of symptoms among children in the control group requires attention. Long COVID must be recognised and multi-disciplinary long COVID clinics for children might be beneficial. FUNDING: A P Møller and Chastine Mc-Kinney Møller Foundation.