Humoral and cellular immune response from first to fourth SARS-CoV-2 mRNA vaccination in anti-CD20-treated multiple sclerosis patients-a longitudinal cohort study.

Background: This study examines the humoral and cellular response in multiple sclerosis (MS) patients on anti-CD20 therapy before and after the 1st to 4th BNT162b2 mRNA SARS-CoV-2 vaccination and the relationship with breakthrough infection. Methods: Participants with McDonald 2017 MS that were treated with ocrelizumab were included. The study duration was throughout the COVID-19 pandemic until four months after fourth mRNA SARS-CoV-2 vaccination (BNT162b2). Longitudinal blood samples were analysed for: IgG antibodies of SARS-CoV-2 spike anti-receptor binding domain (anti-RBD), nucleocapsid IgG antibodies (anti-N) and activation induced marker expressing CD4+, CD8+ T-cells and concentration of ocrelizumab and anti-drug antibodies. Incidences of breakthrough infection were confirmed with SARS-CoV-2 PCR tests. Results: The rate of anti-RBD positive participants increased substantially between the third and fourth vaccination from 22.2% to 55.9% (median 54.7 BAU/mL; IQR: 14.5 - 221.2 BAU/mL and 607.7 BAU/mL; IQR: 29.4 - 784.6 BAU/mL, respectively). Within the same period 75% of participants experienced breakthrough infection. The fourth vaccination resulted in an additional increase in seropositive individuals (64.3%) (median 541.8 BAU/mL (IQR: 19.1-1007 BAU/mL). Breakthrough infection did not influence the cellular response without a significant change after the fourth vaccination. During the study period two participants had detectable anti-N, both after the fourth vaccination. No correlation was found between serum concentration of ocrelizumab and the humoral and cellular response. Discussion: Low levels or absence of specific anti-RBD following vaccination, with a significant increase after breakthrough infections and boosted by the fourth vaccination. T-cell reactivity remained sustained and unaffected by breakthrough infections.

Initial screening for neuronal autoantibodies and their putative impact on survival in patients with small-cell lung cancer.

INTRODUCTION: Small-cell lung cancer (SCLC) may be associated with neuronal autoantibodies and paraneoplastic neurological syndromes. It has been suggested that neuronal autoantibodies, especially antineuronal nuclear antibody type 1 (Hu) autoantibodies, are associated with longer survival of patients with SCLC. The objective of this study was to determine the frequency and distribution of neuronal autoantibodies at the time of diagnosis of SCLC patients and assess survival rates in relation to autoimmunity. METHODS: In this retrospective study, serum from 40 patients with biopsy-proven SCLC at the time of diagnosis was studied prior to treatment. The sera originated from a cancer registry at the Oncology Department, Vejle Hospital from 2007 to 2010. The sera were analyzed blindly to clinical status for the presence of neuronal autoantibodies. Medical records were reviewed for neurological symptoms. RESULTS: Neuronal autoantibodies were detected in 22/40 (55%) of the SCLC patients. A broad range of neurological symptoms was recorded in 28/40 (70%) patients, of which 14/28 (50%) were positive for neuronal autoantibodies. The most frequently detected autoantibodies were Hu (7/40, 17.5%) followed by GAD65 (6/22, 15.0%). Striational and P/Q- or N-type voltage-gated calcium channel antibodies were less common, with each found in five patients (12.5%). Eight patients (20%) had coexisting autoantibodies. Autoantibody-positivity was not associated with survival. CONCLUSION: Neuronal autoantibodies were at time of diagnosis found in approximately half of the treatment-naïve SCLC patients. Neither autoantibody positivity at diagnosis nor neurological manifestations correlated with survival and their clinical importance requires further studies in larger, prospective cohorts.

SARS-CoV-2 Antibodies in Breastmilk Three and Six Months Postpartum in Relation to the Trimester of Maternal SARS-CoV-2 Infection-An Exploratory Study.

The immune system of neonates is immature and therefore knowledge of possible early-life protection against SARS-CoV-2 infection, such as breastfeeding, is of great importance. Few studies have investigated the presence and duration of SARS-CoV-2 antibodies in breastmilk in relation to the trimester of maternal infection during pregnancy, and none with successful participation from all three trimesters. This study has dual objectives (1) in relation to the trimester of infection to examine the frequency, concentration and duration of IgA and IgG antibodies in breastmilk and blood serum in the third and sixth month post-partum in former SARS-CoV-2-infected mothers and (2) to examine the association in pediatric emergency admission of children within the first six months of life compared to children of non-SARS-CoV-2-infected women. The first objective is based on a prospective cohort and the second is based on a nested case-control design. The study participants are women with a former SARS-CoV-2 infection during pregnancy, whose serology IgG tests at delivery were still positive. Maternal blood and breastmilk samples were collected at three and six months postpartum. Serum IgA frequency three months pp was 72.7% (50%, 90% and 60% in the first, second and third trimester) and 82% six months pp (67%, 91% and 82% in the first, second and third trimester). Breastmilk IgA frequency three months pp was 27% (16.6%, 36% and 20% in first, second and third trimester) and 28% six months pp (0%, 38% and 28% in the first, second and third trimester). The highest IgA concentration in breastmilk was found six months post-partum with infection in the third trimester. Serum IgA was detectable more than 400 days post infection, and serum IgG above threshold was found 430 days after date of infection. We found no correlation between serum IgA and breastmilk IgA, nor between serum IgG and breastmilk IgA regardless of the trimester of infection.

Dynamics of inflammation-associated plasma proteins following faecal microbiota transplantation in patients with psoriatic arthritis and healthy controls: exploratory findings from the FLORA trial.

OBJECTIVES: The gut microbiota can mediate both pro and anti-inflammatory responses. In patients with psoriatic arthritis (PsA), we investigated the impact of faecal microbiota transplantation (FMT), relative to sham transplantation, on 92 inflammation-associated plasma proteins. METHODS: This study relates to the FLORA trial cohort, where 31 patients with moderate-to-high peripheral PsA disease activity, despite at least 3 months of methotrexate treatment, were included in a 26-week, double-blind, randomised, sham-controlled trial. Participants were allocated to receive either one gastroscopic-guided healthy donor FMT (n=15) or sham (n=16). Patient plasma samples were collected at baseline, week 4, 12 and 26 while samples from 31 age-matched and sex-matched healthy controls (HC) were collected at baseline. Samples were analysed using proximity extension assay technology (Olink Target-96 Inflammation panel). RESULTS: Levels of 26 proteins differed significantly between PsA and HC pre-FMT (adjusted p<0.05), of which 10 proteins were elevated in PsA: IL-6, CCL20, CCL19, CDCP1, FGF-21, HGF, interferon-γ (IFN-γ), IL-18R1, monocyte chemotactic protein 3, and IL-2. In the FMT group, levels of 12 proteins changed significantly across all timepoints (tumour necrosis factor (TNF), CDCP1, IFN-γ, TWEAK, signalling lymphocytic activation molecule (SLAMF1), CD8A, CD5, Flt3L, CCL25, FGF-23, CD6, caspase-8). Significant differences in protein levels between FMT and sham-treated patients were observed for TNF (p=0.002), IFN-γ (p=0.011), stem cell factor (p=0.024), matrix metalloproteinase-1 (p=0.038), and SLAMF1 (p=0.042). FMT had the largest positive effect on IFN-γ, Axin-1 and CCL25 and the largest negative effect on CCL19 and IL-6. CONCLUSIONS: Patients with active PsA have a distinct immunological plasma protein signature compared with HC pre-FMT. FMT affects several of these disease markers, including sustained elevation of IFN-γ. TRIAL REGISTRATION NUMBER: NCT03058900.

Tick-borne encephalitis as a trigger for anti-N-Methyl-d-aspartate receptor encephalitis.

Tick Borne Encephalitis (TBE) is endemic to an increasing number of countries and is a common cause of meningoencephalitis in Europe and Asia making any potential complications of the disease increasingly relevant to clinicians. We present, what is to our knowledge, the second reported case of N-methyl-d-aspartate receptor (NMDAR) encephalitis following Tick Borne Encephalitis (TBE) in a 47-year-old Lithuanian man. The case provides further evidence of TBE being a possible trigger of NMDAR encephalitis and highlights the importance of being aware of symptoms of autoimmune encephalitis in patients with infectious encephalitis.

Humoral antibody response following mRNA vaccines against SARS-CoV-2 in solid organ transplant recipients; a status after a fifth and bivalent vaccine dose.

Background: In solid organ transplant (SOT) recipients, the humoral response following COVID-19 vaccination is reduced, as a result of their immunosuppressed treatment. In this study, we investigated antibody concentrations after booster vaccinations until the fifth dose, the latter by monovalent or bivalent BA1 or BA4/5 vaccines. In addition, we evaluated the efficacy of vaccination by recording breakthrough infections, hospitalizations, and deaths. Method: This prospective cohort study included 438 SOT recipients (>18 years) vaccinated with mRNA vaccines against COVID-19 from January 2021 until March 2023. Blood samples were drawn before and after each vaccination and tested for SARS-CoV-2 spike RBD IgG antibodies with the lowest and highest cut-off at 7.1 and 5,680 BAU/mL, respectively. Vaccine information, breakthrough infections, and hospitalizations were collected from the medical records. Results: Most participants received BNT162b2 and 61.4% received five vaccine doses. The response proportion in SOT recipients increased from 86.7% after the fourth dose to 93.0% following the fifth dose. Antibody concentration decreased with 142.7 BAU/mL between the third and fourth dose (median 132 days, Quartile 1: 123, Quartile 3: 148) and 234.3 BAU/mL between the fourth and fifth (median 250 days, Quartile 1: 241, Quartile 3: 262) dose among those without breakthrough infection (p=0.34). When comparing the Omicron BA.1 or Omicron BA.4/BA.5 adapted vaccines, no significant differences in antibody concentration were found, but 20.0% of SOT recipients receiving a monovalent fifth vaccine dose had a breakthrough infection compared to 4.0% and 7.9% among those who received BA.1 and BA.4/BA.5 adapted vaccines, respectively (p=0.04). Since January 2021, 240 (54.8%) participants had a breakthrough infection, and 22 were hospitalized, but no deaths were observed. Conclusions: The fifth COVID-19 vaccine dose raised antibody response to 93.0% of the study population. Additional booster doses, as well as bivalent vaccines, led to higher levels of antibody concentration in SOT recipients. We found a lower incidence of breakthrough infections among SOT recipients after receiving a bivalent vaccine as a fifth dose compared to those receiving a monovalent dose. Antibody concentrations did not wane when the time between doses was prolonged from four to eight months.

SARS-CoV-2 and autoantibodies in the cerebrospinal fluid of COVID-19 patients: prospective multicentre cohort study.

Disease mechanisms underlying neurological and neuropsychiatric symptoms after coronavirus disease 2019 (COVID-19), termed neuro-COVID, are poorly understood. Investigations of the cerebrospinal fluid (CSF) for the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and antibodies, as well as autoantibodies against neuronal surface antigens, could improve our understanding in that regard. We prospectively collected CSF and blood from patients investigated by lumbar puncture for neurological or neuropsychiatric symptoms during or after COVID-19. Primary outcomes were the presence of (i) SARS-CoV-2 RNA in CSF via polymerase chain reaction (PCR), (ii) SARS-CoV-2 immunoglobulin G (IgG) anti-S receptor-binding-domain antibodies via the Euroimmun and Wantai assays and (iii) IgG autoantibodies against neuronal surface antigens using commercial cell- and tissue-based assays (Euroimmun). Secondary outcomes were (i) routine CSF investigations and (ii) correlation between SARS-CoV-2 antibody levels in CSF with serum levels, blood-brain barrier permeability and peripheral inflammation. We obtained CSF from 38 COVID-19 patients (mean age 56.5 ± 19.2 years, 53% women) who developed neurological and neuropsychiatric symptoms. CSF pleocytosis (>5 cells) was observed in 9/38 patients (23.7%), elevated CSF protein (>0.50 g/L) in 13/38 (34.2%) and elevated CSF/serum albumin ratio in 12/35 (34.3%). PCR for SARS-CoV-2 RNA in CSF was negative in all. SARS-CoV-2 CSF antibodies were detected in 15/34 (44.1%; Euroimmun assay) and 7/31 (22.6%; Wantai assay) individuals, but there were no signs of intrathecal SARS-CoV-2 IgG production. SARS-CoV-2 CSF antibodies were positively correlated with serum levels (R = 0.93, P < 0.001), blood-brain barrier permeability (R = 0.47, P = 0.006), peripheral inflammation (R = 0.51, P = 0.002) and admission to the intensive care unit [odds ratio (OR) 17.65; 95% confidence interval (CI) 1.18-264.96; P = 0.04; n = 15]. Cell-based assays detected weakly positive NMDAR, LGI1 and CASPR2 antibodies in serum of 4/34 (11.8%) patients but not in CSF. The tissue-based assay showed anti-neuronal fluorescence in CSF from one individual, staining for Purkinje cells. In summary, whereas we did not detect active SARS-CoV-2 infection in the CSF, SARS-CoV-2 antibodies were prevalent. The absence of intrathecal antibody production points towards blood-brain barrier impairment as the origin of CSF SARS-CoV-2 antibodies. In contrast, CSF autoantibodies against neuronal surface antigens were rare. There was no evidence for a clinical correlate of these antibodies. We conclude that, rather than specific autoimmune neuronal injury, non-specific effects of critical illness including an impaired blood-brain barrier are more likely to contribute to neuro-COVID.

Antineuronal Autoantibodies in the Cerebrospinal Fluid and Serum From 106 Patients With Recent-Onset Depression Compared With 106 Individually Matched Healthy Control Subjects.

No large studies have investigated the prevalence of cerebrospinal fluid antineuronal autoantibodies in isolated depression. In this case-control study comparing 106 patients with isolated depression (ICD-10 code F32) with 106 healthy control subjects, cerebrospinal fluid and serum samples were tested for 7 immunoglobulin G autoantibodies using commercial fixed cell-based assays. To explore validity of methods, positive samples were retested twice by cell-based assays and once by tissue-based assays (monkey cerebellum). The prevalence of any of the antineuronal autoantibodies in cerebrospinal fluid was 0.0% in both groups and the seroprevalence was 0.9% in both groups, based on consistent findings in cell-based assays. However, all samples were negative by the tissue-based assay. Evaluation of antineuronal autoantibodies in cerebrospinal fluid cannot be recommended routinely for patients with isolated depression of moderate severity. Future studies of isolated depression should consider much larger sample sizes and evaluation of antineuronal autoantibodies using modalities other than commercial kits.

Small Intestinal Permeability and Metabolomic Profiles in Feces and Plasma Associate With Clinical Response in Patients With Active Psoriatic Arthritis Participating in a Fecal Microbiota Transplantation Trial: Exploratory Findings From the FLORA Trial.

OBJECTIVE: We investigated intestinal permeability and fecal, plasma, and urine metabolomic profiles in methotrexate-treated active psoriatic arthritis (PsA) and how this related to clinical response following one sham or fecal microbiota transplantation (FMT). METHODS: This exploratory study is based on the FLORA trial cohort, in which 31 patients with moderate-to-high peripheral PsA disease activity, despite at least 3 months of methotrexate-treatment, were included in a 26-week, double-blind, 1:1 randomized, sham-controlled trial. Participants were randomly allocated to receive either one healthy donor FMT (n = 15) or sham (n = 16) via gastroscopy. The primary trial end point was the proportion of treatment failures through 26 weeks. We performed a lactulose-to-mannitol ratio (LMR) test at baseline (n = 31) and at week 26 (n = 26) to assess small intestinal permeability. Metabolomic profiles in fecal, plasma, and urine samples collected at baseline, weeks 4, 12, and 26 were measured using 1 H Nuclear Magnetic Resonance. RESULTS: Trial failures (n = 7) had significantly higher LMR compared with responders (n = 19) at week 26 (0.027 [0.017-0.33]) vs. 0.012 [0-0.064], P = 0.013), indicating increased intestinal permeability. Multivariate analysis revealed a significant model for responders (n = 19) versus failures (n = 12) at all time points based on their fecal (P < 0.0001) and plasma (P = 0.005) metabolomic profiles, whereas urine metabolomic profiles did not differ between groups (P = 1). Fecal N-acetyl glycoprotein GlycA correlated with Health Assessment Questionnaire Disability Index (coefficient = 0.50; P = 0.03) and fecal propionate correlated with American College of Rheumatology 20 response at week 26 (coefficient = 27, P = 0.02). CONCLUSION: Intestinal permeability and fecal and plasma metabolomic profiles of patients with PsA were associated with the primary clinical trial end point, failure versus responder.

Low protection from breakthrough SARS-CoV-2 infection and mild disease course in ocrelizumab-treated patients with multiple sclerosis after three mRNA vaccine doses.

BACKGROUND: Our study investigated the rate of breakthrough SARS-CoV-2 infection and clinical outcomes in a cohort of multiple sclerosis (MS) patients who were treated with the anti-CD20 monoclonal antibody (Ab), ocrelizumab, before first, second and third BNT162b2 mRNA vaccinations. To correlate clinical outcomes with the humoral and cellular response. METHODS: The study was a prospective non-randomised controlled multicentre trial observational study. Participants with a diagnosis of MS who were treated for at least 12 months with ocrelizumab prior to the first BNT162b2 mRNA vaccination were prospectively followed up from January 2021 to June 2022. RESULTS: Out of 54 participants, 32 (59.3%) developed a positive SARS-CoV-2 PCR test in the study period. Mild infection was observed in all infected participants. After the third vaccination, the non-infected participants had higher mean Ab levels compared to the infected participants (54.3 binding antibody unit (BAU)/mL vs 26.5 BAU/mL, p=0.030). The difference in reactivity between spike-specific CD4+ and CD8+ T lymphocytes in the two groups was not significant. CONCLUSION AND RELEVANCE: The study results demonstrate rates of 59% in breakthrough infections after the third SARS-CoV-2 mRNA vaccination in ocrelizumab-treated patients with MS, without resulting in critical disease courses. These findings suggest the need for continuous development of prophylactic treatments when proved important in the protection of severe breakthrough infection.

Paraneoplastic neurologic syndromes.

Diagnosis of paraneoplastic neurologic syndromes (PNS) requires an understanding of the clinical, immunologic and oncologic heterogeneity. The 2004 PNS criteria were partially outdated due to advances in the field, and updated consensus criteria for PNS have been proposed in 2021, including the PNS-Care score for assessment of PNS probability. Furthermore, knowledge on the limitations of autoantibody testing is crucial to ensure accurate interpretation. This review presents the updated diagnostic criteria for PNS, in a Danish context.

Antineuronal antibodies in cerebrospinal fluid and serum of 104 patients with psychotic disorders compared to 104 individually matched healthy controls.

BACKGROUND: Antineuronal antibodies can cause psychotic symptoms, particularly NMDAR antibodies; however, studies on the prevalence of antineuronal antibodies in cerebrospinal fluid (CSF) and serum of patients with psychotic disorders compared to matched healthy controls are sparse. METHODS: We included 104 patients with a first-time diagnosis of a psychotic disorder within one year prior to inclusion (50 % outpatients) and 104 individually matched healthy controls, all without any known immunological conditions. CSF and serum were tested for IgG antibodies (Abs) against NMDAR NR1-subunit, GAD65, LGI1, CASPR2, AMPAR1, AMPAR2 and GABAb-receptor B1/B2 using commercial fixed cell-based assays (CBAs) (Euroimmun). Positive samples were retested with CBA twice, and tested with tissue-based assays (TBA). Primary outcomes were the presence of any of the seven anti-neuronal antibodies in CSF or serum. Secondarily, we analyzed the prevalence of each autoantibody. RESULTS: No antineuronal IgG antibodies were consistently found in any CSF sample and NMDAR-antibodies were not consistently present in any of the 208 participants, neither in CSF nor serum. CASPR2-Abs were consistently found in the serum of one patient and one control, and one healthy control, without diabetes, was seropositive for GAD65-Abs. CASPR2 borderline seropositivity was additionally found in one patient and two controls. All samples positive on CBA were negative on TBA. CONCLUSIONS: We found no significant differences between patients and controls. Antineuronal IgG antibodies are very rare when screening a broad group of individuals with recent-onset psychotic disorders without other indications of autoimmune encephalitis. Thus, much larger studies are needed to conclude on potential contrasts in prevalence compared to healthy controls.

Immunogenicity and risk of disease flare after a three-dose regimen with SARS-CoV-2 vaccination in patients with systemic lupus erythematosus: results from the prospective cohort study COVAC-SLE.

OBJECTIVES: To investigate the humoral immune response and risk of disease flare in systemic lupus erythematosus (SLE) patients following three-doses of SARS-CoV-2 vaccines. METHODS: In adult patients with SLE, we measured SARS-CoV-2 spike IgG in blood samples drawn three weeks after the 1st dose (baseline), four and eight weeks after the 2nd dose and after the 3rd dose. A sufficient antibody response was ≥54BAU/mL. SLEDAI-2K, SLAQ and SDI were assessed at baseline and eight weeks after the 2nd dose along with adverse events. Demographic and treatment data were collected from hospital records. RESULTS: Of 123 patients, 115 (93.5%) received the BNT162b2 vaccine, the remaining received the 1st dose of ChAdOx-1 followed by a 2nd and 3rd dose of mRNA-1273. After the 2nd dose 102 (83%) patients had a sufficient antibody response (median 559.2, IQR 288.8-1180.5 BAU/mL), increasing to 115 (93.5%) (median 2416.9, IQR 1289-4603.8 BAU/mL) patients after the 3rd dose. Eight weeks after the 2nd dose patients treated with high dose prednisolone (p=0.034) and DMARDs (p<0.001) had significantly lower antibodies; however, this difference was not significant following the 3rd dose. Disease activity and damage were stable during the study period. Adverse events were more frequent in patients with a sufficient response. Breakthrough infections were reported in 39 (31.7%) patients; all with mild symptoms. CONCLUSIONS: A 3rd dose improved the humoral response to SARS-CoV-2 vaccines in patients with SLE to the level of healthy individuals. Vaccination did not affect SLE disease activity. Subsequent breakthrough infections were mild and did not require hospitalisation.

Pathophysiological Effects of Autoantibodies in Autoimmune Encephalitides.

The heterogeneity of autoantibody targets in autoimmune encephalitides presents a challenge for understanding cellular and humoral pathophysiology, and the development of new treatment strategies. Thus, current treatment aims at autoantibody removal and immunosuppression, and is primarily based on data generated from other autoimmune neurological diseases and expert consensus. There are many subtypes of autoimmune encephalitides, which now entails both diseases with autoantibodies targeting extracellular antigens and classical paraneoplastic syndromes with autoantibodies targeting intracellular antigens. Here, we review the current knowledge of molecular and cellular effects of autoantibodies associated with autoimmune encephalitis, and evaluate the evidence behind the proposed pathophysiological mechanisms of autoantibodies in autoimmune encephalitis.

Salivary gland ultrasound is associated with the presence of autoantibodies in patients with Sjögren's syndrome: A Danish single-centre study.

OBJECTIVES: To investigate whether ultrasound findings of major salivary glands are correlated with serological markers, autoantibodies, patient- or doctor-reported disease activity in a Danish cohort of patients with primary Sjögren's Syndrome (pSS). METHODS: In all, 49 patients at Odense University Hospital with pSS diagnosed according to the 2002 American-European Consensus Group (AECG) classification criteria were included. Patients were characterized using the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI, score of systemic complications) and EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI), serologic markers, Schirmer's test and salivary test. Salivary gland ultrasound (SGUS) was performed of the submandibular and parotid glands and scored according to the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) semi-quantitative scoring system. RESULTS: More patients with abnormal SGUS had antinuclear antibodies (ANA) (p = 0.002), anti-Ro52 (p = 0.001), anti-Ro60 (p<0.001), anti-La (p<0.001) and IgM-RF (p<0.001). Titers for ANA (p = 0.02) and anti-Ro52 (p = 0.03) were higher in patients with abnormal SGUS. Twenty-three of the pSS patients had no pathological findings on SGUS. There was no correlation between SGUS severity and ESSDAI- or ESSPRI-scores. CONCLUSIONS: Abnormal SGUS findings are associated with autoantibodies of high specificity for pSS but not with ESSDAI, ESSPRI or inflammatory markers.

Humoral immune response following a third SARS-CoV-2 mRNA vaccine dose in solid organ transplant recipients compared with matched controls.

Background: Solid organ transplant (SOT) recipients have shown suboptimal antibody response following COVID-19 vaccination. Several risk factors for the diminished response have been identified including immunosuppression and older age, but the influence of different comorbidities is not fully elucidated. Method: This case-control study consisted of 420 Danish adult SOT recipients and 840 sex- and age-matched controls, all vaccinated with a third homologous dose of either BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine. The primary outcome was differences in humoral immune response. The secondary outcome was breakthrough infections. Additionally, we looked for factors that could predict possible differences between the two groups. Results: Response rate increased from 186/382 (49%) to 275/358 (77%) in SOT recipients and remained on 781/790 (99%) to 601/609 (99%) in controls following a third vaccine dose. SOT recipients had significantly lower median antibody concentrations after third dose compared to controls (332.6 BAU/ml vs 46,470.0 BAU/ml, p <0.001). Lowest median antibody concentrations were seen in SOT recipients with liver disease (10.3 BAU/ml, IQR 7.1-319) and diabetes (275.3 BAU/ml, IQR 7.3-957.4). Breakthrough infections occurred similarly frequent, 150 (40%) among cases and 301 (39%) among controls (p = 0.80). Conclusion: A third COVID-19 vaccine dose resulted in a significant increase in humoral immunogenicity in SOT recipients and maintained high response rate in controls. Furthermore, SOT recipients were less likely to produce antibodies with overall lower antibody concentrations and humoral immunity was highly influenced by the presence of liver disease and diabetes. The prevalence of breakthrough infections was similar in the two groups.

[Neuropsychological deficits following thrombotic thrombocytopenic purpura].

Despite significant improvements in the prognosis of thrombotic thrombocytopenic purpura (TTP), long-term neuropsychological deficits are frequent but probably under-recognised. Regular assessment of cognitive impairment using screening tools is therefore recommended. In this case report we describe two patients with neuropsychological late effects severely affecting their work capacity and quality of life. These late effects were not diagnosed until neuropsychological testing. We conclude that screening tools may not be sufficient to capture neuropsychological late effects in TTP.

Antibody response following the third and fourth SARS-CoV-2 vaccine dose in individuals with common variable immunodeficiency.

Background: The antibody response after vaccination is impaired in common variable immunodeficiency (CVID). Objective: We aimed to study the spike receptor-binding domain IgG antibody (anti-S-RBD) levels during a four-dose SARS-CoV-2 vaccination strategy and after monoclonal antibody (mAB) treatment in CVID. Moreover, we assessed the anti-S-RBD levels in immunoglobulin replacement therapy (IgRT) products. Methods: In an observational study, we examined anti-S-RBD levels after the second, third, and fourth dose of mRNA SARS-CoV-2 vaccines. Moreover, we measured anti-S-RBD after treatment with mAB. Finally, anti-S-RBD was assessed in common IgRT products. Antibody non-responders (anti-S-RBD < 7.1) were compared by McNemar's test and anti-S-RBD levels were compared with paired and non-paired Wilcoxon signed rank tests as well as Kruskal-Wallis tests. Results: Among 33 individuals with CVID, anti-S-RBD levels increased after the third vaccine dose (165 BAU/ml [95% confidence interval: 85; 2280 BAU/ml], p = 0.006) and tended to increase after the fourth dose (193 BAU/ml, [-22; 569 BAU/ml], p = 0.080) compared to the previous dose. With increasing number of vaccinations, the proportion of patients who seroconverted (anti-S-RBD ≥ 7.1) increased non-significantly. mAB treatment resulted in a large increase in anti-S-RBD and a higher median level than gained after the fourth dose of vaccine (p = 0.009). IgRT products had varying concentrations of anti-S-RBD (p < 0.001), but none of the products seemed to affect the overall antibody levels (p = 0.460). Conclusion: Multiple SARS-CoV-2 vaccine doses in CVID seem to provide additional protection, as antibody levels increased after the third and fourth vaccine dose. However, anti-S-RBD levels from mAB outperform the levels mounted after vaccination. Clinical Implications: Boosting with SARS-CoV-2 vaccines seems to improve the antibody response in CVID patients. Capsule summary: The third and possibly also the fourth dose of mRNA SARS-CoV-2 vaccine in CVID improve the antibody response as well as stimulate seroconversion in most non-responders.