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BackgroundSystemic sclerosis (SSc) is a severe, progressive multisystem rheumatic disease with high mortality, but without approved disease-modifying treatment to stop or reverse course of disease. Intravenous immunoglobulin G (IgG) may have a positive impact on SSc based upon available literature reports. However, to date, there have been no clinical trials evaluating subcutaneous IgG (SCIG) in SSc. In particular, the impact of pathologically altered skin in SSc on local safety and pharmacokinetics (PK) of SCIG has not been explored yet.ObjectivesThe primary and secondary objectives of this trial (NCT04137224) included safety, including local infusion safety, and bioavailability of subcutaneous IgG (IgPro20) in adults with diffuse cutaneous SSc (dcSSc).MethodsThis was a randomized, open-label, crossover study. Adult subjects with dcSSc diagnosis within 5 years from first non-Raynaud's phenomenon and modified Rodnan Skin Score of 15-45 at screening were randomized 1:1 to sequence A (IgPro20, 20% normal human subcutaneous immunoglobulin followed by IgPro10, 10% normal human intravenous immunoglobulin) or sequence B (IgPro10 followed by IgPro20). Each subject was to complete two treatment periods (16 weeks each), with up to 40 weeks (including screening) study duration for an individual subject. Doses received were 0.5g/kg/week split over two sessions for IgPro20, and 2g/kg/4 weeks split over 2-5 days for IgPro10. The primary endpoint was safety of IgPro20, described as treatment-emergent adverse events (TEAEs) and changes in clinical observations.Results27 subjects were randomized, with 13 subjects to sequence A and 14 subjects to sequence B. In total, 25 subjects completed the study. Of 27 treated subjects, 107 TEAEs occurred in 22 subjects (81.5%) over the 36-week study period, the majority of which were mild or moderate. The most common TEAEs (>10% of subjects) by preferred term (PT) were headache (12 events occurring in 6 subjects [22.2%]), COVID-19 (3 events occurring in 3 subjects [11.1%]), diarrhoea (3 events occurring in 3 subjects [11.1%]), and vomiting (3 events occurring in 3 subjects [11.1%]).A total of 10 serious AEs (SAEs) were reported in 6 subjects (Viral infection, Chronic gastritis, Vomiting, Dehydration, Upper gastrointestinal haemorrhage, Chest pain, Myocardial infarction, Myocardial ischemia, Breast cancer, Interstitial lung disease). Among these, one subject experienced 2 SAEs (myocardial ischemia & myocardial infarction) and was discontinued from study treatment. None of the SAEs were considered related to study treatment by the investigator, and no deaths were reported.For IgPro20, 14 infusion site reactions (ISRs) occurred in 5 subjects (19.2%), all were mild or moderate in severity. The most common ISRs were infusion site pain and infusion site swelling (3 events in 2 subjects each, 7.7%). In total, 686 IgPro20 infusions were performed, resulting in an overall ISR rate per infusion of 0.02, ie 2 ISRs per 100 infusions. No ISRs were reported for IgPro10.No clinically relevant trends in vital signs, body weight, clinical laboratory tests, electrocardiograms, or pulmonary function tests were observed.PK profiles and bioavailability in dcSSc subjects were similar to those observed in other approved indications such as Primary Immunodeficiency. Population relative bioavailability of IgPro20, based on dose-normalized, baseline-corrected AUC0-tau was 0.761 (90% CI: 0.7033, 0.8232), ie 76.1% compared to IgPro10 (intravenous IgG).ConclusionThe overall safety profiles of IgPro20 and IgPro10 in subjects with dcSSc were consistent with that in approved indications such as CIDP, including a relatively low ISR rate for IgPro20. PK profiles and bioavailability were also similar to other indications. This study indicates that subcutaneous administration of IgPro20 has acceptable safety, bioavailability and PK profiles in patients with dcSSc. AcknowledgementsEditorial assistance was provided by Meridian HealthComms Ltd., funded by CSL Behring.Disclosure of InterestsChristopher P Denton Speakers bureau: Ja ssen, Boehringer Ingelheim, Consultant of: GSK, CSL Behring, Boehringer Ingelheim, Merck, Roche, Sanofi, Grant/research support from: GSK, CSL Behring, Inventiva, Horizon, Otylia Kowal-Bielecka Speakers bureau: Abbvie, Janssen-Cilag, Boehringer Ingelheim, Medac, MSD, Novartis, Pfizer, Sandoz, Consultant of: Boehringer Ingelheim and Novartis, Grant/research support from: Received congress support from Abbvie, Boehringer Ingelheim, and Medac, Susanna Proudman Speakers bureau: Boehringer Ingelheim, Grant/research support from: Janssen, Marzena Olesińska Consultant of: AstraZeneca, Margitta Worm Consultant of: Novartis Pharma GmbH, Sanofi-Aventis Deutschland GmbH, DBV Technologies S.A, Aimmune Therapeutics UK Limited, Regeneron Pharmaceuticals, Inc, Leo Pharma GmbH, Boehringer Ingelheim Pharma GmbH &Co.KG, ALK-Abelló Arzneimittel GmbH, Kymab Limited, Amgen GmbH, Abbvie Deutschland GmbH & Co. KG, Pfizer Pharma GmbH, Mylan Germany GmbH (A Viatris Company), AstraZeneca GmbH, Lilly Deutschland GmbH and GlaxoSmithKline GmbH & Co. KG., Nicoletta Del Papa Speakers bureau: Janssen Cilag, Boehringer Ingelheim., Marco Matucci-Cerinic Speakers bureau: Biogen, Sandoz, Boehringer Ingelheim, Consultant of: CSL Behring, Boehringer Ingelheim, Grant/research support from: MSD, Chemomab, Jana Radewonuk Shareholder of: CSL Behring, Employee of: CSL Behring, Jeanine Jochems Shareholder of: CSL Behring, Employee of: CSL Behring, Amgad Shebl Shareholder of: CSL Behring, Employee of: CSL Behring, Anna Krupa Shareholder of: CSL Behring, Employee of: CSL Behring, Jutta Hofmann Shareholder of: CSL Behring, Employee of: CSL Behring, Maria Gasior Shareholder of: CSL Behring, Employee of: CSL Behring.
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Purpose: Mortality from COVID-19 among kidney transplant recipients (KTR) is unacceptably high, and their response to up to three vaccinations against SARSCoV- 2 is strongly impaired. We provide the first systematic analysis of serological response to up to five repeated vaccinations in nonresponding KTR. Method(s): We retrospectively analyzed serological response to basic immunization, as well as administration of three, four and five doses of SARS-CoV-2 vaccine in KTR from December 27, 2020 until December 31, 2021. In particular, the influence of different dose adjustment regimens for mycophenolic acid (MPA) on serological response to fourth vaccination was analyzed. Result(s): In total, 4.277 vaccinations against SARS-CoV-2 in 1.478 patients were analyzed. Serological response was 19.5% after 1.203 basic immunizations, and increased to 29.4%, 55.6%, and 57.5% after 603 third, 250 fourth and 40 fifth vaccinations, resulting in a cumulative response rate of 88.7% (figure 1A-B). Patients with belatacept immunosuppression show impaired cumulative serological response (4.4%, 12.4%, and 16.4%) in comparison to patients with calcineurin inhibitor (CNI)- based immunosuppression (19.1%, 37.6%, and 70.1%) after basic immunization, three, and four vaccinations (figure 1C-F). In patients with CNI and MPA maintenance immunosuppression, pausing MPA and adding 5 mg prednisolone equivalent before the fourth vaccination increased serological response rate to 75% in comparison to no dose adjustment (52%) or dose reduction (46%) without occurence of rejections (figure 2). Conclusion(s): Repeated SARS-CoV-2 vaccination of up to five times effectively induces serological response in kidney transplant recipients. It can be enhanced by pausing MPA at the time of vaccination. Patients with belatacept immunosuppression are unlikely to achieve sufficient serological response and require different approaches.
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HLA molecules are key restrictive elements to present intracellular antigens for an effective T-cell response against SARS-CoV-2. HLA alleles vary with respect to their potential to present immunogenic viral epitopes and may therefore determine disease severity. Therefore, we set out to investigate the impact of individual HLA genotypes on the severity of SARS-CoV-2 infections. In August 2020 and July 2021, we performed cross-sectional studies among stem cell donors registered with DKMS in Germany. Volunteers registered for stem cell donation represent a comparable healthy subset of the working age population. Available genetic information was linked to self-reported COVID-19 outcome data. Multivariable regression models were fitted to determine the risk of contracting SARS-CoV-2, severe respiratory tract infection and respiratory hospitalization. More than 200,000 registered donors provided informed consent and participated in the study. Their age ranged from 18 to 61 years. Altogether 16,121 participants donors reported a history of COVID-19. Asymptomatic courses were reported by 1428 participants, mild/moderate symptoms by 10,353 participants, severe respiratory infections by 3913 not requiring hospitalization and respiratory hospitalizations by 427 patients. Notably, we did not observe a heterozygote advantage. The risk for severe infections was not statistically different among individuals with or without homozygosity at HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1. Of 84 HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1 alleles which were prevalent in more than 400 participants only the presence of HLA-B∗39:01 had significant impact on the risk for respiratory hospitalization (OR 2.23, p = 0.01) at a significance level of 1%. These findings suggest that the HLA genotype is no major factor determining COVID-19 severity. It is therefore possible that the relatively large viral genome of 29.8 kb encodes for abundant epitopes to mount T-cell responses not limited by the HLA genotype.