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Seroconversion after COVID-19 vaccination is impaired in kidney transplant recipients. Emerging variants of concern such as the B.1.617.2 (delta) and the B.1.1.529 (omicron) variants pose an increasing threat to these patients. In this observational cohort study, we measured anti-S1 IgG, surrogate neutralizing, and anti-receptor-binding domain antibodies three weeks after a third mRNA vaccine dose in 49 kidney transplant recipients and compared results to 25 age-matched healthy controls. In addition, vaccine-induced neutralization of SARS-CoV-2 wild-type, the B.1.617.2 (delta), and the B.1.1.529 (omicron) variants was assessed using a live-virus assay. After a third vaccine dose, anti-S1 IgG, surrogate neutralizing, and anti-receptor-binding domain antibodies were significantly lower in kidney transplant recipients compared to healthy controls. Only 29/49 (59%) sera of kidney transplant recipients contained neutralizing antibodies against the SARS-CoV-2 wild-type or the B.1.617.2 (delta) variant and neutralization titers were significantly reduced compared to healthy controls (p < 0.001). Vaccine-induced cross-neutralization of the B.1.1.529 (omicron) variants was detectable in 15/35 (43%) kidney transplant recipients with seropositivity for anti-S1 IgG, surrogate neutralizing, and/or anti-RBD antibodies. Neutralization of the B.1.1.529 (omicron) variants was significantly reduced compared to neutralization of SARS-CoV-2 wild-type or the B.1.617.2 (delta) variant for both, kidney transplant recipients and healthy controls (p < .001 for all)., Dietmar Hopp Stiftung; Heidelberg Faculty of Medicine Rahel Goitein-Straus Program; Heidelberg Faculty of Medicine Physician Scientist Program; German Federal Research Network Applied Surveillance and Testing (BFAST); Network University Medicine; Helmholtz Association Initiative and Networking Fund Project Virological and Immunological Determinants of COVID-19 Pathogenesis

The impaired immune response to coronavirus disease 2019 (COVID-19) vaccination in kidney transplant recipients (KTRs) leads to an urgent need for adapted immunization strategies.Sixty-nine KTRs without seroconversion after ≥3 COVID-19 vaccinations were enrolled, and humoral response was determined after an additional full-dose mRNA-1273 vaccination by measuring severe acute respiratory syndrome coronavirus 2-specific antibodies and neutralizing antibody activity against the Delta and Omicron variants 1 and 3 mo postvaccination. T-cell response was analyzed 3 mo postvaccination by assessing interferon-γ release. Mycophenolic acid (MPA) was withdrawn in 41 KTRs 1 wk before until 4 wk after vaccination to evaluate effects on immunogenicity. Graft function, changes in donor-specific anti-HLA antibodies, and donor-derived cell-free DNA were monitored in KTRs undergoing MPA withdrawal.Humoral response to vaccination was significantly stronger in KTRs undergoing MPA withdrawal 1 mo postvaccination; however, overall waning humoral immunity was noted in all KTRs 3 mo after vaccination. Higher anti-S1 immunoglobulin G levels correlated with better neutralizing antibody activity against the Delta and Omicron variants, whereas no significant association was detected between T-cell response and neutralizing antibody activity. No rejection occurred during study, and graft function remained stable in KTRs undergoing MPA withdrawal. In 22 KTRs with Omicron variant breakthrough infections, neutralizing antibody activity was better against severe acute respiratory syndrome coronavirus 2 wild-type and the Delta variants than against the Omicron variant.MPA withdrawal to improve vaccine responsiveness should be critically evaluated because withdrawing MPA may be associated with enhanced alloimmune response, and the initial effect of enhanced seroconversion rates in KTRs with MPA withdrawal disappears 3 mo after vaccination.

Background and objectives: antibody response after severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) vaccination is impaired in kidney transplant recipients. Emerging variants, such as B.1.617.2 ( d), are of particular concern because of their higher transmissibility and partial immune escape. Little is known about protection against these variants in immunocompromised patients. Design, setting, participants, and measurements: in this prospective two-center study, antispike 1 IgG and surrogate neutralizing antibodies were measured in 173 kidney transplant recipients and 166 healthy controls with different vaccination schedules. In addition, different SARS-CoV-2 epitope antibodies from 135 vaccinated kidney transplant recipients were compared with antibodies in 25 matched healthy controls after second vaccination. In 36 kidney transplant recipients with seroconversion, neutralization against B.1.1.7 ( a), B.1.351 ( b), and B.1.617.2 ( d) was determined on VeroE6 cells and compared with neutralization in 25 healthy controls. Results: kidney transplant recipients had significantly lower seroconversion rates compared with healthy controls. After the second vaccination, antispike 1, antireceptor-binding domain, and surrogate neutralizing antibodies were detectable in 30%, 27%, and 24% of kidney transplant recipients, respectively. This compares with 100%, 96%, and 100% in healthy controls, respectively (P,0.001). Neutralization against B.1.1.7 was detectable in all kidney transplant recipients with seroconversion, with a median serum dilution that reduces infection of cells by 50% of 80 (interquartile range, 80-320). In contrast, only 23 of 36 (64%) and 24 of 36 (67%) kidney transplant recipients showed neutralization against B.1.351 and B.1.617.2, respectively, with median serum dilutions that reduce infection of cells by 50% of 20 (interquartile range, 0-40) and 20 (interquartile range, 0-40), respectively. Neutralization against different variants was significantly higher in healthy controls (P,0.001), with all patients showing neutralization against all tested variants. Conclusions: seroconverted kidney transplant recipients show impaired neutralization against emerging variants of concern after standard two-dose vaccination., Dietmar Hopp Stiftung; German Federal Research Network Applied Surveillance and Testing; Network University Medicine; fightCOVID@DKFZ Initiative; Helmholtz Association Initiative and Networking Fund Project Virological and Immunological Determinants of COVID-19 Pathogenesis; Lessons to Get Prepared for Future Pandemics; Heidelberg Faculty of Medicine Rahel Goitein-Strauss Program; Heidelberg Faculty of Medicine Physician Scientist Program

Objectives: humoral immunity wanes over time after two-dose BNT162b2 vaccination. Emerging variants of concern, such as the B.1.617.2 (delta) variant, are increasingly responsible for breakthrough infections owing to their higher transmissibility and partial immune escape. Longitudinal data on neutralization against the B.1.617.2 (delta) variant are urgently needed to guide vaccination strategies. Methods: in this prospective longitudinal observational study, anti-S1 IgG and surrogate neutralizing antibodies were measured in 234 collected samples from 60 health care workers after two-dose vaccination with BNT162b2 at five different time points over an 8-month period. In addition, antibodies against various severe acute respiratory syndrome coronavirus 2 epitopes, neutralization against wild-type, and cross-neutralization against the B.1.617.2 (delta) variant using a live virus assay were measured 6 weeks (second time point) and 8 months (last time point) after first vaccine dose. Results: median (interquartile range) anti-S1 IgG, surrogate neutralizing, and receptor-binding domain antibodies decreased significantly from a maximum level of 147 (102–298), 97 (96–98), and 20 159 (19 023–21 628) to 8 (4–13), 92 (80–96), and 15 324 (13 055–17 288) at the 8-month follow-up, respectively (p < 0.001 for all). Neutralization against the B.1.617.2 (delta) variant was detectable in all 36 (100%) participants at 6 weeks and in 50 of 53 (94%) participants 8 months after first vaccine dose. Median (interquartile) ID50 as determined by a live virus assay decreased from 160 (80–320) to 40 (20–40) (p < 0.001). Discussion: although humoral immunity wanes over time after two-dose BNT162b2 vaccination in healthy individuals, most individuals still had detectable neutralizing activity against the B.1.617.2 (delta) variant after 8 months., Dietmar Hopp Stiftung; Heidelberg Faculty of Medicine Rahel Goitein-Strauss Program; Heidelberg Faculty of Medicine Physician Scientist Program; German Federal Research Network Applied Surveillance and Testing (BFAST); Network University Medicine; DKFZ@fightCOVID; Helmholtz Association Initiative and Networking Fund Project Virological and Immunological Determinants of COVID-19 Pathogenesis

Hemodialysis patients are at high risk for severe COVID-19, and impaired seroconversion rates have been demonstrated after COVID-19 vaccination. Humoral immunity wanes over time and variants of concern with immune escape are posing an increasing threat. Little is known about protection against the B.1.617.2 (delta) variant of concern in hemodialysis patients before and after third vaccination. We determined anti-S1 IgG, surrogate neutralizing, and IgG antibodies against different SARS-CoV-2 epitopes in 84 hemodialysis patients directly before and three weeks after a third vaccine dose with BNT162b2. Third vaccination was performed after a median (IQR) of 119 (109-165) days after second vaccination. In addition, neutralizing activity against the B.1.617.2 (delta) variant was assessed in 31 seroconverted hemodialysis patients before and after third vaccination. Triple seropositivity for anti-S1 IgG, surrogate neutralizing, and anti-RBD antibodies increased from 31/84 (37%) dialysis patients after second to 80/84 (95%) after third vaccination. Neutralizing activity against the B.1.617.2 (delta) variant was significantly higher after third vaccination with a median (IQR) ID50 of 1:320 (1:160-1:1280) compared with 1:20 (0-1:40) before a third vaccine dose (P, Dietmar Hopp Stiftung; Heidelberg Faculty of Medicine Rahel Goitein-Strauss Program

BackgroundKeeping up motivation to learn when socially isolated during a pandemic can be challenging. In medical schools, the COVID-19 pandemic required a complete switch to e-learning without any direct patient contact despite early reports showing that medical students preferred face-to-face teaching in clinical setting. We designed close to real-life patient e-learning modules to transmit competency-based learning contents to medical students and evaluated their responses about their experience.MethodsWeekly e-learning cases covering a 10-week leading symptom-based curriculum were designed by a team of medical students and physicians. The internal medicine curriculum (HeiCuMed) at the Heidelberg University Medical School is a mandatory part of clinical medical education in the 6thor 7thsemester. Case-design was based on routine patient encounters and covered different clinical settings: preclinical emergency medicine, in-patient and out-patient care and follow-up. Individual cases were evaluated online immediately after finishing the respective case. The whole module was assessed at the end of the semester. Free-text answers were analyzed with MaxQDa following Mayring`s principles of qualitative content analyses.ResultsN = 198 students (57.6% female, 42.4% male) participated and 1252 individual case evaluations (between 49.5% and 82.5% per case) and 51 end-of-term evaluations (25.8% of students) were collected. Students highly appreciated the offer to apply their clinical knowledge in presented patient cases. Aspects of clinical context, interactivity, game-like interface and embedded learning opportunities of the cases motivated students to engage with the asynchronously presented learning materials and work through the cases.ConclusionsSolving and interpreting e-learning cases close to real-life settings promoted students’ motivation during the COVID-19 pandemic and may partially have compensated for missing bedside teaching opportunities.

It has been demonstrated that patients on hemo- or peritoneal dialysis are particularly susceptible to SARS-CoV-2 infection and impaired seroconversion compared to healthy controls. Follow-up data on vaccination response in dialysis patients is limited but is greatly needed to individualize and guide (booster) vaccination strategies. In this prospective, multicenter study we measured anti-spike S1 and neutralizing antibodies in 124 hemodialysis patients, 41 peritoneal dialysis patients, and 20 age- and sex-matched healthy controls over 12 weeks after homologous BNT162b2 vaccination. Compared to healthy controls, both hemodialysis and peritoneal dialysis patients had lower anti-S1 IgG antibodies (median (IQR) 7.0 (2.8–24.3) and 21.8 (5.8–103.9) versus 134.9 (23.8–283.6), respectively, p &lt, 0.001 and p &lt, 0.05) and a reduced SARS-CoV-2 spike protein–ACE2 binding inhibition caused by vaccine-induced antibodies (median (IQR) 56% (40–81) and 77% (52–89) versus 96% (90–98), respectively, 0.01) three weeks after the second vaccination. Twelve weeks after the second vaccination, the spike protein–ACE2 binding inhibition significantly decreased to a median (IQR) of 45% (31–60) in hemodialysis patients and 55% (36–78) in peritoneal dialysis patients, respectively (p &lt, 0.05). Peritoneal dialysis patients mounted higher antibody levels compared with hemodialysis patients at all time points during the 12-week follow-up. Individual booster vaccinations in high-risk individuals without seroconversion or rapidly waning neutralizing antibody levels are required and further data on the neutralization of emerging variants of concern in these patients are urgently needed.

Despite limited data on safety and immunogenicity, heterologous prime-boost vaccination is currently recommended for individuals with ChAdOx1 nCoV-19 prime immunization in certain age groups. In this prospective, single-center study we included 166 health care workers from Heidelberg University Hospital who received either heterologous ChAdOx1 nCoV-19/BNT162b2, homologous BNT162b2 or homologous ChAdOx1 nCoV-19 vaccination between December 2020 and May 2021. We measured anti-S1 IgG, SARS-CoV-2 specific neutralizing antibodies, and antibodies against different SARS-CoV-2 fragments 0–3 days before and 19–21 days after boost vaccination. Before boost, 55/70 (79%) ChAdOx1 nCoV-19-primed compared with 44/45 (98%) BNT162b2-primed individuals showed positive anti-S1 IgG with a median (IQR) anti-S1 IgG index of 1.95 (1.05–2.99) compared to 9.38 (6.26–17.12). SARS-CoV-2 neutralizing antibodies exceeded the threshold in 24/70 (34%) of ChAdOx1 nCoV-19-primed and 43/45 (96%) of BNT162b2-primed individuals. After boosting dose, median (IQR) anti-S1 IgG index in heterologous ChAdOx1 nCoV-19/BNT162b2 vaccinees was 116.2 (61.84–170), compared to 13.09 (7.03–29.02) in homologous ChAdOx1 nCoV-19 and 145.5 (100–291.1) in homologous BNT162b2 vaccinees. All boosted vaccinees exceeded the threshold for neutralization, irrespective of their vaccination scheme. Vaccination was well-tolerated overall. We show that heterologous ChAdOx1 nCoV-19/BNT162b2 vaccination is safe and induces a strong and broad humoral response in healthy individuals.