Sex differences in symptoms following the administration of BNT162b2 mRNA Covid-19 Vaccine in Children below 5 Years of age in Germany (CoVacU5): a retrospective cohort study (preprint)

Background Sex differences exist not only in the efficacy but also in adverse event rates of many vaccines. Here we compared the safety of BNT162b2 vaccine administered off-label in female and male children younger than 5 years in Germany. Methods This is a retrospective cohort study, in which we performed a post-hoc analysis of a dataset collected through an authentication-based survey of individuals having registered children aged 0-<5 years for vaccination against SARS-CoV-2 in six private practices and/or two lay person-initiated vaccination campaigns. We analyzed the safety profiles of the first 3 doses of 3-10g BNT162b2. Primary outcome was comparison in frequencies of 4 common post-vaccination symptom categories such as local, general, musculoskeletal symptoms and fever. Data were analyzed according to sex in bivariate analyses and regression models adjusting for age, weight, and dosage. Interaction between sex and BNT162b2 dosage was assessed. An active-comparator analysis was applied to compare post-vaccination symptoms after BNT162b2 versus non-SARS-CoV-2 vaccines. Results The dataset for the present analysis consisted of 7801 participants including 3842 females (49%) and 3977 males (51%) with an age of 3 years (median, interquartile: 2 years). Among individuals receiving 3g BNT162b2, no sex differences were noted, but after a first dose of 5 or 10g BNT162b2, local injection-site symptoms were more prevalent in girls compared to boys. In logistic regression, female sex was associated with higher odds of local symptoms, odds ratio (OR) of 1.33 (95% confidence interval [CI]: 1.15-1.55, p<0.05) and general symptoms with OR 1.21 (95% CI: 1.01-1.44, p<0.05). Following non-BNT162b2 childhood vaccinations, female sex was associated with a lower odds of post-vaccination musculoskeletal symptoms (OR: 0.29, 95% CI: 0.11-0.82, p<0.05). An active comparator analysis between BNT162b2 and non-SARS-CoV-2 vaccinations revealed that female sex positively influenced the association between BNT162b2 vaccine type and musculoskeletal symptoms. Conclusions Sex differences exist in post-vaccination symptoms after BNT162b2 administration even in young children. These are of importance for the conception of approval studies, for post-vaccination monitoring and for future vaccination strategies. (German Clinical Trials Register ID: DRKS00028759).

Vaccine effectiveness of BNT162b2 mRNA Covid-19 Vaccine in Children below 5 Years in German Primary Care (preprint)

Background Despite the approval of BNT162b2 mRNA vaccine for children aged 6 months to 4 years by the European Medicines Agency (EMA) and the Federal Drug Administration (FDA) in 2022, no data on vaccine effectiveness (VE) of BNT162b2 are available in this age group. We here report on the VE of BNT162b2 during an Omicron BA.1-2 dominant period. Methods An authentication-based retrospective survey was performed between April 14th 2022 and May 9th 2022 in individuals that had registered children for off-label SARS-CoV-2 vaccination in Germany. We used Cox regression to estimate relative VE of two BNT162b2 doses, with the period between first and second vaccine dose as reference period (24.8+-0.6 days) and >=7 days after Dose 2 to before Dose 3 as post-vaccination period (59.5+-23.6 days). Results The present analysis included 4615 children aged 2.8+-1.2 years (mean+-standard deviation) who had received their first dose of BNT162b2 on January 1st 2022 or thereafter. VE was substantial for protection from any SARS-CoV-2 infection (VE: 53.1% [95% confidence interval (CI): 36.3-69.6%], p<0.001), symptomatic SARS-CoV-2 infections (VE: 57.5% [95% CI: 40.8-74.2%], p<0.001), and SARS-CoV-2 infections leading to medication use (VE: 66.2% [95% CI: 43.7-88.7%], p<0.001). Differences in dosage of BNT162b2 yielded no change in VE. Conclusion This study offers a first industry-independent insight in the potential VE of two doses of the BNT162b2 vaccine in children aged below 5 years, as currently only immunogenicity data by the manufacturer Pfizer/BioNTech are available. Limitations include the retrospective study design, and that the reported VE does not necessarily correspond to currently circulating SARS-CoV-2 variants.

Safety of the BNT162b2 mRNA COVID-19 Vaccine in Children below 5 Years in Germany (CoVacU5): An Investigator-initiated Retrospective Cohort Study (preprint)

Background The safety of SARS-CoV-2 vaccines is unknown in children aged <5 years. Here, we retrospectively evaluated the safety of BNT162b2 vaccine used off-label in children of this age group in Germany. Methods An investigator-initiated retrospective cohort study (CoVacU5) included parents or caregivers having children aged <5 years registered for SARS-CoV-2 vaccination in outpatient care facilities in Germany. Reported short-term safety data of 1-3 doses of 3-10ug BNT162b2 in children aged 0 to <60 months are presented. Co-primary outcomes were the frequencies of 11 categories of symptoms post-vaccination with bivariate analyses and regression models adjusting for age, sex, weight and height. On-label non-SARS-CoV-2 vaccines served as controls in an active-comparator design. Results The study included 7806 representing a 41% response rate of 19,000 registered children. 338 children received the first dose of BNT162b2 at age 0-<12 months, n=1272 at age 12-24 months and n=5629 at age [≥]24 to <60 months. A 10ug dosage was more frequently associated with injection-site symptoms compared to lower dosages. The probability of any symptoms (OR: 1.62 [95% confidence interval (CI): 1.36-1.94]), injection-site, musculoskeletal, dermatological or otolaryngological symptom categories were modestly elevated after BNT12b2 compared to non-SARS-CoV-2 vaccines, whereas the probabilities of general symptoms (OR: 0.74 [95% CI: 0.64-0.85]) and fever (OR: 0.43 [95% CI: 0.35-0.51]) were lower after BNT162b2. Symptoms requiring hospitalization (n=10) were reported only at BNT162b2 dosages higher than 3ug. Conclusions The symptoms reported after BNT162b2 administration were overall comparable to on-label non-SARS-CoV-2 vaccines in this cohort of children aged <5 years.

Humoral and cellular immune responses upon SARS-CoV-2 vaccines in patients with anti-CD20 therapies: A systematic review and meta-analysis of 1342 patients (preprint)

BackgroundImmune responses upon SARS-CoV-2 vaccination in patients receiving anti-CD20 therapies are impaired but vary considerably. We conducted a systematic review and meta-analysis of the literature on SARS-CoV-2 vaccine induced humoral and cell-mediated immune response in patients previously treated with anti-CD20 antibodies. MethodsWe searched PubMed, EMBASE, Medrxiv and SSRN using variations of search terms "anti-CD20", "vaccine" and "COVID" and included original studies up to August 21st,2021. We excluded studies with missing data on humoral or cell-mediated immune response, unspecified methodology of response testing, unspecified timeframes between vaccination and blood sampling or low number of participants ([≤] 3). We excluded individual patients with prior SARS-CoV-2 infection or incomplete vaccine courses. Primary endpoints were humoral and cell-mediated immune response rates. Pre-specified subgroups were time of vaccination after anti-CD20 therapy (< vs > 6 months), time point of response testing after vaccination (< vs > 4 weeks) and disease entity (autoimmune vs cancer vs renal transplant). We used random-effects models of proportions. FindingsNinety studies were assessed. Inclusion criteria were met by 23 studies comprising 1342 patients. Overall rate of humoral response was 0.41 (95% CI 0.35 - 0.47). Overall rate of cell-mediated immune responses was 0.71 (95% CI 0.47 - 0.90). Longer time interval since last anti-CD20 therapy was associated with higher humoral response rates > 6 months 0.63 (95% CI 0.53 - 0.72) vs < 6 months 0.2 (95% CI 0.03 - 0.43); p = 0.001. Compared to patients with haematological malignancies or autoimmune diseases, anti-CD20 treated kidney transplant recipients showed the lowest vaccination response rates. InterpretationPatients on anti-CD20 therapies can develop humoral and cell-mediated immune responses after SARS-CoV-2 vaccination, but subgroups such as kidney transplant recipients or those with very recent B-cell depleting therapy are at high risk for non-seroconversion and should be individually assessed for personalized SARS-CoV-2 vaccination strategies. Potential limitations are small patient numbers, heterogeneous diseases and assays used. FundingThis study was funded by Bern University Hospital.

Humoral and cellular responses to mRNA vaccines against SARS-CoV2 in patients with a history of CD20-B-cell depleting therapy (preprint)

Background B-cell depleting therapies increase COVID19 morbidity and mortality. For this specific population, evidence-based vaccination strategies are lacking. Here, we investigated humoral and cell mediated immune responses to SARS-CoV2 mRNA-based vaccines in patients receiving CD20-B-cell depleting agents for autoimmune disease, malignancy, or transplantation. Methods Patients at the Bern University Hospital with a treatment history of anti-CD20 depleting agents (rituximab or ocrelizumab) were enrolled for analysis of humoral and cell-mediated immune responses (by IFN-g release assay) after completing vaccination against SARS-CoV2. Primary outcome was the the anti-spike antibody response in anti-CD20-treated patients (n=96) in comparison to immunocompetent controls (n=29). Results Anti-spike IgG antibodies were detected in 49% of patients 1.79 months after the second vaccine dose (interquartile range, IQR: 1.16-2.48) compared to 100% of controls (p<0.001). SARS-CoV2 specific interferon-g; release was detected in 17% of patients and 86% of healthy controls (p<0.001). Only 5% of patients, but 86% of healthy controls showed positive reactions in both assays, respectively (p<0.001). Time since last anti-CD20 therapy (7.6 months), peripheral CD19+ (>27/ul), and CD4+ lymphocyte count (>653/ul) predicted humoral vaccine response (area under the curve [AUC]: 62% [CI 56-78], 67% [CI 58-80] and 67% [CI 54-79], (positive predictive value [PPV]: 0.76, 0.7 and 0.71). Conclusion This study provides evidence for blunted humoral and cell-mediated immune responses elicited by SARS-CoV2 mRNA vaccines in patients with CD20-depleting treatment history. Lymphocyte subpopulation counts are associated with vaccine response in this highly vulnerable population. (Funded by Bern University Hospital, ClinicalTrials.gov number, NCT04877496)