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PURPOSE: The purpose of this phase 3 study was to evaluate the efficacy, pharmacokinetics (PK), and safety of Immune Globulin Subcutaneous (Human), 20% Caprylate/Chromatography Purified (IGSC 20%) in patients with primary immunodeficiency (PI). METHODS: Immunoglobulin treatment-experienced subjects with PI received 52 weeks of IGSC 20% given weekly at the same dose as the subject's previous IgG regimen (DAF 1:1); the minimum dose was 100 mg/kg/week. The primary endpoint was serious bacterial infections (SBIs [null vs alternative hypothesis: SBI rate per person per year ≥ 1 vs < 1]). IgG subclasses and specific pathogen antibody levels were also measured. RESULTS: Sixty-one subjects (19 children [≤ 12 years], 10 adolescents [> 12-16 years], and 32 adults) were enrolled. The rate of SBIs per person per year was 0.017. The 1-sided 99% upper confidence limit was 0.036 (< 1), and the null hypothesis was rejected. The rate of hospitalization due to infection per person per year was 0.017 (2-sided 95% confidence interval: 0.008-0.033) overall. The mean trough total IgG concentrations were comparable to the previous IgG replacement regimen. The average of the individual mean trough ratios (IGSC 20%:previous regimen) was 1.078 (range: 0.83-1.54). The average steady-state mean trough IgG concentrations were 947.64 and 891.37 mg/dL, respectively. Seven subjects had serious treatment-emergent adverse events (TEAEs); none was drug-related. The rate of all TEAEs, including local infusion site reactions, during 3045 IGSC 20% infusions was 0.135. Most TEAEs were mild or moderate. CONCLUSIONS: IGSC 20% demonstrated efficacy and good safety and tolerability in subjects with PI.

Additional file 1: Table S1. Main characteristics of the LINA sub-cohort analyzed in this study, overall and separately for each wave. Table S2. Results of the longitudinal model, including estimates, standard errors (SE), z values and p values. Significant test predictors are marked with an asterisk and are in bold in the p column. Figure S1. Maternal stress at testing time as measured with the PSQ questionnaire, as a function of parental satisfaction about the social areas in the enviroment they live in (from 0 to 1, i.e. from low to high satisfaction). Circles represent individual responses, and the dashed black line the fitted model unconditional on all the other predictors. Data were jittered horizontally to avoid overplotting. Figure S2. (a) SDQ child behavioral index (from 0 to 1, i.e. from less to more problematic), as a function of prenatal maternal stress, and (b) as a function of maternal stress at testing time; and (c) FBB-HKS child behavioral index (from 0 to 1, i.e. from less to more problematic), as a function of prenatal maternal stress, and (d) as a function of maternal stress at testing time. In all cases, maternal stress was measured with the PSQ questionnaire. Individual responses are represented with black circles for mothers of female children, and with grey crosses for mothers of male children. The dashed black line represents the fitted model unconditional on all the other predictors. Data were jittered horizontally to avoid overplotting.

Background The currently used SARS-CoV-2 mRNA vaccines have proven to induce a strong and protective immune response. However, functional relevance of vaccine-generated antibodies and their temporal progression are still poorly understood. Thus, the central aim of this study is to gain a better understanding of systemic and mucosal humoral immune response after mRNA vaccination with BNT162b2. Methods We compared antibody production against the S1 subunit and the RBD of the SARS-CoV-2 spike protein in sera of BNT162b2 vaccinees, heterologous ChAdOx1-S/BNT162b2 vaccinees and COVID-19 patients. We monitored the neutralizing humoral response against SARS-CoV-2 wildtype strain and three VOCs over a period of up to eight months after second and after a subsequent third vaccination. Results In comparison to COVID-19 patients, vaccinees showed higher or similar amounts of S1- and RBD-binding antibodies but similar or lower virus neutralizing titers. Antibodies peaked two weeks after the second dose, followed by a decrease three and eight months later. Neutralizing antibodies (nAbs) poorly correlated with S1-IgG levels but strongly with RBD-IgGAM titers. After second vaccination we observed a reduced vaccine-induced neutralizing capacity against VOCs, especially against the Omicron variant. Compared to the nAb levels after the second vaccination, the neutralizing capacity against wildtype strain and VOCs was significantly enhanced after third vaccination. In saliva samples, relevant levels of RBD antibodies were detected in convalescent samples but not in vaccinees. Conclusions Our data demonstrate that BNT162b2 vaccinated individuals generate relevant nAbs titers, which begin to decrease within three months after immunization and show lower neutralizing potential against VOCs as compared to the wildtype strain. Large proportion of vaccine-induced S1-IgG might be non-neutralizing whereas RBD-IgGAM appears to be a good surrogate marker to estimate nAb levels. A third vaccination increases the nAb response. Furthermore, the systemic vaccine does not seem to elicit readily detectable mucosal immunity.

Figure S1. Shown are the location of the MEST gene on chromosome 7 (upper part), the 450 K array CpG in the MEST promoter (middle part) and the region covered by the MassARRAY amplicon within the promoter region (CpG sites are depicted in red). (PDF 32 kb)

Table S1. Questionnaire for the assessment of the living environment. Table S2. Impact of maternal perceived stress levels during pregnancy, year 1 and year 2 on longitudinal BMI z-score development in preschool children (birth-age5). Table S3. Gender disparity in susceptibility to maternal stress-related BMI development in preschool children age 1-5 years. Table S4. Comparison of gender-related study characteristics of the analyzed sub-cohort. Table S5. Characteristics of maternal perceived stress scores of the four different stress dimensions at year 1. Table S6. Influence of maternal stress during the first year after birth on breastfeeding duration and introduction of solid food. Table S7. Summary of exploratory factor analysis results of questionnaire items assessing the living environment. Table S8. Association of different stressors with the maternal stress levels at year 1. Table S9. Contribution of separation or divorce on perceived maternal stress at year 1. Figure S1. (A) Associations of different stressors and the four different stress dimensions at year 1. (B) Summary of mediation analysis. (DOCX 241 kb)

Infections play an important role in childhood. For Germany, few data are available on the epidemiology of infectious diseases such as otitis media and pneumonia in children. We therefore described the prevalence, first episode proportions and recurrence of these childhood infection diseases in selected regions of Germany in children up to 6 years of age. The analysis was based on data from the LISA Study, a prospective population-based birth cohort study including 3,097 full-term infants. Information was collected by parent questionnaire. The first episode proportions for the first 6 years of life were high for otitis media (66.7%; 95%CI 0.65-0.69) and pneumonia (13.5%; 95%CI 0.12-0.15). The annual first episode proportions for otitis media ranged from 7.3% to 25.6% and for pneumonia from 1.4% to 3.4%; both peaked during the second year. The average number of otitis media episodes was 2.2 (SD 2.0) episodes per child within the first 2 years. During the first 2 years of life, hospitalisations due to otitis and pneumonia occurred in up to 7.8 per thousand and 3.0 per thousand of the children, respectively. On average, 50.6% of the children with otitis media were treated with antibiotics during the first year of life. In conclusion, this analysis shows that infectious diseases, especially otitis media, are very frequent childhood diseases in Germany. Thus, parents and physicians should not per se worry about a high frequency of otitis media during early childhood.

This paper assesses the impact of social factors on the development of allergic diseases in early childhood. Epidemiological research has shown increasing allergy rates with improvements in social economic status (SES). However, we argue that the pattern of social influences on allergies is too coloured to be reduced to mere correlations between allergy and SES only. We would suggest rather explaining effects of SES on allergic diseases by mediating factors of the social and the physical environment. Hence, in our study we analyzed infants with atopic dermatitis as well as infants with symptoms of wheezing for the influence of SES and other socioeconomic variables. Further, we examined whether SES and socioeconomic variables interact with several risk factors of the social and physical environment. Our results indicate that associations between socioeconomic variables and allergies point to hidden influences of the social and physical environment, which must be revealed in order to understand the social causes of allergies. As we did so we could provide evidence that SES is not a causal risk factor for allergies, as is imprecisely suggested by many epidemiological studies. Indeed, correlations between SES and disease outcomes are a powerful measure to indicate social influences on health and illness. But they might only be a first step in a multi-factorial research approach, which assesses the various pathways through which social factor and human health interact.