A Bivalent Omicron-BA.4/BA.5-Adapted BNT162b2 Booster in ≥12-Year-Olds.

BACKGROUND: Protection against contemporary SARS-CoV-2 variants requires sequence-adapted vaccines. METHODS: In this ongoing phase 2/3 trial, 12-17-year-olds (n=108), 18-55-year-olds (n=313), and >55-year-olds (n=306) who previously received 3 original BNT162b2 30-µg doses, received a fourth dose (second booster) of 30-µg bivalent original/Omicron-BA.4/BA.5-adapted BNT162b2 (BNT162b2-Omi.BA.4/BA.5). For comparisons with original BNT162b2, participants were selected from another phase 3 trial. Immunologic superiority 1-month post-vaccination, with respect to 50% neutralizing titers (GMR lower bound [LB] 2-sided 95%CI >1), and noninferiority with respect to seroresponse rates (rate-difference LB 2-sided 95%CI >-5%), for Omicron BA.4/BA.5 were assessed in >55-year-olds versus original BNT162b2 as a second booster. Noninferiority with respect to neutralizing titer level (GMR LB 2-sided 95%CI >0.67) and seroresponse rate (rate-difference LB 2-sided 95%CI >-10%) of Omicron BA.4/BA.5 immune response for BNT162b2-Omi.BA.4/BA.5 in 18‒55-year-olds versus >55-year-olds was assessed. RESULTS: One-month post-vaccination in >55-year-olds, model-adjusted GMR of Omicron BA.4/BA.5 neutralizing titers for the BNT162b2-Omi.BA.4/BA.5 versus BNT162b2 group (2.91; 95%CI 2.45-3.44) demonstrated superiority of BNT162b2-Omi.BA.4/BA.5. Adjusted difference in percentages of >55-year-olds with seroresponse (26.77%; 95%CI 19.59-33.95) showed noninferiority of BNT162b2-Omi.BA.4/BA.5 to BNT162b2. Noninferiority of BNT162b2-Omi.BA.4/BA.5 in 18‒55-year-olds to >55-year-olds was met for model-adjusted GMR and seroresponse. GMTs in 12-17-year-olds increased from baseline to 1-month post-vaccination. The BNT162b2-Omi.BA.4/BA.5 safety profile was similar to booster doses of bivalent Omicron BA.1-modified BNT162b2 and original BNT162b2 reported in previous studies. CONCLUSIONS: Based on immunogenicity and safety data up to 1-month post-vaccination in participants who previously received 3 original BNT162b2 doses, a BNT162b2-Omi.BA.4/BA.5 30 µg booster has a favorable benefit-risk profile. CLINICAL TRIAL REGISTRATION: NCT05472038.

Placental cytokine expression covaries with maternal asthma severity and fetal sex.

In the presence of maternal asthma, we have previously reported reduced placental blood flow, decreased cortisol metabolism, and reductions in fetal growth in response to maternal asthma and asthma exacerbations. We have proposed that these changes in placental function and fetal development may be related to activation of proinflammatory pathways in the placenta in response to maternal asthma. In the present study, we examined the influence of maternal asthma severity, inhaled glucocorticoid treatment, maternal cigarette use, placental macrophage numbers, and fetal sex on placental cytokine mRNA expression from a prospective cohort study of pregnant women with and without asthma. Placental expression of TNF-alpha, IL-1beta, IL-6, IL-8, and IL-5 mRNA were all increased significantly in placentae of female fetuses whose mothers had mild asthma, but no changes were observed in placentae of male fetuses. The proinflammatory cytokines TNF-alpha, IL-1beta, and IL-6 were negatively correlated with female cord blood cortisol, but there were no such correlations in placentae from males. Multivariate analysis indicated the strongest predictor of both cytokine mRNA expression in the placenta and birth weight was fetal cortisol but only in females. Placental cytokine mRNA levels were not significantly altered by inhaled glucocorticoid use, placental macrophage numbers, cigarette use, moderate-severe asthma, or male sex. These data suggest that placental basal cytokine mRNA expression is sex specifically regulated in pregnancies complicated by asthma, and interestingly these changes are more prevalent in mild rather than severe asthma.

Sex-specific associations between cortisol and birth weight in pregnancies complicated by asthma are not due to differential glucocorticoid receptor expression.

BACKGROUND: Fetal growth inhibition is a known sequelae of in utero glucocorticoid exposure and has long-term consequences for adult health. Sex-specific fetal growth patterns are observed in pregnancies with maternal asthma and may be due to differential sensitivity of the placenta to glucocorticoids. It is currently unknown whether expression of the placental glucocorticoid receptor (GR) becomes altered with asthma or the use of inhaled corticosteroids. METHODS: Pregnant women with mild asthma (n=52), moderate-severe asthma (n=71) and without asthma (n=51) were recruited at John Hunter Hospital, Newcastle, Australia. At delivery, placentae and cord blood were collected, and fetal sex and birth weight were recorded. Placental GR heterogeneous nuclear RNA (hnRNA), mRNA and protein were measured and cord blood cortisol concentrations were assessed. RESULTS: Placental GR gene activity increased with cortisol exposure but decreased with inhaled corticosteroid treatment (p=0.05). With maternal asthma, female birth weight centiles were inversely associated with cortisol (r=-0.286, p=0.017) and, despite a decrease in placental GR mRNA (p=0.003), placental GRalpha protein levels were unchanged. In males, no change to cortisol, birth weight or placental GR were evident in pregnancies with asthma. Together, these results indicate that in pregnancies complicated by asthma, placental GR gene activity, but not mRNA expression or protein levels, is dependent on cortisol and inhaled corticosteroid treatment. CONCLUSIONS: The sex-specific associations between cortisol and birth weight observed in pregnancies with asthma are not due to altered GR expression; however, they may be due to differential glucocorticoid sensitivity via preferential transcription of GR isoforms or post-translational modifications.