Pamela A. Frischmeyer-Guerrerio

Background: Atopic dermatitis (AD), food sensitization (FS), and food allergy (FA) frequently co‐occur in infancy, but the factors underlying distinct atopic phenotypes remain unclear. Although FLG null mutations are major genetic risk factors for AD, they explain only part of disease heritability, suggesting a potential role for the skin microbiome. This study examined how early‐life skin microbiome composition and its interaction with host genetics contribute to distinct atopic phenotypes in infancy. Methods: We analyzed > 1000 skin swabs from 429 infants in the VITALITY cohort using deep shotgun metagenomic sequencing at 2–3 months (pre‐diagnosis) and 12 months (post‐diagnosis). Differential abundance, strain‐level, and microbial genome‐wide association analyses were performed to identify taxonomic and functional features associated with AD, FS, FA, their co‐occurrence, and FLG mutation status. Results: Within AD, microbial signatures differed by co‐occurring FA or FS. At 12 months, Staphylococcus epidermidis was enriched in infants with AD alone, whereas infants with AD and FA showed decreased Staphylococcus hominis and Lactococcus species, and increased Dermacoccus nishinomiyaensis and Malassezia slooffiae . At 2–3 months, early skin dysbiosis characterized by enrichment of Staphylococcus species was associated with later development of AD with FS or FA, but not AD alone. Among infants with AD, FLG mutation carriers showed additional microbial shifts, including reduced Streptococcus species and increased M. slooffiae . Strain‐level analyses revealed mother–infant sharing of AD‐associated taxa, and microbial genome‐wide association analyses identified species‐specific genes linked to AD severity. Conclusions: Infant atopic phenotypes are associated with distinct, phenotype‐specific skin microbiome features that emerge before and after disease onset, highlighting the microbiome as a potential target for early risk stratification.

Background: Systemic allergic reactions (sARs) after vaccination are life‐threatening and can erode vaccine confidence. Distinguishing sARs from immunization stress‐related responses (ISRRs), which require different management, remains a clinical challenge. We sought to identify biomarkers distinguishing sARs from ISRRs, characterize their early immune and metabolic pathways, and determine whether immediate reactions alter subsequent vaccine‐induced immunity. Methods: We profiled samples from a double‐blind, placebo‐controlled BNT162b2 re‐vaccination trial (NCT04977479) in individuals with allergic reactions to a first mRNA vaccine dose. Whole‐blood transcriptomics, plasma proteomics and metabolomics, blood counts, and flow cytometry were assessed 0.5–24 h after the second dose, booster, and placebo. Anti‐spike antibodies were measured longitudinally; anti‐nucleocapsid antibodies identified intercurrent infection. Results: Interferon and antiviral transcriptional programs 24 h post‐vaccination and subsequent anti‐spike antibody responses were preserved across reaction groups. However, longer‐than‐recommended intervals between first and second doses were associated with lower antibody titers. In participants with mild to no reactions, neutrophil activation and degranulation signatures peaked at 6 h; these responses were blunted in ISRRs despite comparable early neutrophil mobilization. ISRRs were also marked by a stress‐metabolic state with early norepinephrine increases; sustained bisphosphoglycerate and 2/3‐phosphoglycerate elevations; reduced basophil activation/recruitment markers (CD63, CD193); downregulation of basophil‐associated transcripts (CPA3, HDC, MS4A3); and upregulation of stress‐linked genes (OTOF, SNORD3). sARs showed opposite metabolic trajectories and trended toward early neutrophil CD63 upregulation. Conclusion: Time‐resolved immune and metabolic signatures identified candidate biomarkers distinguishing ISRRs from sARs, with implications for diagnosis, management, and vaccine adherence. Notably, reactions did not impair vaccine‐elicited antiviral responses or humoral immunity.

Background: Food allergies in children represent a growing clinical and public health concern worldwide, yet their causes remain poorly understood. Objective: To investigate the role of circulating IgG antibodies to food allergens and viral antigens at birth and during early childhood in the development of food allergies, using data from a prospective birth cohort. Methods: This study included 458 children composed of 80 with food allergies, 151 with food sensitization, and 227 who were non‐allergic and non‐sensitized to these food allergens and had no other allergic diseases (asthma, atopic dermatitis, and allergic rhinitis). Phage ImmunoPrecipitation Sequencing (PhIP‐Seq) was used to profile the IgG antibody reactome against thousands of environmental antigens (including allergens and viruses) in matched cord blood and childhood plasma samples from these children. We then investigated whether IgG profiles were associated with allergies to egg, milk, and peanut. Results: Children with food allergies had a significantly elevated diversity of IgG reactivity to thousands of allergen peptides in early childhood compared to non‐allergic controls. No such associations were found in cord blood at birth. We identified that peanut‐allergic children have higher IgG reactivity to 24 peanut peptides, and egg‐allergic children had higher IgG reactivity to 17 egg peptides compared to non‐allergic controls. Additionally, patterns of shared IgG reactivity to wheat peptides were observed across different food allergy groups in early childhood. Notably, milk‐allergic children exhibited lower magnitudes of IgG reactivities to eight milk peptides in cord blood and reduced IgG reactivities to enteroviral peptides during childhood (all FDR < 0.05), relative to non‐allergic controls. Conclusion: These results suggest that unbiased IgG reactome profiling in a prospective birth cohort provides new insights into early life immune regulation and its influence on childhood allergic phenotypes.

Background: Early‐life microbial exposure to microbes may play a role in asthma development. This study tests the hypothesis that mothers born in low‐income countries might have been exposed to diverse microbes—leading to greater diversity and higher levels of transplacental anti‐microbial antibodies, thereby conferring protection against asthma in offspring. Methods: In the prospective Boston Birth Cohort, IgG antibody reactome against microbes (2740 species; 1311 genera) was profiled in cord blood, using Phage ImmunoPrecipitation Sequencing. Multinomial regression models were applied to examine the associations of cord blood IgG reactome with child risk of physician‐diagnosed atopy and asthma. Mediation analysis was performed to examine the inter‐relationships among maternal nativity, IgG reactome and risk of developing childhood asthma. Results: This report included 943 mother–child dyads enrolled at birth and followed prospectively. Compared to children of US‐born mothers, children of foreign‐born mothers had a lower prevalence of asthma (17.5% vs. 30.5%) and greater diversity of cord blood IgG antibodies against hundreds of microbes (FDR < 0.05). Cord blood seropositivity to peptides or proteins from 6 microbes was inversely associated with the risk of asthma in children, and children with more seropositivity to these microbes were at a lower risk of developing asthma ( p < 0.001). IgG seropositivity to A. actinomycetemcomitans , H. pylori , S. flexneri , and T. parva each mediated 17%–62% of the association between maternal nativity and child risk of asthma. Conclusion: In this US prospective birth cohort, maternal transplacental IgG reactivity to four microbes ( A. actinomycetemcomitans , H. pylori , S. flexneri and T. parva ) was associated with a lower risk of childhood asthma, and partly explains the lower risk of asthma in children of mothers born outside the US.

Background: Intestinal barrier dysfunction may lead to a break in tolerance and development of food allergy (FA). There is contradictory evidence on whether intestinal permeability (IP) is altered in IgE‐mediated FA. Thus, we sought to determine whether IP differed between children with eczema who did (FA group) or did not (atopic controls, ACs) develop FA and whether peanut sensitization, allergy, and early introduction impacted IP using serum biomarkers zonulin, soluble CD14, and Intestinal Fatty Acid Binding Protein among randomly selected participants enrolled in the Learning Early About Peanut allergy trial. Methods: FA group was defined as having at least one FA at either baseline (4–11 months) or 60 months of age (V60). ACs had eczema at baseline and no FA at either visit. Serum IP markers (sIPMs) were measured by ELISA at baseline and V60, and their relationship with the clinical characteristics of participants was analyzed using parametric tests and linear regression models. Results: We evaluated 237 FA subjects and 76 ACs. sIPM levels were similar in FA subjects and ACs at baseline and V60. Age when the child first developed any FA (< 1 year vs. > 1 year), eczema severity, peanut sensitization, peanut allergy, and early peanut introduction were not statistically significantly associated with sIPM levels. Total IgE and eosinophil levels, peanut‐specific IgE, IgG4, and IgG4/IgE ratio were not correlated with sIPM levels. Conclusions: No differences in sIPMs were detected to support altered IP in infants with FA compared to ACs or following early peanut introduction among peanut‐sensitized children.