Dissecting Fc signatures of protection in neonates following maternal influenza vaccination in a placebo-controlled trial.

Influenza is an important cause of illness and morbidity for infants. Seasonal influenza vaccination during pregnancy aims to provide protection to mothers, but it can also provide immunity to infants. The precise influence of maternal vaccination on immunity in infants and how vaccine-elicited antibodies provide protection in some but not all infants is incompletely understood. We comprehensively profiled the transfer of functional antibodies and defined humoral factors contributing to immunity against influenza in a clinical trial of maternal influenza vaccination. Influenza-specific antibody subclass levels, Fc ɣ receptor (FCGR) binding levels, and antibody-dependent innate immune functions were all profiled in the mothers during pregnancy and at birth, as well as in cord blood. Vaccination increased influenza-specific antibody levels, antibody binding to FCGR, and specific antibody-dependent innate immune functions in both maternal and cord blood, with FCGR binding most enhanced via vaccination. Influenza-specific FCGR binding levels were lower in cord blood of infants who subsequently developed influenza infection. Collectively these data suggest that in addition to increased antibody amounts, the selective transfer of FCGR-binding antibodies contributes to the protective immune response in infants against influenza.

Dynamics of breast milk antibody titer in the six months following SARS-CoV-2 infection.

BACKGROUND: While a growing body of literature describes antibody dynamics in serum, little is known about breast milk antibody titers in the months following SARS-CoV-2 infection. OBJECTIVES: We evaluated the dynamics of the humoral immune response to SARS-CoV-2 in two women who were breastfeeding when infected. We assessed paired breast milk and serum samples for six months post-infection for antibodies specific to the SARS-CoV-2 receptor binding domain (RBD) of the spike protein. RESULTS: Starting at 10 days after symptom onset, IgA antibody levels were persistent over a 6-month time period in human milk. For both mothers, no detectable IgA was found in the samples collected pre-symptom onset. RBD-specific IgG and IgM antibodies in tandem serum collected from the two donors demonstrated stable IgG levels over the six-month time period post-symptom onset. CONCLUSIONS: We found that breastfeeding mothers produced a durable IgA response for up to six months following COVID-19 infection, suggesting an important role for breast milk in protection of infants.

Alternative splicing in a presenilin 2 variant associated with Alzheimer disease.

OBJECTIVE: Autosomal-dominant familial Alzheimer disease (AD) is caused by by variants in presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP). Previously, we reported a rare PSEN2 frameshift variant in an early-onset AD case (PSEN2 p.K115Efs*11). In this study, we characterize a second family with the same variant and analyze cellular transcripts from both patient fibroblasts and brain lysates. METHODS: We combined genomic, neuropathological, clinical, and molecular techniques to characterize the PSEN2 K115Efs*11 variant in two families. RESULTS: Neuropathological and clinical evaluation confirmed the AD diagnosis in two individuals carrying the PSEN2 K115Efs*11 variant. A truncated transcript from the variant allele is detectable in patient fibroblasts while levels of wild-type PSEN2 transcript and protein are reduced compared to controls. Functional studies to assess biological consequences of the variant demonstrated that PSEN2 K115Efs*11 fibroblasts secrete less Aß 1-40 compared to controls, indicating abnormal γ-secretase activity. Analysis of PSEN2 transcript levels in brain tissue revealed alternatively spliced PSEN2 products in patient brain as well as in sporadic AD and age-matched control brain. INTERPRETATION: These data suggest that PSEN2 K115Efs*11 is a likely pathogenic variant associated with AD. We uncovered novel PSEN2 alternative transcripts in addition to previously reported PSEN2 splice isoforms associated with sporadic AD. In the context of a frameshift, these alternative transcripts return to the canonical reading frame with potential to generate deleterious protein products. Our findings suggest novel potential mechanisms by which PSEN variants may influence AD pathogenesis, highlighting the complexity underlying genetic contribution to disease risk.