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BackgroundOne potential mechanism for protection from SARS-CoV-2 in children is through passive immunity via breast milk from a mother infected with the novel coronavirus. The primary objectives of this study were to establish the presence of SARS-CoV-2-specific IgA and IgG and to characterize the antigenic regions of SARS-CoV-2 proteins that were reactive with antibodies in breast milk.MethodsBetween March 2020 and September 2020, 21 women with confirmed SARS-CoV-2 infection were enrolled in Mommy's Milk. Participants donated serial breast milk samples around their time of illness. Breast milk samples were used to probe a multi-coronavirus protein microarray containing full-length and variable-length overlapping fragments of SARS-CoV-2 proteins. Samples were also tested against S and N proteins by electrochemiluminescence assay.ResultsThe breast milk samples contained IgA reactive with a variety of SARS-CoV-2 antigens. The most IgA-reactive SARS-CoV-2 proteins were N (42.9% of women responded to ≥1 N fragment) and S proteins (23.9% responded to ≥1 fragment of S1 or S2). IgG responses were similar. A striking observation was the dissimilarity between mothers in antibody recognition, giving distinct antibody reactivity and kinetic profiles.ConclusionsIndividual COVID-19 cases had diverse and unique milk IgA profiles following the onset of symptoms.ImpactIn this observational longitudinal case series of 21 women with confirmed SARS-CoV-2 infection, IgA binding to SARS-CoV-2 proteins detected by orthologous proteome microarray and electrochemiluminescence assays was observed in >75% of women, but there was heterogeneity in which antigens and how many were reactive between women. Immunological profiles of protein regions recognized by each woman were distinct. Diverse repertoires of mucosal breast milk antibody to SARS-CoV-2 reflect heterogeneous passive transfer of maternal antibody to exposed breastfeeding infants.

BACKGROUND. The use of high-throughput technologies has enabled rapid advancement in the knowledge of host immune responses to pathogens. Our objective was to compare the repertoire, protection, and maternal factors associated with human milk antibodies to infectious pathogens in different economic and geographic locations. METHODS. Using multipathogen protein microarrays, 878 milk and 94 paired serum samples collected from 695 women in 5 high and low-to-middle income countries (Bangladesh, Finland, Peru, Pakistan, and the United States) were assessed for specific IgA and IgG antibodies to 1,607 proteins from 30 enteric, respiratory, and bloodborne pathogens. RESULTS. The antibody coverage across enteric and respiratory pathogens was highest in Bangladeshi and Pakistani cohorts and lowest in the U.S. and Finland. While some pathogens induced a dominant IgA response (Campylobacter, Klebsiella, Acinetobacter, Cryptosporidium, and pertussis), others elicited both IgA and IgG antibodies in milk and serum, possibly related to the invasiveness of the infection (Shigella, enteropathogenic E. coli 'EPEC', Streptococcus pneumoniae, Staphylococcus aureus, and Group B Streptococcus). Besides the differences between economic regions and decreases in concentrations over time, human milk IgA and IgG antibody concentrations were lower in mothers with high BMI and higher parity, respectively. In Bangladeshi infants, a higher specific IgA concentration in human milk was associated with delayed time to rotavirus infection, implying protective properties of antirotavirus antibodies, whereas a higher IgA antibody concentration was associated with greater incidence of Campylobacter infection. CONCLUSION. This comprehensive assessment of human milk antibody profiles may be used to guide the development of passive protection strategies against infant morbidity and mortality. FUNDING. Bill and Melinda Gates Foundation grant OPP1172222 (to KMJ); Bill and Melinda Gates Foundation grant OPP1066764 funded the MDIG trial (to DER); University of Rochester CTSI and Environmental Health Sciences Center funded the Rochester Lifestyle study (to RJL); and R01 AI043596 funded PROVIDE (to WAP)., Introduction In 2019, 5.3 million liveborn children died before 5 years of age worldwide, nearly half of whom died from infectious diseases, including lower respiratory infections and diarrhea (1). The [...]

Immunization with sporozoites under chloroquine chemoprophylaxis (CPS) induces distinctly preerythrocytic and long-lasting sterile protection against homologous controlled human malaria infection (CHMI). To identify possible humoral immune correlates of protection, plasma samples were collected from 38 CPS-immunized Dutch volunteers for analysis using a whole Plasmodium falciparum proteome microarray with 7,455 full-length or segmented protein features displaying about 91% of the total P. falciparum proteome. We identified 548 reactive antigens representing 483 unique proteins. Using the breadth of antibody responses for each subject in a mixture-model algorithm, we observed a trimodal pattern, with distinct groups of 16 low responders, 19 medium responders, and 3 high responders. Fifteen out of 16 low responders, 12 of the 19 medium responders, and 3 out of 3 high responders were fully protected from a challenge infection. In the medium-responder group, we identified six novel antigens associated with protection (area under the curve [AUC] value of ≥0.75; P

RTS,S/AS01E, the first approved malaria vaccine, demonstrated moderate efficacy during the phase 3 pediatric trial. We previously investigated cell-mediated immune (CMI) responses following the primary 3-dose immunization and now report responses to the booster dose given 18 months later. Thirty CMI markers were measured by Luminex in supernatants of peripheral blood mononuclear cells from 709 children and infants after RTS,S/AS01E antigen stimulation, and their associations with malaria risk and antibodies one month post-booster and one year later were assessed. IL-2, IFN-γ, IL-17, IL-5, and IL-13 were associated with RTS,S/AS01E booster vaccination, and IL-2 responses to the circumsporozoite protein (CSP) remained higher after one year. IL-2 was associated with reduced malaria risk in one site, and IL-10 was associated with increased risk in infants. Anti-CSP IgG and IL-2 were moderately correlated one year after booster. This study highlights the moderate cell-mediated immunogenicity of the RTS,S/AS01E booster dose that aligns with partial recovery of RTS,S/AS01E vaccine efficacy. [ABSTRACT FROM AUTHOR]

Chronic immune activation from persistent malaria infections can induce immunophenotypic changes associated with T-cell exhaustion. However, associations between T and B cells during chronic exposure remain undefined. We analyzed peripheral blood mononuclear cells from malaria-exposed pregnant women from Papua New Guinea and Spanish malaria-naïve individuals using flow cytometry to profile T-cell exhaustion markers phenotypically. T-cell lineage (CD3, CD4, and CD8), inhibitory (PD1, TIM3, LAG3, CTLA4, and 2B4), and senescence (CD28-) markers were assessed. Dimensionality reduction methods revealed increased PD1, TIM3, and LAG3 expression in malaria-exposed individuals. Manual gating confirmed significantly higher frequencies of PD1+CD4+ and CD4+, CD8+, and double-negative (DN) T cells expressing TIM3 in malaria-exposed individuals. Increased frequencies of T cells co-expressing multiple markers were also found in malaria-exposed individuals. T-cell data were analyzed with B-cell populations from a previous study where we reported an alteration of B-cell subsets, including increased frequencies of atypical memory B cells (aMBC) and reduction in marginal zone (MZ-like) B cells during malaria exposure. Frequencies of aMBC subsets and MZ-like B cells expressing CD95+ had significant positive correlations with CD28+PD1+TIM3+CD4+ and DN T cells and CD28+TIM3+2B4+CD8+ T cells. Frequencies of aMBC, known to associate with malaria anemia, were inversely correlated with hemoglobin levels in malaria-exposed women. Similarly, inverse correlations with hemoglobin levels were found for TIM3+CD8+ and CD28+PD1+TIM3+CD4+ T cells. Our findings provide further insights into the effects of chronic malaria exposure on circulating B- and T-cell populations, which could impact immunity and responses to vaccination. Chronic malaria exposure is associated with increased frequencies of T cells with inhibitory markers and expanded atypical memory B cells, which were found to positively correlate with each other. T cells with inhibitory markers and atypical memory B cells had positive correlations with malaria antibodies and negative correlations with hemoglobin levels in the chronically exposed individuals. T-cell subsets with inhibitory markers and B-cell subsets were able to distinguish malaria exposed versus non-exposed individuals using dimensionality reduction analysis. Graphical Abstract [ABSTRACT FROM AUTHOR]

Author(s): Benjamin Mordmller [1]; Gzin Surat [1]; Heimo Lagler [1, 2]; Sumana Chakravarty [3]; Andrew S. Ishizuka [4]; Albert Lalremruata [1]; Markus Gmeiner [1]; Joseph J. Campo [5]; Meral Esen [...]