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COVID-19 mRNA Vaccination in Lactation: Assessment of Adverse Events and Vaccine Related Antibodies in Mother-Infant Dyads.
Golan, Y, Prahl, M, Cassidy, AG, Gay, C, Wu, AHB, Jigmeddagva, U, Lin, CY, Gonzalez, VJ, Basilio, E, Chidboy, MA, et al
Frontiers in immunology. 2021;:777103
Abstract
BACKGROUND Data regarding symptoms in the lactating mother-infant dyad and their immune response to COVID-19 mRNA vaccination during lactation are needed to inform vaccination guidelines. METHODS From a prospective cohort of 50 lactating individuals who received mRNA-based vaccines for COVID-19 (mRNA-1273 and BNT162b2), blood and milk samples were collected prior to first vaccination dose, immediately prior to 2nd dose, and 4-10 weeks after 2nd dose. Symptoms in mother and infant were assessed by detailed questionnaires. Anti-SARS-CoV-2 antibody levels in blood and milk were measured by Pylon 3D automated immunoassay and ELISA. In addition, vaccine-related PEGylated proteins in milk were measured by ELISA. Blood samples were collected from a subset of infants whose mothers received the vaccine during lactation (4-15 weeks after mothers' 2nd dose). RESULTS No severe maternal or infant adverse events were reported in this cohort. Two mothers and two infants were diagnosed with COVID-19 during the study period before achieving full immune response. PEGylated proteins were not found at significant levels in milk after vaccination. After vaccination, levels of anti-SARS-CoV-2 IgG and IgM significantly increased in maternal plasma and there was significant transfer of anti-SARS-CoV-2-Receptor Binding Domain (anti-RBD) IgA and IgG antibodies to milk. Milk IgA levels after the 2nd dose were negatively associated with infant age. Anti-SARS-CoV-2 IgG antibodies were not detected in the plasma of infants whose mothers were vaccinated during lactation. CONCLUSIONS COVID-19 mRNA vaccines generate robust immune responses in plasma and milk of lactating individuals without severe adverse events reported.
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Personalized Profiling Reveals Donor- and Lactation-Specific Trends in the Human Milk Proteome and Peptidome.
Zhu, J, Dingess, KA, Mank, M, Stahl, B, Heck, AJR
The Journal of nutrition. 2021;(4):826-839
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Abstract
BACKGROUND Human milk is the most genuine form of personalized nutrition, whereby its nutritional and bioactive constituents support the changing needs of the growing infant. Personalized proteome profiling strategies may provide insights into maternal-infant relationships. Proteins and endogenous peptides in human milk play an important role as nutrients for growth and have distinct functionality such as immune defense. Comprehensive monitoring of all of the human milk proteinaceous components, including endogenous peptides, is required to fully understand the changing role of the human milk proteome throughout lactation. OBJECTIVE We aimed to investigate the personalized nature of the human milk proteome and peptidome for individual mother-infant dyads. METHODS Two individual healthy milk donors, aged 29 and 32 y and both of a normal BMI, were longitudinally observed over weeks 1, 2, 3, 4, 6, 8, 10, 12, and 16 postpartum. Milk collection was standardized. Comprehensive variations in the human milk proteinaceous components were assessed using quantitative LC-MS/MS methods. RESULTS We longitudinally profiled the concentrations of >1300 milk proteins and 2000 endogenous milk peptides spanning 16 wk of lactation for 2 individual donors. We observed many gradual and alike changes in both donors related to temporal effects, for instance early lactation was marked by high concentrations of proteins and peptides involved in lactose synthesis and immune development. Uniquely, in 1 of the 2 donors, we observed a substantial anomaly in the milk composition, exclusively at week 6, likely indicating a response to inflammation and/or infection. CONCLUSIONS Here, we provide a resource for characterizing the lactational changes in the human milk proteome, encompassing thousands of proteins and endogenous peptides. Further, we demonstrate the feasibility and benefit of personalized profiling to monitor the influence of milk on the development of the newborn, as well as the health status of each individual mother-infant pair.
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Human milk immunomodulatory proteins are related to development of infant body composition during the first year of lactation.
Gridneva, Z, Lai, CT, Rea, A, Tie, WJ, Ward, LC, Murray, K, Hartmann, PE, Geddes, DT
Pediatric research. 2021;(4):911-921
Abstract
BACKGROUND To investigate relationships between infant body composition (BC) and human milk (HM) immunomodulatory proteins (IMPs) during the first 12 months of lactation. METHODS BC of breastfeeding dyads (n = 20) was measured with ultrasound skinfolds (infants) and bioimpedance spectroscopy (infants/mothers) at 2, 5, 9, and/or 12 months post partum. Breastfeeding frequency, 24-h milk intake, and IMP concentrations (lactoferrin, lysozyme, secretory immunoglobulin A (sIgA)) were measured, and calculated daily intakes (CDIs) were determined. We used linear regression/mixed-effects models and adjusted results for multiple comparisons. RESULTS No associations were seen between maternal characteristics and IMP concentrations/CDIs or between IMP concentrations and infant BC. Lactoferrin CDI was negatively associated with infant fat-free mass index (P = 0.002); lysozyme CDI was positively associated with infant fat mass (P = 0.004) and fat mass index (P = 0.004) measured with ultrasound skinfolds. CONCLUSION In this small cohort of infants breastfed on demand during first year of life, we report differential associations of HM IMPs with infant BC, showing that in addition to their critical role in shaping infant immunity, lactoferrin, and lysozyme also influence development of infant BC, highlighting the importance of breastfeeding for 12 months and beyond. IMPACT HM IMPs (concentrations and, most importantly, daily intakes) time-dependently and differentially associate with development of infant lean mass and adiposity during first 12 months of lactation. There is no information on how intakes and concentrations of these components affect development of infant BC. HM contains IMPs-lactoferrin, lysozyme, and sIgA, which not only play a critical role in shaping infant's immunity, but also influence infant growth and development of BC, highlighting the importance of breastfeeding for 12 months and beyond and warranting careful consideration of the dose effects of supplemented formula.
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COVID-19 mRNA vaccine and antibody response in lactating women: a prospective cohort study.
Charepe, N, Gonçalves, J, Juliano, AM, Lopes, DG, Canhão, H, Soares, H, Serrano, EF
BMC pregnancy and childbirth. 2021;(1):632
Abstract
BACKGROUND Immunological protection via breastfeeding is well known. The immunological profile of human milk changes during lactation. No clinical trials have been conducted in lactating women with the newest mRNA vaccines against SARS- CoV-2. A Few studies have shown the presence of antibodies in breastmilk after vaccination. The aim of this work is to study possible antibodies transfer via breastmilk and also the immunological characteristics of lactating women compared to non-lactating women, after using the BNT162b2 Pfizer vaccine. METHODS This is a prospective cohort study with a convenience homogenous sample of 24 healthcare workers (14 lactating and 10 non-lactating women) enrolled at the time of COVID-19 vaccination. Clinical data was registered in a questionnaire. Titers of SARS-CoV-2 spike IgG, IgA and IgM were quantified in post vaccination blood and human milk. Antibody quantification was performed by an in-house ELISA to SARS-CoV-2 trimeric spike protein. RESULTS All women showed immunity after vaccination with positive antibodies for IgM, IgA and IgG antibodies. The dominant serum antibody response was IgG. Modest levels of antibodies in breastmilk of lactating mothers were observed in this study, especially IgG in 42.9%. There was a moderate association between higher titers of IgG and a longer duration of breastfeeding (R= 0.55, p=0.041). CONCLUSIONS Evidence of antibody transfer in human milk after COVID-19 vaccination is scarce. The presence of antibodies in human milk is reported, but immunization through breastfeeding is still to be established.
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Early-Life Effects of Vitamin D: A Focus on Pregnancy and Lactation.
Wagner, CL, Hollis, BW
Annals of nutrition & metabolism. 2020;:16-28
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Abstract
Vitamin D is an endocrine regulator of calcium and bone metabolism. Yet, its effects include other systems, such as innate and adaptive immunity. Unique to pregnancy, circulating 1,25-dihydroxyvitamin D (1,25[OH]2D) increases early on to concentrations that are 2-3 times prepregnant values. At no other time during the lifecycle is the conversion of 25-hydroxyvitamin D (25[OH]D) to 1,25(OH)2D directly related and optimized at ≥100 nmol/L. Vitamin D deficiency appears to affect pregnancy outcomes, yet randomized controlled trials of vitamin D supplementation achieve mixed results depending on when supplementation is initiated during pregnancy, the dose and dosing interval, and the degree of deficiency at the onset of pregnancy. Analysis of trials on an intention-to-treat basis as opposed to the use of 25(OH)D as the intermediary biomarker of vitamin D metabolism yields differing results, with treatment effects often noted only in the most deficient women. Immediately after delivery, maternal circulating 1,25(OH)2D concentrations return to prepregnancy baseline, at a time when a breastfeeding woman has increased demands of calcium, beyond what was needed during the last trimester of pregnancy, making one question why 1,25(OH)2D increases so significantly during pregnancy. Is it to serve as an immune modulator? The vitamin D content of mother's milk is directly related to maternal vitamin D status, and if a woman was deficient during pregnancy, her milk will be deficient unless she is taking higher doses of vitamin D. Because of this relative "deficiency," there is a recommendation that all breastfed infants receive 400 IU vitamin D3/day starting a few days after birth. The alternative - maternal supplementation with 6,400 IU vitamin D3/day, effective in safely raising maternal circulating vitamin D, that of her breast milk, and effective in achieving sufficiency in her recipient breastfeeding infant - remains a viable option. Additional research is needed to understand vitamin D's influence on pregnancy health and the effect of maternal supplementation on breast milk's immune signaling.
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Evidence-Based Updates on the First Week of Exclusive Breastfeeding Among Infants ≥35 Weeks.
Feldman-Winter, L, Kellams, A, Peter-Wohl, S, Taylor, JS, Lee, KG, Terrell, MJ, Noble, L, Maynor, AR, Meek, JY, Stuebe, AM
Pediatrics. 2020;(4)
Abstract
The nutritional and immunologic properties of human milk, along with clear evidence of dose-dependent optimal health outcomes for both mothers and infants, provide a compelling rationale to support exclusive breastfeeding. US women increasingly intend to breastfeed exclusively for 6 months. Because establishing lactation can be challenging, exclusivity is often compromised in hopes of preventing feeding-related neonatal complications, potentially affecting the continuation and duration of breastfeeding. Risk factors for impaired lactogenesis are identifiable and common. Clinicians must be able to recognize normative patterns of exclusive breastfeeding in the first week while proactively identifying potential challenges. In this review, we provide new evidence from the past 10 years on the following topics relevant to exclusive breastfeeding: milk production and transfer, neonatal weight and output assessment, management of glucose and bilirubin, immune development and the microbiome, supplementation, and health system factors. We focus on the early days of exclusive breastfeeding in healthy newborns ≥35 weeks' gestation managed in the routine postpartum unit. With this evidence-based clinical review, we provide detailed guidance in identifying medical indications for early supplementation and can inform best practices for both birthing facilities and providers.
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Single Cell RNA Sequencing of Human Milk-Derived Cells Reveals Sub-Populations of Mammary Epithelial Cells with Molecular Signatures of Progenitor and Mature States: a Novel, Non-invasive Framework for Investigating Human Lactation Physiology.
Martin Carli, JF, Trahan, GD, Jones, KL, Hirsch, N, Rolloff, KP, Dunn, EZ, Friedman, JE, Barbour, LA, Hernandez, TL, MacLean, PS, et al
Journal of mammary gland biology and neoplasia. 2020;(4):367-387
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Abstract
Cells in human milk are an untapped source, as potential "liquid breast biopsies", of material for investigating lactation physiology in a non-invasive manner. We used single cell RNA sequencing (scRNA-seq) to identify milk-derived mammary epithelial cells (MECs) and their transcriptional signatures in women with diet-controlled gestational diabetes (GDM) with normal lactation. Methodology is described for coordinating milk collections with single cell capture and library preparation via cryopreservation, in addition to scRNA-seq data processing and analyses of MEC transcriptional signatures. We comprehensively characterized 3740 cells from milk samples from two mothers at two weeks postpartum. Most cells (>90%) were luminal MECs (luMECs) expressing lactalbumin alpha and casein beta and positive for keratin 8 and keratin 18. Few cells were keratin 14+ basal MECs and a small immune cell population was present (<10%). Analysis of differential gene expression among clusters identified six potentially distinct luMEC subpopulation signatures, suggesting the potential for subtle functional differences among luMECs, and included one cluster that was positive for both progenitor markers and mature milk transcripts. No expression of pluripotency markers POU class 5 homeobox 1 (POU5F1, encoding OCT4) SRY-box transcription factor 2 (SOX2) or nanog homeobox (NANOG), was observed. These observations were supported by flow cytometric analysis of MECs from mature milk samples from three women with diet-controlled GDM (2-8 mo postpartum), indicating a negligible basal/stem cell population (epithelial cell adhesion molecule (EPCAM)-/integrin subunit alpha 6 (CD49f)+, 0.07%) and a small progenitor population (EPCAM+/CD49f+, 1.1%). We provide a computational framework for others and future studies, as well as report the first milk-derived cells to be analyzed by scRNA-seq. We discuss the clinical potential and current limitations of using milk-derived cells as material for characterizing human mammary physiology.
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The Functional Power of the Human Milk Proteome.
Zhu, J, Dingess, KA
Nutrients. 2019;(8)
Abstract
Human milk is the most complete and ideal form of nutrition for the developing infant. The composition of human milk consistently changes throughout lactation to meet the changing functional needs of the infant. The human milk proteome is an essential milk component consisting of proteins, including enzymes/proteases, glycoproteins, and endogenous peptides. These compounds may contribute to the healthy development in a synergistic way by affecting growth, maturation of the immune system, from innate to adaptive immunity, and the gut. A comprehensive overview of the human milk proteome, covering all of its components, is lacking, even though numerous analyses of human milk proteins have been reported. Such data could substantially aid in our understanding of the functionality of each constituent of the proteome. This review will highlight each of the aforementioned components of human milk and emphasize the functionality of the proteome throughout lactation, including nutrient delivery and enhanced bioavailability of nutrients for growth, cognitive development, immune defense, and gut maturation.
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Structural studies on inhibitory mechanisms of antibiotic, corticosteroid and catecholamine molecules on lactoperoxidase.
Sheikh, IA, Jiffri, EH, Ashraf, GM, Kamal, MA, Beg, MA
Life sciences. 2018;:412-419
Abstract
AIM: Lactoperoxidase (LPO) is an essential protein with broad spectrum antimicrobial activity present in mammalian milk. It imparts immunity to infants against wide range of pathogenic infections. Several in vitro studies have shown inhibition of LPO activity by pharmaceutical compounds including commonly used antibiotics such as ampicillin and gentamicin, and molecules like prednisolone, norepinephrine, etc. Prescription of such drugs to lactating mothers might have adverse health effects on infants. The aim of our study was the elucidation of the structural aspects of the inhibitory mechanism of ampicillin, gentamicin, amoxicillin, prednisolone and norepinephrine on LPO. MATERIAL AND METHODS Three dimensional structure of camel LPO (cLPO) was developed using homology modeling and used for in silico experimental studies. The Schrödinger induced fit docking along with binding affinity estimation experiments were performed. The cLPO and Ligands were prepared using Protein Preparation Wizard and Ligprep modules available in Schrodinger suite. For estimating Binding affinity Prime Molecular Mechanics with Generalized Born and Surface Area (MMGB-SA) module was used. KEY RESULTS The five drug ligands formed three to five hydrogen bonding interactions with cLPO. Amino acids Arg-231, Asp-232, Ser-370, Arg-371 and Glu-374 of cLPO were crucial for these interactions. The binding affinity values for gentamicin were highest and for norepinephrine were the lowest. SIGNIFICANCE This study concludes that the five drug molecules show potential ability to inhibit the LPO activity. Further, a very high sequence similarity of cLPO with human LPO imparts high significance to these conclusions in relation to human health especially in new born infants.
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Levels of Growth Factors and IgA in the Colostrum of Women from Burundi and Italy.
Munblit, D, Abrol, P, Sheth, S, Chow, LY, Khaleva, E, Asmanov, A, Lauriola, S, Padovani, EM, Comberiati, P, Boner, AL, et al
Nutrients. 2018;(9)
Abstract
Colostrum is produced in the first days postpartum. It is a known source of immune mediators for a newborn within the first week of life. Although it is still unclear if colostrum composition varies between populations, recent data suggest differences. Hepatocyte growth factor (HGF); transforming growth factor-β (TGF-β) 1, 2, and 3; and immunoglobulin A (IgA) are key immunological components of colostrum that stimulate neonatal gastrointestinal and immune system development. We aimed to investigate the differences in the concentration between immune markers in the colostrum of mothers living in Burundi and Italy, and to identify the factors associated with differences. In this cross-sectional birth cohort study, a total of 99 colostrum samples from Burundian (n = 23) and Italian (n = 76) women were collected at 0 to 6 days postpartum. A clinical chemistry analyser was used for IgA quantification and electro-chemiluminescence, for HGF and TGFβ1-3 assessment. A univariate analysis and multivariate linear regression model were used for statistical testing. The concentrations of TGF-β2 (p = 0.01) and IgA (p < 0.01) were significantly higher in the colostrum from the women residing in Burundi than in Italy, both in a univariate analysis and upon the adjustment for confounding factors. A similar trend is seen for HGF, reaching statistical significance upon a multivariate analysis. We found a moderate to strong positive correlation between the TGF-β isoforms and IgA concentration in both countries (p < 0.01), with stronger concentration in the colostrum from Burundi. The results of this study are in support of previous data, suggesting that concentration of the immune active molecules is higher in the human milk of women residing in developing countries. However, with a small sample size, caution must be applied, as the findings require further confirmation. Future work should also be focused on other factors (e.g., lipid and microbial composition), as well as the investigation into colostrum and between populations comparison, adjusting for potential confounders.