Maternal immune response and placental antibody transfer after COVID-19 vaccination across trimester and platforms

The availability of three COVID-19 vaccines in the United States provides an unprecedented opportunity to examine how vaccine platforms and timing of vaccination in pregnancy impact maternal and neonatal immunity. Here, we characterized the antibody profile after Ad26.COV2.S, mRNA-1273 or BNT162b2 vaccination in 158 pregnant individuals, and evaluated transplacental antibody transfer by profiling maternal and umbilical cord blood in 175 maternal-neonatal dyads. These analyses revealed lower vaccine-induced functions and Fc-receptor binding after Ad26.COV2.S compared to mRNA vaccination, and subtle advantages in titer and function with mRNA-1273 versus BN162b2. mRNA vaccinees had higher titers and functions against SARS-CoV-2 variants of concern. First and third trimester vaccination resulted in enhanced maternal immune responses relative to second trimester. Higher cord:maternal transfer ratios following first and second trimester vaccination reflect placental compensation for waning maternal titers. These results support vaccination early in pregnancy to maximize maternal protection throughout gestation, without compromising neonatal antibody protection.

Fetal Hematopoiesis is Driven by Privileged Expansion and Differentiation of Yolk Sac-Derived Erythro-Myeloid Progenitors

Most blood and immune cells are produced by Hematopoietic Stem Cells (HSC) throughout life. However, several tissue resident immune populations can only be generated from developmentally restricted progenitors. This questions to what extent fetal HSC differentiate in utero, implicating an essential role for HSC-independent progenitors in supporting embryonic viability and innate immunity in the perinatal period. Among them, Erythro-Myeloid Progenitors (EMP) emerge from the extraembryonic yolk sac prior to HSC and their progeny (resident macrophages and skin mast cells) persist in adulthood. Here, we showed that HSC contributed minimally to fetal myelopoiesis as we exposed a developmentally-restricted privilege for erythro-myeloid differentiation from EMP in the fetal liver. EMP-derived myeloid progenitors displayed distinct molecular features and were functionally inequivalent to fetal HSC-derived counterparts. These findings inform future studies of HSC-dependent and HSC-independent hematopoiesis in view of neonatal immunity and pediatric blood disorders for which the cell of origin is poorly understood.

An Insight into Probiotics Bio-Route: Translocation from the Mother’s Gut to the Mammary Gland

Human breast milk (HBM) is unique in its composition as it is adapted to fulfil the newborns’ nutritional requirement and helps in improving the health of newborns. Besides various nutrients, the human milk also contains diverse group of microbiotas. The human milk microbiota has a remarkable impact on the growth and development of a newborn. Additionally, the human milk microbiota enhances the colonization of microbes in the gut of infants. Debates about the origin of HBM microbial flora remain premature and contradictory in some cases. Recent data suggest that the maternal gut microbiota has a major impact on microbial composition, areolar skin, and from the infant’s oral cavity. The current review investigates the possible route of microbial transfer from the maternal gut to mammary gland and suggests that it might occur through the entero-mammary pathway. It involves precise selection of probiotic microorganisms from the gut, as the human gut hosts trillions of microorganisms involved in gut homeostasis and other metabolic pathways. Gastrointestinal lymphatic vessels, macrophages, and dendritic cells are shown to play a significant role in the microbial transmission. Furthermore, the role of microbial factors in the development of neonatal immunity and translocation of secretory IgA (SIgA) cells from the intestinal lumen to GALT and finally to mammary glands via entero-mammary link are discussed.

Microbiota Signals during the Neonatal Period Forge Life-Long Immune Responses

The microbiota regulates immunological development during early human life, with long-term effects on health and disease. Microbial products include short-chain fatty acids (SCFAs), formyl peptides (FPs), polysaccharide A (PSA), polyamines (PAs), sphingolipids (SLPs) and aryl hydrocarbon receptor (AhR) ligands. Anti-inflammatory SCFAs are produced by Actinobacteria, Bacteroidetes, Firmicutes, Spirochaetes and Verrucomicrobia by undigested-carbohydrate fermentation. Thus, fiber amount and type determine their occurrence. FPs bind receptors from the pattern recognition family, those from commensal bacteria induce a different response than those from pathogens. PSA is a capsular polysaccharide from B. fragilis stimulating immunoregulatory protein expression, promoting IL-2, STAT1 and STAT4 gene expression, affecting cytokine production and response modulation. PAs interact with neonatal immunity, contribute to gut maturation, modulate the gut–brain axis and regulate host immunity. SLPs are composed of a sphingoid attached to a fatty acid. Prokaryotic SLPs are mostly found in anaerobes. SLPs are involved in proliferation, apoptosis and immune regulation as signaling molecules. The AhR is a transcription factor regulating development, reproduction and metabolism. AhR binds many ligands due to its promiscuous binding site. It participates in immune tolerance, involving lymphocytes and antigen-presenting cells during early development in exposed humans.

Ante-Natal and Post-Natal Influences on Neonatal Immunity, Growth and Puberty of Calves—A Review

Calf immunity, growth and puberty are important factors affecting heifer productivity. The first four weeks of age are critical for reducing calf morbidity and mortality. It is well documented that colostrum is paramount to neonatal nutrition and passive immunity, however, adaptation to extra-uterine life starts early during embryonic development. Therefore, successful calf rearing strategies are underpinned by adequate maternal nutrition during gestation, and good colostrum management. A deeper understanding of these interactions paves the way for developing strategies to improve immune responses to environmental pathogens, optimal growth and timely attainment of puberty in calves. The literature reviewed here shows that there are opportunities to enhance the future performance of cattle paying attention to the interaction of nutrition and immunity at each developmental stage. Therefore, the objective of this review is to give the reader an overview of interactions between immunity, growth and puberty in dairy calves and highlight how these influence future performances.

Anti-Inflammatory Therapies for Treatment of Inflammation-Related Preterm Brain Injury

Despite the prevalence of preterm brain injury, there are no established neuroprotective strategies to prevent or alleviate mild-to-moderate inflammation-related brain injury. Perinatal infection and inflammation have been shown to trigger acute neuroinflammation, including proinflammatory cytokine release and gliosis, which are associated with acute and chronic disturbances in brain cell survival and maturation. These findings suggest the hypothesis that the inhibition of peripheral immune responses following infection or nonspecific inflammation may be a therapeutic strategy to reduce the associated brain injury and neurobehavioral deficits. This review provides an overview of the neonatal immunity, neuroinflammation, and mechanisms of inflammation-related brain injury in preterm infants and explores the safety and efficacy of anti-inflammatory agents as potentially neurotherapeutics.

Malaria and Early Life Immunity: Competence in Context

Childhood vaccines have been the cornerstone tool of public health over the past century. A major barrier to neonatal vaccination is the “immaturity” of the infant immune system and the inefficiency of conventional vaccine approaches at inducing immunity at birth. While much of the literature on fetal and neonatal immunity has focused on the early life propensity toward immune tolerance, recent studies indicate that the fetus is more immunologically capable than previously thought, and can, in some circumstances, mount adaptive B and T cell responses to perinatal pathogens in utero. Although significant hurdles remain before these findings can be translated into vaccines and other protective strategies, they should lend optimism to the prospect that neonatal and even fetal vaccination is achievable. Next steps toward this goal should include efforts to define the conditions for optimal stimulation of infant immune responses, including antigen timing, dose, and route of delivery, as well as antigen presentation pathways and co-stimulatory requirements. A better understanding of these factors will enable optimal deployment of vaccines against malaria and other pathogens to protect infants during their period of greatest vulnerability.

Vaccination strategies to enhance immunity in neonates

Neonates are particularly susceptible to infection. This vulnerability occurs despite their responsiveness to most vaccines. However, current vaccines do not target the pathogens responsible for most of the severe neonatal infections, and the time it takes to induce protective pathogen-specific immunity after vaccination limits protection in the first days to weeks of life. Alternative strategies include using vaccines to broadly stimulate neonatal immunity in a pathogen-agnostic fashion or vaccinating women during pregnancy to induce protective antibodies that are vertically transferred to offspring within their window of vulnerability. Protection may be further improved by integrating these approaches, namely vaccinating the neonate under the cover of vertically transferred maternal immunity. The rationale for and knowledge gaps related to each of these alternatives are discussed.

FcRn, but not FcγRs, drives maternal-fetal transplacental transport of human IgG antibodies

The IgG Fc domain has the capacity to interact with diverse types of receptors, including FcRn and FcγRs, which confer pleiotropic biological activities. Whereas FcRn regulates IgG epithelial transport and recycling, Fc effector activities, such as ADCC and phagocytosis are mediated by FcγRs, which upon crosslinking transduce signals that modulate the function of effector leukocytes. Despite the well-defined and non-overlapping functional properties of FcRn and FcγRs, recent studies have suggested that FcγRs mediate transplacental IgG transport, as certain Fc glycoforms were reported to be enriched in fetal circulation. To determine the contribution of FcγRs and FcRn to the maternal-fetal transport of IgG, we characterized the IgG Fc glycosylation in paired maternal-fetal samples from patient cohorts from Uganda and Nicaragua. No differences in IgG1 Fc glycan profiles and minimal differences in IgG2 Fc glycans were noted, whereas the presence or absence of galactose on the Fc glycan of IgG1 did not alter FcγRIIIA or FcRn binding, half-life, or their ability to deplete target cells in FcγR/FcRn humanized mice. Modeling maternal/fetal transport in FcγR/FcRn humanized mice confirmed that only FcRn contributed to transplacental transport of IgG; IgG selectively enhanced for FcRn binding resulted in enhanced accumulation of maternal antibody in the fetus. In contrast, enhancing FcγRIIIA binding did not result in enhanced maternal/fetal transport. These results argue against a role for FcγRs in IgG transplacental transport, suggesting Fc engineering of maternally administered antibody to only enhance FcRn binding as a means to improve maternal/fetal transport of IgG.Significance StatementTransport of IgG antibodies from the maternal to the fetal circulation is a key process for neonatal immunity, as neonates cannot sufficiently generate IgG antibodies to reach protective levels during the first months after birth. In humans and other primates, maternal to fetal transport of IgG antibodies is largely mediated through the placental tissue. FcRn has been previously identified as the major driver of IgG transplacental transport. Here we examined whether other receptors, such as FcγRs, also contribute to the maternal-fetal IgG transfer. By characterizing the Fc domain structure of paired maternal-fetal IgG samples and modeling transplacental IgG transport in genetically engineered mouse strains, we determined that FcRn, but not FcγRs, is the major receptor that mediates transplacental IgG transport.