Citations

SARS-CoV-2 mRNA vaccination induces robust humoral and cellular immunity in the circulation; however, it is currently unknown whether it elicits effective immune responses in the respiratory tract, particularly against variants of concern (VOCs), including Omicron. We compared the SARS-CoV-2 S–specific total and neutralizing antibody responses, and B and T cell immunity, in the bronchoalveolar lavage fluid (BAL) and blood of COVID-19–vaccinated individuals and hospitalized patients. Vaccinated individuals had significantly lower levels of neutralizing antibody against D614G, Delta (B.1.617.2), and Omicron BA.1.1 in the BAL compared with COVID-19 convalescents despite robust S-specific antibody responses in the blood. Furthermore, mRNA vaccination induced circulating S-specific B and T cell immunity, but in contrast to COVID-19 convalescents, these responses were absent in the BAL of vaccinated individuals. Using a mouse immunization model, we demonstrated that systemic mRNA vaccination alone induced weak respiratory mucosal neutralizing antibody responses, especially against SARS-CoV-2 Omicron BA.1.1 in mice; however, a combination of systemic mRNA vaccination plus mucosal adenovirus-S immunization induced strong neutralizing antibody responses not only against the ancestral virus but also the Omicron BA.1.1 variant. Together, our study supports the contention that the current COVID-19 vaccines are highly effective against severe disease development, likely through recruiting circulating B and T cell responses during reinfection, but offer limited protection against breakthrough infection, especially by the Omicron sublineage. Hence, mucosal booster vaccination is needed to establish robust sterilizing immunity in the respiratory tract against SARS-CoV-2, including infection by the Omicron sublineage and future VOCs.

Respiratory tissue resident–like CD8 + T cells are associated with chronic lung sequelae post-acute COVID-19.

AbstractProblemCell‐free fetal DNA (cffDNA) shed from the placenta can be detected in maternal blood and increases incrementally during gestation. Concentrations are further elevated with pregnancy complications. Specific activators of cffDNA release in such complications have not been identified. Here, we use trophoblast cells from early and term placenta to examine cffDNA release following apoptosis, infection, and sterile inflammatory stress.Method of StudyHTR8/SVneo cells were used to model first‐trimester trophoblasts, and term cytotrophoblasts (CTBs) were isolated from placentae collected after uncomplicated deliveries. Trophoblasts were treated with varying concentrations of doxorubicin (DOX), lipopolysaccharide (LPS), or high‐mobility group box protein 1 (HMGB1) for 18 h. Cells or supernatants were quantified for caspase‐3/7 cleavage, pro‐inflammatory cytokine secretion, and cffDNA release.ResultsBoth HTR8/SVneo and CTBs underwent caspase‐3/7 cleavage following DOX treatment, with HTR8/SVneo cells more sensitive to apoptosis than term CTBs. Apoptotic cells released more cffDNA in a dose‐dependent manner. Treatment with LPS resulted in an increase in pro‐inflammatory IL‐6 release, particularly in term CTBs compared to early trophoblasts; however, LPS did not affect cffDNA release. Lastly, while neither cell released more TNF‐α following stimulation with HMGB1, both HTR8/SVneo and CTBs released significantly more cffDNA in the presence of HMGB1.ConclusionsThese data show that apoptosis and sterile inflammation induced by DOX and HMGB1, respectively, cause an increase in cffDNA concentrations in both first‐trimester and term trophoblasts. Understanding physiologic release of cffDNA during healthy and complicated pregnancy can identify new targets for the diagnosis and treatment of gestational complications.

Abstract Background Implementation of universal antiretroviral therapy (ART) has significantly lowered vertical transmission rates but has also increased numbers of human immunodeficiency virus (HIV)–exposed uninfected children, who remain vulnerable to morbid effects. In the current study, we investigated whether T-cell alterations in the placenta contribute to altered immune status in HIV-exposed uninfected. Methods We analyzed T cells from term placenta decidua and villous tissue and paired cord blood from pregnant women living with HIV (PWH) who initiated ART late in pregnancy (n = 21) with pregnant women not living with HIV (PWNH) (n = 9). Results Placentas from PWH showed inverted CD4/CD8 ratios and higher proportions of tissue resident CD8+ T cells in villous tissue relative to control placentas. CD8+ T cells in the fetal capillaries, which were of fetal origin, were positively correlated with maternal plasma viremia before ART initiation, implying that imbalanced T cells persisted throughout pregnancy. In addition, the expanded memory differentiation of CD8+ T cells was confined to the fetal placental compartment and cord blood but was not observed in the maternal decidua. Conclusions T-cell homeostatic imbalance in the blood circulation of PWH is reflected in the placenta. The placenta may be a causal link between HIV-induced maternal immune changes during gestation and altered immunity in newborn infants in the absence of vertical transmission.

AbstractAimThis study is a comprehensive review with the purpose of collecting the most relevant data in several sections including current treatment guidelines in the paediatric population.MethodsLiterature was systematically searched in different databases. Results were limited to 2019+ and English, French and Spanish language.ResultsChildren can exhibit mild and less severe COVID‐19 disease than adults and also have asymptomatic carriage of SARS‐CoV‐2, while severe disease is more frequently noted during infancy (<1 year). SARS‐CoV‐2 binds the angiotensin‐converting enzyme 2 (ACE‐2) receptor; age‐, racial‐, and gender‐specific differences in ACE‐2 expression need to be elucidated in order to explain the differential clinical profiles between children and adults. Multisystem inflammatory syndrome in children (MIS‐C) is an important condition to recognise in children. The decision to use antiviral or immunomodulatory therapy in a child or adolescent should be individualised based on the clinical scenario. Remdesivir is the only FDA‐approved therapy available for children older than 12 years old who require hospitalisation for COVID‐19.ConclusionFurther studies are urgently required to address prevention and treatment in at‐risk and infected children, especially with underlying comorbidities. The chapter on the overall impact of COVID‐19 in children has not yet been written. Nevertheless, SARS‐CoV‐2 has now joined a long list of human pandemics, which may forever change the world's history.

Abstract Problem Prenatal exposure to metabolic dysregulation arising from maternal obesity can have negative health consequences in post‐natal life. To date, the specific effects of maternal obesity on fetal immunity at a cellular level have not been well characterized. Method of Study Using cord blood mononuclear cells (CBMCs) and cord plasma (n = 9/group) isolated from infants born to women with a high body mass index (BMI>25kg/m 2 ) compared to women with a normal BMI (18‐25kg/m 2 ), we evaluated differences in immune cell populations using single‐cell mass cytometry (CyTOF). CBMCs were matched according to potentially confounding variables, such as maternal and gestational age, ethnicity, smoking status, and gravidity. Statistical results were adjusted for fetal sex. Data were analyzed by viSNE and FlowSOM softwares in Cytobank ™ . Results In newborn CBMCs from women with high BMI, we observed changes in frequency and phenotype of immune cell populations, including significant increases in CD4 + T cells and decreases in myeloid cell populations. IL‐12p40 and MDC concentrations were significantly elevated in the high BMI group compared to control. Conclusion This study demonstrates an association between maternal obesity and fetal immunity. Our results warrant following long‐term immunologic outcomes and associated clinical risks in children born to women with a high pre‐pregnancy BMI.

Abstract During human pregnancy, proinflammatory responses in the placenta can cause severe fetal complications, including growth restriction, preterm birth, and stillbirth. Villitis of unknown etiology (VUE), an inflammatory condition characterized by the infiltration of maternal CD8+ T cells into the placenta, is hypothesized to be secondary to either a tissue rejection response to the haploidentical fetus or from an undiagnosed infection. In this study, we characterized the global TCR β-chain profile in human T cells isolated from placentae diagnosed with VUE compared with control and infectious villitis–placentae by immunoSEQ. Immunosequencing demonstrated that VUE is driven predominantly by maternal T cell infiltration, which is significantly different from controls and infectious cases; however, these T cell clones show very little overlap between subjects. Mapping TCR clones to common viral epitopes (CMV, EBV, and influenza A) demonstrated that Ag specificity in VUE was equal to controls and significantly lower than CMV-specific clones in infectious villitis. Our data indicate VUE represents an allograft response, not an undetected infection. These observations support the development of screening methods to predict those at risk for VUE and the use of specific immunomodulatory therapies during gestation to improve outcomes in affected fetuses.