Immunotherapy: ALLOGENEIC UMBILICAL CORD BLOOD REGULATORY T CELLS DECREASE INFLAMMATION AND PRESERVE ANTI-TUMOR ACTIVITY OF CAR T CELLS

Background & Aim: With larger accessibility and increased number of patients being treated with CART cell therapy, real-world toxicity continues to remain a significant challenge to its widespread adoption. We have previously shown that allogeneic umbilical cord blood derived (UCB) regulatory T cells (Tregs) can resolve uncontrolled inflammation and can treat acute and immune mediated lung injury in a xenogenic model as well as in patients suffering from COVID-19 acute respiratory distress syndrome. The unique properties of UCB Tregs including: i) lack of plasticity when exposed to inflammatory micro-environments;ii) no requirement for HLA matching;iii) long shelf life of cryopreserved Tregs;and iv) immediate product availability for on demand treatment, makes them an attractive source for treating acute inflammatory syndromes. Therefore, we hypothesized that add-on therapy with UCB derived Tregs may resolve uncontrolled inflammation responsible for CART cell therapy associated toxicity. Methods, Results & Conclusion(s): UCB Tregs were added in 1:1 ratio to CART cells, where no interference in their ability to kill CD19+ Raji cells, was detected at different ratios : 8:1 (80.4% vs. 81.5%);4:1 (62.0% vs. 66.2%);2:1 (50.1% vs. 54.7%);1:1 (35.4% vs. 44.1%) (Fig 1A). In a xenogenic B cell lymphoma model, multiple injections of Tregs were administered after CART injection (Fig 1B), which did not impact distribution of CD8+ T effector cells (Fig 1C) or CART cells cells (Fig 1D) in different organs. No decline in the CAR T levels was observed in the Tregs recipients (Fig 1E). Specifically, no difference in tumor burden was detected between the two arms (Fig 2A). No tumor was detected in CART+Tregs in liver (Fig 2B) or bone marrow (Fig 2C). A corresponding decrease in multiple inflammatory cytokines in peripheral blood was observed in CART+Tregs when compared to CART alone (Fig 2D). Here we show "proof of concept" for add-on therapy with Tregs to mitigate hyper-inflammatory state induced by CART cells without interference in their on-target anti-tumor activity. The timing of Tregs administration after CART cells have had sufficient time for forming synapse with tumor cells allows for preservation of their anti-tumor cytotoxicity, such that the infused Tregs home to the areas of tissue damage to bind to the resident antigen presenting cells which in turn collaborate with Tregs to resolve inflammation. Such differential distribution of cells allow for a Treg "cooling blanket" and lays ground for clinical study. [Figure presented]Copyright © 2023 International Society for Cell & Gene Therapy

Perinatal aspects of sars-cov-2 infection during pregnancy: A potential cause for concern

Ever since the beginning of COVID-19 pandemic, uncertainty regarding clinical presentation and differences among various subpopulations exist. With more than 209,870,000 confirmed cases and more than 4,400,000 deaths worldwide, we are facing the new era of health crisis which will undoubtedly impair global health, economic and social circumstances. In the past year, numerous genetic mutations which code SARS-CoV-2 proteins led to the occurrence of new viral strains, with higher transmission rates. Apart from the implementation of vaccination, the effect of SARS-CoV-2 on pregnancy outcome and maternal fetal transmission remains an important concern. Although neonates diagnosed with COVID-19 were mostly asymptomatic or presented with mild disease, the effect on early pregnancy is yet to be evident. While positive finding of SARS-CoV-2 RNA in some samples such as amniotic fluid, placental tissue, cord blood and breast milk exists, additional research should confirm its association with transplacental transmission.Copyright © 2022, Dr. Mladen Stojanovic University Hospital. All rights reserved.

Impact of SARS-CoV-2 infection in pregnancy on fetal immune state

SARS-CoV-2 infection during pregnancy is associated with increased risk of adverse maternal and pregnancy outcomes. Maternal COVID- 19 is associated with immune activation and inflammatory response in the pregnant individual and an altered immune repertoire in the placenta. Mother-to-child transmission of infection is reported but uncommon. Still, the potential impact of maternal SARS-CoV-2 infection on the immunologic and inflammatory state of the infant is of interest, both for the acute health of the newborn and longer-term outcomes. In this talk, we will discuss the mixed data from cord blood and infant studies of cytokine profiles, transcriptomics, immunophenotyping, and functional studies. We will address the timing and severity of maternal infection as we explore the potential immunological consequences of in utero exposure to maternal SARS-CoV-2 infection.

Transplacental transfer of SARS-CoV-2 variant antibodies following COVID-19 vaccination during pregnancy

Problem: Despite being over 3 years into the pandemic, infants remain highly undervaccinated and at a high risk for hospitalization due to COVID-19. Further investigation as to how maternal health decisions for immunization can reduce morbidity from infant COVID-19 by providing passive immunity is necessary. The objective of this study was to describe the rates of SARS-CoV-2 variant antibody transfer from mother to infant cord blood by trimester ofmaternal vaccination. Methods of study: This is an observational cohort study including mother-infant dyads receiving primary or subsequent booster COVID- 19 vaccines during pregnancy.Unvaccinated, but SARS-CoV-2 infected dyads with were included as a comparison group. We quantified median titer and interquartile range (IQR) for SARS-CoV-2 receptor binding domain (RBD) IgG in infant cord blood samples at delivery using the mesoscale discovery platform (electrochemiluminescence). Primary outcome was infant cord IgG titer by trimester of vaccination for the WA1/2022 RBD IgG and current circulating, immune evasive XBB RBD IgG. Secondary outcome is the percent detectable IgG for each variant. Sensitivity analysis was performed based on known SARS-CoV-2 infection. Result(s): Eighty-three mother-infant dyads were included in this analysis. Seven were vaccinated in the first trimester, 37 in the second trimester, 33 in the third trimester, and 6 were unvaccinated and infected. Twenty-three (30%) of the vaccinated group had known SARS-CoV-2 infection. Most received monovalent mRNA COVID-19 vaccines during pregnancy, aside from two who received the viralvectored Ad26.COV2.S, and two received the bivalent mRNA vaccine during pregnancy. The median cord blood WA1/2020 RBD IgG titer was 5370 (412-7296) for first, 1225 (589-3289) for second, 2623 (664-5809) for third trimester in individuals who received aCOVID-19 vaccine dose during pregnancy, and 45 (10-187) in those unvaccinated and infected. After excluding thosewith infection, the cord blood IgG was 514 (106-4182), 1070 (518-2317), and 2477 (664-4470) for first, second, and third trimester, respectively. The rate of detectable WA1/2020 RBD IgG was 100% for all three trimesters, even when excluding infected individuals. For theXBBvariant, cord bloodRBDIgG titer was 284 (43-1296) for first, 66 (32-227) for second, 173 (45-389) for third trimester, and 10 (10-11) in the unvaccinated/infected group. Excluding infections, the cord blood XBB RBD IgG was 54 (10-128), 44 (25-181), and 152 (45-360) for first, second, and third trimester vaccination, respectively. The rate of detectable XBB IgG in those who received a vaccine during pregnancy were 83%, 91%, and 90% for first, second, and third trimester respectively, compared to 17% in the unvaccinated/infected group. Excluding infections, the rate of XBB RBD IgG detection was 66%, 89%, and 95% for first, second, and third trimester vaccination, respectively. Conclusion(s): Vaccination during pregnancy leads to high rates of detectable cord blood IgG specific to SARS-CoV-2 WA1/2020 variant and current circulating variants (XBB), regardless of trimester of vaccination. Infection history leads to higher cord blood IgG in vaccinated;however, infection alone without vaccination leads to lower titer and greater rates of undetectable cord IgG at delivery.

POLYFUNCTIONAL SARS-CoV-2-SPECIFIC T CELLS PERSIST IN TISSUE OF COVID-19 CONVALESCENTS

Background: T cells play an essential role in SARS-CoV-2 immunity, including in defense against severe COVID-19. However, most studies analyzing SARSCoV- 2-specific T cells have been limited to analysis of blood. Furthermore, the role of T cells in SARS-CoV-2 immunity in pregnant women, which are at disproportionately higher risk of severe COVID-19, is poorly understood. Method(s): Here, we quantitated and deeply phenotyped SARS-CoV-2-specific T cells from convalescent women (n=12) that had mild (non-hospitalized) COVID-19 during pregnancy. Endometrial, maternal blood, and fetal cord blood specimens were procured at term, which ranged from 3 days to 5 months post-infection. SARS-CoV-2-specific T cells were deeply analyzed by CyTOF using a tailored phenotyping panel designed to assess the effector functions, differentiation states, and homing properties of the cells. Result(s): SARS-CoV-2-specific T cells were more abundant in the endometrium than in maternal or fetal cord blood. In a particularly striking example, in one donor sampled 5 months after infection, SARS-CoV-2-specific CD8+ T cells comprised 4.8% of total endometrial CD8+ T cells, while it only reached 1.4% in blood. Endometrial SARS-CoV-2-specific T cells were more frequently of the memory phenotype relative to their counterparts in maternal and fetal cord blood, which harbored higher frequencies of naive T cells. Relative to their counterparts in blood, endometrial SARS-CoV-2-specific T cells exhibited unique phenotypic features, including preferential expression of the T resident memory marker CD69, inflammatory tissue-homing receptor CXCR4, and the activation marker 4-1BB. Endometrial T cells were highly polyfunctional, and could secrete IFNg, TNFa, MIP1b, IL2, and/or IL4 in response to spike peptide stimulation. By contrast, their counterparts in blood preferentially produced the cytolytic effectors perforin and granzyme B. Conclusion(s): Polyfunctional SARS-CoV-2-specific T cells primed by prior exposure to the virus are abundant and persist in endometrial tissue for months after infection. These cells exhibit unique phenotypic features including preferential expression of select chemokine receptors and activation molecules. Compared to their blood counterparts, the effector functions of these cells are more cytokine-driven and less cytolytic. The long-term persistence of these cells in the endometrium may help protect future pregnancies from SARS-CoV-2 re-infection.

SARS-CoV-2 ANTIBODY RESPONSES POST-INFECTION IN PREGNANCY BY VACCINATION STATUS

Background: We evaluated SARS-CoV-2 antibody binding and neutralization responses at delivery among pregnant persons with prior SARS-CoV-2 infection by vaccine status. Method(s): We enrolled participants with evidence of prior SARS-CoV-2 infection detected in pregnancy (anti-nucleocapsid [anti-N] IgG+ on enrollment or prior RT-PCR+ or antigen+) and followed them through delivery. Maternal delivery and cord blood samples were tested for SARS-CoV-2 binding antibodies to spike (anti-S) (from vaccination and/or infection) and anti-N (from infection only) IgG by Abbott Architect followed by neutralizing antibodies (classified as neutralizing if serum dilution inhibited infection by 50% [ND50 heat] >=20 and R2 >=0.9) if sample volume allowed. Positive IgG thresholds were Abbott index >=1.4 for anti-N and >=50 AU/mL for anti-S. Chi-squared test was used to compare differences in proportions between groups. Wilcoxon rank sum test was used to compare medians. Result(s): Among 71 participants with delivery and cord samples, median age was 33 years (interquartile range [IQR] 30-35) and median gestational age was 31.7 weeks (IQR 18.0-37.9) at enrollment in pregnancy. By delivery, 17 (24%) participants were unvaccinated, 21 (30%) were partially vaccinated or had completed a primary series, and 33 (46%) were boosted. Median time from infection (RT-PCR+ or antigen+ result) to delivery was 16.7 weeks (IQR 9.7- 24.3). At delivery, 33 (46%) of maternal (median 3.2 index) and 37 (52%) of cord samples (median 3.1 index) were anti-N IgG+. Participants with >=1 vaccine were more likely to be anti-S IgG+ than those unvaccinated (100% vs. 82%, p< 0.01), have higher median anti-S IgG+ (25,000 vs 1,019 AU/ml, p< 0.01), and have neutralizing antibodies (100% vs. 81%, p< 0.01) with higher median log10 neutralization (1:4.00 vs 1:2.41, p< 0.01) at delivery. Similarly, cord blood from participants with >=1 vaccine was more likely to be anti-S IgG+ than those unvaccinated (100% vs. 82%, p< 0.01), have higher median anti-S IgG+ (25,000 vs 1,188 AU/ml, p< 0.01), and have neutralizing antibodies (100% vs. 75%, p< 0.01) with higher median log10 neutralization (1:4.00 vs 1:2.41, p< 0.01) at delivery. Conclusion(s): Among pregnant people with prior SARS-CoV-2 infection detected during pregnancy, maternal and cord blood antibody binding and neutralization responses were higher among those receiving SARS-CoV-2 vaccination prior to delivery. (Table Presented).

Covid-19 Vaccinated Maternal/Cord Blood Dont Have Neutralization for Omicron Variants

Background: Maternally derived antibodies are crucial for neonatal immunity. Understanding the binding and -cross neutralization capacity of maternal/ cord antibody responses to COVID-19 vaccination during pregnancy can inform neonatal immunity. Method(s): Here we characterized binding and neutralizing antibody profile at delivery in 24 pregnant individuals following two doses of Moderna mRNA-1273 or Pfizer BNT162b2 vaccination. We evaluated the transplacental antibody transfer by profiling maternal and umbilical cord blood. We analyzed for SARS-CoV-2 multivariant cross-neutralizing antibody levels for wildtype Wuhan, Delta, Omicron BA1, BA2, and BA4/BA5 variants by enzyme-linked immunosorbent assay Results: Our results reveal that current vaccination induced significantly higher (p=0.003) RBD-specific binding IgG titers in cord blood compared to maternal blood for both Wuhan and Omicron BA1 strain. Interestingly, binding IgG antibody levels for the Omicron BA1 strain were significantly lower (P< 0.0001) when compared to the Wuhan strain in both maternal and cord blood. In contrast to the binding, the Omicron BA1, BA2, BA4/5 specific neutralizing antibody levels were significantly lower (P< 0.0001) compared to the Wuhan and Delta variants. It is interesting to note that the BA4/5 neutralizing capacity was not at all detected in both maternal and cord blood. Conclusion(s): Our data suggest that the initial series of COVID-19 mRNA vaccines were immunogenic in pregnant women, and vaccine-elicited binding antibodies were detectable in cord blood at significantly higher levels for Wuhan and Delta variants but not for Omicron variants. Interestingly, the vaccination did not induce neutralizing antibodies for Omicron variants. These results provide novel insight into the impact of vaccination on maternal humoral immune response and transplacental antibody transfer for SARS-CoV-2 variants and support the need for boosters as new variants emerge.

Antibody levels to SARS-CoV-2 spike protein in mothers and children from delivery to six months later.

INTRODUCTION: Pregnant women are vulnerable to severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection. Neutralizing antibodies against the SARS-CoV-2 spike (S) protein protect from severe disease. This study analyzes the antibody titers to SARS-CoV-2 S protein in pregnant women and their newborns at delivery, and six months later. METHODS: We conducted a prospective study on pregnant women with confirmed SARS-CoV-2 infection and newborns. Antibody (IgG, IgM, and IgA) titers were determined using immunoassays in serum and milk samples. An angiotensin-converting enzyme 2 (ACE2) receptor-binding inhibition assay to the S protein was performed on the same serum and milk samples. RESULTS: At birth, antibodies to SARS-CoV-2 spike protein were detected in 81.9% of mothers' sera, 78.9% of cord blood samples, and 63.2% of milk samples. Symptomatic women had higher antibody titers (IgG, IgM, and IgA) than the asymptomatic ones (P < 0.05). At six months postpartum, IgG levels decreased drastically in children's serum (P < 0.001) but remained high in mothers' serum. Antibody titers correlated positively with its capacity to inhibit the ACE2-spike protein interaction at baseline in maternal sera (R2  = 0.203; P < 0.001), cord sera (R2  = 0.378; P < 0.001), and milk (R2  = 0.564; P < 0.001), and at six months in maternal sera (R2  = 0.600; P < 0.001). CONCLUSIONS: High antibody levels against SARS-CoV-2 spike protein were found in most pregnant women. Due to the efficient transfer of IgG to cord blood and high IgA titers in breast milk, neonates may be passively immunized to SARS-CoV-2 infection. Our findings could guide newborn management and maternal vaccination policies.

Epidemiological study of COVID-19 pneumonia in pregnant woman and their neonates, report of thirteen confirmed COVID-19 pregnant women

Background: In new pandemic, the probable effects of COVID-19 pneumonia on pregnant woman and their infant is one of new critical challenge for health care. Here we presented clinical symptoms, laboratory findings and outcome of COVID-19 pneumonia in pregnant woman. Method(s): In a case series study, from 15 Feb to 15 June 2020, all women with RT-PCR COVID-19 who referred to two hospitals (Taleghani and Qods Hospital) affiliated to Arak University of Medical Sciences were selected. The epidemiological and demographic variables, laboratory test and outcomes obtained from patient's medical records. Result(s): In this case series, we presented thirteen confirmed COVID-19 pregnant women. Their mean age was 34.6 (S.D.: 5.9) years and the mean gestational age was 32.4 (S.D.: 7.3) weeks. Most of patient didn't show any maternal complication and intrauterine vertical transmission. The large number of pregnant women had normal HRCT and also in terms of laboratory most of the patients had normal laboratory tests. Amniotic fluids, cord blood, the throat swab of neonate in our pregnant woman with delivery were tested for COVID-19 and all of them were negative. Conclusion(s): The COVID-19 mothers and their infant didn't have higher risk for morbidity and mortality and this virus didn't associate with intrauterine vertical transmission.Copyright © 2020 Ubiquity Press. All rights reserved.

Fetal effects of mild maternal COVID-19 infection: metabolomic profiling of cord blood.

INTRODUCTION: The impact of maternal coronavirus disease 2019 (COVID-19) infection on fetal health remains to be precisely characterized. OBJECTIVES: Using metabolomic profiling of newborn umbilical cord blood, we aimed to investigate the potential fetal biological consequences of maternal COVID-19 infection. METHODS: Cord blood plasma samples from 23 mild COVID-19 cases (mother infected/newborn negative) and 23 gestational age-matched controls were analyzed using nuclear magnetic spectroscopy and liquid chromatography coupled with mass spectrometry. Metabolite set enrichment analysis (MSEA) was used to evaluate altered biochemical pathways due to COVID-19 intrauterine exposure. Logistic regression models were developed using metabolites to predict intrauterine exposure. RESULTS: Significant concentration differences between groups (p-value < 0.05) were observed in 19 metabolites. Elevated levels of glucocorticoids, pyruvate, lactate, purine metabolites, phenylalanine, and branched-chain amino acids of valine and isoleucine were discovered in cases while ceramide subclasses were decreased. The top metabolite model including cortisol and ceramide (d18:1/23:0) achieved an Area under the Receiver Operating Characteristics curve (95% CI) = 0.841 (0.725-0.957) for detecting fetal exposure to maternal COVID-19 infection. MSEA highlighted steroidogenesis, pyruvate metabolism, gluconeogenesis, and the Warburg effect as the major perturbed metabolic pathways (p-value < 0.05). These changes indicate fetal increased oxidative metabolism, hyperinsulinemia, and inflammatory response. CONCLUSION: We present fetal biochemical changes related to intrauterine inflammation and altered energy metabolism in cases of mild maternal COVID-19 infection despite the absence of viral infection. Elucidation of the long-term consequences of these findings is imperative considering the large number of exposures in the population.

Impact of COVID-19 during pregnancy on placental pathology, maternal and neonatal outcome - A cross-sectional study on anemic term pregnant women from a tertiary care hospital in southern India.

Background: SARS-CoV-2 infection during pregnancy may cause adverse maternal, neonatal and placental outcomes. While tissue hypoxia is often reported in COVID-19 patients, pregnant women with anemia are suspected to be more prone to placental hypoxia-related injuries. Methods: This hospital-based cross-sectional study was conducted between August-November 2021, during COVID-19 second wave in India. Term pregnant women (N=212) admitted to hospital for delivery were enrolled consecutively. Since hospital admission mandated negative RT-PCR test for SARS-CoV-2 virus, none had active infection. Data on socio-demography, COVID-19 history, maternal, obstetric, and neonatal outcomes were recorded. Pre-delivery maternal and post-delivery cord blood samples were tested for hematological parameters and SARS-CoV-2 IgG. Placentae were studied for histology. Results: Of 212 women, 122 (58%) were seropositive for SARS-CoV-2 IgG, but none reported COVID-19 history; 134 (63.2%) were anemic. In seropositive women, hemoglobin (p=0.04), total WBC (p=0.009), lymphocytes (p=0.005) and neutrophils (p=0.02) were significantly higher, while ferritin was high, but not significant and neutrophils to lymphocytes (p=0.12) and platelets to lymphocytes ratios (p=0.03) were lower. Neonatal outcomes were similar. All RBC parameters and serum ferritin were significantly lower in anemic mothers but not in cord blood, except RDW that was significantly higher in both, maternal (p=0.007) and cord (p=0.008) blood from seropositive anemic group compared to other groups. Placental histology showed significant increase in villous hypervascularity (p=0.000), dilated villous capillaries (p=0.000), and syncytiotrophoblasts (p=0.02) in seropositive group, typically suggesting placental hypoxia. Maternal anemia was not associated with any histological parameters. Univariate and multivariate logistic regression analyses of placental histopathological adverse outcomes showed strong association with SARS-CoV-2 seropositivity but not with maternal anemia. When adjusted for several covariates, including anemia, SARS-CoV-2 seropositivity emerged as independent risk factor for severe chorangiosis (AOR 8.74, 95% CI 3.51-21.76, p<0.000), dilated blood vessels (AOR 12.74, 95% CI 5.46-29.75, p<0.000), syncytiotrophoblasts (AOR 2.86, 95% CI 1.36-5.99, p=0.005) and villus agglutination (AOR 9.27, 95% CI 3.68-23.32, p<0.000). Conclusion: Asymptomatic COVID-19 during pregnancy seemed to be associated with various abnormal placental histopathologic changes related to placental hypoxia independent of maternal anemia status. Our data supports an independent role of SARS-CoV-2 in causing placental hypoxia in pregnant women.

Mesenchymal Stem Cells: A Potent Cell Source for COVID-19

Coronaviruses are enveloped positive-stranded RNA viruses that cause mild to acute respiratory illness. Coronaviruses can merge envelope proteins with the host cell membranes and de-liver their genetic material. Coronavirus disease 2019 (COVID-19) is the seventh coronavirus clos-est to the severe acute respiratory syndrome (SARS) in bats that infects humans. COVID-19 at-tacks the respiratory system and stimulates the host inflammatory responses, promotes the recruit-ment of immune cells, and enhances angiotensin-converting enzyme 2 (ACE2) activities. Patients with confirmed COVID-19 have experienced fever, dry cough, headache, dyspnea, acute kidney injury (AKI), acute respiratory distress syndrome (ARDS), and acute heart injury. Several strategies such as oxygen therapy, ventilation, antibiotic or antiviral therapy, and renal replacement therapy are commonly used to decrease COVID-19-associated mortality. Inflammation is a common and important factor in the pathogenesis of COVID-19. In recent years, stem cell-based therapies represent a promising therapeutic option against various diseases. Mesenchymal stem cells (MSCs) are multipotent stem cells that can self-renew and differentiate into various tissues of mesodermal ori-gin. MSCs can be derived from bone marrow, adipose tissue, and umbilical cord blood. MSCs, with their unique immunomodulatory properties, represent a promising therapeutic alternative against diseases associated with inflammation. Several previous studies have shown that MSCs with a strong safety profile can improve the treatment of patients with COVID-19. The information in this review provides a summary of the prevention and diagnosis of COVID-19. Also, we focus on the current clinical application of MSCs for treatments of patients with COVID-19.Copyright © 2021 Bentham Science Publishers.

Impact of COVID-19 Vaccination on Pregnant Women.

In light of the COVID-19 pandemic, researchers across the world hastened to develop vaccines that would aid in bolstering herd immunity. Utilizing mRNA coding and viral vector technology, the currently approved vaccines were required to undergo extensive testing to confirm their safety for mass usage in the general population. However, clinical trials failed to test the safety and efficacy of the COVID-19 vaccines in groups with weakened immune systems, especially pregnant women. Lack of information on the effects of vaccinations in pregnancy and the safety of fetuses are among the topmost reasons preventing pregnant women from receiving immunization. Thus, the lack of data examining the effects of COVID-19 vaccinations on pregnant women must be addressed. This review focused on the safety and efficacy of the approved COVID-19 vaccinations in pregnancy and their impact on both maternal and fetal immune responses. For that, we took the approach of combined systematic review/meta-analysis and compiled the available data from the original literature from PubMed, Web of Science, EMBASE and Medline databases. All articles analyzed presented no adverse effects of vaccination in pregnancy, with varying conclusions on the degree of effectiveness. The majority of the findings described robust immune responses in vaccinated pregnant women, successful transplacental antibody transfer, and implications for neonatal immunity. Hence, findings from the cumulative data available can be helpful in achieving COVID-19 herd immunization, including pregnant women.

Feasibility Study of Cord Tissue Derived Mesenchymal Stromal Cells in COVID-19-Related Acute Respiratory Distress Syndrome.

BACKGROUND: Treatment options for patients with COVID-19-related acute respiratory distress syndrome (ARDS) are desperately needed. Allogeneic human umbilical cord derived mesenchymal stromal cells (hCT-MSCs) have potential therapeutic benefits in these critically ill patients, but feasibility and safety data are lacking. MATERIALS AND METHODS: In this phase I multisite study, 10 patients with COVID-19-related ARDS were treated with 3 daily intravenous infusions of hCT-MSCs (1 million cells/kg, maximum dose 100 million cells). The primary endpoint assessed safety. RESULTS: Ten patients (7 females, 3 males; median age 62 years (range 39-79)) were enrolled at 2 sites and received a total of 30 doses of study product. The average cell dose was 0.93 cells/kg (range 0.56-1.45 cells/kg and total dose range 55-117 million cells) with 5/30 (17%) of doses lower than intended dose. Average cell viability was 85% (range 63%-99%) with all but one meeting the >70% release criteria. There were no infusion-related reactions or study-related adverse events, 28 non-serious adverse events in 3 unique patients, and 2 serious adverse events in 2 unique patients, which were expected and unrelated to the study product. Five patients died: 3 by day 28 and 5 by day 90 of the study (median 27 days, range 7-76 days). All deaths were determined to be unrelated to the hCT-MSCs. CONCLUSION: We were able to collect relevant safety outcomes for the use of hCT-MSCs in patients with COVID-19-related ARDS. Future studies to explore their safety and efficacy are warranted.

Examination of cord blood at birth in women with SARS-CoV-2 exposure and/or vaccination during pregnancy and relationship to fetal complete blood count, cortisol, ferritin, vitamin D, and CRP.

Background: SARS-CoV-2 is known to manifest a robust innate immune response. However, little is known about inflammatory influences from maternal SARS-CoV-2 infection or maternal mRNA vaccination upon the fetus. In addition, it is unknown if Vitamin D deficiency influences fetal homeostasis or if an anti-inflammatory mechanism to the development of possible innate cytokines or acute phase reactants by the maternal/fetal dyad, in the form of cortisol elevations, occur. In addition, effects on Complete Blood Count (CBC) are not known. Objective: To evaluate the neonatal acute phase reactants and anti-inflammatory responses after maternal SARS-CoV-2 disease or mRNA vaccination. Methods: Samples and medical records reviews from mother/baby dyads (n = 97) were collected consecutively, and were categorized into 4 groups; no SARS-CoV-2 or vaccination exposure (Control), Vaccinated mothers, maternal SARS-CoV-2 disease positive/IgG titer positive fetal blood, and maternal SARS-CoV-2 positive/IgG titer negative fetal blood. SARS-CoV-2 IgG/IgM/IgA titers, CBC, CRP, ferritin, cortisol, and Vitamin D were obtained to examine the possible development of an innate immune response and possible anti-inflammatory response. Student's t-test, Wilcoxon rank-sum, and Chi-squared with Bonferroni corrections were used to compare groups. Multiple imputations were performed for missing data. Results: Cortisol was higher in babies of both mothers who were vaccinated (p = 0.001) and SARS-CoV-2 positive/IgG positive (p = 0.009) as compared to the control group suggesting an attempt to maintain homeostasis in these groups. Measurements of ferritin, CRP, and vitamin D did not reach statistical significance. CBC showed no variation, except for the mean platelet volume (MPV), which was elevated in babies whose mothers were vaccinated (p = 0.003) and SARS-CoV-2 positive/IgG positive (p = 0.007) as compared to the control group. Conclusion: Acute phase reactant elevations were not noted in our neonates. Vitamin D levels were unchanged from homeostatic levels. Cord blood at birth, showed Cortisol and MPV higher in vaccinated and SARS-CoV-2 IgG positive mother/baby dyads as compared to the Control group, indicating that possible anti-inflammatory response was generated. The implication of possible inflammatory events and subsequent cortisol and/or MPV elevation effects upon the fetus after SARS-CoV-2 disease or vaccination is unknown and merits further investigation.

Safety and efficacy of inactivated COVID-19 vaccines in women vaccinated during the first trimester of pregnancy.

OBJECTIVES: This study aimed to investigate the safety of the inactivated COVID-19 vaccines in early pregnant women in view of their adverse-effect profile and associated maternal-fetal complications, as well as to evaluate their immunogenicity. METHODS: In this prospective observational cohort study, 232 women in their first trimester or those in the periconception period who inadvertently received two doses of inactivated COVID-19 vaccine between January 21, 2021, and January 14, 2022 were analyzed. Meanwhile, 735 unvaccinated early pregnancy women were also included in the study at a case-to-control ratio of 1:3. RESULTS: The vaccination group did not have an increased miscarriage rate compared with that of the control group (P = 0.918). Furthermore, the birth defect rates in the vaccine group and control group were 0.83% and 1.0%, respectively. Vaccination did not increase the risk of small for gestational age, gestational diabetes mellitus, preterm, or hypertensive disorders of pregnancy (P >0.01). Within 12 weeks after the second dose, the inactivated vaccine effectively produced neutralizing antibody (NAb) against SARS-CoV-2. The NAb levels in the paired umbilical cord serum and maternal serum samples during delivery were negative in both groups. The T-cell subset remained within the normal range in both groups. CONCLUSION: Therefore, our study proves that inactivated COVID-19 vaccines are safe for mothers and fetuses and also effective in producing NAb against SARS-CoV-2.

Is antenatal or early-life vitamin D associated with eczema or food allergy in childhood? A systematic review.

OBJECTIVE: To summarise the associations between antenatal or early-life blood vitamin D and the development of eczema/food allergy in childhood. DESIGN: A systematic review and meta-analyses were conducted to synthesize the published literature. Two reviewers independently performed the study selection and data extraction on Covidence. We assessed the risk of bias for observational studies by using the Newcastle-Ottawa Scale and the Cochrane Risk of Bias tool for clinical trials. The certainty of the evidence was assessed using Grading of Recommendations, Assessment, Development and Evaluations (GRADE). DATA SOURCES: We systematically searched PubMed and Embase from inception and April 2022. ELIGIBILITY CRITERIA: Human studies that investigated prospective associations between antenatal or early-life blood vitamin D levels, dietary intake or supplementation and childhood eczema/food allergy. RESULTS: Forty-three articles including six randomised controlled trials (RCTs) were included. Four RCTs of vitamin D supplementation during pregnancy showed no evidence of an effect on the incidence of eczema (pooled odds ratio [OR] = 0.85; 0.67-1.08, I2  = 6.7%, n = 2074). Three RCTs reported null associations between supplementation in pregnancy/infancy and food allergy. From six cohort studies, increasing cord blood vitamin D levels were associated with reduced prevalence of eczema at/close to age one (OR per 10 nmol/L increase = 0.89; 0.84-0.94, I2  = 0%, 2025 participants). We found no evidence of an association between maternal antenatal or infant vitamin D level or dietary intake and the development of food allergy or eczema in offspring. CONCLUSIONS: We found an association between higher vitamin D levels in cord blood and reduced risk of eczema in cohort studies. Further trials with maternal and infant supplementation are needed to confirm if vitamin D supplementation can effectively prevent eczema or food allergy in childhood. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, No. CRD42013005559.

Longitudinal antibody response kinetics following SARS-CoV-2 messenger RNA vaccination in pregnant and nonpregnant persons.

BACKGROUND: For some vaccine-preventable diseases, the immunologic response to vaccination is altered by a pregnant state. The effect of pregnancy on SARS-CoV-2 vaccine response remains unclear. OBJECTIVE: We sought to characterize the peak and longitudinal anti-S immunoglobulin G, immunoglobulin M, and immunoglobulin A responses to messenger RNA-based SARS-CoV-2 vaccination in pregnant persons and compare them with those in nonpregnant, reproductive-aged persons. STUDY DESIGN: We conducted 2 parallel prospective cohort studies among pregnant and nonpregnant persons who received SARS-CoV-2 messenger RNA vaccinations. Blood was collected at the time of first and second vaccine doses, 2 weeks post second dosage, and with serial longitudinal follow-up up to 41.7 weeks post vaccination initiation. Anti-S immunoglobulin M, immunoglobulin G, and immunoglobulin A were analyzed by enzyme-linked immunosorbent assay. We excluded those with previous evidence of SARS-CoV-2 infection by history or presence of antinucleocapsid antibodies. In addition, for this study, we did not include individuals who received a third or booster vaccine dosage during the study period. We also excluded pregnant persons who were not fully vaccinated (14 days post receipt of the second vaccine dosage) by time of delivery and nonpregnant persons who became pregnant through the course of the study. We studied the effect of gestational age at vaccination on the anti-S response using Spearman correlation. We compared the peak anti-S antibody responses between pregnant and nonpregnant persons using a Mann-Whitney U test. We visualized and studied the longitudinal anti-S antibody response using locally weighted scatterplot smoothing, Mann-Whitney U test, and mixed analysis of variance test. RESULTS: Data from 53 pregnant and 21 nonpregnant persons were included in this analysis. The median (interquartile range) age of the pregnant and nonpregnant participants was 35.0 (33.3-37.8) years and 36.0 (33.0-41.0) years, respectively. Six (11.3%) participants initiated vaccination in the first trimester, 23 (43.3%) in the second trimester, and 24 (45.3%) in the third trimester, with a median gestational age at delivery of 39.6 (39.0-40.0) weeks. The median (interquartile range) follow-up time from vaccine initiation to the last blood sample collected was 25.9 (11.9) weeks and 28.9 (12.9) weeks in the pregnant and nonpregnant cohort, respectively. Among pregnant persons, anti-S immunoglobulin G, immunoglobulin A, and immunoglobulin M responses were not associated with gestational age at vaccine initiation (all P>.05). The anti-S immunoglobulin G response at 2 weeks post second dosage was not statistically different between pregnant and nonpregnant persons (P>.05). However, the anti-S immunoglobulin M and immunoglobulin A responses at 2 weeks post second dosage were significantly higher in nonpregnant persons (P<.001 for both). The anti-S immunoglobulin G and immunoglobulin M levels 6 to 8 months after vaccine initiation fell to comparable proportions of the peak 2 weeks post second dosage antibody levels between pregnant and nonpregnant persons (immunoglobulin G P=.77; immunoglobulin M P=.51). In contrast, immunoglobulin A levels 6 to 8 months after vaccine initiation fell to statistically significantly higher proportions of peak 2 weeks post second dosage antibody levels in pregnant compared with nonpregnant persons (P=.002). Maternal anti-S immunoglobulin G levels were strongly correlated with umbilical cord anti-S immunoglobulin G levels (R=0.8, P<.001). CONCLUSION: The anti-S immunoglobulin A, immunoglobulin M, and immunoglobulin G response to SARS-CoV-2 vaccination in pregnancy is independent of gestational age of vaccine initiation. Maintenance of the immunoglobulin G response is comparable between pregnant and nonpregnant persons. The differential peak response of immunoglobulin M and immunoglobulin A and the differential decline of anti-S immunoglobulin A between pregnant and nonpregnant persons requires further investigation.

COVID-19 pandemic and neonatal health: What we know so far?

COVID-19 first time appeared in December 2019 in Wuhan, China. The number of cases increased rapidly in china and outside and the World Health Organization declared a pandemic on 11th March 2020. The pregnant and postpartum women, child, and neonatal populations are vulnerable to this disease due to immunological and physiological changes. This paper analyzed the published evidence for assessing the effect of COVID-19 on neonatal health and health care. Online published literature was searched from PubMed, Google Scholar, and other official webpages using keywords: "coronavirus/COVID-19/new coronavirus 2019"/SARS-CoV-2 and neonatal health/care/outcomes" and reviewed to prepare this article. COVID-19 is the potential to transmit either mother to fetus or mother/caregiver to neonates. However, neonates born from infected mothers did not show significant clinical features. Pharyngeal-swab, amniotic-fluid, cord-blood, and breast-milk test results were not found positive. Health facility-based vaginal/caesarian delivery was considered a low risk of transmission. However, recommended to separate neonates with infected mothers/caregivers and test immediately after birth to avoid the possible transmission. Mothers/caregivers should take routine preventive measures such as washing hands frequently and avoiding contact with infected people. If neonates suffered from the server acute respiratory distress requires intensive care urgently. Despite the possibility of the intrauterine transmission of COVID-19 direct evidence is still lacking so it needs more studies for further confirmation. The International Pediatric Association suggested preventive programs, curative care, vaccination, and telemedicine care as the minimum services and called on its members to address these cares during the pandemic. Copyright © 2020, Kathmandu University. All rights reserved.

Anomalous Marginal Insertion of Umbilical Cord in Placentas of COVID-19-Affected Pregnant Mothers: A Cross-Sectional Study.

Aim Study the effect of coronavirus disease-19 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), on the placenta and in turn study its effects on pregnancy and newborn outcomes. Methods In this cross-sectional study, which was conducted in the term pregnant women who underwent delivery, their placentas were collected after delivery along with the mothers' blood and cord blood. Results Among the 212 pregnant women recruited, the prevalence of marginal cord insertion (MCI) in the placentas after delivery, was found to be 23% (n=48). Among these 48 cases (n=48) with MCI, 58.33% (n=28) were COVID-19 positive. The placentas with MCI had significantly lower minimum placental circumference (probability value/p value=0.04) and significantly longer umbilical cord (p-value=0.05). COVID-19 antibodies transfer from the mother to the umbilical cord (C/M antibodies ratio) was observed to be lower, albeit insignificantly. Both the weight of newborns (p value=0.03) and their COVID-19 antibodies levels (p-value=0.05) were observed to be significantly lower in the MCI group. Univariate analysis shows that a body mass index (BMI) ≥ 23 of the mothers was significantly associated with abnormal MCI. Conclusion The prevalence of MCI was observed to be high in COVID-19-affected mothers in our study. MCI was associated with lower placental size, newborn weight, lesser transfer of COVID-19 antibodies from the mother to the fetus across the umbilical cord, and lower antibody levels in the cord blood when compared to maternal blood.