Long Covid, or Post-Acute Sequelae of COVID-19 (PASC), involves a spectrum of chronic symptoms following resolution of acute SARS-CoV-2 infection. Current hypotheses for the pathogenesis of Long Covid include persistent SARS-CoV-2, activation of other viruses, tissue damage, autoimmunity, endocrine insufficiency, immune dysfunction, and complement activation. We evaluated 142 participants, including uninfected controls (N=35), acutely infected individuals (N=54), convalescent controls (N=25), and Long Covid patients (N=28), by comprehensive immunologic, virologic, transcriptomic, and proteomic analyses. Long Covid was characterized by persistent inflammatory pathways compared with convalescent controls and uninfected controls, including upregulation of IL-6 and JAK-STAT pathways as well as activation of coagulation, complement, metabolism, and T cell exhaustion pathways. Moreover, robust activation of these pathways during acute COVID-19 infection correlated with the subsequent development of Long Covid. In an independent validation cohort (N=47), Long Covid patients had higher levels of plasma IL-6R compared with convalescent controls and uninfected controls. These data demonstrate that Long Covid is characterized by persistent activation of chronic inflammatory pathways, suggesting novel therapeutic targets and biomarkers of disease.### Competing Interest StatementThe authors have declared no competing interest.

The COVID-19 Biorepository at Beth Israel Deaconess Medical Center in Boston was initiated in 2020 to address questions about COVID-19 infection and vaccination in a time of urgent need. From April 2020 through July 2024, we enrolled 1018 participants and collected thousands of biospecimens. We enrolled participants from the general population as well as from specific populations that were not well represented in clinical trials, including immunosuppressed, pregnant, and lactating individuals. Our observational study was designed to accommodate the rapidly changing landscape of the pandemic, including the introduction of new vaccines and boosters, breakthrough infections, and emerging variants. Reflecting on the past four years of this experience, we believe that teamwork, collaboration, and flexibility were key factors for the success of this effort, which generated data in real time about COVID-19 vaccine responses in multiple populations, hybrid immunity following breakthrough infections, immune evasion of emerging variants, and immune imprinting following booster immunizations. Rapid dissemination of data through preprints, peer-reviewed publications, and public communications allowed for the real time use of our findings to address public health issues and to inform vaccine policies. The dedication of the study participants, clinical investigators, and laboratory investigators made this research program possible.

The COVID-19 pandemic has generated an unprecedented amount of novel and repurposed vaccines and therapeutics that have been rapidly developed and implemented into clinical use. Unfortunately, pregnant persons have been excluded from most phase III clinical studies; therefore, our understanding regarding their safety for use in this population stems from understanding of theoretic risks and observational data. In this review, the authors discuss pregnancy-specific considerations for COVID-19 therapeutics.

OBJECTIVE:To evaluate whether the use of inhaled nitric oxide (iNO)200 improves respiratory function.METHODS:This retrospective cohort study used data from pregnant patients hospitalized with severe bilateral coronavirus disease 2019 (COVID-19) pneumonia at four teaching hospitals between March 2020 and December 2021. Two cohorts were identified: 1) those receiving standard of care alone (SoC cohort) and 2) those receiving iNO200 for 30 minutes twice daily in addition to standard of care alone (iNO200 cohort). Inhaled nitric oxide, as a novel therapy, was offered only at one hospital. The prespecified primary outcome was days free from any oxygen supplementation at 28 days postadmission. Secondary outcomes were hospital length of stay, rate of intubation, and intensive care unit (ICU) length of stay. The multivariable-adjusted regression analyses accounted for age, body mass index, gestational age, use of steroids, remdesivir, and the study center.RESULTS:Seventy-one pregnant patients were hospitalized for severe bilateral COVID-19 pneumonia: 51 in the SoC cohort and 20 in the iNO200 cohort. Patients receiving iNO200 had more oxygen supplementation-free days (iNO200: median [interquartile range], 24 [23-26] days vs standard of care alone: 22 [14-24] days, P=.01) compared with patients in the SoC cohort. In the multivariable-adjusted analyses, iNO200 was associated with 63.2% (95% CI 36.2-95.4%; P<.001) more days free from oxygen supplementation, 59.7% (95% CI 56.0-63.2%; P<.001) shorter ICU length of stay, and 63.6% (95% CI 55.1-70.8%; P<.001) shorter hospital length of stay. No iNO200-related adverse events were reported.CONCLUSION:In pregnant patients with severe bilateral COVID-19 pneumonia, iNO200 was associated with a reduced need for oxygen supplementation and shorter hospital stay.

Individuals on immunosuppressive (IS) therapy have increased mortality from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and delayed viral clearance may lead to new viral variants. IS therapy reduces antibody responses following coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccination; however, a comprehensive assessment of vaccine immunogenicity is lacking. Here we show that IS therapy reduced neutralizing, binding, and nonneutralizing antibody functions in addition to CD4 and CD8 T-cell interferon-γ responses following COVID-19 mRNA vaccination compared to immunocompetent individuals. Moreover, IS therapy reduced cross-reactivity against SARS-CoV-2 variants. These data suggest that the standard COVID-19 mRNA vaccine regimens will likely not provide optimal protection in immunocompromised individuals.

Breakthrough infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have been reported frequently in vaccinated individuals with waning immunity. In particular, a cluster of over 1000 infections with the SARS-CoV-2 delta variant was identified in a predominantly fully vaccinated population in Provincetown, Massachusetts in July 2021. In this study, vaccinated individuals who tested positive for SARS-CoV-2 ( n = 16) demonstrated substantially higher serum antibody responses than vaccinated individuals who tested negative for SARS-CoV-2 ( n = 23), including 32-fold higher binding antibody titers and 31-fold higher neutralizing antibody titers against the SARS-CoV-2 delta variant. Vaccinated individuals who tested positive also showed higher mucosal antibody responses in nasal secretions and higher spike protein–specific CD8 + T cell responses in peripheral blood than did vaccinated individuals who tested negative. These data demonstrate that fully vaccinated individuals developed robust anamnestic antibody and T cell responses after infection with the SARS-CoV-2 delta variant. Moreover, these findings suggest that population immunity will likely increase over time by a combination of widespread vaccination and breakthrough infections.

The successful development of several coronavirus disease 2019 (COVID-19) vaccines has substantially reduced morbidity and mortality in regions of the world where the vaccines have been deployed. However, in the wake of the emergence of viral variants that are able to evade vaccine-induced neutralizing antibodies, real-world vaccine efficacy has begun to show differences across the two approved mRNA platforms, BNT162b2 and mRNA-1273; these findings suggest that subtle variation in immune responses induced by the BNT162b2 and mRNA-1273 vaccines may confer differential protection. Given our emerging appreciation for the importance of additional antibody functions beyond neutralization, we profiled the postboost binding and functional capacity of humoral immune responses induced by the BNT162b2 and mRNA-1273 vaccines in a cohort of hospital staff. Both vaccines induced robust humoral immune responses to wild-type severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and to variants of concern. However, differences emerged across epitope-specific responses, with higher concentrations of receptor binding domain (RBD)- and N-terminal domain-specific IgA observed in recipients of mRNA-1273. Antibodies eliciting neutrophil phagocytosis and natural killer cell activation were also increased in mRNA-1273 vaccine recipients as compared to BNT162b2 recipients. RBD-specific antibody depletion highlighted the different roles of non-RBD-specific antibody effector functions induced across the mRNA vaccines. These data provide insights into potential differences in protective immunity conferred by these vaccines.

ABSTRACT The SARS-CoV-2 Omicron variant (B.1.1.529) has three major lineages BA.1, BA.2, and BA.3 1 . BA.1 rapidly became dominant and has demonstrated substantial escape from neutralizing antibodies (NAbs) induced by vaccination 2-4 . BA.2 has recently increased in frequency in multiple regions of the world, suggesting that BA.2 has a selective advantage over BA.1. BA.1 and BA.2 share multiple common mutations, but both also have unique mutations 1 ( Fig. 1A ). The ability of BA.2 to evade NAbs induced by vaccination or infection has not yet been reported. We evaluated WA1/2020, Omicron BA.1, and BA.2 NAbs in 24 individuals who were vaccinated and boosted with the mRNA BNT162b2 vaccine 5 and in 8 individuals who were infected with SARS-CoV-2 ( Table S1 ).

BACKGROUND:Remdesivir is efficacious for severe coronavirus disease 2019 (COVID-19) in adults, but data in pregnant women are limited. We describe outcomes in the first 86 pregnant women with severe COVID-19 who were treated with remdesivir. METHODS:The reported data span 21 March to 16 June 2020 for hospitalized pregnant women with polymerase chain reaction-confirmed severe acute respiratory syndrome coronavirus 2 infection and room air oxygen saturation ≤94% whose clinicians requested remdesivir through the compassionate use program. The intended remdesivir treatment course was 10 days (200 mg on day 1, followed by 100 mg for days 2-10, given intravenously). RESULTS:Nineteen of 86 women delivered before their first dose and were reclassified as immediate "postpartum" (median postpartum day 1 [range, 0-3]). At baseline, 40% of pregnant women (median gestational age, 28 weeks) required invasive ventilation, in contrast to 95% of postpartum women (median gestational age at delivery 30 weeks). By day 28 of follow-up, the level of oxygen requirement decreased in 96% and 89% of pregnant and postpartum women, respectively. Among pregnant women, 93% of those on mechanical ventilation were extubated, 93% recovered, and 90% were discharged. Among postpartum women, 89% were extubated, 89% recovered, and 84% were discharged. Remdesivir was well tolerated, with a low incidence of serious adverse events (AEs) (16%). Most AEs were related to pregnancy and underlying disease; most laboratory abnormalities were grade 1 or 2. There was 1 maternal death attributed to underlying disease and no neonatal deaths. CONCLUSIONS:Among 86 pregnant and postpartum women with severe COVID-19 who received compassionate-use remdesivir, recovery rates were high, with a low rate of serious AEs.

Successful pregnancy relies on maternal immunologic tolerance mechanisms limit maladaptive immune responses against the semi-allogeneic fetus and placenta and support fetal growth. Preeclampsia is a common disorder of pregnancy that affects 4–10% of pregnancies and is a leading cause of maternal and neonatal morbidity and mortality. Preeclampsia clinically manifests as maternal hypertension, proteinuria, and progressive multi-organ injury likely triggered by hypoxic injury to the placenta, resulting in local and systemic anti-angiogenic and inflammatory factor production. Despite the steady rising rates of preeclampsia in the United States, effective treatment options are limited to delivery, which improves maternal status often at the cost of prematurity in the newborn. Preeclampsia also increases the lifelong risk of cardiovascular disease for both mother and infant. Thus, identifying new therapeutic targets is a high priority area to improve maternal, fetal, and infant health outcomes. Immune abnormalities in the placenta and in the maternal circulation have been reported to precede the clinical onset of disease. In particular, excessive systemic and placental complement activation and impaired adaptive T cell tolerance with Th1/Th2/Th17/Treg imbalance has been reported in humans and in animal models of preeclampsia. In this review, we focus on the evidence for the immune origins of preeclampsia, discuss the promise of immune modulating therapy for prevention or treatment, and highlight key areas for future research.

The rapid spread of the highly mutated SARS-CoV-2 Omicron variant has raised substantial concerns about the protective efficacy of currently available vaccines. We assessed Omicron-specific humoral and cellular immune responses in 65 individuals who were vaccinated with two immunizations of BNT162b2 and were boosted after at least 6 months with either Ad26.COV2.S (Johnson & Johnson; N=41) or BNT162b2 (Pfizer; N=24) ([Table S1][1]). ### Competing Interest Statement DHB is a co-inventor on provisional vaccine patents (63/121,482; 63/133,969; 63/135,182). The authors report no other conflict of interest. ### Clinical Trial NCT04999111 ### Funding Statement The authors acknowledge Janssen Vaccines & Prevention, NIH grant CA260476, the Massachusetts Consortium for Pathogen Readiness, the Ragon Institute, and the Musk Foundation (D.H.B.). The authors also acknowledge the Reproductive Scientist Development Program from the Eunice Kennedy Shriver National Institute of Child Health & Human Development and Burroughs Wellcome Fund HD000849 (A.Y.C.). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The BIDMC institutional review board approved this study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript The datasets generated during and/or analysed during the current study and the analysis codes used to produce the figures and tables are available in the Open Science Framework repository, <https://doi.org/10.17605/OSF.IO/HQNKR>. <https://doi.org/10.17605/OSF.IO/HQNKR>. [1]: #T1

More than 82,000 pregnant women in the United States have tested positive for SARS-CoV-2.1Centers for Disease Control and PreventionCOVID data tracker.2020https://covid.cdc.gov/covid-data-tracker/?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F2019-ncov%2Fcases-updates%2Fcases-in-us.htmlDate accessed: December 28, 2020Google Scholar Published estimates of the incidence of vertical transmission—the passage of SARS-CoV-2 from the mother to her infant during pregnancy or childbirth—range from 1% to 3%, but these reports may be limited in their methodology.2Kotlyar AM Grechukhina O Chen A et al.Vertical transmission of coronavirus disease 2019: a systematic review and meta-analysis.Am J Obstet Gynecol. 2021; 224 (35–53.e3)Google Scholar, 3Flaherman VJ Afshar Y Boscardin WJ et al.Infant outcomes following maternal infection with SARS-CoV-2: first report from the PRIORITY study.Clin Infect Dis. 2020; ([Epub ahead of print])Crossref PubMed Scopus (31) Google Scholar, 4Woodworth KR Olsen EO Neelam V et al.Birth and infant outcomes following laboratory-confirmed SARS-CoV-2 infection in pregnancy - SET-NET, 16 Jurisdictions, March 29-October 14, 2020.MMWR Morb Mortal Wkly Rep. 2020; 69: 1635-1640Crossref PubMed Scopus (0) Google Scholar To date, the largest systematic review and meta-analysis reports a pooled estimate of 3.2%2Kotlyar AM Grechukhina O Chen A et al.Vertical transmission of coronavirus disease 2019: a systematic review and meta-analysis.Am J Obstet Gynecol. 2021; 224 (35–53.e3)Google Scholar and includes data from cohort studies and case series published early in the pandemic, when reports on outcomes of newborns with SARS-CoV-2 infection were urgently needed to guide clinical management and potentially overrepresented. Here, we provided additional data on vertical transmission from a multicenter cohort of pregnant women with SARS-CoV-2 infection. Women with a positive nasopharyngeal polymerase chain reaction (PCR) for SARS-CoV-2 during pregnancy who delivered from March 22, 2020, to December 20, 2020, at 1 of 3 hospitals in Boston, MA—Massachusetts General Hospital (MGH), Brigham and Women's Hospital (BWH), and Beth Israel Deaconess Medical Center (BIDMC)—were included. These hospitals perform approximately 15,000 deliveries per year, accounting for approximately 75% of annual deliveries in Boston. The Mass General Brigham and BIDMC Institutional Review Boards approved this study. Some of the participants included in this study of vertical transmission have been included in previous studies describing different outcomes. Inpatient universal testing protocols for SARS-CoV-2 were in place in early April 2020 (MGH or BWH) or May 2020 (BIDMC). Outpatient testing was performed by clinical indication, that is, a known exposure or symptoms. Consistent with the American Academy of Pediatrics (AAP) guidelines released on April 2, 2020,5The American Academy of PediatricsFAQs: management of infants born to mothers with suspected or confirmed COVID-19.2020https://services.aap.org/en/pages/2019-novel-coronavirus-covid-19-infections/clinical-guidance/faqs-management-of-infants-born-to-covid-19-mothers/Date accessed: January 15, 2021Google Scholar neonatal testing by nasopharyngeal PCR was performed at 24 hours of life only in newborns of mothers with SARS-CoV-2 infection who were considered infectious at the time of delivery and at 48 hours or later at the discretion of the provider or infection control. There was no case of SARS-CoV-2 infection identified in 369 newborns born to 354 women who tested positive for SARS-CoV-2 during pregnancy. Of the 369 delivered newborns, 159 newborns (43%) were tested at least once for SARS-CoV-2 during the delivery hospitalization, with 149 newborns (94%) receiving a test at 24 hours of life. Of the 354 women infected with SARS-CoV-2 during pregnancy included in this cohort, 140 (40%) delivered within 14 days from diagnosis of SARS-CoV-2 infection. The median interval from maternal diagnosis of SARS-CoV-2 infection to delivery was 29 days (interquartile range, 2–108). Asymptomatic or mild disease was noted in 259 women (73%). The Table depicts maternal and neonatal characteristics.TableCharacteristics of pregnant women testing positive for SARS-CoV-2 and frequency of newborn SARS-CoV-2 testingCharacteristicAll (N=354)MGH (n=144)BWH (n=130)BIDMC (n=80)Maternal disease severityaDefined by the National Institute of Health and endorsed by the Society for Maternal-Fetal MedicineAsymptomatic66 (19)31 (22)22 (17)13 (16)Mild192 (54)76 (53)75 (58)41 (51)Moderate59 (17)22 (15)23 (18)14 (18)Severe25 (7)11 (8)7 (5)7 (8)Critical12 (3)4 (3)3 (2)5 (6)GA at diagnosis in completed weeks32 (22–38)32 (23–38)33 (23–37)32 (19–36)GA at diagnosis by trimesterFirst37 (10)12 (8)16 (12)9 (11)Second92 (26)38 (26)29 (22)25 (31)Third225 (64)94 (65)85 (65)46 (58)GA at delivery in completed weeks39 (37–39)39 (38–39)39 (37–39)38 (37–39)Mode of deliveryVaginal delivery221 (62)89 (62)83 (64)49 (61)Cesarean delivery133 (38)55 (38)47 (36)31 (39)Preterm birth (<37 wk)bIncludes both iatrogenic and spontaneous preterm births53 (15)18 (13)18 (14)17 (21)Days from first positive test to delivery29 (2–108)33 (2–101)27 (2–106)26 (3–113)Women delivering <14 d from date of diagnosis140 (40)56 (39)49 (38)33 (41)Total newborns, n36915013584Positive for SARS-CoV-2cBy clinically available nasopharyngeal polymerase chain reaction for SARS-CoV-20 (0)0 (0)0 (0)0 (0)Negative for SARS-CoV-2cBy clinically available nasopharyngeal polymerase chain reaction for SARS-CoV-2159 (43)69 (46)60 (44)30 (36)Not tested for SARS-CoV-2cBy clinically available nasopharyngeal polymerase chain reaction for SARS-CoV-2210 (57)81(54)75 (56)54 (64)Incidence of vertical transmission, % (95% CI)dNumber of newborns testing positive for SARS-CoV-2 divided by number of newborns delivered to women with SARS-CoV-2 infection (all hospitals, 369; MGH, 150; BWH, 135; BIDMC, 84). The 95% CI was calculated using the exact (Clopper-Pearson) method.0 (0.0–1.0)0 (0.0–2.4)0 (0.0–2.7)0 (0.0–4.3)Newborns tested for SARS-CoV-2cBy clinically available nasopharyngeal polymerase chain reaction for SARS-CoV-2 after birth, n159696030Tested at 24 h only105 (66)49 (71)38 (63)18 (60)Tested at 24 h and 48 h–72 h31 (20)15 (22)4 (7)12 (40)Tested at 24 h and 4 d–14 d13 (8)4 (6)9 (15)0 (0)Tested at other time points10 (6)1 (1)9 (15)0 (0)Data are presented as number (percentage) or median (interquartile range), unless otherwise indicated.BIDMC, Beth Israel Deaconess Medical Center; BWH, Brigham and Women's Hospital; CI, confidence interval; GA, gestational age; MGH, Massachusetts General Hospital.Shook. Vertical transmission of SARS-CoV-2. Am J Obstet Gynecol MFM 2021.a Defined by the National Institute of Health and endorsed by the Society for Maternal-Fetal Medicineb Includes both iatrogenic and spontaneous preterm birthsc By clinically available nasopharyngeal polymerase chain reaction for SARS-CoV-2d Number of newborns testing positive for SARS-CoV-2 divided by number of newborns delivered to women with SARS-CoV-2 infection (all hospitals, 369; MGH, 150; BWH, 135; BIDMC, 84). The 95% CI was calculated using the exact (Clopper-Pearson) method. Open table in a new tab Data are presented as number (percentage) or median (interquartile range), unless otherwise indicated. BIDMC, Beth Israel Deaconess Medical Center; BWH, Brigham and Women's Hospital; CI, confidence interval; GA, gestational age; MGH, Massachusetts General Hospital. Shook. Vertical transmission of SARS-CoV-2. Am J Obstet Gynecol MFM 2021. We identified no case of vertical transmission in our cohort, which includes a large proportion of women with asymptomatic or mild disease. Newborns were tested per hospital infection control policies (eg, not tested if born to convalescent mothers). Although vertical transmission does occur, data from our centers suggest that the incidence of SARS-CoV-2 vertical transmission, as detected via neonatal nasopharyngeal swab, is likely lower than the 1% to 3% estimated incidence in previous reports.2Kotlyar AM Grechukhina O Chen A et al.Vertical transmission of coronavirus disease 2019: a systematic review and meta-analysis.Am J Obstet Gynecol. 2021; 224 (35–53.e3)Google Scholar, 3Flaherman VJ Afshar Y Boscardin WJ et al.Infant outcomes following maternal infection with SARS-CoV-2: first report from the PRIORITY study.Clin Infect Dis. 2020; ([Epub ahead of print])Crossref PubMed Scopus (31) Google Scholar, 4Woodworth KR Olsen EO Neelam V et al.Birth and infant outcomes following laboratory-confirmed SARS-CoV-2 infection in pregnancy - SET-NET, 16 Jurisdictions, March 29-October 14, 2020.MMWR Morb Mortal Wkly Rep. 2020; 69: 1635-1640Crossref PubMed Scopus (0) Google Scholar The challenge in selecting the denominator for calculating the incidence of vertical transmission is illustrated by the Centers for Disease Control and Prevention (CDC) report on 2869 newborns of women with SARS-CoV-2 infection during pregnancy.4Woodworth KR Olsen EO Neelam V et al.Birth and infant outcomes following laboratory-confirmed SARS-CoV-2 infection in pregnancy - SET-NET, 16 Jurisdictions, March 29-October 14, 2020.MMWR Morb Mortal Wkly Rep. 2020; 69: 1635-1640Crossref PubMed Scopus (0) Google Scholar Test results were available on 610 newborns—only 21% of the cohort—of which 16 (2.6%) tested positive for SARS-CoV-2. More than 60% of newborns without testing information were delivered >10 days from maternal infection. These newborns either were not tested or had a negative result, which is not mandated to be reported to the state, unlike a positive result. If all newborns born to women with SARS-CoV-2 infection during pregnancy were included in the denominator, the incidence of identified vertical transmission would be 0.6% (16 of 2869), not 2.6%. Consensus on how to define, detect, and report vertical transmission of SARS-CoV-2 is lacking. Although both the AAP and CDC recommend testing all infants born to mothers with active SARS-CoV-2 infection at the time of delivery, the optimal strategy for evaluating vertical transmission in the setting of early (first- and second-trimester) pregnancy infections is not known. Although nasopharyngeal PCR-based testing of infants born to convalescent women is likely to be low yield, sampling the fetal compartment during maternal SARS-CoV-2 infection to assess for transmission could incur risk without a clear benefit. Estimates of the incidence of vertical transmission that exclude untested newborns should be interpreted with caution, as untested newborns cannot demonstrate their presumed SARS-CoV-2–negative status. We assert that the appropriate denominator to estimate the incidence of vertical transmission includes all newborns of women with SARS-CoV-2 infection during pregnancy.

The successful development of several COVID-19 vaccines has substantially reduced morbidity and mortality in regions of the world where the vaccines have been deployed. However, in the wake of the emergence of viral variants, able to evade vaccine induced neutralizing antibodies, real world vaccine efficacy has begun to show differences across the mRNA platforms, suggesting that subtle variation in immune responses induced by the BNT162b2 and mRNA1273 vaccines may provide differential protection. Given our emerging appreciation for the importance of additional antibody functions, beyond neutralization, here we profiled the postboost binding and functional capacity of the humoral response induced by the BNT162b2 and mRNA-1273 in a cohort of hospital staff. Both vaccines induced robust humoral immune responses to WT SARS-CoV-2 and VOCs. However, differences emerged across epitopespecific responses, with higher RBD- and NTD-specific IgA, as well as functional antibodies (ADNP and ADNK) in mRNA-1273 vaccine recipients. Additionally, RBD-specific antibody depletion highlighted the different roles of non-RBD-specific antibody effector function induced across the mRNA vaccines, providing novel insights into potential differences in protective immunity generated across these vaccines in the setting of newly emerging VOCs.

Emerging SARS-CoV-2 variants of concern that overcome natural and vaccine-induced immunity threaten to exacerbate the COVID-19 pandemic. Increasing evidence suggests that neutralizing antibody (NAb) responses are a primary mechanism of protection against infection. However, little is known about the extent and mechanisms by which natural immunity acquired during the early COVID-19 pandemic confers cross-neutralization of emerging variants. In this study, we investigated cross-neutralization of the B.1.1.7 and B.1.351 SARS-CoV-2 variants in a well-characterized cohort of early pandemic convalescent subjects. We observed modestly decreased cross-neutralization of B.1.1.7 but a substantial 4.8-fold reduction in cross-neutralization of B.1.351. Correlates of cross-neutralization included receptor binding domain (RBD) and N-terminal domain (NTD) binding antibodies, homologous NAb titers, and membrane-directed T cell responses. These data shed light on the cross-neutralization of emerging variants by early pandemic convalescent immune responses. IMPORTANCE Widespread immunity to SARS-CoV-2 will be necessary to end the COVID-19 pandemic. NAb responses are a critical component of immunity that can be stimulated by natural infection as well as vaccines. However, SARS-CoV-2 variants are emerging that contain mutations in the spike gene that promote evasion from NAb responses. These variants may therefore delay control of the COVID-19 pandemic. We studied whether NAb responses from early COVID-19 convalescent patients are effective against the two SARS-CoV-2 variants, B.1.1.7 and B.1.351. We observed that the B.1.351 variant demonstrates significantly reduced susceptibility to early pandemic NAb responses. We additionally characterized virological, immunological, and clinical features that correlate with cross-neutralization. These studies increase our understanding of emerging SARS-CoV-2 variants.

Previous studies have reported that a third dose of the BNT162b2 (Pfizer) COVID-19 vaccine increased antibody titers and protective efficacy. Here we compare humoral and cellular immune responses in 65 individuals who were vaccinated with the BNT162b2 vaccine and were boosted after at least 6 months with either Ad26.COV2.S (Johnson & Johnson; N=41) or BNT162b2 (Pfizer; N=24).

Tight intrapartum maternal glucose control in pregestational diabetes is recommended to reduce the risk of neonatal hypoglycemia and neonatal intensive care unit (NICU) admission. Minimal evidence supports the relationship between intrapartum maternal glycemic control and neonatal hypoglycemia. The objective of the study is to compare the incidence of neonatal hypoglycemia with well-controlled blood glucose versus elevated glucose immediately prior to delivery in mothers with pregestational diabetes. This is a single-site, retrospective cohort study of singleton births with maternal pregestational diabetes from 1/2017-6/2019. Pre-delivery maternal glucose was defined as elevated if >110 mg/dL. The primary outcome was neonatal hypoglycemia (defined as < 45 mg/dL) within one hour of life. Secondary neonatal outcomes included neonatal hypoglycemia within 24 hours of birth, lowest neonatal glucose within 24 hours, and NICU admission. 164 deliveries were included; 59% had Type I diabetes (T1DM) and 42% had Type II diabetes (T2DM). Maternal pre-delivery glucose was elevated in 34% of all deliveries and similar by diabetes type. Incidence of neonatal hypoglycemia within 1 hr of birth in those with elevated glucose was similar to those with normal glucose (Table 1). NICU admissions were more frequent in the elevated maternal glucose group, but this was not statistically significant. Among those with elevated pre-delivery glucose, T1DM was associated with higher rates of neonatal hypoglycemia compared to T2DM, (68% vs. 41%, p=0.048, Table 2). Normal pre-delivery maternal glucose did not reduce the incidence of neonatal hypoglycemia compared to elevated glucose in women with pregestational diabetes. T1DM was associated with higher neonatal hypoglycemia rates regardless of pre-delivery maternal glucose control. Our results add to growing evidence that intrapartum glucose control may not be associated with a lower risk of neonatal hypoglycemia or NICU admissions. This supports the need to identify other interventions to reduce morbidity for infants of mothers with diabetes.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

PROBLEM:Evaluation of Zika virus (ZIKV)-specific humoral and cellular immune response in pregnant women exposed to ZIKV.METHOD OF STUDY:In this observational, prospective cohort study, we recruited pregnant women presenting for prenatal ultrasound for ZIKV exposure at a single academic teaching hospital in Boston, MA from November 2016 to December 2018. We collected blood, urine, and cervicovaginal swabs antepartum, intrapartum, and postpartum; and cord blood and placenta at delivery. We used experimental assays to calculate quantitative viral loads, ZIKV-specific immunoglobulin titers, and ZIKV-specific T-cell responses.RESULTS:We enrolled 22 participants, three of which had serologic-confirmed ZIKV infection. No participants demonstrated sustained ZIKV shedding. ZIKV-specific IgG/IgM antibody was sustained throughout pregnancy and postpartum. ZIKV envelope and capsid-specific T-cell responses were also observed, albeit inconsistent. No newborns in this cohort had congenital Zika syndrome. Infant cord blood of infected mothers exhibited ZIKV-specific IgG, but not IgM antibodies.CONCLUSION:We detected a robust, prolonged maternal humoral immune response to ZIKV during pregnancy and postpartum. We also demonstrated evidence for efficient transplacental antibody transfer from mother to infant at birth, supporting the importance of neonatal passive immunity to ZIKV. Maternal T-cell responses were less consistent among pregnant women infected with ZIKV.

Aim: We conducted a systematic review evaluating race/ethnicity representation in DNA methylomic studies of preterm birth. Data sources: PubMed, EMBASE, CINHAL, Scopus and relevant citations from 1 January 2000 to 30 June 2019. Study appraisal & synthesis methods: Two authors independently identified abstracts comparing DNA methylomic differences between term and preterm births that included race/ethnicity data. Results: 16 studies were included. Black and non-Hispanic Black deliveries were well represented (28%). However, large studies originating from more than 95% White populations were excluded due to unreported race/ethnicity data. Most studies were cross-sectional, allowing for reverse causation. Most studies were also racially/ethnically homogeneous, preventing direct comparison of DNA methylomic differences across race/ethnicities. Conclusion: In DNA methylomic studies, Black women and infants were well represented. However, the literature has limitations and precludes drawing definitive conclusions.