Publications

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.

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.

BACKGROUND: A cluster of over a thousand infections with the SARS-CoV-2 delta variant was identified in a predominantly fully vaccinated population in Provincetown, Massachusetts in July 2021. Immune responses in breakthrough infections with the SARS-CoV-2 delta variant remain to be defined.

METHODS: Humoral and cellular immune responses were assessed in 35 vaccinated individuals who were tested for SARS-CoV-2 in the Massachusetts Department of Public Health outbreak investigation.

RESULTS: Vaccinated individuals who tested positive for SARS-CoV-2 demonstrated substantially higher antibody responses than vaccinated individuals who tested negative for SARS-CoV-2, including 28-fold higher binding antibody titers and 34-fold higher neutralizing antibody titers against the SARS-CoV-2 delta variant. Vaccinated individuals who tested positive also showed 4.4-fold higher Spike-specific CD8+ T cell responses against the SARS-CoV-2 delta variant than vaccinated individuals who tested negative.

CONCLUSIONS: Fully vaccinated individuals developed robust anamnestic antibody and T cell responses following infection with the SARS-CoV-2 delta variant. These data suggest important immunologic benefits of vaccination in the context of breakthrough infections.

Endothelial dysfunction accompanies the microvascular thrombosis commonly observed in severe COVID-19. Constitutively, the endothelial surface is anticoagulant, a property maintained at least in part via signaling through the Tie2 receptor. During inflammation, the Tie2 antagonist angiopoietin-2 (Angpt-2) is released from endothelial cells and inhibits Tie2, promoting a prothrombotic phenotypic shift. We sought to assess whether severe COVID-19 is associated with procoagulant endothelial dysfunction and alterations in the Tie2/angiopoietin axis. Primary HUVECs treated with plasma from patients with severe COVID-19 upregulated the expression of thromboinflammatory genes, inhibited the expression of antithrombotic genes, and promoted coagulation on the endothelial surface. Pharmacologic activation of Tie2 with the small molecule AKB-9778 reversed the prothrombotic state induced by COVID-19 plasma in primary endothelial cells. Lung autopsies from patients with COVID-19 demonstrated a prothrombotic endothelial signature. Assessment of circulating endothelial markers in a cohort of 98 patients with mild, moderate, or severe COVID-19 revealed endothelial dysfunction indicative of a prothrombotic state. Angpt-2 concentrations rose with increasing disease severity, and the highest levels were associated with worse survival. These data highlight the disruption of Tie2/angiopoietin signaling and procoagulant changes in endothelial cells in severe COVID-19. Our findings provide rationale for current trials of Tie2-activating therapy with AKB-9778 in COVID-19.

OBJECTIVE: Compare the incidence of hypoglycemia in neonates born to patients with diabetes, based on last maternal glucose before delivery.

STUDY DESIGN: Cohort of singleton births from individuals with pregestational and gestational diabetes (GDM) from 2017 to 2019.

RESULTS: We included 853 deliveries. Maternal hyperglycemia before delivery was associated with 1.8-fold greater risk of neonatal hypoglycemia (glucose < 45 mg/dL) in patients with GDM on medication (adjusted risk ratio (aRR): 1.8; 95% CI: 1.1-2.7), compared with euglycemia. This association was not seen in diet-controlled GDM (0.5; 0.23-1.1), nor in Type 1 (1.1; 0.88-1.4), or Type 2 pregestational diabetes (1.1; 0.61-1.9). Further, pregestational diabetes, compared to GDM, regardless of intrapartum maternal glucose control, was associated with neonatal hypoglycemia and NICU admission.

CONCLUSION: Maternal hyperglycemia before delivery only carried a higher risk of neonatal hypoglycemia in those with GDM on medications. Other interventions to reduce neonatal hypoglycemia are needed.

Antibody transfer via breastmilk represents an evolutionary strategy to boost immunity in early life. Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibodies have been observed in the breastmilk, the functional quality of these antibodies remains unclear. Here, we apply systems serology to characterize SARS-CoV-2-specific antibodies in maternal serum and breastmilk to compare the functional characteristics of antibodies in these fluids. Distinct SARS-CoV-2-specific antibody responses are observed in the serum and breastmilk of lactating individuals previously infected with SARS-CoV-2, with a more dominant transfer of immunoglobulin A (IgA) and IgM into breastmilk. Although IgGs are present in breastmilk, they are functionally attenuated. We observe preferential transfer of antibodies capable of eliciting neutrophil phagocytosis and neutralization compared to other functions, pointing to selective transfer of certain functional antibodies to breastmilk. These data highlight the preferential transfer of SARS-CoV-2-specific IgA and IgM to breastmilk, accompanied by select IgG subpopulations, positioned to create a non-pathologic but protective barrier against coronavirus disease 2019 (COVID-19).

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.

BACKGROUND: The COVID-19 pandemic caused by the SARS-CoV-2 has increased the demand for inpatient healthcare resources; however, approximately 80% of patients with COVID-19 have a mild clinical presentation and can be managed at home.

OBJECTIVE: This study aimed to describe the feasibility and clinical and process outcomes associated with a multidisciplinary telemedicine surveillance model to triage and manage obstetrical patients with known exposures and symptoms of COVID-19.

STUDY DESIGN: We implemented a multidisciplinary telemedicine surveillance model with obstetrical physicians and nurses to standardize ambulatory care for obstetrical patients with confirmed or suspected COVID-19 based on the symptoms or exposures at an urban academic tertiary care center with multiple hospital-affiliated and community-based practices. All pregnant or postpartum patients with COVID-19 symptoms, exposures, or hospitalization were eligible for inclusion in the program. Patients were assessed by means of regular nursing phone calls and were managed according to illness severity. Patient characteristics and clinical and process outcomes were abstracted from the electronic medical record.

RESULTS: A total of 135 patients were enrolled in the multidisciplinary telemedicine model from March 17 to April 19, 2020, of whom 130 were pregnant and 5 were recently postpartum. In this study, 116 of 135 patients (86%) were managed solely in the outpatient setting and did not require an in-person evaluation; 9 patients were ultimately admitted after ambulatory or urgent evaluations, and 10 patients were observed after hospital discharge. Although only 50% of the patients were tested secondary to limitations in ambulatory testing, 1 in 3 of those patients received positive results for SARS-CoV-2 (N=22, 16% of entire cohort). Patients were enrolled in the telemedicine model for a median of 7 days (interquartile range, 4-8) and averaged 1 phone call daily, resulting in 891 nursing calls and 20 physician calls over 1 month.

CONCLUSION: A multidisciplinary telemedicine surveillance model for outpatient management of obstetrical patients with COVID-19 symptoms and exposures is feasible and resulted in rates of ambulatory management similar to those seen in nonpregnant patients. A centralized model for telemedicine surveillance of obstetrical patients with COVID-19 symptoms may preserve inpatient resources and prevent avoidable staff and patient exposures, particularly in centers with multiple ambulatory practice settings.