Publications

Thrombosis with thrombocytopenia syndrome (TTS) is a rare but potentially severe adverse event following immunization with adenovirus vector-based COVID-19 vaccines such as Ad26.COV2.S (Janssen) and ChAdOx1 (AstraZeneca). However, no case of TTS has been reported in over 1.5 million individuals who received a second immunization with Ad26.COV2.S in the United States. Here we utilize transcriptomic and proteomic profiling to compare individuals who receive two doses of Ad26.COV2.S with those vaccinated with BNT162b2 or mRNA-1273. Initial Ad26.COV2.S vaccination induces transient activation of platelet and coagulation and innate immune pathways that resolve by day 7; by contrast, patients with TTS show robust upregulation of these pathways on days 15-19 following initial Ad26.COV2.S vaccination. Meanwhile, a second immunization or a reduced initial dose of Ad26.COV2.S induces lower activation of these pathways than does the full initial dose. Our data suggest a role of coagulation and proinflammatory pathways in TTS pathogenesis, which may help optimize vaccination regimens to reduce TTS risk.

BACKGROUND: Serial growth scans are routinely recommended for twin pregnancies to identify fetal growth restriction (defined as an estimated fetal weight of <10th percentile), which can result in increased perinatal morbidity and mortality. However, the clinical significance of early intertwin growth discordance in the absence of fetal growth restriction remains unclear.

OBJECTIVE: This study aimed to compare the rates of small-for-gestational-age infants among twin pregnancies with intertwin growth discordance in the absence of fetal growth restriction with that among twin pregnancies with concordant, normal growth identified by ultrasound between 24 0/7 and 31 6/7 weeks' gestation.

STUDY DESIGN: This was a retrospective cohort study of twin deliveries at a single hospital from 2010 to 2019. Pregnancies without fetal growth restriction were categorized as discordant or concordant using the earliest prenatal growth ultrasound between 24 0/7 and 31 6/7 weeks' gestation. Discordance was defined as an estimated fetal weight difference of ≥18% between twins. Pregnancies with major fetal anomalies, no growth ultrasound between 24 0/7 and 31 6/7 weeks' gestation, or twin-twin transfusion syndrome were excluded. The cohort was stratified by chorionicity. Our primary outcome was small-for-gestational-age defined as <10th percentile per the Fenton growth curve at delivery. Secondary outcomes included gestational age at delivery, mode of delivery, neonatal intensive care unit admission, length of stay, and neonatal complications and placental pathology.

RESULTS: Of the 707 twin pregnancies that met the inclusion criteria, 558 (79%) were dichorionic and 149 (21%) were monochorionic. Most pregnancies were concordant on ultrasound between 24 0/7 and 31 6/7 weeks' gestation (dichorionic, 93%; monochorionic, 87%). Regardless of chorionicity, twin pregnancies with discordance at ultrasound, were more likely to have a small-for-gestational-age infant than concordant twin pregnancies (dichorionic: 51% vs 29%; P=.002; monochorionic: 65% vs 24%; P<.001). Furthermore, women with twin pregnancies with discordance were delivered at an earlier gestational age (dichorionic: 36 weeks [interquartile range, 33-36] vs 34 weeks [interquartile range, 34-38]; P<.001; monochorionic: 34 weeks [interquartile range, 32-34] vs 36 weeks [interquartile range, 34-37]; P=.003). Pregnancies with growth discordance were more likely to be delivered by cesarean delivery (dichorionic: 90% vs 72%; P=.01; monochorionic: 65% vs 60%; P=.70), although this was only statistically significant for dichorionic twin pregnancies. Neonates of pregnancies with growth discordance had a higher incidence of respiratory distress syndrome (dichorionic: 54% vs 37%; P=.04; monochorionic: 70% vs 45%; P=.04) and neonatal intensive care unit admission (dichorionic: 71% vs 50%; P=.01; monochorionic: 90% vs 65%; P=.03). Furthermore, dichorionic infants had longer neonatal intensive care unit stays (30 [interquartile range, 18-61] vs 18 [interquartile range, 10-35] days; P=.02).

CONCLUSION: Regardless of chorionicity, twin pregnancies with discordance without fetal growth restriction identified on growth ultrasound between 24 0/7 and 31 6/7 weeks' gestation were nearly twice as likely to develop small-for-gestational-age neonates, deliver earlier in gestation, and experience greater neonatal morbidity than twin pregnancies without discordance. Patients with pregnancies complicated by isolated intertwin discordance between 24 0/7 and 31 6/7 weeks' gestation will need counseling regarding adverse perinatal outcomes.

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.

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 ).

The highly mutated SARS-CoV-2 Omicron (B.1.1.529) variant has been shown to evade a substantial fraction of neutralizing antibody responses elicited by current vaccines that encode the WA1/2020 spike protein1. Cellular immune responses, particularly CD8+ T cell responses, probably contribute to protection against severe SARS-CoV-2 infection2-6. Here we show that cellular immunity induced by current vaccines against SARS-CoV-2 is highly conserved to the SARS-CoV-2 Omicron spike protein. Individuals who received the Ad26.COV2.S or BNT162b2 vaccines demonstrated durable spike-specific CD8+ and CD4+ T cell responses, which showed extensive cross-reactivity against both the Delta and the Omicron variants, including in central and effector memory cellular subpopulations. Median Omicron spike-specific CD8+ T cell responses were 82-84% of the WA1/2020 spike-specific CD8+ T cell responses. These data provide immunological context for the observation that current vaccines still show robust protection against severe disease with the SARS-CoV-2 Omicron variant despite the substantially reduced neutralizing antibody responses7,8.

The highly mutated SARS-CoV-2 Omicron (B.1.1.529) variant has been shown to evade a substantial fraction of neutralizing antibody responses elicited by current vaccines that encode the WA1/2020 Spike immunogen 1 , resulting in increased breakthrough infections and reduced vaccine efficacy. Cellular immune responses, particularly CD8+ T cell responses, are likely critical for protection against severe SARS-CoV-2 disease 2-6 . Here we show that cellular immunity induced by current SARS-CoV-2 vaccines is highly cross-reactive against the SARS-CoV-2 Omicron variant. Individuals who received Ad26.COV2.S or BNT162b2 vaccines demonstrated durable CD8+ and CD4+ T cell responses that showed extensive cross-reactivity against both the Delta and Omicron variants, including in central and effector memory cellular subpopulations. Median Omicron-specific CD8+ T cell responses were 82-84% of WA1/2020-specific CD8+ T cell responses. These data suggest that current vaccines may provide considerable protection against severe disease with the SARS-CoV-2 Omicron variant despite the substantial reduction of neutralizing antibody responses.

BACKGROUND: Ischaemic placental disease (IPD) affects 16%-23% of pregnancies in the United States. In vitro fertilisation (IVF) is a risk factor for IPD, and the magnitude of increase in risk differs for individuals using donor oocytes (donor IVF) versus their own oocytes (autologous IVF). In addition, multifoetal gestations, which are more common in IVF than non-IVF pregnancies, also are a risk factor for IPD.

OBJECTIVE: To quantify the contribution of multifoetal gestations to the association between IVF and IPD.

METHODS: We conducted a retrospective cohort study at a tertiary hospital from 1 January, 2000 to 1 August 2018 using electronic medical records and state vital statistics data. IPD was defined as preeclampsia, placental abruption, small for gestational age (SGA) birth or an intrauterine foetal demise due to placental insufficiency. We used mediation analysis to decompose the total effect of IVF on IPD into a natural direct effect and an indirect effect through multifoetal gestations. We repeated the analyses separately for donor and autologous IVF. All models were adjusted for maternal age, race, parity, insurance, year of delivery and account for multiple pregnancies per person.

RESULTS: We identified 86,514 deliveries, of which 281 resulted from donor IVF and 4173 resulted from autologous IVF. IVF pregnancies had 1.99 (95% CI 1.88, 2.10) times the risk of IPD compared to non-IVF pregnancies, and 75.5% of this increased risk was mediated by multifoetal gestations. Autologous IVF pregnancies had 1.95 (95% CI 1.84, 2.07) times the risk of IPD compared to non-IVF pregnancies, and the per cent mediated was 78.8%. Donor IVF pregnancies had 2.50 (95% CI 2.09, 2.92) times the risk of IPD, but the per cent mediated was 37.5%.

CONCLUSION: The majority of the association between autologous IVF and IPD was mediated through multifoetal gestations; however, this was not the case for donor IVF pregnancies.

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.