Activation of Coagulation and Proinflammatory Pathways in Thrombosis with Thrombocytopenia Syndrome and Following COVID-19 Vaccination

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

Differential Kinetics of Immune Responses Elicited by Covid-19 Vaccines

To the Editor: Previous studies have shown that the BNT162b2 (Pfizer–BioNTech), mRNA-1273 (Moderna), and Ad26.COV2.S (Johnson & Johnson–Janssen) vaccines provide robust protective efficacy against coronavirus disease 2019 (Covid-19). Here, we report comparative kinetics of humoral and cellular immune responses elicited by the two-dose BNT162b2 vaccine (in 31 participants), the two-dose mRNA-1273 vaccine (in 22 participants), and the one-dose Ad26.COV2.S vaccine (in 8 participants). We evaluated antibody and T-cell responses from peak immunity at 2 to 4 weeks after the second immunization in recipients of the messenger RNA (mRNA) vaccines or after the first immunization in recipients of the Ad26.COV2.S vaccine to 8 months (Table S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org)

Resilience as a potential modifier of racial inequities in preterm birth

PURPOSE: In the United States, preterm birth is 55% more common among Black compared to White individuals and psychosocial stressors may contribute. Resilience is associated with improved health outcomes outside of pregnancy. However, whether resilience modifies preterm birth inequity is unknown. We hypothesized that high resilience would reduce inequities in preterm birth risk. METHODS: This study analyzes data from 535 pregnancies among Black (n=101, 19%) and White (n=434, 81%) participants from the Spontaneous Prematurity and Epigenetics of the Cervix prospective cohort. Participants completed the Connor-Davidson Resilience Scale. We calculated risk ratios (RR) for preterm birth among Black compared to White participants, stratified by resilience tertiles, to test for effect measure modification. RESULTS: Among those in the lowest resilience tertile, there were 6 (20.7%) preterm births among Black and 7 (4.9%) among White participants (RR: 4.26; 95% confidence interval (CI): 1.53, 11.81). Among those in the highest resilience tertile, there were 8 (18.2%) preterm births among Black and 14 (9.5%) among White participants (RR: 1.92; 95% CI: 0.87, 4.24. Adjusting for education and income, the Black:White RR was 2.00 (95% CI 0.47, 8.64) in the lowest tertile, and 3.49 (95% CI 1.52, 8.01) in the highest tertile. CONCLUSIONS: Black-White preterm birth inequity did not differ among resilience strata and remained significant in the highest tertile. Our findings suggest that high resilience is inadequate to overcome Black:White racial inequity in preterm birth

Selective functional antibody transfer into the breastmilk after SARS-CoV-2 infection

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)

Selective SARS-CoV2 BA.2 escape of antibody Fc/Fc-receptor interactions

Summary: The number of mutations in the omicron (B.1.1.529) BA.1 variant of concern led to an unprecedented evasion of vaccine induced immunity. However, despite rise in global infections, severe disease did not increase proportionally and is likely linked to persistent recognition of BA.1 by T cells and non-neutralizing opsonophagocytic antibodies. Yet, the emergence of new sublineage BA.2, which is more transmissible than BA.1 despite relatively preserved neutralizing antibody responses, has raised the possibility that BA.2 may evade other vaccine-induced responses. Here, we comprehensively profiled the BNT162b2 vaccine-induced response to several VOCs, including omicron BA.1 and BA.2. While vaccine-induced immune responses were compromised against both omicron sublineages, vaccine-induced antibody isotype titers, and non-neutralizing Fc effector functions were attenuated to the omicron BA.2 spike compared to BA.1. Conversely, FcγR2a and FcγR2b binding was elevated to BA.2, albeit lower than BA.1 responses, potentially contributing to persistent protection against severity of disease