Individuals with potential exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) do not necessarily develop PCR or antibody positivity, suggesting that some individuals may clear subclinical infection before seroconversion. T cells can contribute to the rapid clearance of SARS-CoV-2 and other coronavirus infections1–3. Here we hypothesize that pre-existing memory T cell responses, with cross-protective potential against SARS-CoV-2 (refs. 4–11), would expand in vivo to support rapid viral control, aborting infection. We measured SARS-CoV-2-reactive T cells, including those against the early transcribed replication–transcription complex (RTC)12,13, in intensively monitored healthcare workers (HCWs) who tested repeatedly negative according to PCR, antibody binding and neutralization assays (seronegative HCWs (SN-HCWs)). SN-HCWs had stronger, more multispecific memory T cells compared with a cohort of unexposed individuals from before the pandemic (prepandemic cohort), and these cells were more frequently directed against the RTC than the structural-protein-dominated responses observed after detectable infection (matched concurrent cohort). SN-HCWs with the strongest RTC-specific T cells had an increase in IFI27, a robust early innate signature of SARS-CoV-2 (ref. 14), suggesting abortive infection. RNA polymerase within RTC was the largest region of high sequence conservation across human seasonal coronaviruses (HCoV) and SARS-CoV-2 clades. RNA polymerase was preferentially targeted (among the regions tested) by T cells from prepandemic cohorts and SN-HCWs. RTC-epitope-specific T cells that cross-recognized HCoV variants were identified in SN-HCWs. Enriched pre-existing RNA-polymerase-specific T cells expanded in vivo to preferentially accumulate in the memory response after putative abortive compared to overt SARS-CoV-2 infection. Our data highlight RTC-specific T cells as targets for vaccines against endemic and emerging Coronaviridae.

Correlates of protection for COVID-19 vaccines are urgently needed to license additional vaccines. We measured immune responses to four COVID-19 vaccines of proven efficacy using a single serological platform. IgG anti-Spike antibodies were highly correlated with ID50 neutralization in a validated pseudoviral assay and correlated significantly with efficacies for protection against infection with wild-type, alpha and delta variant SARS-CoV-2 virus. The protective threshold for each vaccine was calculated for IgG anti-Spike antibody. The mean protective threshold for all vaccine studies for WT virus was 154 BAU/ml (95 %CI 42–559), and for studies with antibody distributions that enabled precise estimation of thresholds (i.e. leaving out 2-dose mRNA regimens) was 60 BAU/ml (95 %CI 35–102). We propose that the proportion of individuals with responses above the appropriate protective threshold together with the geometric mean concentration can be used in comparative non-inferiority studies with licensed vaccines to ensure that new vaccines will be efficacious.

Human mannose-binding lectin (MBL) is a serum protein of the innate immune system that circulates as a complex with a group of so-called MBL-associated serine proteases (MASP-1, MASP-2, and MASP-3). Complexes of MBL-MASP2 are able to activate the complement system in an Ab and C1-independent fashion after binding of the lectin to appropriate microbial sugar arrays. We have evaluated the additive effect of the lectin pathway relative to other complement activation pathways and the subsequent effect on neutrophil phagocytosis. Complement activation in the sera of MBL-deficient individuals was studied with and without the addition of exogenous MBL-MASP. Flow cytometry was used to measure the deposition of C4, factor B, C3b, and iC3b on Staphylococcus aureus. Deposition of the first cleavage product of the lectin pathway, C4b, was increased using the sera of three different MBL-deficient individuals when exogenous MBL-MASP was added. Factor B was deposited in association with C4, but there was no evidence of independent alternative pathway activation. Similar enhancement of C3b deposition was also observed, with evidence of elevated amounts of C3b processed to iC3b. The increase in opsonic C3 fragments mediated by MBL was associated with a significant increase in the uptake of organisms by neutrophils. We also observed significant increases in phagocytosis with MBL-MASPs that were independent of complement activation. We conclude that MBL-MASP makes a major contribution to complement-mediated host defense mechanisms.

Highlights Simultaneous measurement of IgG to several SARS-CoV-2 antigens. Sensitive and specific assay for Trimeric spike, RBD and Nucleocapsid antigen. IgG values correlates well with pseudoneutralization measured on the same platform. No pseudoneutralisation from cross reactive seasonal coronoavirus antibodies.

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Patients with hematological malignancies are at increased risk of severe COVID-19 outcomes due to compromised immune responses, but the insights of these studies have been compromised due to intrinsic limitations in study design. Here we present the PROSECO prospective observational study (NCT04858568) on 457 patients with lymphoma that received two or three COVID-19 vaccine doses. We show undetectable humoral responses following two vaccine doses in 52% of patients undergoing active anticancer treatment. Moreover, 60% of patients on anti-CD20 therapy had undetectable antibodies following full vaccination within 12 months of receiving their anticancer therapy. However, 70% of individuals with indolent B-cell lymphoma displayed improved antibody responses following booster vaccination. Notably, 63% of all patients displayed antigen-specific T-cell responses, which increased after a third dose irrespective of their cancer treatment status. Our results emphasize the urgency of careful monitoring of COVID-19-specific immune responses to guide vaccination schemes in these vulnerable populations.

Introduction: Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) specific antibodies have been shown to neutralize the virus in-vitro. Understanding antibody dynamics following SARS-CoV-2 infection is therefore crucial. Sensitive measurement of SARS-CoV-2 antibodies is also vital for large seroprevalence surveys which inform government policies and public health interventions. However, rapidly waning antibodies following SARS-CoV-2 infection could jeopardize the sensitivity of serological testing on which these surveys depend. Methods: This prospective cohort study of SARS-CoV-2 humoral dynamics in a central London hospital analyzed 137 serial samples collected from 67 participants seropositive to SARS-CoV-2 by the Meso-Scale Discovery assay. Antibody titers were quantified to the SARS-CoV-2 nucleoprotein (N), spike (S-)protein and the receptor-binding-domain (RBD) of the S-protein. Titers were log-transformed and a multivariate log-linear model with time-since-infection and clinical variables was fitted by Bayesian methods. Results: The mean estimated half-life of the N-antibody was 52 days (95% CI 42-65). The S- and RBD-antibody had significantly longer mean half-lives of 81 days (95% CI 61-111) and 83 days (95% CI 55-137) respectively. An ACE-2-receptor competition assay demonstrated significant correlation between the S and RBD-antibody titers and ACE2-receptor blocking in-vitro. The time-to-a-negative N-antibody test for 50% of the seropositive population was predicted to be 195 days (95% CI 163-236). Discussion: After SARS-CoV-2 infection, the predicted half-life of N-antibody was 52 days with 50% of seropositive participants becoming seronegative to this antibody at 195 days. Widely used serological tests that depend on the N-antibody will therefore significantly underestimate the prevalence of infection following the majority of infections.

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