The emergence of SARS-CoV-2 variants with mutations in the spike protein is raising concerns about the efficacy of infection- or vaccine-induced antibodies. We compared antibody binding and live ...virus neutralization of sera from naturally infected and Moderna-vaccinated individuals against two SARS-CoV-2 variants: B.1 containing the spike mutation D614G and the emerging B.1.351 variant containing additional spike mutations and deletions. Sera from acutely infected and convalescent COVID-19 patients exhibited a 3-fold reduction in binding antibody titers to the B.1.351 variant receptor-binding domain of the spike protein and a 3.5-fold reduction in neutralizing antibody titers against SARS-CoV-2 B.1.351 variant compared to the B.1 variant. Similar results were seen with sera from Moderna-vaccinated individuals. Despite reduced antibody titers against the B.1.351 variant, sera from infected and vaccinated individuals containing polyclonal antibodies to the spike protein could still neutralize SARS-CoV-2 B.1.351, suggesting that protective humoral immunity may be retained against this variant.
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•Antibodies from infected and vaccinated individuals bind to the B.1.351 RBD•Convalescent sera through eight months can neutralize the B.1.351 variant•Serum from vaccinated individuals retains neutralization against the B.1.351 variant
In this study, Edara et al. (2021) report that, despite reduced antibody binding to the B.1.351 RBD, sera from infected (acute and convalescent) and Moderna (mRNA-1273)-vaccinated individuals were still able to neutralize the SARS-CoV-2 B.1.351 variant, suggesting that protective humoral immunity may be retained against this variant.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) omicron variant emerged in November 2021 and consists of several mutations within the spike. We use serum from mRNA-vaccinated ...individuals to measure neutralization activity against omicron in a live-virus assay. At 2–4 weeks after a primary series of vaccinations, we observe a 30-fold reduction in neutralizing activity against omicron. Six months after the initial two-vaccine doses, sera from naive vaccinated subjects show no neutralizing activity against omicron. In contrast, COVID-19-recovered individuals 6 months after receiving the primary series of vaccinations show a 22-fold reduction, with the majority of the subjects retaining neutralizing antibody responses. In naive individuals following a booster shot (third dose), we observe a 14-fold reduction in neutralizing activity against omicron, and over 90% of subjects show neutralizing activity. These findings show that a third dose is required to provide robust neutralizing antibody responses against the omicron variant.
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•Omicron has a significant impact on vaccine-induced neutralizing antibody (nAb) titers•Naive vaccinated individuals lost nAb titers against omicron variant after 6 months•A booster (third dose) is required to maintain neutralizing activity against omicron
Here in this study, Edara et al. report that 6 months after the primary series (initial two doses) of mRNA vaccination, the majority of the subjects lost detectable neutralizing antibody titers against omicron. The data suggest that a third booster dose is necessary to sustain neutralizing activity against omicron.
Bruton's tyrosine kinase (BTK) mediates B cell signaling and is also present in innate immune cells but not T cells. BTK propagates B cell receptor (BCR) responses to antigen-engagement as well as to ...stimulation via CD40, toll-like receptors (TLRs), Fc receptors (FCRs) and chemokine receptors. Importantly, BTK can modulate signaling, acting as a "rheostat" rather than an "on-off" switch; thus, overexpression leads to autoimmunity while decreased levels improve autoimmune disease outcomes. Autoreactive B cells depend upon BTK for survival to a greater degree than normal B cells, reflected as loss of autoantibodies with maintenance of total antibody levels when BTK is absent. This review describes contributions of BTK to immune tolerance, including studies testing BTK-inhibitors for treatment of autoimmune diseases.
To examine COVID-19 mRNA vaccine-induced binding and neutralizing antibody responses in patients with non-small-cell lung cancer (NSCLC) to SARS-CoV-2 614D (wild type WT) strain and variants of ...concern after the primary 2-dose and booster vaccination.
Eighty-two patients with NSCLC and 53 healthy volunteers who received SARS-CoV-2 mRNA vaccines were included in the study. Blood was collected longitudinally, and SARS-CoV-2-specific binding and neutralizing antibody responses were evaluated by Meso Scale Discovery assay and live virus Focus Reduction Neutralization Assay, respectively.
A majority of patients with NSCLC generated binding and neutralizing antibody titers comparable with the healthy vaccinees after mRNA vaccination, but a subset of patients with NSCLC (25%) made poor responses, resulting in overall lower (six- to seven-fold) titers compared with the healthy cohort (
= < .0001). Although patients age > 70 years had lower immunoglobulin G titers (
= < .01), patients receiving programmed death-1 monotherapy, chemotherapy, or a combination of both did not have a significant impact on the antibody response. Neutralizing antibody titers to the B.1.617.2 (Delta), B.1.351 (Beta), and in particular, B.1.1.529 (Omicron) variants were significantly lower (
= < .0001) compared with the 614D (WT) strain. Booster vaccination led to a significant increase (
= .0001) in the binding and neutralizing antibody titers to the WT and Omicron variant. However, 2-4 months after the booster, we observed a five- to seven-fold decrease in neutralizing titers to WT and Omicron viruses.
A subset of patients with NSCLC responded poorly to the SARS-CoV-2 mRNA vaccination and had low neutralizing antibodies to the B.1.1.529 Omicron variant. Booster vaccination increased binding and neutralizing antibody titers to Omicron, but antibody titers declined after 3 months. These data highlight the concern for patients with cancer given the rapid spread of SARS-CoV-2 Omicron variant.
IL-33 is an IL-1 family member protein that is a potent driver of inflammatory responses in both allergic and nonallergic disease. This proinflammatory effect is mediated primarily by extracellular ...release of IL-33 from stromal cells and binding of the C-terminal domain of IL-33 to its receptor ST2 on targets such as CD4
Th2 cells, ILC2, and mast cells. Notably, IL-33 has a distinct N-terminal domain that mediates nuclear localization and chromatin binding. However, a defined in vivo cell-intrinsic role for IL-33 has not been established. We identified IL-33 expression in the nucleus of progenitor B (pro-B) and large precursor B cells in the bone marrow, an expression pattern unique to B cells among developing lymphocytes. The IL-33 receptor ST2 was not expressed within the developing B cell lineage at either the transcript or protein level. RNA sequencing analysis of wild-type and IL-33-deficient pro-B and large precursor B cells revealed a unique, IL-33-dependent transcriptional profile wherein IL-33 deficiency led to an increase in E2F targets, cell cycle genes, and DNA replication and a decrease in the p53 pathway. Using mixed bone marrow chimeric mice, we demonstrated that IL-33 deficiency resulted in an increased frequency of developing B cells via a cell-intrinsic mechanism starting at the pro-B cell stage paralleling IL-33 expression. Finally, IL-33 was detectable during early B cell development in humans and
mRNA expression was decreased in B cell chronic lymphocytic leukemia samples compared with healthy controls. Collectively, these data establish a cell-intrinsic, ST2-independent role for IL-33 in early B cell development.
Ending the COVID-19 pandemic will require long-lived immunity to SARS-CoV-2. Here, we evaluate 254 COVID-19 patients longitudinally up to 8 months and find durable broad-based immune responses. ...SARS-CoV-2 spike binding and neutralizing antibodies exhibit a bi-phasic decay with an extended half-life of >200 days suggesting the generation of longer-lived plasma cells. SARS-CoV-2 infection also boosts antibody titers to SARS-CoV-1 and common betacoronaviruses. In addition, spike-specific IgG+ memory B cells persist, which bodes well for a rapid antibody response upon virus re-exposure or vaccination. Virus-specific CD4+ and CD8+ T cells are polyfunctional and maintained with an estimated half-life of 200 days. Interestingly, CD4+ T cell responses equally target several SARS-CoV-2 proteins, whereas the CD8+ T cell responses preferentially target the nucleoprotein, highlighting the potential importance of including the nucleoprotein in future vaccines. Taken together, these results suggest that broad and effective immunity may persist long-term in recovered COVID-19 patients.
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Most recovered COVID-19 patients mount broad, durable immunity after infectionNeutralizing antibodies show a bi-phasic decay with half-lives >200 daysSpike IgG+ memory B cells increase and persist post-infectionDurable polyfunctional CD4 and CD8 T cells recognize distinct viral epitope regions
Cohen et al. evaluate immune responses longitudinally in 254 COVID-19 patients over 8 months. SARS-CoV-2-specific binding and neutralizing antibodies exhibit biphasic decay, suggesting long-lived plasma cell generation. Memory B cells remain stable; CD4 and CD8 memory T cells are polyfunctional. Thus, broad and effective immunity may persist long-term following COVID-19.
Bruton's tyrosine kinase (
) deficiency preferentially eliminates autoreactive B cells while sparing normal humoral responses, but has not been studied in mucosal immunity. Commensal microbes and ...intact BTK signaling have been independently shown to be essential for arthritis development in K/BxN mice. Here, we examine how BTK-mediated signaling interfaces with the gut microbiome.
-deficient K/BxN mice were found to have small Peyer's Patches with reduced germinal center and IgA class-switched B cells. IgA-switched plasma cells in small intestines were reduced, especially in villi of
-deficient mice. IgH CDR3 sequencing showed similar V gene diversity and somatic hypermutation frequency despite
deficiency but showed reduced CDR3 amino acid polarity, suggesting potential qualitative differences in the gut plasma cell repertoire. Small intestinal IgA was low and IgA coating of commensal bacteria was reduced. IgA-seq showed a shift in small intestinal microbes that are normally IgA-coated into the uncoated fraction in
-deficient mice. Overall, this study shows that BTK supports normal intestinal IgA development in response to commensals. This manuscript was previously published as a preprint at: https://www.biorxiv.org/content/10.1101/2021.03.10.434762v2.
Bruton's tyrosine kinase (Btk) propagates B cell signaling, and BTK inhibitors are in clinical trials for autoimmune disease. Although autoreactive B cells fail to develop in the absence of Btk, its ...role in mature cells is unknown. To address this issue, a model of conditional removal (
/
) was used to excise
from mature transgenic B cells that recognize the pathophysiologic autoantigen insulin. Anti-insulin B cells escape central tolerance and promote autoimmune diabetes, mimicking human autoreactive cells. Lifelong
deficiency was previously shown to eliminate 95% of anti-insulin B cells, but in this model, mature anti-insulin B cells survived for weeks after targeted
deletion, even when competing with a polyclonal repertoire. BCR-stimulated cells could still signal via Syk, PLCy2, and CD22, but failed to upregulate the antiapoptotic protein Bcl-xL, and proliferation was impaired. Surprisingly,
-depleted anti-insulin B cells could still present Ag and activate T cells, a critical function in promoting T cell-mediated islet cell destruction. Thus, pharmacologic targeting of Btk may be most effective by blocking expansion of established autoreactive cells, and preventing emergence of new ones.
The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic highlights the importance of determining the breadth and durability of humoral immunity to SARS-CoV-2 mRNA ...vaccination. Herein, we characterize the humoral response in 27 naive and 40 recovered vaccinees. SARS-CoV-2-specific antibody and memory B cell (MBC) responses are durable up to 6 months, although antibody half-lives are shorter for naive recipients. The magnitude of the humoral responses to vaccination strongly correlates with responses to initial SARS-CoV-2 infection. Neutralization titers are lower against SARS-CoV-2 variants in both recovered and naive vaccinees, with titers more reduced in naive recipients. While the receptor-binding domain (RBD) is the main neutralizing target of circulating antibodies, Moderna-vaccinated naives show a lesser reliance on RBDs, with >25% neutralization remaining after depletion of RBD-binding antibodies. Overall, we observe that vaccination induces higher peak titers and improves durability in recovered compared with naive vaccinees. These findings have broad implications for current vaccine strategies deployed against the SARS-CoV-2 pandemic.
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•Single vaccine dose effectively boosts B cell responses in recovered subjects•SARS-CoV-2-specific MBCs remain activated and increase over time in naive subjects•Antibody response to vaccination is broader and more durable in recovered versus naive subjects•Naive vaccinees have higher proportion of non-RBD-specific neutralizing antibodies
Mantus et al. find that kinetics, breadth, and durability of humoral immune responses to mRNA vaccination are dependent on pre-existing immunity to SARS-CoV-2. Cellular and serological SARS-CoV-2-specific immunity is detected in both recovered and naive individuals after vaccination, with broader and more durable serological responses detected in recovered individuals.
Bruton's tyrosine kinase (Btk) is a crucial regulator of B cell signaling and is a therapeutic target for lymphoma and autoimmune disease. BTK-deficient patients suffer from humoral immunodeficiency, ...as their B cells fail to progress beyond the bone marrow. However, the role of Btk in fully developed, mature peripheral B cells is not well understood. Analysis using BTK inhibitors is complicated by suboptimal inhibition, off-target effects, or failure to eliminate BTK's adaptor function. Therefore a
mouse model was developed and used to excise
after B cell populations were established. Mice lacking
from birth are known to have reduced follicular (FO) compartments, with expanded transitional populations, suggesting a block in development. In adult
mice,
excision did not reduce FO B cells, which persisted for weeks. Autoimmune-prone B1 cells also survived conditional
excision, contrasting their near absence in global
-deficient mice. Therefore, Btk supports BCR signaling during selection into the FO and B1 compartments, but is not needed to maintain these cell populations. B1-related natural IgM levels remained normal, contrasting global
deficiency, but B cell proliferation and T-independent type II immunization responses were blunted. Thus, B cells have nuanced signaling responses that are differentially regulated by Btk for development, survival, and function. These findings raise the possibility that Btk may also be expendable for survival of mature human B cells, therefore requiring prolonged dosing to be effective, and that success of BTK inhibitors may depend in part on off-target effects.
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