Recruitment of plasma cells to the bone marrow in primary and secondary immune reactions (preprint)

Bone marrow plasma cells (BMPC) emerge as a consequence of immune reactions and are considered the source of antibodies that protect against recurrent infectious diseases throughout life. Despite their importance, it remains unclear if these cells reflect different activation environments or the differentiation/maturation stages of their precursors. Here we track the recruitment of plasma cells, generated in primary and secondary immune reactions to SARS-CoV-2 spike protein vaccines, to the human bone marrow. Trajectories based on single cell transcriptomes and antigen-receptor clonotypes of antibody-secreting cells exiting the immune reaction and of those residing in the bone marrow, allow to follow the evolution of the immune response to these vaccines, leading to sequential colonization of these cells to different compartments (clans) of BMPC, and their establishment as long-lived (memory) plasma cells. In primary immune reactions, both CD19low (clans 1 and 4) and CD19high (clan 0) BMPC are generated. In secondary immune reactions, mostly CD19high BMPC of the largest compartment (clan 0) are generated, resulting from the reactivation of memory B lymphocytes. The latter is also observed in vaccinated convalescent individuals and upon recall vaccination against diphtheria/tetanus/pertussis (DTP). Thus, humoral immunological memory, i.e. serum antibodies secreted by long-lived memory BMPC, is generated already in the primary immune response, more so in the secondary, and it represents the evolution of the immune response.

B cell numbers predict humoral and cellular response upon SARS-CoV-2 vaccination among patients treated with rituximab (preprint)

Objectives Patients with autoimmune inflammatory rheumatic diseases receiving rituximab (RTX) therapy show substantially impaired anti-SARS-CoV-2 vaccine humoral but partly inducible cellular immune responses. However, the complex relationship between antigen-specific B and T cells and the level of B cell repopulation necessary to achieve anti-vaccine responses remain largely unknown. Methods Antibody responses to SARS-CoV-2 vaccines and induction of antigen-specific B and CD4/CD8 T cell subsets were studied in 19 rheumatoid arthritis (RA) and ANCA-associated vasculitis (AAV) patients receiving RTX, 12 RA patients on other therapies and 30 healthy controls after SARS-CoV-2 vaccination with either mRNA or vector based vaccines. Results A minimum of 10 B cells/µL in the peripheral circulation was necessary in RTX patients to mount seroconversion to anti-S1 IgG upon SARS-CoV-2 vaccination. RTX patients lacking IgG seroconversion showed reduced antigen-specific B cells, lower frequency of TfH-like cells as well as less activated CD4 and CD8 T cells compared to IgG seroconverted RTX patients. Functionally relevant B cell depletion resulted in impaired IFNγ secretion by spike-specific CD4 T cells. In contrast, antigen-specific CD8 T cells were reduced in patients independently of IgG formation. Conclusions Patients receiving rituximab with B cell numbers above 10 B cells/µl were able to mount humoral and more robust cellular responses after SARS-CoV-2 vaccination that may permit optimization of vaccination in these patients. Mechanistically, the data emphasize the crucial role of co-stimulatory B cell functions for the proper induction of CD4 responses propagating vaccine-specific B and plasma cell differentiation.

COVID-19 Associated Coagulopathy Is a Reversible Phenomenon - 3-Month Follow Up Reveals Normalization of Coagulation Status Associated With Complete Venous Recanalization in Patients After Severe COVID-19 (preprint)

Background: COVID 19 is associated with a hypercoagulable state and frequent thromboembolic complications. For how long this acquired abnormality lasts potentially requiring preventive measures, such as anticoagulation remains to be delineated.Methods: We used viscoelastic rotational thrombelastometry (ROTEM) in a single center cohort of 13 critical ill patients and performed follow up examinations three months after discharge from ICU.Results: We found clear signs of a hypercoagulable state due to severe hypofibrinolysis and a high rate of thromboembolic complications during the phase of acute illness. Three month follow up revealed a normalization of the initial coagulation abnormality together without evidence of venous thrombosis in all thirteen patients. Conclusion: In our cohort the coagulation profile was completely normalized three months after COVID-19. It thus appears reasonable that anticoagulation can be discontinued beyond this timepoint in patients with complete venous reperfusion.

Equally Affected? Health-Related and Socioeconomic Adversities of the COVID-19 Pandemic in Vienna (preprint)

Previous pandemics have rarely affected everyone equally and the COVID-19 pandemic will likely be no exception. Most of the emerging evidence answers why incidence rate, hospitalisation rate and mortality due to COVID-19 are higher among people in lower socioeconomic position (SEP), but so far only few empirical studies assessed the unequal distribution of this pandemic’s collateral public health damage. Using a stratified random sample of 1004 participants living in Vienna, a central European city with approximately 1.9 Million inhabitants, this study investigated the incidence rate of health-related and socioeconomic adversities attributable to the COVID-19 pandemic along socioeconomic strata. To this end, we estimated the incidence rate of 10 adversities by SEP and each of its components using zero-inflated Poisson regression models, adjusted for age and gender. Data were collected between April, 27th and May, 17th 2020. Differences in the incidence rate of COVID-19 attributable adversities between the two lowest and two highest SEP groups were clearly visible. Participants in the lowest SEP category had a 32.96% higher incidence rate (IRR=1.333 [95%CI: 1.079 – 1.639]) and participants in the second lowest SEP category had a 44.69% higher incidence rate (IRR=1.447 [95%CI: 1.190 – 1.760]) compared to participants in the highest SEP category. In sum, 6 out of 10 COVID-19-related adversities were, to a greater or lesser extent, disproportionately experienced by Viennese residents in lower SEP. This study strengthens and extends the current evidence on the unequally distributed burden of the COVID-19 pandemic along socioeconomic strata. Inequalities were most visible along income groups and for the adversities job loss, worsening of the financial situation, and worse mental health. In light of effect heterogeneity across SEP components, we encourage future investigators to pay increased attention to their operationalisation of SEP. Such awareness will help to correctly identify those in most urgent need of supportive policies.