Persistent but atypical germinal center reaction among 3rd SARS-CoV-2 vaccination after rituximab exposure

Abstract

BackgroundDurable vaccine-mediated immunity relies on the generation of long-lived plasma cells and memory B cells (MBCs), differentiating upon germinal center (GC) reactions. SARS-CoV-2 mRNA vaccination induces a strong GC response in healthy volunteers (HC), but limited data is available about response longevity upon rituximab treatment.MethodsWe evaluated humoral and cellular responses upon 3rd vaccination in seven patients with rheumatoid arthritis (RA) who initially mounted anti-spike SARS-CoV-2 IgG antibodies after primary 2x vaccination and got re-exposed to rituximab (RTX) 1-2 months after the second vaccination. Ten patients with RA on other therapies and ten HC represented the control groups. As control for known long-lived induced immunity, we analyzed humoral and cellular tetanus toxoid (TT) immune responses in steady-state.ResultsAfter 3rd vaccination, 5/7 seroconverted RTX patients revealed lower anti-SARS-CoV-2 IgG levels but similar neutralizing capacity compared with HC. Antibody levels after 3rd vaccination correlated with values after 2nd vaccination. Despite significant reduction of circulating total and antigen-specific B cells in RTX re-exposed patients, we observed the induction of IgG+ MBCs upon 3rd vaccination. Notably, only RTX treated patients revealed a high amount of IgA+ MBCs before and IgA+ plasmablasts after 3rd vaccination. IgA+ B cells were not part of the steady state TT+ B cell pool. TNF-secretion and generation of effector memory CD4 spike-specific T cells were significantly boosted upon 3rd vaccination.SummaryOn the basis of pre-existing affinity matured MBCs within primary immunisation, RTX re-exposed patients revealed a persistent but atypical GC immune response accompanied by boosted spike-specific memory CD4 T cells upon SARS-CoV-2 recall vaccination.

Microfluidic antibody profiling after repeated SARS-CoV-2 vaccination links antibody affinity and concentration to impaired immunity and variant escape in patients on anti-CD-20 therapy

“…Another small study demonstrated an inverse correlation between Rituximab dose and seroconversion and that antibody levels persisted after a subsequent dose of Rituximab among those who had already seroconverted(50). A fall in antibody levels following a dose of Rituximab between a second and third SARS-CoV-2 vaccine dose was recently reported, although neutralisation capacity was preserved in seroconverted patients (51). In an open-label study of a fourth dose of mRNA vaccine among Rituximab treated patients, predominantly those with rheumatoid arthritis or connective tissue diseases, a moderate improvement in seroconversion from 33% to 58% was demonstrated after the fourth dose (30).…”

Microfluidic antibody profiling after repeated SARS-CoV-2 vaccination links antibody affinity and concentration to impaired immunity and variant escape in patients on anti-CD20 therapy

“…Another small study demonstrated an inverse correlation between rituximab dose and seroconversion and showed that antibody levels persisted after a subsequent dose of rituximab among those who had already been seroconverted ( 50 ). A fall in antibody levels following a dose of rituximab between the second and third SARS-CoV-2 vaccine doses was recently reported, although neutralisation capacity was preserved in seroconverted patients ( 51 ). In an open-label study of a fourth dose of mRNA vaccine among rituximab-treated patients, predominantly those with rheumatoid arthritis or connective tissue diseases, a moderate improvement in seroconversion from 33% to 58% was demonstrated after the fourth dose ( 30 ).…”

Poor immunogenicity upon SARS-CoV-2 mRNA vaccinations in autoimmune SLE patients is associated with pronounced EF-mediated responses and anti-BAFF/Belimumab treatment

“…Previous studies have reported reduced immunogenicity of the COVID-19 vaccines administered to subjects diagnosed with a wide spectrum of autoimmune disorders [21][22][23] , including lupus 24 . Underlying, pre-existing immune system defects and the concomitant treatment with a combination of immunomodulatory drugs can predispose those subjects to poor immunogenicity upon certain vaccinations 25,26 and a higher risk and severity of bacterial and viral infections 27 .…”