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

Novel mRNA vaccines have resulted in a reduced number of SARS-CoV-2 infections and hospitalizations. Yet, there is a paucity of studies regarding their effectiveness on immunocompromised autoimmune subjects. In this study, we enrolled subjects naive to SARS- CoV-2 infections from two cohorts of healthy donors (HD, n=56) and systemic lupus erythematosus (SLE, n=69). Serological assessments of their circulating antibodies revealed a significant reduction of potency and breadth of neutralization in the SLE group, only partially rescued by a 3rd booster dose. Immunological memory responses in the SLE cohort were characterized by a reduced magnitude of spike-reactive B and T cell responses that were strongly associated with poor seroconversion. Vaccinated SLE subjects were defined by a distinct expansion and persistence of a DN2 spike-reactive memory B cell pool and a contraction of spike-specific memory cTfh cells, contrasting with the sustained germinal center (GC)-driven activity mediated by mRNA vaccination in the healthy population. Among the SLE-associated factors that dampened the vaccine responses, treatment with the monoclonal antibody anti-BAFF/Belimumab (a lupus FDA- approved B cell targeting agent) profoundly affected the vaccine responsiveness by restricting the de novo B cell responses and promoting stronger extra-follicular (EF)-mediated responses that were associated with poor immunogenicity and impaired immunological memory. In summary, this study interrogates antigen-specific responses and characterized the immune cell landscape associated with mRNA vaccination in SLE. The identification of factors associated with reduced vaccine efficacy illustrates the impact of SLE B cell biology on mRNA vaccine responses and provides guidance for the management of boosters and recall vaccinations in SLE patients according to their disease endotype and modality of treatment.

Evidence of Persisting Autoreactivity in Post-Acute Sequelae of SARS-CoV-2 Infection (preprint)

Recent studies have demonstrated significant breadth of emerging autoreactivity in severe SARS-CoV-2 infection. Importantly, we have identified a relaxation of peripheral tolerance within early antibody secreting cells that emerge in patients with COVID-19 as important drivers of those responses. While often viral-specific, these extrafollicular-derived cells also display cross reactivity to autoantigens present in the inflammatory lung environment, and despite resolution of most autoreactivity within 6 months, they persisted in some patients. These results raise questions regarding autoreactive antibodies that arise during acute SARS-CoV-2 infection and their persistence in patients with symptoms in Post-Acute Sequelae of SARS-CoV-2 infection (PASC). Through clinical autoreactive antibody screening of 95 patients with PASC and no history of autoimmune disease, we identify significant autoreactive profiles in patients with ongoing symptoms post-recovery, with 80% of patients returning positive tests for at least one autoantigen, and 40% showing breaks in tolerance to 2 or more. Anti-nuclear antigen positivity was most common, displaying positivity in 63% of patients, however, positive tests were broad and included reactivities against carbamylated protein responses, RNA polymerase III, and phospholipids. We also identify patients with reactivity against dsDNA in the PASC cohort – a reactivity not observed in acute infection even in the critically ill. These results demonstrate evidence of elevated serum autoantibodies in patients who present to PASC clinics with persistent symptoms up 14 months following SARS-CoV-2 infection, and further confirm the growing linkage between COVID-19 and observed clinical autoreactivity – even into the recovery phase of disease.

Broadly-targeted autoreactivity is common in severe SARS-CoV-2 Infection (preprint)

Severe SARS-CoV-2 infection is linked to the presence of autoantibodies against multiple targets, including phospholipids and type-I interferons. We recently identified activation of an autoimmune-prone B cell response pathway as correlate of severe COVID-19, raising the possibility of de novo autoreactive antibody production during the antiviral response. Here, we identify autoreactive antibodies as a common feature of severe COVID-19, identifying biomarkers of tolerance breaks that may indicate aggressive immunomodulation.

Early impact of the COVID-19 pandemic and social distancing measures on routine childhood vaccinations in England, January to April 2020 (preprint)

Electronic health records were used to assess the early impact of COVID-19 on routine childhood vaccination in England to 26 April 2020. MMR vaccination counts fell from February 2020, and in the three weeks after introduction of social distancing measures were 19.8% lower (95% CI -20.7 to -18.9%) than the same period in 2019, before improving in mid-April. A gradual decline in hexavalent vaccination counts throughout 2020 was not accentuated on introduction of social distancing.

Critically ill SARS-CoV-2 patients display lupus-like hallmarks of extrafollicular B cell activation (preprint)

Wide heterogeneity of disease course ranging from asymptomatic spread to respiratory failure and death has become a hallmark of the SARS-CoV-2 pandemic. While this clinical spectrum is well documented, its immunologic underpinnings are less clear. We have therefore, initiated studies of the B cell responses as they would participate in both early effector responses and in the initiation of memory formation. In terms of effector responses, we were particularly interested in the engagement and clinical correlates of the extra-follicular pathway (EF), we recently described in flaring SLE. In this systemic autoimmune disease, the EF pathway is initiated by newly activated naive B cell (aN) leading to large expansion of autoantibody-producing antibody-secreting cells through the generation of an epigenetically primed B cell precursor which are double negative (DN) for naive (IgD) and memory markers (CD27) and lacking expression of CXCR5 and CD21 (DN2). These highly activated D2 cells are also distinguished by high expression of CD11c and T-bet and are TLR7-driven. Both, TLR7-stimulation which is triggered by ssRNA and the central role played by their murine counterparts (typically characterized as Age-Associated B cells), in viral clearance, strongly supported the hypothesis that DN2 cells and the global EF pathway could be prominently engaged in COVID-19 patients. Also of note, EF B cell activation is particularly prominent in SLE patients of African-American ancestry, a population disproportionately represented in severe COVID-19. In this study we find that critically-ill patients with COVID-19 robustly upregulate constituents of the extrafollicular pathway, produce enormous numbers of antibody secreting cells, and lose unique transitional B cell populations that correlate with positive prognosis. This patient cluster associates tightly with biomarkers of poor outcomes and exhibits high rates of mortality. Thus, this B cell phenotype might serve as an immunological marker of severe COVID infection at early stages and could therefore identify a patient subset likely to benefit from targeted immunomodulatory therapy aimed at alleviating disease burden.