Delayed generation of functional virus-specific circulating T follicular helper cells correlates with severe COVID-19 (preprint)

Effective humoral immune responses require well-orchestrated cellular interactions between B and T follicular helper (Tfh) cells. Whether this interaction is impaired and associated with COVID-19 disease severity is unknown. Here, longitudinal acute and convalescent blood samples from 49 COVID-19 patients across mild to severe disease were analysed. We found that during acute infection activated and SARS-CoV-2-specific circulating Tfh (cTfh) cell frequencies expanded with increasing disease severity. The frequency of activated and SARS-CoV-2-specific cTfh cells correlated with plasmablast frequencies and SARS-CoV-2 antibody titers, avidity and neutralization. Furthermore, cTfh cells but not other memory CD4 T cells, isolated from severe patients induced more pronounced differentiation of autologous plasmablast and antibody production in vitro compared to cTfh cells isolated from mild patients. However, the development of virus-specific cTfh cells was delayed in patients that displayed or later developed severe disease compared to those that maintained a mild or moderate disease. This correlated with a delayed induction of high-avidity and neutralizing virus-specific antibodies. Our study therefore suggests that impaired generation of functional virus-specific cTfh cells delays the production of high-quality antibodies to combat the infection at an early stage and thereby enabling progression to more severe COVID-19 disease.

Safety and efficacy of the mRNA BNT162b2 vaccine against SARS-CoV-2 in five groups of immunocompromised patients and healthy controls in a prospective open-label clinical trial (preprint)

BackgroundPatients with immunocompromised disorders have mainly been excluded from clinical trials of vaccination against COVID-19. Thus, the aim of this prospective clinical trial was to investigate the safety and efficacy after two doses of BNT162b2 mRNA vaccination in five selected groups of immunocompromised patients and healthy controls. Methods539 study subjects (449 patients and 90 controls) were included in the clinical trial. The patients had either primary (n=90), or secondary immunodeficiency disorders due to human immunodeficiency virus infection (n=90), allogeneic hematopoietic stem cell transplantation/chimeric antigen receptor T cell therapy (n=90), solid organ transplantation (SOT) (n=89), or chronic lymphocytic leukemia (CLL) (n=90). The primary endpoint was seroconversion rate two weeks after the second dose. The secondary endpoints were safety and documented SARS-CoV-2 infection. FindingsAdverse events were generally mild, but one case of fatal suspected unexpected serious adverse reaction occurred. 72{middle dot}2% of the immunocompromised patients seroconverted compared to 100% of the controls (p=0.004). Lowest seroconversion rates were found in the SOT (43{middle dot}4%) and CLL (63{middle dot}3%) patient groups with observed negative impact of treatment with mycophenolate mofetil and ibrutinib, respectively. InterpretationThe results showed that the mRNA BNT162b2 vaccine was safe in immunocompromised patients. The rate of seroconversion was substantially lower than in healthy controls, with a wide range of rates and antibody titres among predefined patient groups and subgroups. This clinical trial highlights the need for additional vaccine doses in certain immunocompromised patient groups and/or subgroups to improve immunity. FundingKnut and Alice Wallenberg Foundation, Nordstjernan AB, Region Stockholm, Swedish Research Council, Karolinska Institutet, and organizations for PID/CLL-patients in Sweden.