Portraying Immunity to Sars-Cov-2 after mRNA-Vaccination in Patients with Multiple Myeloma

Abstract

Multiple Myeloma (MM) is a plasma-cell neoplasia that is associated with severe suppression of the humoral and cellular immune system. Therefore, MM patients are confronted with a high risk of COVID-19 in the still ongoing pandemic. mRNA-based vaccination against SARS-CoV-2 is implemented to counteract the mortality from COVID-19 in MM patients. Ambiguous results regarding sufficient humoral and cellular responses to mRNA-based vaccination were reported for patients with MM.1,2 To date, there is no conclusive data allowing a molecular understanding of the differences in the functional immune response of such patients. Therefore, we implemented a comprehensive immune phenotyping framework to monitor the humoral and cellular immune responses against the relevant virus variants at different timepoints following three doses of mRNA-based vaccination in 100 patients with MM and 23 healthy controls. Compared to healthy controls, the humoral immune response of patients with MM was reduced and further impaired by concomitant anti-MM therapy. Low CD19+ lymphocyte counts were associated with diminished humoral immune response. After the third dose, anti-SARS-CoV-2 serum antibody levels and neutralization titers were increased relative to the second dose but were still impaired in comparison to healthy controls. T-cell response levels were also reduced in patients with MM after two doses but displayed no significant differences after three doses compared to healthy individuals. Both antibody and T-cell response levels were markedly diminished against Omicron variant-of-concern (VOC) compared to the wild-type (WT) strain. Remarkably, most patients with MM achieved a sufficient T-cell response against the WT strain after three doses of vaccination (86.7% CD4+ responder, 76.7% CD8+ responder) highlighting an adequate immunogenicity despite the disease-associated immunological impairment.3 To gain detailed molecular insight, we next performed single-cell RNA sequencing combined with surface proteome analysis of peripheral mononuclear blood cell-derived B-, T- and NK-cells from humoral and cellular (non)-responders. Thereby, the different B-, T- and NK-cell subpopulations were characterized in the context of vaccination response after the second and third vaccination dose and in case of breakthrough infections after three doses. The generated immune response single-cell data highlighted relevant alterations in gene and surface protein expression as well as cell type abundancy between healthy and MM individuals. Patients with MM and breakthrough infections showed prominent humoral and cellular response levels with characteristic molecular patterns at single-cell resolution. Further, the functional response levels were associated with differences in the CD8+ central and effector memory compartment. Together, patients with MM exhibited ambiguous humoral immune responses but sufficient T-cell responses against the WT strain after three doses of mRNA-based vaccination against SARS-CoV-2. Importantly, both response levels were reduced for the Omicron VOC calling attention to the immune escape of emerging VOCs and the need for variant-adapted vaccination trials. Our recent molecular analysis by single-cell sequencing of the peripheral immune cell compartment further identified characteristic patterns that may be beneficial for the design of improved and variant-adapted vaccination strategies in such immunocompromised patients.