Scientist Icahn School of Medicine at Mount Sinai, New York, United States
Introduction: Bivalent (Ancestral and Omicron BA.4/BA.5) mRNA booster vaccines have been deployed starting in Fall of 2022 to provide continued immunity against the antigenically diverse Omicron variants. We analyzed the immune responses to bivalent booster vaccination in Multiple Myeloma (MM) patients and identified a subset of patients with suboptimal vaccine responses necessitating further investigation into the underlying immune mechanisms.
Methods: We studied the humoral and cellular immune responses before and after bivalent booster immunization in 44 MM patients. Spike binding IgG antibody levels were measured by ELISA (FDA EUA approved Kantaro). Immune profiling was performed using high-dimensional flow cytometry. The frequencies of dendritic cells (DCs), B cells, Natural Killer (NK) cells and T follicular help cells (TFH) were compared between responders and non-responders. Additionally, we measured spike specific T cell function using the QuantiFERON SARS-CoV-2 (Qiagen) assay as well as flow cytometry-based T cell assays quantifying interferon-gamma (IFNg) production.
Results: We stratified the antibody responses from 44 MM patients post vaccination into non responders ( < 100 AU/mL, n=8, median post-vaccine: 38 AU/mL) and responders (>100 AU/mL, n=36, post vaccine: 281 AU/mL). All non-responders were either on anti-B cell maturation antigen (BCMA) bispecific or anti-CD38 directed therapy. Non-responders exhibited a deficiency in several components of the immune machinery expressing CD38 and BCMA responsible for the production of the humoral and cellular responses. After bivalent vaccination, non-responders exhibited lower frequency of cDCs (p < 0.01), B Cells (p < 0.05) and activated TFH cells (p < 0.05). Furthermore, immature NK cells were the predominant population in non-responders while responders had more cytotoxic mature NK phenotype (p < 0.05) after bivalent vaccination. T cell responses to SARS-CoV-2 correlated with spike binding antibody levels: Non responders also had reduced T cell activity reinforcing the notion that T cell fail to compensate in MM patients. Of note, QuantiFERON SARS-CoV-2 Ag1/Ag2 results correlated with Ancestral strain IFNg production measured by FACS-based T cell assays (R2 = 0.52, p = 0.013).
Conclusions: Our study highlights the variability of the immune response to bivalent COVID-19 vaccination in MM patients. A subset of MM patients receiving anti-CD38 and anti-BCMA therapy develop defects in cDCs, B cells , NK cells and TFH cells, thereby unable to develop antibody and T cell responses to SARS-CoV-2 vaccinations. Our results indicate that the QuantiFERON SARS-CoV-2 assay could be deployed for clinical use bridging the need for suitable laboratory tests to measure SARS-CoV-2 specific T cell responses. Ongoing studies will determine whether the compromised immune machinery and reduced T cell activity identified here can discriminate patients at high risk for infectious complications from anti-BCMA therapies.
