Monovalent XBB1.5 Vaccination Augments Humoral and Cellular Immunity to Novel Sars-Cov-2 Variants in Immunocompromised Patients with Multiple Myeloma

Background: Highly transmissible SARS-CoV-2 variants of concern such as Omicron XBB1.5 are of concern for patients that are immunocompromised. Patients with Multiple Myeloma (MM) remain particularly vulnerable due to therapies that deplete the machinery necessary for efficient humoral and cellular responses. MM patients continue to have an increased risk of severe COVID-19 manifestations, highlighting the necessity for continued evaluation of monovalent mRNA vaccine efficacy on adaptive immune activation in this population. Here, we assess the impact of the first monovalent Omicron XBB 1.5 vaccine (season 2023-2024) on serological and cellular immune responses in patients with MM.

Methods: We investigated the humoral and cellular immune responses prior to and after administration of the monovalent XBB1.5 vaccine in 37 MM patients. Spike binding IgG antibody levels were measured, using a SARS-CoV-2 spike binding ELISA assay. Serum neutralization activity was measured by SARS-CoV-2 multi-cycle microneutralization assays (ancestral and Omicron lineages XBB.1.5, JN.1, LB.1) as well as lentivirus-based Coronavirus spike-based entry assays (SARS-CoV-1, ancestralSARS-CoV-2). To assess SARS-CoV-2 specific T cell activity, peripheral blood mononuclear (PBMCs) from a subset of 31 MM patients were stimulated with XBB1.5 peptides and intracellular cytokine staining (ICS) was performed. We compared aggregate cytokine production from CD4+ and CD8+ cells collected before receiving the monovalent XBB1.5 vaccine with cells collected post-vaccination to evaluate changes in T lymphocyte function. Spectral flow cytometry-based immunophenotyping was employed to quantify differences in lymphocyte subpopulations, including dendritic cells (DCs), B cells, Natural Killer (NK) cells, and T follicular helper cells (TFH), among patients on Anti-BCMA therapy, Anti-CD38 therapy, and other therapies.

Results: Spike binding antibody titers were high before and after vaccination in most patients with MM with those having low binding antibodies benefiting the most from vaccination. Sera from MM patients displayed a threefold increase in XBB1.5. neutralization 28 days post-vaccination (median pre-vaccination 11 to median 99 post-vaccination p<0.01). Strikingly, neutralization capacity to other Omicron variants such as JN.1 also increased two-fold 28 days post-vaccination (median pre-vaccination 38 to median 109 post-vaccination p<0.01). 15 patients tested below limit of detection for XBB1.5 neutralization and 10 patients tested below the limit of detection for JN.1. Remarkably, the breadth of the polyclonal immune response broadened after XBB 1.5 vaccination to such extent that SARS-CoV-1 was efficiently inhibited by 40.5% (N = 15) of the patients with MM. XBB1.5 T cell-specific activity was enhanced by the monovalent XBB1.5 vaccine. The monovalent XBB1.5 vaccine augmented T cell function as measured by aggregate interferon-gamma (IFNg), TNFa, IL-2, and GMCSF production from CD4+ cells following incubation with XBB1.5 anti-S peptides (p=0.021). CD8+ total cytokine production also showed an increase post-vaccination; however, it did not reach significance (p=0.28). Phenotypic composition among our patient cohorts exposed deficiencies in cell types essential for robust antibody generation, such as frequency of B cells, plasma cells and CCR6+CCR4+TFH cells in patients depending on therapy (p=0.045).

Conclusion: The present study dissects the multifaceted effects of the monovalent XBB1.5 vaccine on immune responses in MM patients. The observed augmentation of T cell activity and neutralizing capacity following XBB1.5 vaccine administration in patients undergoing anti-BCMA therapy, anti-CD38 therapy and other therapies that typically impede antibody production highlights the advantageous effects of updated vaccinations to current circulating variants for the MM patients. Our results offer insights into optimal protection strategies for MM patients as novel variants and sub-variants continue to develop with SARS-CoV-2. The observed broadening of immune responses in MM patients following XBB1.5 vaccination highlights the value of continued vaccination against SARS-CoV-2 variants in MM patients.

Kappes:GRAIL, Inc.: Research Funding. Jagannath:IMS and SOHO: Membership on an entity's Board of Directors or advisory committees; Janssen, BMS, Caribou, Legend Biotech, Regeneron, Takeda, Sanofi, Posieda Therapeutics, GRAIL: Consultancy.