Dysregulated Humoral and Cellular Response to Sars-Cov-2 Vaccination in Patients with MGUS and SMM

Introduction Patients with hematological malignancies, including multiple myeloma (MM), experience sub-optimal responses to SARS-CoV-2 vaccination. Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Multiple Myeloma (SMM) are precursors to MM and are associated with immune dysregulation. MGUS and SMM affect approximately 5% of individuals over 50 years of age, who remain largely undiagnosed. Here, we present the results from a prospective observational cohort study which we launched in November 2020 to characterize the effect of plasma cell premalignancies on response to SARS-CoV-2 vaccination.

Methods As of March 2022, 3,821 individuals had completed a questionnaire regarding prior infection and vaccination status. We performed ELISA to measure the titer of IgG antibodies against SARS-CoV-2 S protein on 1,995 peripheral blood samples from 759 participants with MGUS (n=254), SMM (n=285), and MM (n=79), as well as healthy donors (n=141). Moreover, we performed 5’ single-cell RNA-sequencing (scRNA-seq) along with single-cell T cell receptor (TCR)-sequencing (scTCRseq) on 224 peripheral blood mononuclear cell (PBMC) samples drawn serially before and after vaccination from patients with MGUS (n=20), SMM (n=48), and MM (n=24), as well as healthy donors (n=26).

Results Most participants received a full vaccination course (n=3,501, 92%) (i.e., two doses of BNT162b or mRNA-1273 or one dose of Ad26.COV2.S), including 1,599 individuals (41.8%) who received a third dose. Two hundred seventy individuals (7.1%) remained unvaccinated. SARS-CoV-2 infection was reported in 492 participants (12.8%), including 183 who experienced a breakthrough infection after a full vaccination course.

To assess the humoral immune response to SARS-CoV-2 vaccination, we compared post-vaccination antibody titers of patients with MGUS (n=183) or SMM (n=137) and healthy donors (n=74) without prior history of COVID-19 who received mRNA vaccine. Patients with MGUS or SMM had comparable titers to healthy donors 14-50 days after the second dose (MGUS: Mean: 1.90; 95% CI: 1.76-2.03; SMM: Mean: 1.70; 95% CI: 1.55-1.85; healthy donors: Mean: 1.87; 95% CI: 1.50-2.23). However, we observed significantly lower antibody titers 50-100 days after the second dose in patients with MGUS (Mean: 1.46, 95% CI: 1.32-1.59, Wilcoxon rank-sum test p=0.014) and SMM (Mean: 1.31, 95% CI: 1.12-1.51, p=0.007), compared to healthy donors (Mean: 1.79, 95% CI: 1.43-2.14). In participants who received a third dose, we observed a significant increase in antibody titer in those with MGUS (paired t-test, p<0.001) and SMM (p<0.001), compared to their titers following the second dose. However, even after a third dose, antibody titers waned faster in patients with SMM, who showed significantly lower titers 50-100 days after the third dose compared to healthy donors (Wilcoxon rank-sum test, p=0.020).

To assess differences in cellular immune response between patients and healthy donors, we performed scRNA-seq on 2,025,611 peripheral blood immune cells from 224 samples of healthy donors and patients with MGUS, SMM, MM before and after vaccination for SARS-CoV-2. By comparing immune cell abundance between pre- and post-vaccination samples, we observed a significant increase in the abundance of Th2, Th17 cells, and Tregs post-vaccination in patients with MGUS and SMM, an effect which we did not observe in healthy donors. This finding may potentially indicate a dysregulated T-cell response to SARS-CoV-2 vaccines in patients with plasma cell premalignancy. Additional analyses are ongoing to determine whether these helper T-cell responses are specific to SARS-CoV-2 antigens or perhaps occur in response to general changes in the cytokine milieu.

Conclusion Taken together, our results indicate that antibody titers decline significantly faster in patients with MGUS and SMM, a defect that may persist following a third dose of vaccination, and that patients with MGUS and SMM may have altered cellular responses to vaccination. These findings highlight that despite the absence of symptoms, plasma cell premalignancy may represent an immunocompromised state. Additional analyses of our large single-cell sequencing dataset, coupled with antigen stimulation experiments in vitro may provide further insights into the dysregulation of cellular immune responses to SARS-CoV-2 vaccination in patients with plasma cell premalignancy.

Auclair:AstraZeneca: Current Employment, Other: No conflicts to declare during the conduct of this study. Now an employee of AstraZeneca. Fischer:Proximity Therapeutics: Current equity holder in publicly-traded company, Other: founder, scientific advisory board member; Novartis: Consultancy, Research Funding; Deerfield: Consultancy; EcoR1 Capital: Consultancy; Civetta Therapeutics: Current equity holder in publicly-traded company, Other: founder, scientific advisory board member; Photys Therapeutics: Current equity holder in publicly-traded company, Other: scientific advisory board member; Sanofi: Consultancy; Avilar Therapeutics: Current equity holder in publicly-traded company, Other: scientific advisory board member; Neomorph Inc.: Current equity holder in publicly-traded company, Other: founder, scientific advisory board member; Ajax: Research Funding; Astellas: Research Funding. Getz:MSIDetect: Patents & Royalties; MSMutSig: Patents & Royalties; MSMuTect: Patents & Royalties; SignatureAnalyzer-GPU: Patents & Royalties; Pharmacyclics: Research Funding; IBM: Research Funding; Scorpion Therapeutics: Consultancy, Current equity holder in publicly-traded company, Other: Founder; POLYSOLVER: Patents & Royalties. Ghobrial:AbbVie: Honoraria; Menarini Silicon Biosystems: Honoraria; Novartis: Research Funding; Huron Consulting: Honoraria; GSK: Honoraria; Janssen: Honoraria; Pfizer: Honoraria; Oncopeptides: Honoraria; Bristol Myers Squibb: Honoraria; Aptitude Health: Honoraria; Vor Biopharma: Honoraria; Veeva Systems: Honoraria; Amgen: Honoraria; Adaptive: Honoraria; Window Therapeutics: Other: Advisory board participation; The Binding Site: Honoraria; Takeda: Honoraria; Sognef: Honoraria; Sanofi: Honoraria; Celgene: Research Funding.