Quantitative analysis of mRNA-1273 COVID-19 vaccination response in immunocompromised adult hematology patients

Abstract

Vaccination guidelines for patients treated for hematological diseases are typically conservative. Given their high risk for severe COVID-19, it is important to identify those patients that benefit from vaccination. We prospectively quantified serum immunoglobulin G (IgG) antibodies to spike subunit 1 (S1) antigens during and after 2-dose mRNA-1273 (Spikevax/Moderna) vaccination in hematology patients. Obtaining S1 IgG ≥ 300 binding antibody units (BAUs)/mL was considered adequate as it represents the lower level of S1 IgG concentration obtained in healthy individuals, and it correlates with potent virus neutralization. Selected patients (n = 723) were severely immunocompromised owing to their disease or treatment thereof. Nevertheless, >50% of patients obtained S1 IgG ≥ 300 BAUs/mL after 2-dose mRNA-1273. All patients with sickle cell disease or chronic myeloid leukemia obtained adequate antibody concentrations. Around 70% of patients with chronic graft-versus-host disease (cGVHD), multiple myeloma, or untreated chronic lymphocytic leukemia (CLL) obtained S1 IgG ≥ 300 BAUs/mL. Ruxolitinib or hypomethylating therapy but not high-dose chemotherapy blunted responses in myeloid malignancies. Responses in patients with lymphoma, patients with CLL on ibrutinib, and chimeric antigen receptor T-cell recipients were low. The minimal time interval after autologous hematopoietic cell transplantation (HCT) to reach adequate concentrations was <2 months for multiple myeloma, 8 months for lymphoma, and 4 to 6 months after allogeneic HCT. Serum IgG4, absolute B- and natural killer-cell number, and number of immunosuppressants predicted S1 IgG ≥ 300 BAUs/mL. Hematology patients on chemotherapy, shortly after HCT, or with cGVHD should not be precluded from vaccination. This trial was registered at Netherlands Trial Register as #NL9553.

Graphical abstract

Figure 1.

Study synopsis. Study protocol synopsis (A) and patient inclusion (B).

Figure 2.

S1 binding antibody concentration and neutralization. (A) IgG S1 concentration for each timepoint. Red and green: previously uninfected patients (U); blue and purple: previously infected patients (I). Dotted lines indicate seroconversion (S1 IgG > 10 BAUs/mL) and sufficient S1 IgG concentration (≥300 BAUs/mL). *P < .05. (B) Correlation of IgG S1 concentration and pseudovirus neutralization (r = 0.85; P < .001). ID₅₀, 50% inhibitory dose.

Figure 3.

IgG S1 concentration over time for each patient. Thin lines depict previously uninfected patients (red) and previously infected patients (orange); thick lines indicate the median IgG S1 concentrations. Dotted lines specify seroconversion (S1 IgG > 10 BAUs/mL) and sufficient S1 IgG concentration (≥300 BAUs/mL). *P < .05. BEAM, carmustine, etoposide, cytarabine, melphalan.

Figure 4.

Multivariable analyses of factors associated with S1 IgG responses. (A) Variables significantly associated with S1 IgG ≥ 300 BAUs/mL as a dichotomous outcome tested in a multivariate model per subcategory of variables. (B) Significant variables of model 1 tested in an overall model.

Figure 5.

IgG S1 concentration and B cell numbers related to time after end of rituximab or HCT. (A) Patients with lymphoma after autologous HCT or after rituximab. (B) Multiple myeloma after autologous HCT. (C) Allogeneic HCT. Left panels: S1 IgG concentration with dotted lines specifying seroconversion (S1 IgG > 10 BAUs/mL) and sufficient S1 IgG concentration (≥300 BAUs/mL). Right panels: B-cell number with dotted lines at upper and lower limit of normal.