Sickle Cell Disease Patients Mount Adequate Humoral but Reduced Cellular Responses to COVID-19 Vaccination

Abstract

Introduction Sickle cell disease patients have an increased risk of severe and fatal coronavirus disease (COVID)-19 compared to the healthy population, even after immunization with the primary 2-dose COVID-19 mRNA vaccination schedule. We longitudinally investigated antibody and T cell responses to three mRNA COVID-19 vaccinations in sickle cell disease patients treated with hydroxyurea. Methods Serum and peripheral blood mononuclear cells (PBMC) were collected from patients with sickle cell disease prior to and 4 weeks after each vaccination and in the months ensuing. Serum was used to quantify severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific spike glycoprotein 1 immunoglobulin G (S1 IgG) concentrations against the first serum standard for COVID-19 (20/136), as provided by the National Institute for Biological Standards Control and recommended by the WHO, and to measure antibody neutralization capacity of SARS-CoV-2 wild-type and variants of concern. PBMC were stimulated with SARS-CoV-2 spike peptides to measure spike-specific CD4+ and CD8+ T cell responses by activation marker expression and cytokine production, and stained with peptide-HLA tetramers to detect spike-specific CD8+ T cells. Antibody concentrations were compared to concentrations obtained from age-matched 2-dose- and 3-dose-vaccinated, healthy individuals extracted from the PIENTER and VITAL cohort, respectively, both population-based studies conducted by the Dutch National Institute for Public Health and the Environment. T cell responses were compared to results obtained from in-house healthcare workers. Participants were excluded from further analyses when SARS-CoV-2 infected, identified as having nucleocapsid (N) IgG >14.3 BAU/ml. Results In total, 31 sickle cell disease patients, all receiving hydroxyurea, were included in the study. In 26 study participants evaluable after the 2nd dose, S1 IgG antibody concentrations correlated with antibody neutralization capacity (r=0.70; p=0.037) and were not significantly lower than in age-matched healthy individuals after the primary 2-dose schedule (p=0.86; Figure 1A) (Haggenburg et al., Blood Adv 2022). Vaccination-induced spike-specific CD4+ T cell responses were present in 10/10 sickle cell disease patients analyzed, in similar percentages compared to healthy individuals (Figure 1B). However, IL-2, IFN-γ, and/or TNF-α production by spike-specific CD4+ T cells was 1.7 fold lower than in healthy individuals (p=0.002; Figure 1B). SARS-CoV-2-specific CD8+ T cell responses were detected in 8/10 patients analyzed, which is comparable to the heterogeneous CD8+ T cell response of healthy individuals, but cytokine production by spike-specific CD8+ T cells was 3.0 fold lower (p=0.017; Figure 1B). Six and 9 months after the 2nd vaccination median S1 IgG concentration decreased from 2921 to 423 and 395 BAU/ml, respectively (Figure 1A), while 6 months after the 2nd vaccination spike-specific CD4+ and CD8+ T cell responses persisted at comparable frequencies in 5/5 and 4/5 patients, respectively (not shown). Twelve sickle cell disease patients and 16 age-matched healthy controls received a 3rd mRNA vaccination, 9 and 8 months after the 2nd vaccination, respectively. A 3rd mRNA vaccination in sickle cell disease patients led to S1 IgG concentrations not significantly lower than in 3-dose vaccinated healthy controls (Figure 1A: median 13663 BAU/ml versus 4460 BAU/ml; p=0.99). The effect of this 3rd vaccination on cellular immunity is currently investigated. Conclusion Sickle cell disease patients receiving hydroxyurea do not have an impaired antibody response to mRNA COVID-19 vaccinations compared to healthy controls. Although spike-specific CD4+ and CD8+ T cells were found in similar percentages compared to healthy controls after 2 COVID-19 vaccinations, cytokine production by CD4+ and CD8+ spike-specific T cells was significantly lower, similar as previously reported in sickle cell disease patients after influenza vaccination. Population-based studies are needed to determine whether a 3rd vaccination in sickle cell disease patients provides better protection against adverse outcomes of COVID-19 compared to the standard 2-dose schedule. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal