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

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 2^nd 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 2^nd vaccination median S1 IgG concentration decreased from 2921 to 423 and 395 BAU/ml, respectively (Figure 1A), while 6 months after the 2^nd 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 3^rd mRNA vaccination, 9 and 8 months after the 2^nd vaccination, respectively. A 3^rd 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 3^rd 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 3^rd vaccination in sickle cell disease patients provides better protection against adverse outcomes of COVID-19 compared to the standard 2-dose schedule.

Zweegman:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kater:Astra Zeneca, BMS, Roche/Gennetech, Janssen, Abbvie, LAVA: Membership on an entity's Board of Directors or advisory committees; Abbvie, Astra Zeneca, Janssen: Other: Speakers fee; Abbvie, Astra Zeneca, BMS, Janssen, Roche/Genentech: Research Funding; Janssen, LAVA: Patents & Royalties: Pending; Amsterdam UMC, University of Amsterdam: Current Employment. van Meerten:Kite, a Gilead Company: Consultancy, Honoraria; Genentech: Research Funding; Celgene/BMS: Research Funding; Janssen: Consultancy. Mutsaers:GSK: Consultancy; Astra Zeneca: Research Funding; BMS: Consultancy.