Exposure of progressive immune dysfunction by SARS-CoV-2 mRNA vaccination in patients with chronic lymphocytic leukemia: A prospective cohort study

• Published in: PLoS medicine 2023-06, Vol.20 (6), p.e1004157-e1004157
• Main Authors: Qin, Kai, Honjo, Kazuhito, Sherrill-Mix, Scott, Liu, Weimin, Stoltz, Regina M, Oman, Allisa K, Hall, Lucinda A, Li, Ran, Sterrett, Sarah, Frederick, Ellen R, Lancaster, Jeffrey R, Narkhede, Mayur, Mehta, Amitkumar, Ogunsile, Foluso J, Patel, Rima B, Ketas, Thomas J, Cruz Portillo, Victor M, Cupo, Albert, Larimer, Benjamin M, Bansal, Anju, Goepfert, Paul A, Hahn, Beatrice H, Davis, Randall S
• Format: Article
• Language: English
• Subjects: 2019-nCoV Vaccine mRNA-1273; Aged patients; Analysis; Antibodies; Antigens; Biology and Life Sciences; BNT162 Vaccine; Cancer; Care and treatment; CD20 antigen; CD4 antigen; CD8 antigen; Chronic lymphocytic leukemia; Cohort analysis; Coronaviruses; COVID-19 - prevention & control; COVID-19 vaccines; Diagnosis; Drug dosages; Effector cells; Enzyme-linked immunosorbent assay; Enzymes; Health aspects; Humans; Immunoglobulins; Immunological memory; Immunotherapy; Infections; Intravenous administration; Kinases; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphocytes T; Medicine and Health Sciences; Memory cells; Messenger RNA; Middle East respiratory syndrome; Mortality; mRNA; Older people; Oncology, Experimental; Pharmaceutical industry; Plasma; Prophylaxis; Prospective Studies; Proteins; Respiratory diseases; Risk factors; SARS-CoV-2; Seroconversion; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Software; T cells; Testing; Vaccination; Vaccines; γ-Interferon
• ISSN: 1549-1676; 1549-1277; 1549-1676
• DOI: 10.1371/journal.pmed.1004157

Patients with chronic lymphocytic leukemia (CLL) have reduced seroconversion rates and lower binding antibody (Ab) and neutralizing antibody (NAb) titers than healthy individuals following Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mRNA vaccination. Here, we dissected vaccine-mediated humoral and cellular responses to understand the mechanisms underlying CLL-induced immune dysfunction. We performed a prospective observational study in SARS-CoV-2 infection-naïve CLL patients (n = 95) and healthy controls (n = 30) who were vaccinated between December 2020 and June 2021. Sixty-one CLL patients and 27 healthy controls received 2 doses of the Pfizer-BioNTech BNT162b2 vaccine, while 34 CLL patients and 3 healthy controls received 2 doses of the Moderna mRNA-1273 vaccine. The median time to analysis was 38 days (IQR, 27 to 83) for CLL patients and 36 days (IQR, 28 to 57) for healthy controls. Testing plasma samples for SARS-CoV-2 anti-spike and receptor-binding domain Abs by enzyme-linked immunosorbent assay (ELISA), we found that all healthy controls seroconverted to both antigens, while CLL patients had lower response rates (68% and 54%) as well as lower median titers (23-fold and 30-fold; both p < 0.001). Similarly, NAb responses against the then prevalent D614G and Delta SARS-CoV-2 variants were detected in 97% and 93% of controls, respectively, but in only 42% and 38% of CLL patients, who also exhibited >23-fold and >17-fold lower median NAb titers (both p < 0.001). Interestingly, 26% of CLL patients failed to develop NAbs but had high-titer binding Abs that preferentially reacted with the S2 subunit of the SARS-CoV-2 spike. Since these patients were also seropositive for endemic human coronaviruses (HCoVs), these responses likely reflect cross-reactive HCoV Abs rather than vaccine-induced de novo responses. CLL disease status, advanced Rai stage (III-IV), elevated serum beta-2 microglobulin levels (β2m >2.4 mg/L), prior therapy, anti-CD20 immunotherapy (