key: cord-0690366-rqdua7w0
authors: Gavriatopoulou, Maria; Terpos, Evangelos; Kastritis, Efstathios; Briasoulis, Alexandros; Gumeni, Sentiljana; Ntanasis-Stathopoulos, Ioannis; Sklirou, Aimilia D.; Malandrakis, Panagiotis; Eleutherakis-Papaiakovou, Evangelos; Migkou, Magdalini; Trougakos, Ioannis P.; Dimopoulos, Meletios A.
title: Low neutralizing antibody responses in WM, CLL and NHL patients after the first dose of the BNT162b2 and AZD1222 vaccine
date: 2021-07-20
journal: Clin Exp Med
DOI: 10.1007/s10238-021-00746-4
sha: f85b35bef6e6ead01cbc3e476a3f5e56f21b404f
doc_id: 690366
cord_uid: rqdua7w0

Vaccination against SARS-CoV-2 is considered as the most important preventive strategy against COVID-19, but its efficacy in patients with hematological malignancies is largely unknown. We investigated the development of neutralizing antibodies (NAbs) against SARS-CoV-2 in patients with Waldenstrom Macroglobulinemia (WM), Chronic Lymphocytic Leukemia (CLL) and Non-Hodgkin Lymphoma (NHL). After the first dose of the vaccine, on D22, WM/CLL/NHL patients had lower NAb titers compared to controls: the median NAb inhibition titer was 17% (range 0–91%, IQR 8–27%) for WM/CLL/NHL patients versus 32% (range 2–98%, IQR 19–48%) for controls (P < 0.001). Only 8 (14%) patients versus 114 (54%) controls developed NAb titers ≥ 30% on D22 (p < 0.001). Our data indicate that the first dose of both BNT162b2 and AZD1222 leads to lower production of NAbs against SARS-CoV-2 in patients with WM/CLL/NHL compared to controls of similar age and gender and without malignant disease. Even though the response rates were not optimal, vaccination is still considered essential and if possible should be performed before treatment initiation. These patients with suboptimal responses should be considered to be prioritized for booster doses.

Patients with lymphoproliferative disorders including those with Waldenström Macroglobulinemia (WM) and Chronic Lymphocytic Leukemia (CLL) are at increased risk of bacterial and viral infections and also at increased risk for severe disease and death from COVID-19 [1] , due to their immunocompromised status, older age and comorbidities [2] [3] [4] .

Due to defects in immune effector cells [5] , associated with the B-cell disorder and the use of certain therapies, there may be a suboptimal immune response to vaccines. Vaccination against SARS-CoV-2 is considered as the most important preventive strategy against COVID-19, but its efficacy in patients with hematological malignancies is largely unknown [6] . The BNT162b2 mRNA and the AZD1222 viral vector vaccines against SARS-CoV-2 have shown significant efficacy in healthy adults [7, 8] . The first BNT162b2 dose confers some protection among nursing facility members [9, 10] , health workers and octogenarians [11] . However, among 167 patients with CLL, only 39.5% had a positive antibody-mediated response to the BNT162b2 vaccine [12] . Low antibody responses have been also shown among 48 elderly myeloma patients who received the first dose of BNT162b2 vaccine [13] . However, in contrast to CLL and myeloma, patients with myeloproliferative neoplasms present an antibody response to BNT162b2, which is similar to that of the general population [14] [15] [16] . In this context, we report the development of neutralizing antibodies (NAbs) against SARS-CoV-2 in patients with WM, CLL and other NHLs after the first dose of the BNT162b2 and AZD1222 vaccines.

Major inclusion criteria for the study included: (i) age above 18 years; (ii) presence of asymptomatic or active WM, CLL, or other low-grade NHL irrespective of the treatment phase; and (iii) eligibility for vaccination. Volunteer controls of similar age and gender were also included in this analysis. Major exclusion criteria for both patients and controls included the presence of: (i) autoimmune disorders or active malignant disease; (ii) HIV or active hepatitis B and C infection and (iii) end-stage renal disease. The patients and controls enrolled participate in a large prospective study (NCT04743388) for the kinetics of anti-SARS-CoV-2 antibodies after COVID-19 vaccination in healthy subjects and patients with hematological malignancies or solid tumors.

After vein puncture, the serum of both patients and controls was collected on day 1 (D1; before the first BNT162b2 or AZD1222 dose) and on day 22 (D22; before the second dose of the BNT162b2 or 3 weeks post the first AZD1222 dose). Serum was separated within 4 h from blood collection and stored at −80 °C until the day of measurement. NAbs against SARS-CoV-2 were measured using FDA approved methodology (ELISA, cPass™ SARS-CoV-2 NAbs Detection Kit; GenScript, Piscataway, NJ, USA) [17] on the above-mentioned timepoints. Samples of the same patient or control were measured in the same ELISA plate. The study was approved by the respective Ethical Committees in accordance with the Declaration of Helsinki and the International Conference on Harmonization for Good Clinical Practice. All patients and controls provided written informed consent prior enrollment in the study.

Study population included 58 patients (28 males/30 females; median age: 75 years, range: 40-88 years, IQR: 63-81 years) and 213 controls (100 males/113 females; median age: 75 years, range: 61-95 years, IQR: 63-83 years), who were vaccinated during the same period, at the same vaccination center (Alexandra Hospital, Athens, Greece). The patients were vaccinated based on the Greek vaccination program that prioritizes patients with malignancies for COVID-19 immunization. Forty-four patients (76%) were vaccinated with the BNT162b2 and 14 (24%) with the AZD1222 vaccine. Among the control group the proportion was similar with the patient group; 149 (70%) were vaccinated with the BNT162b2 and 64 (30%) with the AZD1222 vaccine (p = 0.38).

The characteristics of the patients are depicted in Table 1 . At the time of vaccination, 17 (46%) out of 37 symptomatic patients were receiving therapy, 19 (51%) were in remission after prior treatment and did not receive any therapy at the On D1, 6 (10.3%) patients and 21 (9.9%) controls had NAb titers of ≥ 30% (positivity cut-off); there was no difference regarding the NAb titers between patients and controls on D1 (p = 0.9). None of them had a prior history of known COVID-19. After the first dose of the vaccine, on D22, WM/CLL/NHL patients had lower NAb titers compared to controls: the median NAb inhibition titer was 17% (range 0-91%, IQR:8-27%) for WM/CLL/ NHL patients versus 32% (range 2-98%, IQR:19-48%) for controls; P < 0.001 (Fig. 1) . More, specifically, only 8 (14%) patients versus 114 (54%) controls developed NAb titers ≥ 30% on D22 (p < 0.001). The respective number of patients and controls who developed NAb titers ≥ 50% (clinically relevant viral inhibition [18] ) was 3 (5%) and 50 (24%), respectively (p = 0.002). Out of these 3 patients, 2 had symptomatic WM and 1 asymptomatic CLL. The WM patients were in remission, without receiving any therapy (1 in complete remission and 1 in partial remission) both after treatment with anti-CD20 based therapeutic regimens (dexamethasone-cyclophosphamiderituximab; DRC). Both patients had the uninvolved immunoglobulins after treatment within normal limits and were off treatment for more than 12 months. The remaining 5 patients that developed positivity ≥ 30% were all WM (4 asymptomatic/1 symptomatic). The symptomatic patient was in remission, out of treatment for more that 12 months and had been previously treated with DRC. The univolved immunoglobulins were within normal ranges for all 5 patients. Among the symptomatic patients with low response rates (< 30%) (n = 37), 17 were on active treatment at the time of vaccination (7 with ibrutinib, 3 with ibrutinib-rituximab, 2 with ibrutinib-bortezomibrituximab, 1 with venetoclax, 2 with rituximab and 2 with bendamustine-rituximab).

Our data indicate that the first dose of both BNT162b2 and AZD1222 leads to lower production of NAbs against SARS-CoV-2 in patients with WM/CLL/NHL compared to controls of similar age and gender and without malignant disease. To our knowledge this is the first report for the effects of AZD1222 vaccine in patients with low grade lymphoproliferative neoplasms. The results were independent of the vaccine type. Therapeutic regimens that deplete B-cells may impair immune response to vaccines. Patients treated with ibrutinib, venetoclax and/or anti-CD20 antibodies were unlikely to respond to a single dose of vaccine and this is confirmed by our results. Ibrutinib blocks the B-cell receptor signaling, in both malignant and normal B-cells and therefore impairs the humoral response to vaccination. The exposure to B-cell depleting agents, including anti-CD20 antibodies, reduces response to influenza vaccine, pneumococcal polysaccharide vaccine and other vaccines [19] . Furthermore, hypoglobulinemia might be associated with inferior antibody response among patients with CLL and COVID-19 [20] . Interestingly, it seems that patients who completed their treatment and remained in response at the time of vaccination were more likely to produce NAbs Fig. 1 Kinetics of neutralizing antibodies in WM/CLL/ NHL patients and age-matched controls after vaccination with the first dose of the BNT162b2 mRNA and AZD1222 vaccine. On D22, patients had lower production of NAb inhibition titers compared to controls of similar age and gender (see text). Only 3 patients had NAb titers of equal or more than 50% and this is probably related to a reconstitution of humoral immunity.

Our results also suggest that a second timely vaccine dose is necessary for patients with hematological malignancies that deregulate the immune homeostasis, and especially for the elderly [21] . A shorter time interval between the two doses of the AZD1222 would be relevant, as well [22] . Similarly, patients with solid cancer present a suboptimal humoral response following the first dose of the BNT162b2 and they should receive an early second dose (21 days after the first shot) [23] [24] [25] . Unfortunately, we did not have an adequate number of patients in order to perform statistically robust subgroup analysis according to type of therapy or presence/absence of hypogammaglobulinemia. Targeted therapies seem to negatively affect the NAb production (after a single dose), although higher patient numbers are required to evaluate the exact effect of each regimen on the immune responses of anti-SARS-CoV-2 vaccination.

In summary, the antibody-mediated response to SARS-CoV-2 vaccines in patients with WM/CLL/NHL is considerably affected by both the underlying disease and the treatment. Even though the response rates were not optimal, vaccination is still considered essential and if possible should be performed before treatment initiation. These patients with suboptimal responses should be considered to be prioritized for booster doses, potentially with a different vaccine type [26] . For these patients prolonged self-protection measures, such as mask wearing and social distancing, are necessary.

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We thank Ioanna Charitaki, RN 1 ; Tina Bagratuni, PhD 1 ; Christine Ivy Liacos, PhD 1 ; Nikoletta-Aikaterini Kokkali, RN 1 ; Nefeli Mavrianou-Koutsoukou, PhD 1 ; Dimitrios Patseas, PhD 1 and Mrs Stamatia Skourti 1 for administrative, technical, or material support;