Short Research Communication Anti-Spike Antibody Response to COVISHIELD™ (SII-ChAdOx1 nCoV-19) Vaccine in Patients with B-Cell and Plasma Cell Malignancies and Hematopoietic Cell Transplantation Recipients.

Introduction: There is limited data on the serologic antibody responses after the ChAdOx1 vaccine in patients with hematological malignancies and hematopoietic cell transplantation recipients. There is no data on the safety and efficacy of the Indian COVISHIELD™ vaccine in this population.
Methods: This study reports the anti-S antibody response to the COVISHIELD™ vaccine in a prospective cohort of patients with B-cell and plasma cell malignancies and HCT recipients at a single center. The quantitative antibodies to the SARS-CoV-2 S protein receptor-binding domain in human plasma were determined by the validated Roche Elecsys Anti-SARS-CoV-2 S kit.
Results: A total of 118 patients were included over the study period from April 2021 to August 2021. The seropositivity rate at baseline and after the first and second dose of the vaccine was 39%, 66%, and 79%, respectively (p < 0.0001). The seronegative cohort had a higher median age (65 vs. 60 years, p = 0.03), were more likely to be males (81% vs. 42%, p = 0.009), had a diagnosis of B-CLPD (100% vs. 42%, p < 0.001) and were more likely to be on ibrutinib therapy (56% vs. 15%, p = 0.001). Conclusions: This study confirms the safety and efficacy of the COVISHIELD™ vaccine in patients with hematological malignancies. © Indian Society of Hematology and Blood Transfusion 2022.

Introduction

The Oxford-AstraZeneca (ChAdOx1) nCoV- 19 Corona Virus vaccine is a recombinant, replication-deficient chimpanzee adenovirus vector encoding the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike (S) glycoprotein, produced in genetically modified human embryonic kidney (HEK) 293 cells. It is manufactured in India by the Serum Institute and is available as COVISHIELD™. It was rolled out in India for people > 45 years of age and comorbidities from March 2021 and for > 18 years from May 2021. Despite no data on the safety or efficacy of a replication-deficient viral vector vaccine in immunocompromised patients, the vaccine was approved in this population wherever it was the only option considering the possible benefits over the risks of COVID-19. Most countries in the developed world resorted to mRNA vaccines in this population. The studies have uniformly shown that about ~ 50–80% of patients with hematological malignancies mount an immune response and have lower anti-S IgG titers [1-6]. The serologic antibody responses after the ChAdOx1 vaccine have also shown similar responses to the mRNA vaccines [7-10]. All studies have identified CLL, lymphoma, and myeloma patients receiving anti-B-cell therapies (BTK inhibitors, venetoclax, anti-CD20/CD38 antibodies) and HCT recipients to be associated with lesser immune responses.

Methods

This study reports the anti-S antibody response to the COVISHIELD™ vaccine in a prospective cohort of patients with hematological malignancies at a single center. The institute ethics committee approved the study. Data on demographic variables (age, sex, cancer diagnosis), treatments, prior COVID-19, vaccine type and administration dates, and side effects of vaccination were collected. A total of 118 patients were included over the study period from April 2021 to August 2021 after informed consent. There were 63 patients with chronic lymphoproliferative disorders (chronic lymphocytic leukemia CLL, n = 48), plasma cell dyscrasia (n = 40), and post-hematopoietic cell transplantation (HCT, n = 15). As an institute policy we were advising COVID vaccination starting at 3 months post-HCT, preferably 6 months after rituximab-based therapy for B-CLPDs and anytime for plasma cell dyscrasias. Blood samples were collected at baseline and one month after the first and second doses of the vaccine. The antibodies to the SARS-CoV-2 S protein receptor-binding domain (RBD) in human plasma were determined by the Roche Elecsys Anti-SARS-CoV-2 S kit, as per the manufacturer’s instructions. This immunoassay is validated for the in vitro quantitative determination of antibodies within the range of 0.40‑250 U/mL. Analyte concentrations of < 0.80 U/mL were considered negative, while ≥ 0.80 U/mL were considered positive. The sensitivity and specificity of this assay are 98.8% and 99.9%, respectively. The positive agreement rate with the pseudo-neutralization assay is 92.3%.

Results

A total of 46 patient samples were available at baseline before any dose of the vaccine was administered. Out of these, 18 (39%) were already seropositive for anti-S. While five patients had titers > 250 U/ml at baseline, the titer of another seven patients increased to > 250 U/ml following subsequent vaccine doses. Only one patient had reported an unconfirmed COVID-like illness in this cohort. Of the 28 seronegative patients at baseline, 15 (54%) seroconverted after the first/ second vaccine dose. There were no differences in the diagnosis and treatments received by the seropositive or seronegative patients at baseline. Post the first vaccine, a total of 71 patient samples were available. The seropositivity rate in this cohort was 66%. Only three patients had reported prior confirmed COVID-19 in this cohort. Again, there were no differences in the diagnosis and treatments between the seropositive and negative cohorts. Post the second vaccine, a total of 76 patient samples were available for analysis. The seropositivity rate after the second vaccine dose was 79%. 68% of these had anti-S antibodies > 250 U/ml. The median anti-S antibody titers at baseline and after the first and second COVISHIELD doses were 0.4 (IQR 0.4-5), 11 (IQR 0.4–250), 250 (IQR 3.5–250), respectively (p < 0.0001) (Fig. 1). The seronegative cohort of 16 patients had a higher median age (65 vs. 60 years, p = 0.03), were more likely to be males (81% vs. 42%, p = 0.009), had a diagnosis of B-CLPD (100% vs. 42%, p < 0.001), more specifically CLL (88% vs. 32%, p < 0.0001) and were more likely to be on ibrutinib therapy (56% vs. 15%, p = 0.001). Patients with plasma cell dyscrasias on bortezomib or immunomodulatory therapy were all seropositive after the second vaccine. Only two patients in the seronegative and seropositive cohort reported having confirmed COVID-19 within a month after the second vaccination (Table I). The test was positive (90% had titers > 100 U/mL) in all ten health care workers who served as healthy controls and had received both doses of the vaccine 1–5 months before. The vaccine was well tolerated in the immunocompromised population. There were no serious adverse events reported in this study. The reporting of minor adverse events was not rigorous and hence nor reported in the study.

Fig. 1

Anti-S antibody titers at baseline and one month after first and second COVISHIELD dose in patients with B-cell and plasma cell malignancies and HCT recipients (Titers > 250 U/mL were capped at 250 for representation purposes as it is the upper limit of detection of the assay)

Table 1

PAnti-S antibody response to COVISHIELD™ vaccine as per patient, disease, and treatment characteristics

Characteristic	Baseline (pre-vaccination)N = 46		p	Post 1st vaccine doseN = 71		p	Post 2nd vaccine doseN = 75		p
	Seronegative	Seropositive		Seronegative	Seropositive		Seronegative	Seropositive
N (%)	28 (61%)	18 (39%)		24 (34%)	47 (66%)		16 (21%)	59 (79%)
Age	61 (53–68)	56 (50–69)	NS	61 (58–67)	60 (49–65)	NS	65 (61–71)	60 (53–66)	0.03
Female Male	6 (21%) 22 (79%)	3 (17%) 15 (83%)	NS	7 (29%) 17 (71%)	16 (34%) 31 (66%)	NS	3 (19%) 13 (81%)	34 (58%) 25 (42%)	0.009
Diagnosis Post-HCT B-CLPD Plasma cell dyscrasia	6 (21%) 16 (58%) 6 (21%)	3 (17%) 8 (44%) 7 (39%)	NS NS NS	4 (17%) 16 (66%) 4 (17%)	8 (17%) 20 (43%) 19 (40%)	NS NS NS	0 16 (100%) 0	8 (14%) 25 (42%) 26 (44%)	NS < 0.0001 0.002
Prior COVID	0	1 (6%)	NS	0	3 (6%)	NS	0	3 (5%)	NS
Current Rx Observation Ibrutinib Rituximab + Borte/IMid/dex Other IST	11 (39%) 7 (25%) 2 (7%) 7 (25%) 1 (4%)	7 (39%) 2 (11%) 1 (6%) 6 (33%) 2 (11%)	NS NS NS NS NS	11 (46%) 3 (12%) 3 (12%) 6 (25%) 1 (4%)	16 (34%) 5 (11%) 4 (8%) 17 (36%) 5 (11%)	NS NS NS NS NS	5 (31%) 9 (56%) 1 (6%) 0 (0%) 1 (6%)	21 (36%) 9 (15%) 1 (2%) 26 (44%) 2 (3%)	NS 0.001 NS 0.007 NS
Post-vaccination COVID	-	-	-	1 (4%)	0	NS	1 (6%)	1 (2%)	NS

NS: not significant, B-CLPD: B-cell chronic lymphoproliferative disorders, HCT: hematopoietic cell transplantation, Rituximab +: RCVP/RHOP/BR/R-chlorambucil, Borte/IMid/dex: bortezomib/ immunomodulator/ dexamethasone, IST: immunosuppressive therapy

Discussion

This study highlights the high seroprevalence (~ 40%) even in the immunocompromised patients, in contrast to > 80% seroprevalence in the general population in recent regional serosurveys [11]. The seropositivity rate increased to ~ 80% after the second dose. Only CLPD patients on anti-B-cell therapies failed to mount an immune response despite the second dose of the vaccine. This is in concordance with previous studies [5-7]. The U.S. Food and Drug Administration (FDA) amended the emergency use authorization for the mRNA vaccines to allow a booster dose for immunocompromised patients based on higher immunogenicity [12]. A similar booster study showed seroconversion in 55% of the patients with B-cell malignancies [13]. Though similar data is not available for the ChAdOx1 vaccines, it is likely to be the same given similar overall responses with the two vaccines in the immunocompromised patients. The major limitation of this study is the lack of serial antibody levels in all patients and that the T-cell repertoire was not studied. However, patients with CLL have impaired T-cell function, the primary group of patients who did not mount a B-cell response to the vaccines [14]. This study aims to highlight the safety and efficacy of the COVISHIELD™ vaccine in patients with hematological malignancies. At the same time, we caution specific groups of patients that their protection against COVID-19 may still be suboptimal. It is essential to continue COVID-appropriate behavior and get the immediate family contacts vaccinated, as these patients’ mortality rates remain high [15]. These patients may need additional booster doses pending approval by the government regulatory agencies.