TO THE EDITOR:

Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2 infection, has affected tens of millions of people globally.1 To overcome this pandemic, vaccination remains the most effective tool in preventing the disease and limiting the spread of infection. Several randomized trials have established the safety and efficacy of various types of vaccines in preventing severe symptomatic SARS-CoV-2 infection.2-5 Data from phase 3 trials of messenger RNA vaccines through November 2020 showed 94.1% efficacy for the prevention of symptomatic severe acute SARS-CoV-2 infection at 14 days after the second dose of mRNA1273 vaccine (Moderna)2 and 95% efficacy at 7 days after the second dose of BTN162b2 vaccine (Pfizer).4 Additionally, other vaccines using different platforms have shown efficacy ranging from 66% to 92%.3,5 Although vaccines are effective, the actual benefit to patients with hematological malignancies remains to be determined; several reports suggest inadequate immune response in these patients.6-9 Given the variable degree of immunosuppression associated with hematopoietic cell transplantation (HCT) and chimeric antigen receptor (CAR) T-cell therapy, it is often recommended that patients receive these vaccines ∼6 months after the procedure to allow for adequate immune recovery. However, data are lacking on immune response to SARS-CoV-2 vaccination in patients after HCT and CAR T-cell therapy. Therefore, we sought to assess immune response to COVID-19 vaccination after HCT and CAR T-cell therapy.

In the United States, Pfizer, Moderna, and Johnson & Johnson vaccines have been approved by US Food and Drug Administration for use in adults age ≥18 years (age ≥12 years for Pfizer). Both Pfizer and Moderna vaccines are administered as 2 doses 3 to 4 weeks apart, whereas only 1 dose is administered for the Johnson & Johnson vaccine. We retrospectively assessed serological response following completed COVID-19 vaccination in patients after HCT and cellular therapy for hematological malignancies at our institution. Patients were eligible ≥2 weeks after fully completing their vaccination and being checked for SARS-CoV-2 antibodies. The blood samples were tested using an enzyme immunoassay (EUROIMMUN) that tests for antibodies to the S1 domain of the SARS-CoV-2 spike protein.8,10 The sensitivity and specificity of the EUROIMMUN assay were 87.1% and 98.9%, respectively, for detection of the antispike humoral response to SARS-CoV-2 infection.10 This semiquantitative assay has consistently correlated with neutralizing immunity.10,11 Patient, disease, and treatment characteristics were compared by vaccine response using the Student t test for continuous variables and χ2 test for categorical variables. Statistical significance was determined at α <0.05, and all tests were 2 sided. Data collection and analysis were approved by Medical College of Wisconsin Institutional Review Board.

A total of 130 patients (autologous HCT [auto-HCT], n = 45; allogeneic HCT [allo-HCT], n = 71; CAR T-cell therapy, n = 14) were included in the analysis (Table 1). Of the 130 patients, 79 (60%) tested positive for SARS-CoV-2 antibodies postvaccination. The positivity rate was 60%, 69%, and 11% for patients undergoing auto-HCT, allo-HCT, and CAR T-cell therapy, respectively.

Table 1.

Comparison of patient, disease, and treatment characteristics by vaccine response in auto-HCT, allo-HCT, and CAR T-cell therapy

Vaccine response
PositiveNegativeP
Total patients (N = 130) 79 (60) 51 (40) NA 
 Vaccine type   .38 
  Pfizer 43 (56) 34 (44)  
  Moderna 32 (68) 15 (32)  
  Johnson & Johnson 4 (67) 2 (34)  
Auto-HCT (n = 45)    
 All patients 27 (60) 18 (40) NA 
 Median (range) age, y 65 (48-70) 65 (45-75) .50 
 Interval between auto-HCT and vaccination, mo   .20 
  <12 11 (73) 4 (27)  
  ≥12 16 (53) 14 (47)  
 Auto-HCT indication   .52 
  Lymphoma 8 (53) 7 (47)  
  Myeloma 19 (63) 11 (37)  
 Patients on maintenance therapy* 8 (67) 4 (33) .58 
 Disease relapse before vaccine 8 (47) 9 (53) .18 
 Prior COVID infection — 
 Patients with IgG <400 mg/dL 8 (57) 6 (43) .79 
 Median (range) time from auto-HCT to vaccine, mo 30 (3-173) 30 (2-96) .50 
 Median (range) IgG level per mg/dL 474 (146- 1481) 429 (40-990) .29 
Allo-HCT (n = 71)    
 All patients 49 (69) 22 (31) NA 
 Median (range) age, y 64 (25-70) 68.5 (37-77) .07 
 Interval between allo-HCT and vaccination, mo   .22 
  <12 11 (58) 8 (42)  
  ≥12 38 (73) 14 (27)  
 IST status   .69 
  Off IST 18 (72) 7 (28)  
  Ongoing IST drugs 31 (67) 15 (33)  
 GVHD status   .99 
  No active GVHD 20 (69) 9 (31)  
  Active GVHD 29 (69) 13 (31)  
 Active chronic GVHD 23 (65) 12 (34) .55 
 Disease relapse before vaccine 4 (57) 3 (43) .47 
 Positive patients with either CD4 <100/μL or CD8 <100/μL and/or IgG <400 mg/dL 12 (55) 10 (45) .08 
 Median (range) time from allo-HCT to vaccine, mo 26 (4-154) 25 (3-155) .68 
 Prednisone use at time of vaccination 4 (31) 9 (69) .001 
 Prior COVID infection  
 Median (range) CD4 count, per μL 327 (44-1165) 274 (56- 576) .10 
 Median (range) CD8 count, per μL 278 (46-1739) 276 (34-1440) .73 
 Median (range) IgG level, per mg/dL 577 (189-2090) 408 (153-1187) .01 
CAR T-cell therapy (n = 14)    
 All patients 3 (21) 11 (79) NA 
 Prior COVID infection — 
 Median (range) time from CAR T-cell therapy to vaccine, mo 24 (8-31) 6 (3-37) .09 
 Disease relapse before vaccine .59 
 Median (range) IgG level, per mg/dL 535 (191-1562) 535 (191-4843) — 
Vaccine response
PositiveNegativeP
Total patients (N = 130) 79 (60) 51 (40) NA 
 Vaccine type   .38 
  Pfizer 43 (56) 34 (44)  
  Moderna 32 (68) 15 (32)  
  Johnson & Johnson 4 (67) 2 (34)  
Auto-HCT (n = 45)    
 All patients 27 (60) 18 (40) NA 
 Median (range) age, y 65 (48-70) 65 (45-75) .50 
 Interval between auto-HCT and vaccination, mo   .20 
  <12 11 (73) 4 (27)  
  ≥12 16 (53) 14 (47)  
 Auto-HCT indication   .52 
  Lymphoma 8 (53) 7 (47)  
  Myeloma 19 (63) 11 (37)  
 Patients on maintenance therapy* 8 (67) 4 (33) .58 
 Disease relapse before vaccine 8 (47) 9 (53) .18 
 Prior COVID infection — 
 Patients with IgG <400 mg/dL 8 (57) 6 (43) .79 
 Median (range) time from auto-HCT to vaccine, mo 30 (3-173) 30 (2-96) .50 
 Median (range) IgG level per mg/dL 474 (146- 1481) 429 (40-990) .29 
Allo-HCT (n = 71)    
 All patients 49 (69) 22 (31) NA 
 Median (range) age, y 64 (25-70) 68.5 (37-77) .07 
 Interval between allo-HCT and vaccination, mo   .22 
  <12 11 (58) 8 (42)  
  ≥12 38 (73) 14 (27)  
 IST status   .69 
  Off IST 18 (72) 7 (28)  
  Ongoing IST drugs 31 (67) 15 (33)  
 GVHD status   .99 
  No active GVHD 20 (69) 9 (31)  
  Active GVHD 29 (69) 13 (31)  
 Active chronic GVHD 23 (65) 12 (34) .55 
 Disease relapse before vaccine 4 (57) 3 (43) .47 
 Positive patients with either CD4 <100/μL or CD8 <100/μL and/or IgG <400 mg/dL 12 (55) 10 (45) .08 
 Median (range) time from allo-HCT to vaccine, mo 26 (4-154) 25 (3-155) .68 
 Prednisone use at time of vaccination 4 (31) 9 (69) .001 
 Prior COVID infection  
 Median (range) CD4 count, per μL 327 (44-1165) 274 (56- 576) .10 
 Median (range) CD8 count, per μL 278 (46-1739) 276 (34-1440) .73 
 Median (range) IgG level, per mg/dL 577 (189-2090) 408 (153-1187) .01 
CAR T-cell therapy (n = 14)    
 All patients 3 (21) 11 (79) NA 
 Prior COVID infection — 
 Median (range) time from CAR T-cell therapy to vaccine, mo 24 (8-31) 6 (3-37) .09 
 Disease relapse before vaccine .59 
 Median (range) IgG level, per mg/dL 535 (191-1562) 535 (191-4843) — 

Data presented as n (%) unless otherwise indicated.

GVHD, graft-versus-host disease; IST, immunosuppressive therapy; NA, not applicable.

*

Maintenance therapy included lenalidomide ± other drugs (n = 9), rituximab (n = 2), or nivolumab (n = 1).

IST in vaccine responders (n = 29 [ruxolitinib ± other drugs, n = 16; sirolimus ± other drugs, n = 5; mycophenolate moefetil, n = 3; tacrolimus, n = 2; prednisone, n = 2; and ibrutinib, n = 1]) and nonresponders (n = 14 [ruxolitinib ± other drugs, n = 6; mycophenolate moefetil, n = 4; tacrolimus, n = 3; and prednisone, n = 1]).

Active acute or chronic GVHD defined as either active signs or symptoms of GVHD or ongoing IST drugs used to treat GVHD. Ongoing use of GVHD prophylaxis in the absence of signs or symptoms of GVHD was not considered active GVHD. Group off IST consisted of patients off all systemic medications to treat or prevent GVHD for ≥2 weeks.

On subgroup analysis for auto-HCT, there was no difference in seropositivity rates based on patient age, interval between HCT and vaccination, disease type, or immunoglobulin G (IgG) level. Similarly, for allo-HCT, the seropositivity rates did not differ by patient age, interval between allo-HCT and vaccination, immunosuppression status, presence of active graft-versus-host disease, or recipient CD4 and CD8 counts at the time of vaccination. Among the 71 patients who underwent allo-HCT, higher IgG levels were seen among those who were seropositive (median, 577 [range, 189-2090] vs 408 [153-1187] mg/dL; P = .01). Corticosteroid use for treatment of graft-versus-host disease following allo-HCT was associated with significantly lower seropositivity rates compared with no corticosteroids (n = 4 [31%] vs 9 [69%]; P = .001). Among the small subset of patients who were vaccinated <6 months after HCT (n = 19 [auto-HCT, n = 4; allo-HCT, n = 8; CAR T-cell therapy, n = 7]), 2 (50%), 3 (37%), and 0 (0%) patients were seropositive in the auto-HCT, allo-HCT, and CAR T-cell therapy groups, respectively.

To our knowledge, this is the first report describing the immunogenicity of SARS-CoV-2 vaccines in patients with hematological malignancies treated with HCT and CAR T-cell therapy. Our results show that approximately one-third of patients undergoing HCT and 79% of those receiving CAR T-cell therapy did not mount an appreciable immune response to COVID-19 vaccination. Antibody response was associated with higher IgG levels in those undergoing allo-HCT, whereas no other predictors of vaccine response were identified for patients undergoing auto-HCT or receiving CAR T-cell therapy.

Several factors may contribute to blunted immune response and affect vaccine efficacy in HCT and CAR T-cell settings. Further investigation to determine factors affecting vaccine response in these patients remains an unmet need. Consensus guidelines generally recommend initiating most vaccinations at ∼6 months post-HCT,12,13 and although American Society of Hematology/American Society for Transplantation and Cellular Therapy statements recommend COVID vaccination as early as 3 months after HCT,14 our limited data indicated lower vaccine responses within 6 months.

Recent evidence points to inadequate immune response to COVID-19 vaccination in patients with cancer, including those with hematological malignancies6,9,15,16 and those undergoing solid organ transplantation.8,17 Seropositivity rates vary across these studies, and this is attributed to different patient populations and variability in laboratory tests. It is important to note that patients receiving CAR T-cell therapy had low seroconversion rates in our study, but the small sample size precludes definite conclusions. Whether this is due to underlying immune suppression, disease characteristics, or preceding cytokine release syndrome must be evaluated.

Limitations of our study include the lack of concurrent non-HCT and non–CAR T-cell therapy control groups, lack of serial measurements after vaccination, and assessment of humoral response only, with no information on B-cell numbers.

The findings of low antispike antibodies in patients undergoing HCT and receiving CAR T-cell therapy after COVID-19 vaccination suggest that such patients may remain at high risk of COVID-19 infection despite vaccination. Current guidelines do not recommend routine serological testing in patients undergoing HCT or in CAR T-cell recipients, given the lack of evidence. However, the results observed in this study underscore the importance of masking, social distancing, and household vaccination for patients undergoing HCT and receiving CAR T-cell therapy, even after vaccination. Additional studies examining the wider immune repertoire with characterization of memory B- and T-cell immune responses over time and neutralizing antibody capacity are needed to better assess immunological response; these comprise the subject of a recently activated trial by the Blood and Marrow Transplant Clinical Trials Network in the United States. In patients who do not achieve optimal immune response, studies examining the role of booster doses or revaccination are needed.

Authorship

Contribution: B.D. and M.H. designed the study; T.F., P.H., M.H., S.A., S.C., N.L., and B.D. collected data; B.D. and M.H. analyzed the data; B.D. wrote the first draft of the manuscript; and all authors provided critical input.

Conflict-of-interest disclosure: B.D. has served on the advisory boards of Takeda, Amgen, and Jansen and received an honorarium from Celgene. M.H. reports research support/funding from Takeda Pharmaceutical Company, Otsuka Pharmaceutical, Spectrum Pharmaceuticals, and Astellas Pharma; consultancy for Medimmune LLC, Janssen R&D, Incyte Corporation, ADC Therapeutics, Cellerant Therapeutics, Celgene Corporation, Pharmacyclics, Magenta Therapeutics, Omeros, AbGenomics, Verastem, and TeneoBio; and speaker’s bureau for Sanofi Genzyme and AstraZeneca. The remaining authors declare no competing financial interests.

Correspondence: Mehdi Hamadani, Division of Blood and Marrow Transplant and Cellular Therapy, Medical College of Wisconsin, 9200 W Wisconsin Ave, Milwaukee, WI 53226; e-mail; mhamadani@mcw.edu.

There is a Blood Commentary on this article in this issue.

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