1. Medicine

Study of efficacy and longevity of immune response to third and fourth doses of COVID-19 vaccines in patients with cancer: A single arm clinical trial

  1. Astha Thakkar
  2. Kith Pradhan
  3. Benjamin Duva
  4. Juan Manuel Carreno
  5. Srabani Sahu
  6. Victor Thiruthuvanathan
  7. Sean Campbell
  8. Sonia Gallego
  9. Tushar D Bhagat
  10. Johanna Rivera
  11. Gaurav Choudhary
  12. Raul Olea
  13. Maite Sabalza
  14. Lauren C Shapiro
  15. Matthew Lee
  16. Ryann Quinn
  17. Ioannis Mantzaris
  18. Edward Chu
  19. Britta Will
  20. Liise-anne Pirofski
  21. Florian Krammer
  22. Amit Verma  Is a corresponding author
  23. Balazs Halmos  Is a corresponding author
  1. Department of Oncology, Montefiore Einstein Cancer Center, Albert Einstein College of Medicine, United States
  2. Department of Epidemiology and Population Health, Albert Einstein College of Medicine, United States
  3. Department of Microbiology, Icahn School of Medicine at Mount Sinai, United States
  4. Center for Vaccine Research and Pandemic Preparedness (C-VARPP), Icahn School of Medicine at Mount Sinai, United States
  5. Department of Pathology, Montefiore Medical Center, United States
  6. Department of Medicine, Albert Einstein College of Medicine, United States
  7. Euroimmun, United States
  8. Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, United States
https://doi.org/10.7554/eLife.83694
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Cite this article
  1. Astha Thakkar
  2. Kith Pradhan
  3. Benjamin Duva
  4. Juan Manuel Carreno
  5. Srabani Sahu
  6. Victor Thiruthuvanathan
  7. Sean Campbell
  8. Sonia Gallego
  9. Tushar D Bhagat
  10. Johanna Rivera
  11. Gaurav Choudhary
  12. Raul Olea
  13. Maite Sabalza
  14. Lauren C Shapiro
  15. Matthew Lee
  16. Ryann Quinn
  17. Ioannis Mantzaris
  18. Edward Chu
  19. Britta Will
  20. Liise-anne Pirofski
  21. Florian Krammer
  22. Amit Verma
  23. Balazs Halmos
(2023)
Study of efficacy and longevity of immune response to third and fourth doses of COVID-19 vaccines in patients with cancer: A single arm clinical trial
eLife 12:e83694.
https://doi.org/10.7554/eLife.83694
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2 figures, 6 tables and 1 additional file

Figures

Figure 1 with 1 supplement
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Immunogenicity of third dose of coronavirus disease 2019 (COVID-19) vaccine in seronegative cancer patients.

(A) Figure showing change in anti-SARS-CoV-2 (anti-S) antibody titer at 4 weeks for entire cohort n=106. (B) Figure showing change in anti-S antibody titer at 4 weeks split by cancer type (solid cancer, lymphoid cancer, and myeloid cancer) n=106. (C) Figure showing effect of Bruton’s tyrosine kinase inhibitor (BTKi) therapy on anti-S antibody titer at baseline and 4 weeks of third dose n=12 patients that received BTKi Kruskal-Wallis test. (D) Figure showing effect of anti-CD20 antibody therapy on anti-S antibody titer at baseline and 4 weeks of third dose n=25 patients that received anti-CD20 antibody, Kruskal-Wallis test. (E) Figure showing effect of prior COVID-19 infection on anti-S antibody titer at baseline and 4 weeks of third dose n=9 patients with COVID infection, Kruskal-Wallis test. (F) Figure showing effect of booster type (BNT162b2 vs mRNA 1273) on anti-S antibody titer at baseline and 4 weeks of third dose. (G) Line diagram showing correlation between anti-spike IgG titer and baseline T-cell activity at baseline and 4 weeks n=88 for baseline, n=89 for 4 weeks; Spearman’s test. (H) Line diagram showing correlation between anti-S titer and signal inhibition for neutralization against wild-type (WT) virus at baseline and 4 weeks. n=103 for baseline, n=100 for 4 weeks; Spearman’s test. (I) Anti-spike IgG titers at baseline, 4 weeks, and 6 months after third dose of COVID-19 vaccine in cancer patients. Line shows means with error bars (SD).n=47. All statistical tests performed at a pre-determined threshold of p<0.05 for statistical significance.

Figure 1—figure supplement 1
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CONSORT diagram showing enrollment and follow-up of study subjects.
Figure 2
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Immunogenicity of the fourth dose of coronavirus disease 2019 (COVID-19) vaccine in cancer patients with seronegativity after three doses.

(A) Anti-spike IgG levels after the fourth dose of COVID-19 vaccine for the entire cohort n=18. (B) Correlation of baseline IgM levels with response to fourth dose of vaccine, n=18 Kruskal-Wallis test. (C) Line diagram showing correlation between anti-SARS-CoV-2 (anti-S) titer and neutralization activity for wild-type (WT) virus at baseline and 4 weeks, n=18, Spearman’s test. (D) Line diagram showing correlation between titer and neutralization activity for Omicron strain at baseline and 4 weeks n=18, Spearman’s test. All statistical tests performed at a pre-determined threshold of p<0.05 for statistical significance.

Tables

Key resources table
Reagent type (species) or resourceDesignationSource or referenceIdentifiersAdditional information
Software, algorithmRStudio, v3.6.2positRRID:SCR_000432
Commercial assay, kitAdviseDx Abbott SARS-CoV-2 anti-S antibody assayAbbottI1000SR instrument
OthercPass SARS-CoV-2 Neutralization Antibody Detection KitGenScriptL00847EUA by FDA; https://www.genscript.com/covid-19-detection-cpass.html
OtherQuan-T-Cell SARS-CoV-2 and Quan-T-Cell ELISAEUROIMMUNET 2606 and EQ 6841CE-marked and for Research Use Only in the United States https://www.coronavirus-diagnostics.com/immune-response-test-systems-for-covid-19.html IFN-γ ELISA: plasma diluted 1:5
OthermAb 1 C7C7 anti-SARS nucleoprotein antibodyCenter for Therapeutic Antibody Development at the ISMMS (Same clone as Sigma Millipore)ZMS1075Working dilution 1 μg/ml
Other(H&L) Antibody Peroxidase ConjugatedGoat PolyclonalRockland610–13021:3000 dilution
OtherSIGMAFAST OPD (o-Phenylenediamine dihydrochloride)Sigma-AldrichCat# P9187
Other3-molar hydrochloric acidThermo Fisher ScientificCat# S25856
Table 1
Baseline characteristics for third dose cohort.
Baseline characteristicsn=106
Age (median, IQR)68 (63.25–76.5)
Sex
Male48 (45%)
Female58 (55%)
Race
Caucasian36 (34%)
African-American33 (31%)
Hispanic27 (25%)
Asian9 (8%)
Other1 (1%)
Previous vaccine given
BNT162b272 (68%)
mRNA-127328 (26%)
Ad26.CoV2.S6 (6%)
Type of booster vaccine
BNT162b278 (74%)
mRNA-127328 (26%)
Malignancy category
Hematologic malignancy66 (62%)
Solid Malignancy40 (38%)
Lymphoid/myeloid/solid
Lymphoid55 (52%)
Myeloid11 (10%)
Solid40 (38%)
Cancer status
Active69 (65%)
Progressive3 (3%)
Recurrent3 (3%)
Relapse7 (7%)
Remission24 (23%)
On treatment at the time of booster
Yes80 (75%)
No26 (25%)
Table 2
Results for third dose of vaccine.
Spike antibody resultsn=106
Four-week negativeFour-week positiveSeroconversion ratep value
Baseline negative152057%<0.001*
Baseline positive071
Total1591
Rise in spike antibody titers overall (AU/mL)MedianIQR
Titer at baseline212.150–2873
Titer at 4 weeks9997880.7–47,063
Rise in spike antibody titers (AU/mL)MedianIQR
Hematologic malignancy21670–10,131<0.001*
Solid malignancy31,0109531–44,464
Rise in spike antibody titers by solid/lymphoid/myeloid (AU/mL)
Lymphoid cancers11690–8661<0.001*
Myeloid cancers94244381–20,444
Solid cancers31,0109531–44,464
Association with certain cancer-directed therapies
Bruton’s tyrosine kinase inhibitors
Change in spike antibody titers (AU/mL)MedianIQR
Patients on BTKi (n=12)00–3393<0.001*
Patients not on BTKi9355877.3–34,410
Anti-CD20 antibody treatment
Change in spike antibody titers (AU/mL)MedianIQR
Patients on CD20 (n=25)00–910.50.0133*
Patients not on CD20127352842–38,863
Anti-CD20 antibody treatment within 6 monthsMedianIQR
Yes00–00.05482
No5870–4314
Change in spike antibody titer by prior COVID infectionMedianIQR
Yes (n=9)19,3509286–32,1510.3051
No (n=96)6706444.1–33,831
Change in spike antibody titer by type of booster givenMedianIQR
BNT162b25534433.8–18,0740.09014
mRNA-127331451515.5–45,057
Change in spike antibody titer by ageMedianIQR
Age <65 years274512641–50,0000.03438*
Age ≥65 years6152558.9–41,765
T-cell activity
Baselinen=88%
Positive6574%
Negative2326%
Four-weekn=89
Positive7685%
Negative1315%
Baseline neutralization activity assay (all evaluable patients, WT virus)
Anti-S antibody negativeAnti-S antibody positiveTotalp value
Neutralizing antibodies detected04747<0.001
Neutralizing antibodies not detected352156
Total3568103
Four-week neutralization activity assay (all evaluable patients, WT virus)
Anti-S antibody negativeAnti-S antibody positiveTotalp value
Neutralizing antibodies detected07777<0.001
Neutralizing antibodies not detected15823
Total1585100
Four-week neutralization assay (seronegative cohort 4 weeks)n=35
Wild type
Negative1954%
Positive1646%
Omicron
Negative2983%
Positive617%
  1. *

    Statistically significant.

Table 3
Baseline characteristics of the fourth dose cohort.
N (%)
Baseline seronegative7 (39%)
Baseline low positive (spike ab <1000 AU/mL)11 (61%)
Cancer diagnosis
CLL7 (39%)
Waldenstrom’s macroglobulinemia3 (17%)
DLBCL2 (11%)
Multiple myeloma2 (11%)
Mantle cell Lymphoma1 (6%)
Marginal zone lymphoma1 (6%)
Hodgkins lymphoma1 (6%)
MDS1 (6%)
Fourth dose vaccine type
BNT162b215 (83%)
Ad26.CoV2.S3 (17%)
Table 4
Correlation of fourth dose vaccine response with baseline characteristics.
Non-responder (n=6)Responder (n=12)p value
Age79.567.50.01293*
Baseline WBC4.955.150.45
Baseline ANC2.63.50.26
Baseline ALC1.21.30.57
Baseline AMC0.50.650.73
Baseline absolute CD3773835.50.57
Baseline absolute CD4406.5407.50.71
Baseline absolute CD83102470.40
Baseline absolute CD191113.50.04874*
Baseline absolute CD16/56243.52000.57
Baseline IgG7777570.51
Baseline IgA90.51180.57
Baseline IgM1760.50.001442†
4-Week WBC5.15.80.40
4-Week ANC2.73.450.57
4-Week ALC1.11.40.60
4-Week AMC0.550.650.60
4-Week absolute CD37549830.40
4-Week absolute CD4461.5369.50.93
4-Week absolute CD8297.52690.40
4-Week absolute CD192.51050.07
4-Week absolute CD16/56232.52190.93
4-Week IgG†741.58320.62
4-Week IgA†861120.69
4-Week IgM†15620.003561†
  1. *

    Statistically significant.

  2. †

    n=11.

Table 5
Results for fourth dose study.
Overall response18
Responder1267%
Non-responder633%
Median ageIQR
Responder67.563.75–70.750.01293*
Non-responder79.572.75–81.75
Median baseline IgM
Responder60.50.001442 *
Non-responder17
Median spike antibody at baseline (AU/mL)131.1<50–432.9
Median spike antibody at 4 weeks (AU/mL)170064.3–18627
T-cell activity at baselinen=14
Positive1179%
Negative321%
T-cell activity at 4 weeksn=18
Positive1794%
Negative16%
Baseline
Neutralization assay baselineNegativePositive
WT6 (33%)12 (67%)
Omicron18 (100%)0 (0%)
Neutralization assay 4 weekNegativePositive
WT5 (28%)13 (72%)
Omicron12 (67%)6 (33%)
  1. *

    Statistically significant.

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  1. Astha Thakkar
  2. Kith Pradhan
  3. Benjamin Duva
  4. Juan Manuel Carreno
  5. Srabani Sahu
  6. Victor Thiruthuvanathan
  7. Sean Campbell
  8. Sonia Gallego
  9. Tushar D Bhagat
  10. Johanna Rivera
  11. Gaurav Choudhary
  12. Raul Olea
  13. Maite Sabalza
  14. Lauren C Shapiro
  15. Matthew Lee
  16. Ryann Quinn
  17. Ioannis Mantzaris
  18. Edward Chu
  19. Britta Will
  20. Liise-anne Pirofski
  21. Florian Krammer
  22. Amit Verma
  23. Balazs Halmos
(2023)
Study of efficacy and longevity of immune response to third and fourth doses of COVID-19 vaccines in patients with cancer: A single arm clinical trial
eLife 12:e83694.
https://doi.org/10.7554/eLife.83694