Adaptive immunity and neutralizing antibodies against SARS-CoV-2 variants of concern following vaccination in patients with cancer: The CAPTURE study

Abstract

CAPTURE (NCT03226886) is a prospective cohort study of COVID-19 immunity in patients with cancer. Here we evaluated 585 patients following administration of two doses of BNT162b2 or AZD1222 vaccines, administered 12 weeks apart. Seroconversion rates after two doses were 85% and 59% in patients with solid and hematological malignancies, respectively. A lower proportion of patients had detectable neutralizing antibody titers (NAbT) against SARS-CoV-2 variants of concern (VOCs) vs wildtype (WT). Patients with hematological malignancies were more likely to have undetectable NAbT and had lower median NAbT vs solid cancers against both WT and VOCs. In comparison with individuals without cancer, patients with haematological, but not solid, malignancies had reduced NAb responses. Seroconversion showed poor concordance with NAbT against VOCs. Prior SARS-CoV-2 infection boosted NAb response including against VOCs, and anti-CD20 treatment was associated with undetectable NAbT. Vaccine-induced T-cell responses were detected in 80% of patients, and were comparable between vaccines or cancer types. Our results have implications for the management of cancer patients during the ongoing COVID-19 pandemic.

Keywords: Adaptive Immunity; Antibody Response; COVID-19; Cancer; Neutralising Antibodies; Prospective Study; SARS-CoV-2; T-cell Response; Vaccine.

Conflict of interest statement

Competing interests ST has received speaking fees from Roche, Astra Zeneca, Novartis and Ipsen. ST has the following patents filed: Indel mutations as a therapeutic target and predictive biomarker PCTGB2018/051892 and PCTGB2018/051893 and Clear Cell Renal Cell Carcinoma Biomarkers P113326GB. N.Y. has received conference support from Celegene. A.R. received a speaker fee from Merck Sharp & Dohme. J.L. has received research funding from Bristol-Myers Squibb, Merck, Novartis, Pfizer, Achilles Therapeutics, Roche, Nektar Therapeutics, Covance, Immunocore, Pharmacyclics, and Aveo, and served as a consultant to Achilles, AstraZeneca, Boston Biomedical, Bristol-Myers Squibb, Eisai, EUSA Pharma, GlaxoSmithKline, Ipsen, Imugene, Incyte, iOnctura, Kymab, Merck Serono, Nektar, Novartis, Pierre Fabre, Pfizer, Roche Genentech, Secarna, and Vitaccess. I.C. has served as a consultant to Eli-Lilly, Bristol Meyers Squibb, MSD, Bayer, Roche, Merck-Serono, Five Prime Therapeutics, Astra-Zeneca, OncXerna, Pierre Fabre, Boehringer Ingelheim, Incyte, Astella, GSK, Sotio, Eisai and has received research funding from Eli-Lilly & Janssen-Cilag. He has received honorarium from Eli-Lilly, Eisai, Servier. A.O. acknowledges receipt of research funding from Pfizer and Roche; speakers fees from Pfizer, Seagen, Lilly and AstraZeneca; is an advisory board member of Roche, Seagen, and AstraZeneca; has received conference support from Leo Pharmaceuticals, AstraZeneca/Diachi-Sankyo and Lilly. C.S. acknowledges grant support from Pfizer, AstraZeneca, Bristol Myers Squibb, Roche-Ventana, Boehringer-Ingelheim, Archer Dx Inc (collaboration in minimal residual disease sequencing technologies) and Ono Pharmaceutical, is an AstraZeneca Advisory Board member and Chief Investigator for the MeRmaiD1 clinical trial, has consulted for Amgen, Pfizer, Novartis, GlaxoSmithKline, MSD, Bristol Myers Squibb, Celgene, AstraZeneca, Illumina, Genentech, Roche-Ventana, GRAIL, Medicxi, Metabomed, Bicycle Therapeutics, and the Sarah Cannon Research Institute, has stock options in Apogen Biotechnologies, Epic Bioscience, GRAIL, and has stock options and is co-founder of Achilles Therapeutics. Patents: C.S. holds European patents relating to assay technology to detect tumour recurrence (PCT/GB2017/053289); to targeting neoantigens (PCT/EP2016/059401), identifying patent response to immune checkpoint blockade (PCT/EP2016/071471), determining HLA LOH (PCT/GB2018/052004), predicting survival rates of patients with cancer (PCT/GB2020/050221), identifying patients who respond to cancer treatment (PCT/GB2018/051912), a US patent relating to detecting tumour mutations (PCT/US2017/28013) and both a European and US patent related to identifying insertion/deletion mutation targets (PCT/GB2018/051892). L.P. has received research funding from Pierre Fabre, and honoria from Pfizer, Ipsen, Bristol-Myers Squibb, and EUSA Pharma. S.B. has recieved institutional research funding from Astrazeneca, Tesaro, GSK; speakers fees from Amgen, Pfizer, Astrazeneca, Tesaro, GSK, Clovis, Takeda, Immunogen, Mersana and has an advisor role for Amgen, Astrazeneca, Epsilogen, Genmab, Immunogen, Mersana, MSD, Merck Serono, Oncxerna, Pfizer, Roche. W.C. has received honoraria from Janssen and AstraZeneca. Remaining authors have no conflicts of interest to declare.

Figures

Figure 1. Seroconversion in cancer patients after COVID-19 vaccination

a) Sampling and analysis schema within the CAPTURE study. Baseline samples were collected immediately before the first dose. Follow-up samples were collected: 2-4 weeks post-first dose (FU1), on the day and immediately before the second dose (FU2; ie, the additional post-first dose timepoint implemented due to delayed 12 week dosing interval), and 2-4 weeks post-second dose (FU3). S1-reactive antibody (i.e., seroconversion) and neutralising antibody assays were performed in all available follow-up samples from 585 patients. b) Proportion of infection naive patients (n= 328/323/256/312 patients at BL/FU1/FU2/FU3) with S1-reactive antibodies at each timepoint. Differences were analysed using Chi-Square test. p-values < 0.05 were considered significant. c) proportion of infection patients with S1-reactive Ab grouped by solid (n= 270/234/192/234 patients at BL/FU1/FU2/FU3) and haematological malignancies (n=58/89/64/78 patients at BL/FU1/FU2/FU3). Differences were analysed by the Chi-Square test. p-values < 0.05 were considered significant. Ab, antibodies; BL, baseline; FU1, 21-56 days post first-vaccine; FU2, 14-28 days prior to second-vaccine; FU3, 14-28days post second-vaccine

Figure 2. Neutralising antibodies against WT SARS-CoV-2 and VOCs

a) NAbT in infection-naive patients were categorised as undetectable/low (<40), medium (40-256), or high (>256) are shown for WT SARS-CoV-2 and the three VOCs. Differences were analysed using Chi-Square test. p-values < 0.05 were considered significant. Numbers in the panel indicate sample numbers. b) NAbT in infection-naive patients against WT SARS-CoV-2, Alpha, Beta, and Delta VOCs. Median fold-decrease in NAbT is shown for each VOC in comparison to WT SARS-CoV-2 (n= 318/316/253/307 patients at BL/FU1/FU2/FU3). Dotted line at <40 denotes the lower limit of detection, dotted line at >2560 denotes the upper limit of detection. Violin plots denote density of data points. PointRange denotes the median and the 25 and 75 percentiles. Dots represent individual samples. Samples from individual patients are connected. Significance was tested by Kruskal Wallis test, p < 0.05 was considered significant, post-hoc test: two-sided Mann Whitney-U test with Bonferroni correction was used for pairwise comparisons. Only comparisons with the prior timepoint are denoted in the graph. c) Comparison of NAbT in infection-naive patients with solid (n= 262/232/189/232 patients at BL/FU1/FU2/FU3) vs haematological malignancies patients (n= 56/84/64/75 patients at BL/FU1/FU2/FU3). Dotted line at <40 denotes the lower limit of detection, dotted line at >2560 denotes the upper limit of detection. Violin plots denote density of data points. PointRange denotes the median and the 25 and 75 percentiles. Dots represent individual samples. Significance was tested by two-sided Wilcoxon-Mann-Whitney U test, p < 0.05 was considered significant. NAbT, neutralising antibody titre. NA, not tested. BL, baseline; FU1, 21-56 days post firstvaccine; FU2, 14-28 days prior to second-vaccine; FU3, 14-28days post second-vaccine.

Figure 3. Neutralising response against WT SARS-CoV-2 and VOCs by prior SARS-CoV-2 infection status and type of COVID-19 vaccine

a) Comparison of NAbT against WT SARS-CoV-2, Alpha, Beta, and Delta in patients with previous infection before vaccination vs infection naive patients post-second dose (n= 133/306 patients at BL/FU3). Significance was tested by two-sided Wilcoxon-Mann-Whitney U test, p < 0.05 was considered significant. b) Comparison of NAbT against WT SARS-CoV-2, Alpha, Beta, and Delta in infection naive (n= 318/316/253/307 patients at BL/FU1/FU2/FU3) vs patients previously infected with SARS-CoV-2 (n= 133/163/115/144 patients at BL/FU1/FU2/FU3). c) Comparison of NAbT against WT SARS-CoV-2, Alpha, Beta, and Delta in infection-naive patients receiving AZ (n= 262/246/212/229 patients at BL/FU1/FU2/FU3) vs PZ (n= 56/70/41/77 patients at BL/FU1/FU2/FU3, 1 patient with unknown vaccine type not included), and d) in patients with previous SARS-CoV-2 infection receiving AZ (n= 99/117/92/91 patients at BL/FU1/FU2/FU3) vs PZ (n=34/46/23/53) patients at BL/FU1/FU2/FU3). Dotted line at <40 denotes the lower limit of detection, dotted line at >2560 denotes the upper limit of detection. Violin plots denote density of data points. PointRange denotes the median and the 25 and 75 percentiles. Dots represent individual samples. Significance in b-d was tested by two sided Wilcoxon-Mann-Whitney U test, p < 0.05 was considered significant. AZ, AstraZeneca; NAbT, neutralising antibody titres; PZ, Pfizer; VOC, variant of concern. NA, not tested. BL, baseline; FU1, 21-56 days post first-vaccine; FU2, 14-28 days prior to second-vaccine; FU3, 1428days post second-vaccine.

Figure 4. WT SARS-CoV-2-specific T-cell responses in cancer patients following vaccination

a) Exemplar ELISPOT illustrating WT SARS-CoV-2 specific T-cell response. PBMC were stimulated with 15-mer peptide pools spanning the S1 or S2 subunit of spike. T-cell responses represent the sum of SFU/106 PBMC after stimulation with WT S1 or S2 peptide pools. b) SFU/106 PBMC in infection-naive patients after vaccination (n= 165/195/122/160 patients at BL/FU1/FU2/FU3). Dotted line at <24 denotes the threshold for positivity. Violin plots denote density, PointRange the median and 25 and 75 percentiles. Dots represent individual samples. Samples from individual patients are connected. Significance was tested by Kruskal Wallis test, post-hoc test: two-sided Wilcoxon-Mann-Whitney U test with Bonferroni correction. Only comparisons with the prior timepoint are denoted in the graph. c) Comparison of SFU/106 PBMC in patients with (n= 70/88/49/69 patients at BL/FU1/FU2/FU3) and without prior SARS-CoV-2 infection (n= 165/195/122/160 patients at BL/FU1/FU2/FU3) and in d) patients with solid (n= 136/161/98/130 patients at BL/FU1/FU2/FU3) vs haematological malignancies (n= 29/34/24/30 patients at BL/FU1/FU2/FU3). Violin plots denote density, PointRange the median and 25 and 75 percentiles. Dots represent individual samples. Significance in c-d was tested by two-sided Wilcoxon-Mann-Whitney U test. e) Binary logistic regression of SFU per million PBMCs in patients with solid tumours vs haematological malignancies. Dots denote odds ratio (blue, positive odds ratio red, negative odds ratio); whiskers denote the IQR times 1.5. f) Comparison of SFU per million in patients with haematological malignancies and solid tumours pre-first dose and post-second dose. Dotted line at <24 denotes the lower limit of detection. Violin plots denote density. PointRange denotes the median and the 25 and 75 percentiles. Dots represent individual samples. Significance was tested by Kruskal Wallis test, p < 0.05 was considered significant, post-hoc test: two sided Wilcoxon-Mann-Whitney U test with Bonferroni correction. PBMC, peripheral blood mononuclear cells; NC, negative control; PC, positive control; SFU, spot-forming unit. BL, baseline; FU1, 21-56 days post first-vaccine; FU2, 14-28 days prior to second-vaccine; FU3, 14-28days post second-vaccine.