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Omicron neutralising antibodies after third COVID-19 vaccine dose in patients with cancer

2022; Elsevier BV; Volume: 399; Issue: 10328 Linguagem: Inglês

10.1016/s0140-6736(22)00147-7

1474-547X

Annika Fendler, Scott T.C. Shepherd, Lewis Au, Mary Wu, Ruth Harvey, Andreas M. Schmitt, Zayd Tippu, Benjamin Shum, Sheima Farag, Aljosja Rogiers, Eleanor Carlyle, Kim Edmonds, Lyra Del Rosario, Karla Lingard, Mary Mangwende, Lucy Holt, Hamid Ahmod, Justine Korteweg, Tara Foley, Taja Barber, Andrea Emslie-Henry, Niamh Caulfield-Lynch, Fiona Byrne, Daqi Deng, Svend Kjær, Ok‐Ryul Song, Christophe J. Queval, Caitlin Kavanagh, Emma Wall, Edward J Carr, Simon Caidan, Mike Gavrielides, James I. MacRae, Gavin Kelly, Kema Peat, Denise Kelly, Aida Murra, Kayleigh Kelly, Molly O’Flaherty, Robyn Shea, Gail Gardner, Darren R. Murray, Nadia Yousaf, Shaman Jhanji, Kate Tatham, David Cunningham, Nicholas van As, Kate Young, Andrew J.S. Furness, Lisa Pickering, Rupert Beale, Charles Swanton, Sonia Gandhi, Steve Gamblin, David L.V. Bauer, George Kassiotis, Michael Howell, Emma Nicholson, Susanna Walker, James Larkin, Samra Turajlic,

Long-Term Effects of COVID-19

Patients with cancer are at greater risk of severe COVID-19 and have been prioritised for COVID-19 vaccination globally. We previously showed that following two doses of COVID-19 vaccines, neutralising antibody (nAb) responses against the B.1.1.7 (alpha), B.1.351 (beta), and B.1.617.2 (delta) variants of concern (VOCs) are decreased compared to the wild type (WT) SARS-CoV-2, particularly in patients with blood cancer.1Fendler A Shepherd STC Au L et al.Adaptive immunity and neutralizing antibodies against SARS-CoV-2 variants of concern following vaccination in patients with cancer: the CAPTURE study.Nature Cancer. 2021; (published online Oct 27.)https://doi.org/10.1038/s43018-021-00274-wGoogle Scholar More recently, we reported that following a third vaccine dose, nAb responses to these VOCs increase in most patients with cancer, including those with no or waning response following two vaccine doses.2Fendler A Shepherd STC Au L et al.Immune responses following third COVID-19 vaccination are reduced in patients with hematologic malignancies compared to patients with solid cancer.Cancer Cell. 2022; (published online Dec 29.)https://doi.org/10.1016/j.ccell.2021.12.013Google Scholar Since November, 2021, the B.1.1.529 (omicron) VOC has rapidly become the dominant SARS-CoV-2 VOC globally. Omicron partially evades vaccine-induced immunity,3Cele S Jackson L Khoury D et al.Omicron extensively but incompletely escapes Pfizer BNT162b2 neutralization.Nature. 2021; (published online Dec 23.)https://doi.org/10.1038/s41586-021-04387-1Google Scholar but a third vaccine dose increases omicron nAb responses in the general population.4Gruell H Vanshylla K Tober-Lau P et al.mRNA booster immunization elicits potent neutralizing serum activity against the SARS-CoV-2 Omicron variant.Research Square. 2021; (published online Dec 27.) (preprint).https://doi.org/10.21203/rs.3.rs-1168453/v1Google Scholar, 5Nemet I Kliker L Lustig Y et al.Third BNT162b2 vaccination neutralization of SARS-CoV-2 Omicron infection.N Engl J Med. 2021; (published online Dec 29.)https://doi.org/10.1056/NEJMc2119358Google Scholar, 6Wu M Wall EC Carr EJ et al.Three-dose vaccination elicits neutralising antibodies against omicron.Lancet. 2022; (published online Jan 19.)https://doi.org/10.1016/S0140-6736(22)00092-7Google Scholar Comparable data in patients with cancer are lacking, leaving patients and cancer physicians without the means to calibrate infection risk7Schmidt AL Labaki C Hsu CY et al.COVID-19 Vaccination and Breakthrough Infections in Patients with Cancer.Ann Oncol. 2021; (published online Dec 24.)https://doi.org/10.1016/j.annonc.2021.12.006Google Scholar while maintaining necessary cancer treatments. We used live-virus micro-neutralisation assays to evaluate response to omicron following three doses of COVID-19 vaccine in participants of the CAPTURE study (NCT03226886), a prospective, longitudinal cohort of patients with cancer. We evaluated 199 patients with cancer, 115 (58%) of whom had solid cancer and 84 (42%) blood cancer, all of whom received a third dose of BNT162b2 (appendix p 1) after two doses of either BNT162b2 (33%) or ChAdOx1 (67%). A matched sample obtained before the third dose was also evaluated in 179 of 199 patients (100 of 115 patients with solid cancer; 79 of 84 with blood cancer). The median time between the second and third doses was 176 days (IQR 166–188). 23 of 199 patients had a history of SARS-CoV-2 infection, all before the second vaccine dose, and none with omicron. nAb titres (nAbT) against delta and omicron were measured at a median of 11 days (IQR 0–78) before and 23 days (19–29) after the third vaccine dose. As described previously for this assay, nAbT was categorised as undetectable ( 40).1Fendler A Shepherd STC Au L et al.Adaptive immunity and neutralizing antibodies against SARS-CoV-2 variants of concern following vaccination in patients with cancer: the CAPTURE study.Nature Cancer. 2021; (published online Oct 27.)https://doi.org/10.1038/s43018-021-00274-wGoogle Scholar, 8Wall EC Wu M Harvey R et al.AZD1222-induced neutralising antibody activity against SARS-CoV-2 delta VOC.Lancet. 2021; 398: 207-209Google Scholar, 9Wall EC Wu M Harvey R et al.Neutralising antibody activity against SARS-CoV-2 VOCs B.1.617.2 and B.1.351 by BNT162b2 vaccination.Lancet. 2021; 397: 2331-2333Google Scholar Among the 100 patients with solid cancer, after two vaccine doses, nAbT against omicron was detectable in 37 (37%) patients (appendix p 4), whereas nAbT against delta was detectable in 56 (56%) patients (McNemar test, p=0·0002) and nAbT against WT SARS-CoV-2 was detectable in 97 (97%) patients (p<0·0001).2Fendler A Shepherd STC Au L et al.Immune responses following third COVID-19 vaccination are reduced in patients with hematologic malignancies compared to patients with solid cancer.Cancer Cell. 2022; (published online Dec 29.)https://doi.org/10.1016/j.ccell.2021.12.013Google Scholar Among the 115 patients with solid cancer who had a third vaccine dose, nAbT against omicron was detectable in 104 (90%) patients, whereas nAbT against delta was detectable in 112 (97%) patients (p=0·013), and nAbT against WT SARS-CoV-2 was detectable in 114 (99%) patients (p=0·0044).2Fendler A Shepherd STC Au L et al.Immune responses following third COVID-19 vaccination are reduced in patients with hematologic malignancies compared to patients with solid cancer.Cancer Cell. 2022; (published online Dec 29.)https://doi.org/10.1016/j.ccell.2021.12.013Google Scholar Among 79 patients with blood cancer, after two vaccine doses, nAbT against omicron was detectable in 15 (19%) patients (appendix p 4), whereas nAbT against delta was detetable in 31 (39%) patients (McNemar test, p=0·0002) and nAbs against WT SARS-CoV-2 was detectable in 31 (89%) patients (p<0.0001).2 Among the 84 patients who received a third vaccine dose, nAbs against omicron was detectable in 47 (56%) patients, whereas nAbT against delta was detectable in 60 (71%) patients (p=0.0009), and nAbT against WT SARS-CoV-2 was detectable in 72 (86%) patients (p<0·0001).2Fendler A Shepherd STC Au L et al.Immune responses following third COVID-19 vaccination are reduced in patients with hematologic malignancies compared to patients with solid cancer.Cancer Cell. 2022; (published online Dec 29.)https://doi.org/10.1016/j.ccell.2021.12.013Google Scholar Considering the 64 of 79 patients with blood cancer who had undetectable nAbT against omicron after two vaccine doses, 29 (45%) developed nAbs against omicron after the third dose, indicating effective boosting in many patients. The nAbT against omicron correlated with nAbT against WT SARS-CoV-2 and delta, respectively (appendix p 4) but were consistently lower. Overall, our data from patients with cancer highlight the higher immune evasive capacity of omicron than delta, which is consistent with the observations in the general population. We found that a third vaccine dose boosted the neutralising response against omicron in patients with cancer, but the effect was blunted in patients with blood cancer compared to those with solid cancer. Multivariable logistic regression analysis (appendix p 3) confirmed that after three doses, detectable nAbT against omicron was significantly associated with cancer type (solid vs blood cancer odds ratio [OR] 7·51 [95% CI 4·05–14·63], p<0·001) but not age, sex, or the vaccine type administered as first and second dose (BNT162b2 vs ChAdOx1). In a separate multivariable logistic regression analysis, we considered only patients with blood cancer. Treatment with anti-CD20 monoclonal antibodies within 12 months, and Bruton's tyrosine kinase inhibitors (BTKi) within 28 days of the third vaccine dose was significantly associated with undetectable nAbT against omicron (OR 0·04 [95% CI 0·003–0·21], p=0·0074. None of ten patients who received anti-CD20 and one of five patients who received BTKi had detectable nAbT against omicron following three vaccine doses. The presence of progressive disease versus complete response following the most recent anticancer treatment was also significantly associated with undetectable NAbT against omicron (OR 0·08 [95% CI 0·01–0·46], p=0·027). Blood cancer subtype, vaccine type administered as first and second dose, and age were not significantly associated with detectable NAbT against omicron. Finally, we evaluated omicron nAbT in four patients with a history of breakthrough delta infection after two vaccine doses. The time from the second vaccine dose to infection ranged from 112 to 176 days. COVID-19 symptoms were mild (n=3 patients, WHO COVID-19 severity index 2–3, including fever [n=2], coryza [n=2], cough [n=2]), and one patient was asymptomatic. None of the patients had detectable nAbT against omicron or delta2) before infection. Following infection, all patients developed detectable nAbT against omicron (as well as delta2Fendler A Shepherd STC Au L et al.Immune responses following third COVID-19 vaccination are reduced in patients with hematologic malignancies compared to patients with solid cancer.Cancer Cell. 2022; (published online Dec 29.)https://doi.org/10.1016/j.ccell.2021.12.013Google Scholar; appendix p 5), suggesting that two vaccine doses and a third antigenic challenge via delta infection can lead to a functional immune response against omicron.6Wu M Wall EC Carr EJ et al.Three-dose vaccination elicits neutralising antibodies against omicron.Lancet. 2022; (published online Jan 19.)https://doi.org/10.1016/S0140-6736(22)00092-7Google Scholar There are limitations to our study. Additional subgroup analyses were limited by the heterogeneity and size of the blood cancer cohort and will require more patients. The exact correlates of immune protection against VOC remain undefined; however, multiple studies have shown that higher nAbT correlate with reduced risk of symptomatic infection.10Cromer D Steain M Reynaldi A et al.Neutralising antibody titres as predictors of protection against SARS-CoV-2 variants and the impact of boosting: a meta-analysis.Lancet Microbe. 2022; 3: e52-e61Google Scholar, 11Khoury DS Cromer D Reynaldi A et al.Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection.Nature Med. 2021; 27: 1205-1211Google Scholar Finally, we did not evaluate vaccine-induced cellular responses to omicron as we had for other VOCs.2 We note that emerging reports suggest T-cell responses against omicron remain comparable to ancestral variants in the general population without cancer.12Gao Y Cai C Grifoni A et al.Ancestral SARS-CoV-2-specific T cells cross-recognize Omicron.Nature Med. 2022; (published online Jan 14.)https://doi.org/10.1038/s41591-022-01700-xGoogle Scholar, 13GeurtsvanKessel CH Geers D Schmitz KS et al.Divergent SARS CoV-2 Omicron-specific T- and B-cell responses in COVID-19 vaccine recipients.medRxiv. 2021; (published online Dec 29.) (preprint).https://doi.org/10.1101/2021.12.27.21268416Google Scholar In conclusion, we show that most of the patients with cancer in the CAPTURE cohort lacked detectable nAbT against omicron following two vaccine doses, independent of the vaccine type. A third dose of BNT162b2 resulted in a significant increase in patients with nAbT against omicron. Whereas only a few patients with solid cancer lacked nAbT against omicron after three vaccine doses, a substantial proportion of patients with blood cancer, especially those on B-cell-depleting therapies or with progressive cancer, did not mount a detectable response. We previously showed that T-cell responses against delta are detected in patients with cancer even in the absence of humoral response.1Fendler A Shepherd STC Au L et al.Adaptive immunity and neutralizing antibodies against SARS-CoV-2 variants of concern following vaccination in patients with cancer: the CAPTURE study.Nature Cancer. 2021; (published online Oct 27.)https://doi.org/10.1038/s43018-021-00274-wGoogle Scholar T cells probably continue to offer a degree of protection against severe COVID-19, and we note that ancestral SARS-CoV-2-specific T cells cross-recognise omicron.12 Given the high transmissibility and current prevalence of omicron, continued mask-wearing, physical distancing, and vaccination of close contacts will be crucial to protecting patients with blood cancer. Further, early treatment with neutralising monoclonal antibodies⁶ or antivirals might be beneficial and are being deployed to vulnerable patient groups in the UK.14UK Department of Health and Social CarePress release: UK's most vulnerable people to receive life-saving COVID-19 treatments in the community.https://www.gov.uk/government/news/uks-most-vulnerable-people-to-receive-life-saving-covid-19-treatments-in-the-communityDate: Dec 8, 2021Date accessed: December 14, 2021Google Scholar The incremental benefit of a third vaccine dose in boosting nAb responses in patients with blood cancer lends support for a fourth dose in this population, as per UK guidance at the time of writing. For UK guidance on booster vaccine see https://www.nhs.uk/conditions/coronavirus-covid-19/coronavirus-vaccination/coronavirus-booster-vaccine/ For UK guidance on booster vaccine see https://www.nhs.uk/conditions/coronavirus-covid-19/coronavirus-vaccination/coronavirus-booster-vaccine/ DC has received institutional grant funding from MedImmune/AstraZeneca, Clovis, Eli Lilly, 4SC, Bayer, Celgene, Leap, Roche. DLVB has received grant funding from AstraZeneca. CS is funded by CRUK (TRACERx, PEACE and CRUK Cancer Immunotherapy Catalyst Network), the CRUK Lung Cancer Centre of Excellence (C11496/A30025), the Rosetrees Trust, Butterfield and Stoneygate Trusts, the Novo Nordisk Foundation (ID16584), a Royal Society Professorship Enhancement award (RP/EA/180007), the National Institute of Health Research (NIHR) Biomedical Research Centre at University College London Hospitals, the CRUK University College London Centre, the Experimental Cancer Medicine Centre and the Breast Cancer Research Foundation (BCRF 20-157). This work was supported by a Stand Up To Cancer‐LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational research grant (SU2C-AACR-DT23-17 to SMD and AES). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C. CS received an ERC Advanced Grant (PROTEUS) from the European Research Council under the European Union's Horizon 2020 research and innovation programme (835297). CS is a Royal Society Napier Research Professor (RP150154). ST is funded by Cancer Research UK (A29911); the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC10988), the UK Medical Research Council (FC10988), and the Wellcome Trust (FC10988); the NIHR Biomedical Research Centre at the Royal Marsden Hospital and Institute of Cancer Research (grant reference number A109), the Royal Marsden Cancer Charity, The Rosetrees Trust (A2204), Ventana Medical Systems (grant reference numbers 10467 and 10530), the National Institute of Health (U01 CA247439) and Melanoma Research Alliance (686061). 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 PCTGB2018/051893 and Clear Cell Renal Cell Carcinoma Biomarkers P113326GB. All other authors declare no competing interests. AF, STCS, LA, MW, and RH contributed equally. Download .pdf (.85 MB) Help with pdf files Supplementary appendix