Fendler, A

Shepherd, STC

Au, L

Wilkinson, KA

Wu, M

Schmitt, AM

Tippu, Z

Farag, S

Rogiers, A

Harvey, R

Carlyle, E

Edmonds, K

Del Rosario, L

Lingard, K

Mangwende, M

Holt, L

Ahmod, H

Korteweg, J

Foley, T

Barber, T

Emslie-Henry, A

Caulfield-Lynch, N

Byrne, F

Shum, B

Gerard, CL

Deng, D

Kjaer, S

Song, O-R

Queval, C

Kavanagh, C

Wall, EC

Carr, EJ

Namjou, S

Caidan, S

Gavrielides, M

MacRae, JI

Kelly, G

Peat, K

Kelly, D

Murra, A

Kelly, K

O'Flaherty, M

Shea, RL

Gardner, G

Murray, D

Yousaf, N

Jhanji, S

Van As, N

Young, K

Furness, AJS

Pickering, L

Beale, R

Swanton, C

Crick COVID19 consortium, .

Gandhi, S

Gamblin, S

Bauer, DLV

Kassiotis, G

Howell, M

Nicholson, E

Walker, S

Wilkinson, RJ

Larkin, J

Turajlic, S

CAPTURE consortium, .

English

UCL Discovery

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Please cite this article in press as: Fendler et al., Immune responses following third COVID-19 vaccination are reduced in patients with hematologicalmalignancies compared to patients with solid cancer, Cancer Cell (2021), https://doi.org/10.1016/j.ccell.2021.12.013llLetterImmuneresponsesfollowingthirdCOVID-19vaccinationare reduced in patients with hematologicalmalignancies compared to patients with solid cancerAnnika Fendler,1,30 Scott T.C. Shepherd,1,2,30 Lewis Au,1,2,30 Katalin A. Wilkinson,3,4,30 Mary Wu,5,30 Andreas M. Schmitt,2Zayd Tippu,1,2 Sheima Farag,2 Aljosja Rogiers,2 Ruth Harvey,6 Eleanor Carlyle,2 Kim Edmonds,2 Lyra Del Rosario,2Karla Lingard,2 Mary Mangwende,2 Lucy Holt,2 Hamid Ahmod,2 Justine Korteweg,2 Tara Foley,2 Taja Barber,1Andrea Emslie-Henry,1 Niamh Caulfield-Lynch,1 Fiona Byrne,1 Benjamin Shum,1,2 Camille L. Gerard,1 Daqi Deng,1Svend Kjaer,7 Ok-Ryul Song,5 Christophe Queval,5 Caitlin Kavanagh,5 Emma C. Wall,3,9 Edward J. Carr,10 Sina Namjou,11Simon Caidan,11 Mike Gavrielides,12 James I. MacRae,13 Gavin Kelly,14 Kema Peat,2 Denise Kelly,2 Aida Murra,2Kayleigh Kelly,2 Molly O’Flaherty,2 Robyn L. Shea,15,16 Gail Gardner,16 Darren Murray,16 Nadia Yousaf,17,18Shaman Jhanji,19 Nicholas Van As,20 Kate Young,2 Andrew J.S. Furness,2 Lisa Pickering,2 Rupert Beale,9,29Charles Swanton,21,22 Crick COVID19 consortium, Sonia Gandhi,23,24 Steve Gamblin,8 David L.V. Bauer,25George Kassiotis,26 Michael Howell,5 Emma Nicholson,27 Susanna Walker,18 Robert J. Wilkinson,3,4,28 James Larkin,2Samra Turajlic,1,2,* and CAPTURE consortium1Cancer Dynamics Laboratory, The Francis Crick Institute, London, NW1 1AT, UK2Skin and Renal Units, The Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK3Tuberculosis Laboratory, The Francis Crick Institute, London, NW1 1AT, UK4Wellcome Center for Infectious Disease Research in Africa, University of Cape Town, Observatory 7925, Republic of South Africa5High Throughput Screening Laboratory, The Francis Crick Institute, London, NW1 1AT, UK6Worldwide Influenza Centre, The Francis Crick Institute, London, NW1 1AT, UK7Structural Biology STP, The Francis Crick Institute, London NW1 1AT, UK8Structural Biology of Disease Processes Laboratory, The Francis Crick Institute, London, NW1 1AT, UK9University College London Hospitals NHS Foundation Trust Biomedical Research Centre, London, WC1E 6BT, UK10Cell Biology of Infection Laboratory, The Francis Crick Institute, London, NW1 1AT, UK11Safety, Health & Sustainability, The Francis Crick Institute, London, NW1 1AT, UK12Scientific Computing Scientific Technology Platform, The Francis Crick Institute, London, NW1 1AT, UK13Metabolomics Scientific Technology Platform, The Francis Crick Institute, London, NW1 1AT, UK14Department of Bioinformatics and Biostatistics, The Francis Crick Institute, London, UK15Department of Pathology, The Royal Marsden NHS Foundation Trust, London, NW1 1AT, UK16Translational Cancer Biochemistry Laboratory, The Institute of Cancer Research, London, SW7 3RP, UK17Lung Unit, The Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK18Acute Oncology Service, The Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK19Anaesthetics, Perioperative Medicine, and Pain Department, The Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK20Clincal Oncology Unit, The Royal Marsden NHS Foundation Trust, London, NW1 1AT, UK21Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, NW1 1AT, UK22University College London Cancer Institute, London WC1E 6DD, UK23Neurodegeneration Biology Laboratory, The Francis Crick Institute, London, NW1 1AT, UK24UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK25RNA Virus Replication Laboratory, The Francis Crick Institute, London, NW1 1AT, UK26Retroviral Immunology Laboratory, The Francis Crick Institute, London, NW1 1AT, UK27Haemato-oncology Unit, The Royal Marsden NHS Foundation Trust, London, SW3 6JJ, UK28Department of Infectious Disease, Imperial College London, London, W12 0NN, UK29Division of Medicine, University College London, London NW1 2PG, UK30These authors contributed equally*Correspondence: samra.turajlic@crick.ac.ukhttps://doi.org/10.1016/j.ccell.2021.12.013Patients with cancer are at higher risk ofsevere COVID-19 (Grivas et al., 2021; Ku-derer et al., 2020), and they are currentlyprioritized globally for a third COVID-19vaccine dose. Humoral and cellular im-mune responses are detected after twoprimary COVID-19 vaccine doses inmost patients with cancer (Ehmsenet al., 2021; Fendler et al., 2021; Oostinget al., 2021), although neutralizing re-sponses against variants of concern(VOCs) are reduced. Neutralizing re-sponses are frequently impaired in pa-tients with hematological malignancies,especially those receiving B cell-depleting therapies (Ehmsen et al.,2021; Fendler et al., 2021; Thakkaret al., 2021). Because neutralizing anti-body (NAb) responses are directly asso-ciated with vaccine efficacy (Gilbertet al., 2021; Khoury et al., 2021), thesepatients without a neutralizing responseare at higher risk of breakthrough infec-tions (Hippisley-Cox et al., 2021). Here,Cancer Cell 40we report follow-up results fromCAPTURE (NCT03226886), a longitudi-nal, prospective cohort study of vaccineresponse in patients with cancer, relativeto the duration of response after twodoses of either the BNT162b2 (Pfizer)or ChAdOx1 (AstraZeneca) vaccine;and following third vaccination withBNT162b2. We present data on NAband T cell responses against wholelive virus, including wild-type SARS-CoV-2 (WT), Beta, and Delta VOCs. We, February 14, 2022 ª 2021 Elsevier Inc. 1LetterllPlease cite this article in press as: Fendler et al., Immune responses following third COVID-19 vaccination are reduced in patients with hematologicalmalignancies compared to patients with solid cancer, Cancer Cell (2021), https://doi.org/10.1016/j.ccell.2021.12.013specifically evaluated responses to Betaand Delta given their known immune-evasive capacity.We assessed the durability of NAb re-sponses in 353 patients (77% [n = 271]with solid cancer and 23% [n = 82]with he-matological malignancies; Table S1)following two doses of COVID-19 vaccine(72% [n = 255] ChAdOx1 and 28% [n =98] BNT162b2). NAbs against WT wereundetectable after 14–28 days and up to110 days (range 84–153) following the sec-ond dose in 4% (n = 12) of patients withsolid cancer and 30% (n = 25) of patientswith hematological malignancies. In thosewho initially had detectable post-second-dose NAb against WT (n = 316, 71%against Beta, and 62% against Delta), weobserved a time-dependent decline inNAb titers (NAbT) during follow-up (me-dian of 111 days, range 37–252 days afterthe second vaccine dose; Figure S1A). Af-ter an initial response to two vaccinedoses, in patients with solid cancer (n =259), 1% (n = 3) had undetectable NAbsagainst WT, 16% (n = 43) against Beta,and 18% (n = 47) against Delta; in patientswith hematological malignancies (n = 57),7% (n = 4) had undetectable NAbT againstWT, 9% (n = 5) against Beta, and 16%(n = 9) against Delta. The proportions ofthosewithwaningNAbdid not differ signif-icantly among patients with solid cancer orhematological malignancies apart fromWT (Chi2 test: WT, p value = 0.02; Beta,p value = 0.16; Delta, p value = 0.67).We previously reported that T cell re-sponses, measured 14–28 days after thesecond dose, are comparable betweenpatients with solid cancer and hematolog-ical malignancies and can also be de-tected in those without NAb responses(Fendler et al., 2021). During follow-up(median of 93 days [range: 63–171 days]after the second dose), we evaluatedT cell responses in 55 patients. Patientswithout a detectable T cell responsefollowing the second dose remainednegative. In those with an initial response(n = 43 with solid cancer and n = 12 withhematological malignancy; Figure S1B),it was maintained in 49% (n = 21) of pa-tients with solid cancer and 42% (n = 5)with hematological malignancies (Wil-coxon signed rank test, p = 0.56).During the course of routine clinicalcare, eight CAPTURE participants (n = 7with solid cancer and n = 1 with hemato-logical malignancies) were diagnosed2 Cancer Cell 40, February 14, 2022with SARS-COV-2 following two vaccinedoses between July and October 2021(median time between second vaccinedose and infection: 118 days [range: 59–173]), and these were likely to have beencaused by the Delta variant that was domi-nant in the UK at that time. The symptomswere either mild (n = 7 patients; WHOseverity score 2–3; fever [n = 5], coryza[n = 4], anosmia [n = 4], and cough [n =3]) or absent (n = 1 patient), no patientrequiring hospital care, and all recovered.We evaluated immune responses prior toinfection following two vaccine doses;although all patients had detectableNAbT against WT SARS-CoV-2, only onehad detectable NAbT against Delta.Following infection, all patients mounteddetectable neutralizing responses to Delta(Figure S1C). T cell responses were evalu-able in five patients prior to infection and inseven patients following infection.Although only 1/5 patients had detectableT cell responses to WT prior to infection,5/7 had a detectable T cell responsesfollowing infection, including 2/4 patientswho had undetectable T cell responsesbefore infection (Figure S1D).We next evaluated 199 cancer patients(n = 115 [58%] with solid cancer) whoreceived a third vaccine dose per UKguidelines. Patients who tested positiveviaRT-PCR forSARS-CoV-2between theirsecond and third doses were excludedfrom this analysis. All patients received athird dose of BNT162b2 following twodoses of either BNT162b2 (33%) or ChA-dOx1 (67%) (Table S1). The median timebetween second and third vaccine dosewas176days (range65–274days), and im-mune responses were measured at a me-dian of 23 days after the third dose (range:11–47 days). Prior to the third dose, 88%(n = 176) had detectable NAb against WT,but given the dominance of Delta, weconsidered all patients with undetectableNAb against Delta to be ‘‘non-responders’’to two doses (51% [n = 102]; 43% [n = 50]of patients with solid cancer and 62%[n = 52] of patients with hematologicalmalignancy; Table S1).Considering non-responders to Deltaafter two vaccine doses, in solid cancerpatients (n = 50), following the thirddose, 94% (n = 47) had detectable NAbagainst Delta and 88% (n = 44) againstBeta (Figure S1E); in patients with hema-tological malignancy (n = 52), followingthe third dose, 54% (n = 28) had detect-able NAb against Delta and 54% (n = 28)against Beta. The proportion of thosewith detectable NAb after third dose wassignificantly higher in patients with solidcancer (Chi2 test: Beta, p value =0.0002; Delta, p value < 0.0001). Finally,following the third dose, we observed anincrease in median NAbT against all vari-ants in initial responders (patients withdetectable NAbs against Delta after twovaccine doses).Our data indicate that a third vaccinedose can generate NAb in patients whoare non-responders following two doses,and it further boosts NAbT against VOCsin responders. However, the proportionof patients with hematological malig-nancies who have undetectable NAbTagainst Delta following the third vaccinedose remains significant (46%).Multivariable binary regression analysisshowed that the presence of hematologi-cal malignancy was significantly associ-ated with undetectable NAb againstBeta or Delta after the third dose (vari-ables included: cancer type, age, primaryvaccine type, and sex). Considering pa-tients with hematological malignanciesin a further multivariable analysis (seeTable S1 for included variables), primaryvaccination with BNT162b2 (n = 17)versus ChAdOx1 (n = 35) was significantlyassociated with lack of neutralizingresponses against Beta and Delta(BNT162b2: Delta, 29% [n = 5]; Beta,35% [n = 6]. ChAdOx1: Delta, 66%[n = 23]; Beta, 63% [n = 22]), and theseresults suggest a benefit of the heterolo-gous vaccination approach. Followingthe third vaccine dose, in patients whohad received anti-CD20 in the 12 monthsprior to the first vaccine dose, 1/6had detectable NAbT against Deltaand 2/6 against Beta. In the group ofpatients who commenced anti-CD20therapy between the second and thirddose, 3/4 patients had detectable NAbTagainst Delta and Beta following the thirddose.Following stimulation with WT, Beta,and Delta spike-specific peptide pools,T cell responses were measured usingIFN-y ELISPOT (Fendler et al., 2021) in asubset of 48 patients (69% [n = 33] withsolid cancer) who are representative ofthe cohort that received a third dose. Priorto third dose, 33% (n = 11) of patients withsolid cancer and 40% (n = 6) of patientswith hematological malignancies hadLetterllPlease cite this article in press as: Fendler et al., Immune responses following third COVID-19 vaccination are reduced in patients with hematologicalmalignancies compared to patients with solid cancer, Cancer Cell (2021), https://doi.org/10.1016/j.ccell.2021.12.013detectable T cell responses. Following thethird vaccine dose, this rose to 73% (n =24) and 73% (n = 11), respectively. Thenumber of Spot Forming Units (SFU)/106was significantly increased after the thirddose relative to post-second dose(Figure S1F).Our data show that a third dose ofCOVID-19 vaccine boosts NAb responsesin patients with cancer, including thosethat had undetectable NAbT followingtwo vaccine doses or for whom NAbTwaned. We found that NAbT were higherin patients who received two doses ofChAdOx1 and a third dose of BNT162b2compared to three doses of BNT162b2.Further, we show that T cell responsesare amplified following the third vaccinedose, and this likely offers additional pro-tection—especially in individuals with lowor absent neutralizing responses. Encour-agingly, the proportion of patients withsolid cancer who had detectable re-sponses after third vaccination is highand comparable to individuals withoutcancer. In contrast, a significant numberof patients with hematological malig-nancies still had undetectable neutralizingresponses following a third vaccine dose,especially against VOCs, and remain atrisk of breakthrough infection. These find-ings are particularly pertinent given re-ports of reduced vaccine efficacy andNAb activity against the emerging Omi-cron VOC compared to Delta (Celeet al., 2021).SUPPLEMENTAL INFORMATIONSupplemental information can be found online athttps://doi.org/10.1016/j.ccell.2021.12.013.DECLARATION OF INTERESTSThe authors declare no competing interests.REFERENCESCele, S., Jackson, L., Khan, K., Khoury, D.S.,Moyo-Gwete, T., Tegally, H., Scheepers, C.,Amoako, D., Karim, F., Bernstein, M., et al.(2021). 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Immune responses following third COVID-19 vaccination are reduced in patients with hematological malignancies compared to patients with solid cancer

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Immune responses following third COVID-19 vaccination are reduced in patients with hematological malignancies compared to patients with solid cancer

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