key: cord-1030058-zholecuu authors: Jiménez, Moraima; Roldán, Elisa; Fernández-Naval, Candela; Villacampa, Guillermo; Martinez-Gallo, Mónica; Medina-Gil, Daniel; Peralta-Garzón, Soraya; Pujadas, Gemma; Hernández, Cristina; Pagès, Carlota; Gironella, Mercedes; Fox, Laura; Orti, Guillermo; Barba, Pere; Pumarola, Tomás; Cabirta, Alba; Catalá, Eva; Valentín, Mercedes; Marín-Niebla, Ana; Orfao, Alberto; González, Marcos; Campins, Magda; Ruiz-Camps, Isabel; Valcárcel, David; Bosch, Francesc; Hernández, Manuel; Crespo, Marta; Esperalba, Juliana; Abrisqueta, Pau title: Cellular and humoral immunogenicity of the mRNA-1273 SARS-CoV-2 vaccine in patients with hematologic malignancies date: 2021-12-01 journal: Blood Adv DOI: 10.1182/bloodadvances.2021006101 sha: e7892842c2caecbc897e3844e8706ca22e889840 doc_id: 1030058 cord_uid: zholecuu Recent studies have demonstrated a suboptimal humoral response to SARS-CoV-2 mRNA vaccinesin patients diagnosedwith hematologic malignancies, however data about cellular immunogenicity is scarce. In this study we aimed to evaluate both the humoral and cellular immunogenicity one month after the second dose ofthe mRNA-1273 vaccine. Antibody titers were measured by the Elecsys and LIAISON Anti-SARS-CoV-2 S assay while T-cell response was assessed by Interferon-Gamma-Release-immuno-Assay technology.Overall, 76.3% (184/241)of patients developed humoral immunity and the cellular response rate was 79% (184/233).Hypogammaglobulinemia, lymphopenia, active hematological treatmentand anti-CD20 therapy during the last 6 months were associated with an inferior humoral response. Conversely,age over 65 years, active disease, lymphopenia and immunosuppressive treatment for GvHD were associated with an impaired cellular response.A significant dissociation between humoral and cellular response was observed in patients treated with anti-CD20 therapy, being the humoral response of 17.5% whereas the cellular response was 71.1%. In these patients B-cell aplasia was confirmed whileT cell counts were preserved. In contrast, humoral response was observed in 77.3% of patients under immunosuppressivetreatment for GvHD, while only 52.4% had cellular response.The cellular and humoral response to the SARS-CoV-2 mRNA-1273 vaccine in patients with hematological malignancies is highly influenced by the presence of treatments like anti-CD20 therapy and immunosuppressive agents. This observation has implications for the further management of these patients. showing the worst response. 12-18 Humoral immunogenicity seems mainly impaired by B-104 cell directed therapies such as Bruton's tyrosine kinase (BTK) inhibitors or anti-CD20 7 monoclonal antibodies with rates of seroconversion from 0 to 21% within 2-8 weeks 106 following two doses of the vaccine. 12 Therefore, the objective of our study was to evaluate immunogenicity (including both 116 cellular and humoral response) one month after a second dose of the mRNA-1273 SARS- The study cohort was the entire pool of patients diagnosed with lymphoid neoplasia, 145 monoclonal gammopathies and patients who underwent allogeneic stem cell 146 transplantation (allo-SCT) from 2015 to 2021 at the Vall d'Hebron Hematology department. 147 The median time from transplant to vaccination was 29.6 months (range 3.7-70.3 months). 148 They voluntarily accepted to participate in the study and to receive the complete scheme 149 of vaccination (n=270). 150 To assess the humoral immune response to the vaccine two commercial For original data, please contact the corresponding author. 182 A total of 270 patients were included in this study. Patients' baseline demographic and 185 clinical characteristics are summarized in Table 1 . The median age of the patients was 63 186 years (IQR 53-71 years) and 137 patients (51.5%) were female. 187 In subsequent analysis patients were divided into two different subgroups. First, the cohort 188 of lymphoid malignancies and MM (n=200), the underlying malignancy was lymphoma in 189 42.5% (n=85) of the patients, followed by MM in 31.5% (n=63) and CLL in 26% (n=52). 190 Secondly, patients that had undergone an allo-SCT (n=70) were considered a different 191 subgroup regardless of malignancy due to their specific immunological situation and the 192 immunosuppressive therapy used to prevent or treat graft versus host disease (GvHD). 193 In the cohort of lymphoid malignancies and MM, 65% of the patients were on active 194 therapy or had been previously treated within the prior 6 months. Of those, 47 (36.2%) 195 patients were exposed to anti-CD20 therapy in monotherapy or associated with Table 2 ). In the case of lymphoma patients, the cellular response was preserved, 75% 276 In our series, significant dissociation between humoral and cellular response was mainly 290 observed in two scenarios, lymphoma patients treated with anti-CD20 therapy and in the 291 context of immunosuppressive therapy for GvHD (Figure 3) . 292 In the case of lymphoma patients (n=40) treated with anti-CD20 (humoral response of 293 17.1% and cellular response of 70%), the discordance rate between responses was 294 67.5%. A 60% (24/40) of patients obtained cellular but not humoral response and only a 295 7.5% (3/40) obtained humoral but not cellular response. Only 10% (4/40) of the patients 296 presented both cellular and humoral response and 22.5% (9/40) did not develop any 297 response to the vaccine. 298 Regarding allo-SCT patients with immunosuppressive therapy for GvHD (n=21), the 299 discordance rate was 28.6% because 6 patients developed only humoral response. We 300 observed that 52.4% (11/21) of patients presented both humoral and cellular response and 301 19% (4/21) did not develop any response to the vaccine. 302 In view of these results, we hypothesized that the main cause of impaired serological 303 response in patients treated with anti-CD20 was the presence of B cell aplasia before 304 vaccination. Subsequently, and in order to confirm this hypothesis, we studied the 305 lymphoid subpopulations by immunophenotyping of cryopreserved PBMCs obtained 306 before vaccination in 40 lymphoma patients under treatment in the last 6 months with anti-307 CD20. We observed that 92% (37/40) of these patients presented a low count of CD19+ 308 lymphocytes with just 18% of them (7/40) developing specific anti-spike antibodies. 309 Conversely, 75% of these patients (30/40) had preserved CD3+ counts and if we selected 310 only the patients that had received anti-CD20 therapy alone without associated 311 chemotherapy the value was higher as 85% (23/27). In accordance with these data, a 312 cellular response of 83% was observed in patients with normal CD3+ counts, while only 313 In the allo-SCT cohort we found a normal CD19+ count in 79.2% (38/48) of the patients 316 who achieved a humoral response. Conversely, 4 out of 11 (36.4%) patients with abnormal 317 CD19+ count did not develop humoral response after vaccination. 318 It appears that the cellular response in allo-SCT may be influenced by the number of 319 CD4+, we found that those patients who had low level of CD4+ presented a lower 320 response to the vaccine (44.4% vs. 77.3%) (Figure 1) . 321 Finally, we observed that 10 out of 16 (62.5%) cellular non-responders were on treatment 322 with immunosuppressive drugs for GvHD. Impaired humoral response, predominantly with BNT162b2 mRNA vaccine has also been 338 described in patients with hematologic malignancies, 12-20,28-29 particularly in B-cell 339 neoplasms, and especially in the context of different immunosuppressive treatments. In 340 our cohort patients with lymphoma, current treatment or treatment during the last 6 341 months, treatment with anti-CD20 monoclonal antibodies, lymphopenia and low levels of 342 immunoglobulins at the time of vaccination were significantly associated with an inferior 343 humoral response. In agreement with our finding of a 53.4% humoral response in 344 lymphoma patients, Ghione and Lim et al. 18, 19 have also reported a low serological 345 response rate in this population. In our series, the main factor associated with the inferior 346 humoral response was treatment with anti-CD20 therapy. In those patients we observed 347 the lowest rate of seroconversion, with only 17.1% developing antibodies; this response 348 Outcomes of patients with hematologic 464 malignancies and COVID-19: a systematic review and meta-analysis of 3377 465 patients COVID-19 in Immunocompromised Hosts: What We Know So 467 Clinical characteristics and risk factors 469 associated with COVID-19 severity in patients with haematological malignancies in 470 Italy: a retrospective, multicentre, cohort study COVID-19 in persons with haematological cancers Patterns of seroconversion for SARS-CoV-475 IgG in patients with malignant disease and association with anticancer 476 therapy Failure to Develop Anti-SARS-CoV-2 Antibodies During Rituximab Maintenance 479 Therapy for Follicular Lymphoma Short term results of vaccination with 482 adjuvanted recombinant varicella zoster glycoprotein E during initial BTK inhibitor 483 therapy for CLL or lymphoplasmacytic lymphoma Effect of Bruton tyrosine kinase inhibitor on 486 efficacy of adjuvanted recombinant hepatitis B and zoster vaccines Immunogenicity and safety of the adjuvanted 489 recombinant zoster vaccine in adults with haematological malignancies Safety and Efficacy of the BNT162b2 493 mRNA Covid-19 Vaccine Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine vaccine in patients with chronic lymphocytic leukemia COVID-19 vaccine efficacy in patients 500 with chronic lymphocytic leukemia Low neutralizing antibody 502 responses against SARS-CoV-2 in older patients with myeloma after the first 503 BNT162b2 vaccine dose Coronavirus Disease 2019 Messenger RNA Vaccines in Patients With Hematologic 506 Malignancies: A Need for Vigilance in the Postmasking Era Antibody responses after first and second 509 Covid-19 vaccination in patients with chronic lymphocytic leukaemia Fifth-week immunogenicity and safety of 512 anti-SARS-CoV-2 BNT162b2 vaccine in patients with multiple myeloma and 513 myeloproliferative malignancies on active treatment: preliminary data from a single 514 institution Antibody responses after SARS-CoV-2 516 vaccination in patients with lymphoma vaccination in patients with lymphoma receiving B-cell directed therapies Immunity to SARS-CoV-2 in Acute COVID-19 and Associations with Age and 522 Antibody and T cell immune 524 responses following mRNA COVID-19 vaccination in patients with cancer Safety and immunogenicity of one versus 527 two doses of the COVID-19 vaccine BNT162b2 for patients with cancer: interim 528 analysis of a prospective observational study Safety and Immunogenicity of the 530 BNT162b2 mRNA Covid-19 Vaccine in Patients after Allogeneic HCT or CD19-531 based CART therapy -a Single Center Prospective Cohort Study Commercialized kits to assess T-cell responses against SARS-CoV-2 S peptides. A pilot study in health care 535 Stable disease/Progressive disease, n (%) 32 (13.4%) Laboratory parameters, median (IQR) Absolute neutrophil count N (%) and antibody test, median (IQR) was expected by the B-cell depletion caused by anti-CD20 and its adverse impact on the 349 production of antibodies. 18-19 350 In CLL, Herishanu et al. 12 demonstrated a humoral response rate of 39.5%; Roeker et al. 13 351 up to 52% and Parry et al. 16 a 75% rate. In these series active treatment with BTK 352 inhibitors and anti-CD20 immunotherapy were correlated with a considerably lower rate of 353 antibody production, while younger age, treatment-naïve disease and absence of active 354 treatment were factors associated with a better humoral response to the vaccine. 12, 13, 16 In 355 our cohort, CLL patients did not demonstrate an inferior response in comparison with other 356 underlying malignancies. 357It should also be noted that in our series, 35% of CLL patients were treatment-naïve and 358 all of them developed antibodies, while 82% of CLL patients with active treatment were 359 receiving BTK inhibitors for a long period of time (median of 18 months). Additionally, 360 89.2% of them had a complete/partial response to treatment for their disease and 57.1% of 361 them had normal levels of immunoglobulins. We observed a high humoral response in 362 patients treated with BTK of 86.7% (data apparently contradictory to that described by 363Herishanu et al. 12 ) however we must highlight that the methodology used to perform the 364 antibody testing is different between the studies and recently published data suggest a 365 higher humoral immunogenicity of the mRNA-1273 vaccine in comparison with the 366 BNT162b2 vaccine in healthy population 30,31 that could explain the higher seroconversion 367 rate in our cohort; we also measured serum anti-SARS-CoV-2 IgG antibodies and verified 368 that this response was quantitatively weaker with lower levels of anti-S antibodies in 369 comparison with treatment-naïve CLL patients (supplementary Figure 1) . The majority (79%) of patients in our series developed cellular response after vaccination 384 regardless of the hematologic disease. Factors associated with lower probability of cellular 385 response included age higher than 65 years, status of the hematologic disease (stable or 386 progressive disease), treatment with chemotherapy +/-anti-CD20 monoclonal antibodies, 387 lymphopenia, or active GvHD and immunosuppressive therapy for GvHD. 388We would like to highlight the significant difference between a suboptimal humoral 389 response and a well-preserved cellular response to the vaccine in lymphoma patients, 390 even if they were under treatment with B-cell depleting therapy such as anti-CD20 391 antibodies. Lymphoma patients achieved a cellular response rate of 75.3%, and 70% in 392 patients treated with antiCD-20 antibodies +/-chemoimmunotherapy during the last 6 393 months. In line with these results, previous data has shown discordance between 394 production of neutralizing antibodies and T cell response in the context of the varicella 395 zoster virus vaccine 33 and more recently in a small number of patients with multiple 396 sclerosis on anti-CD20 therapy receiving SARS-CoV-2 mRNA vaccination. 34 Through a 397 flow-cytometric evaluation of lymphocyte subpopulations we confirmed that among the 398 patients that had received anti-CD20 therapy the B-cell aplasia, 90.1% of the humoral non-399 responders presented a low CD19+ count. Meanwhile, a preserved CD3+ cell count was 400 20 present in 75% of the cellular-responders; chemotherapy-induced leukopenia with a low 401 count of CD3+ influenced the cellular response negatively. In this analysis, we also 402 observed that in the subgroup of allo-SCT the lower cellular response was associated with 403 a lower CD4+ count and with the use of immunosuppressive agents, reflecting both a 404 quantitative and a qualitative T cell defect in these patients.