key: cord-0758358-8r7hnpij authors: Piñana, José Luis; López‐Corral, Lucia; Martino, Rodrigo; Montoro, Juan; Vazquez, Lourdes; Pérez, Ariadna; Martin‐Martin, Gabriel; Facal‐Malvar, Ana; Ferrer, Elena; Pascual, María‐Jesús; Sanz‐Linares, Gabriela; Gago, Beatriz; Sanchez‐Salinas, Andrés; Villalon, Lucia; Conesa‐Garcia, Venancio; Olave, Maria T.; López‐Jimenez, Javier; Marcos‐Corrales, Sara; García‐Blázquez, Marta; Garcia‐Gutiérrez, Valentín; Hernández‐Rivas, José Ángel; Saus, Ana; Espigado, Ildefonso; Alonso, Carmen; Hernani, Rafael; Solano, Carlos; Ferrer‐Lores, Blanca; Guerreiro, Manuel; Ruiz‐García, Montserrat; Muñoz‐Bellido, Juan Luis; Navarro, David; Cedillo, Angel; Sureda, Anna title: SARS‐CoV‐2‐reactive antibody detection after SARS‐CoV‐2 vaccination in hematopoietic stem cell transplant recipients: Prospective survey from the Spanish Hematopoietic Stem Cell Transplantation and Cell Therapy Group date: 2021-11-02 journal: Am J Hematol DOI: 10.1002/ajh.26385 sha: e9fc12115fcb1c287eb1eab3b7050b76d77f4bde doc_id: 758358 cord_uid: 8r7hnpij This is a multicenter prospective observational study that included a large cohort (n = 397) of allogeneic (allo‐HSCT; (n = 311) and autologous (ASCT) hematopoietic stem cell transplant (n = 86) recipients who were monitored for antibody detection within 3–6 weeks after complete severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccination from February 1, 2021, to July 20, 2021. Most patients (n = 387, 97.4%) received mRNA‐based vaccines. Most of the recipients (93%) were vaccinated more than 1 year after transplant. Detectable SARS‐CoV‐2‐reactive antibodies were observed in 242 (78%) of allo‐HSCT and in 73 (85%) of ASCT recipients. Multivariate analysis in allo‐HSCT recipients identified lymphopenia < 1 × 10(9)/ml (odds ratio [OR] 0.33, 95% confidence interval [95% CI] 0.16–0.69, p = .003), active graft versus host disease (GvHD; OR 0.51, 95% CI 0.27–0.98, p = .04) and vaccination within the first year of transplant (OR 0.3, 95% CI 0.15–0.9, p = .04) associated with lower antibody detection whereas. In ASCT, non‐Hodgkin's lymphoma (NHL; OR 0.09, 95% CI 0.02–0.44, p = .003) and active corticosteroid therapy (OR 0.2, 95% CI 0.02–0.87, p = .03) were associated with lower detection rate. We report an encouraging rate of SARS‐CoV‐2‐reactive antibodies detection in these severe immunocompromised patients. Lymphopenia, GvHD, the timing of vaccine, and NHL and corticosteroids therapy should be considered in allo‐HSCT and ASCT, respectively, to identify candidates for SARS‐CoV‐2 antibodies monitoring. The coronavirus infectious disease 2019 (COVID-19) pandemic caused by the new zoonotic coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) is causing a massive impact globally, including patients with hematological malignancies and recipients of hematopoietic stem cell transplantation (HSCT) whose overall mortality exceeds 25%. [1] [2] [3] [4] [5] [6] Vaccination is expected to mitigate the severe course of COVID- 19 in immunocompromised patients such as recipients of autologous stem cell transplantation (ASCT) and allogeneic HSCT (allo-HSCT) recipients. However, prior experience with influenza vaccines indicated a lower serological response in immunocompromised patients compared to healthy individuals. [7] [8] [9] [10] Despite these observations, influenza vaccination showed clinical benefit in allo-HSCT recipients. 11 New vaccine technologies led to the development of mRNA vaccines which could improve efficacy and robustness of serological response in immunocompromised patients as seen in the general population (> 90% seroconversion rates). [12] [13] [14] Initial reports on antibody response after full SARS-CoV-2 vaccination in hematological patients confirm the lower antibody response rates compared to the general population. 15 This is a prospective observational multicenter registry study conducted by the Infectious Complications Subcommittee (GRUCINI) of the GETH-TC in collaboration with the Spanish Society of Hematology and Hemotherapy. The local ethical committee of the Hospital Clínico Universitario of Valencia approved the registry and study protocol (reference code 35.21). This multicenter registry included consecutive adult patients with a prior history of hematological malignancies who were vaccinated against SARS-CoV-2 from December 30, 2020, to June 30, 2020, in 21 participating Spanish centers. All patients included in this registry gave their signed informed consent according to the declaration of Helsinki. The primary objectives of the current registry are (i) the assessment of antibody detection at 3-6 weeks, and its durability at 3, 6, and 12 months after full dose vaccination with any type of SARS-CoV-2 vaccines; (ii) to clinically monitor these patients for the occurrence of symptomatic COVID-19 after vaccination; (iii) and, finally, to assess the timing and the side effects of these vaccines in this immunocompromised population in Spain. Adult patients with a history of hematological malignancy were prioritized for early vaccination with any available SARS-CoV-2 vaccine type by the Spanish health authorities on March 11, 2021. The status of all included patients was updated on July 30, 2021. During the study period, hematological patients vaccinated against COVID-19 from participating centers were prospectively registered through REDCap online platform in the GETH database by completing an essential medical data form, including patient and disease characteristics, date of vaccination, type of vaccination, self-reported adverse events (AEs) after vaccination, prior history of COVID-19, serological status before vaccination, the serological response at 3 week and at 3, 6, and 12 months after complete vaccination, and data regarding characteristics of later COVID-19 when applicable. Details on the treatment(s) of the underlying malignancy, conditioning regimens, type of donor, graft versus host disease (GvHD) prophylaxis, immunosuppressive drugs, GvHD status, and status disease at the time of vaccination were also registered. Also baseline laboratory variables before SARS-CoV-2 vaccination (absolute lymphocyte and neutrophil counts) were also collected. As of July 30, 2021, 1546 patients with hematological malignancies who had been fully vaccinated against COVID-19 were registered in the GETH-TC database. With the aim of assessing antibody detection rates and its predictive factors in HSCT recipients, we first identified 457 such patients in our database. Sixty patients were finally excluded since they did not have a serological assessment at 3-6 weeks after complete vaccination. Thus, only recipients with available serological testing 3-6 weeks after full vaccination were included (n = 397). CAR-T recipients were excluded from this study. The protective threshold levels of anti-SARS-CoV-2 antibodies below which the humoral defense against different SARS-CoV-2 variants is suboptimal have not been established yet. We defined antibody detection or seropositivity when SARS-CoV-2-reactive IgG antibodies recognition at any level was above the lower limit level of detection for each of the tests used. The rate of SARS-CoV-2-reactive IgG antibodies seroconversion was analyzed in the subgroup of patients with documented negative SARS-CoV-2 serostatus within 2 weeks prior to the first vaccine dose. We assessed seropositivity using serological ELISA or chemiluminescence immunoassay assays following manufacturer instructions according to their availability at the microbiology services of each participating center. Table S1 summarizes the technical characteristics of serological tests used. All test used in the microbiology departments in the participating Spanish centers were able to detect SARS-CoV-2-reactive IgG antibodies. Overall results were reported as positive or negative detection. However, in a relevant number of cases (n = 163), antibody assessment was per- The primary objective of the study was to assess seropositivity rates in HSCT recipients at 3-6 weeks after full COVID-19 vaccination. We also analyzed potential predictive factors for SARS-CoV-2-reactive IgG antibodies detection in each subgroup of recipients. The main characteristics of patients were reported by descriptive statistics on the total of the available information, median and range were used for continuous variables, while absolute and percentage frequency were used for categorical variables. Variables of interest were tested using logistic regression models. Variables with a p-value < .1 in the univariate model were included in the multivariate analysis. A p-value < .05 was considered statistically significant. All p-values are two-sided. A median test subanalysis to check variables associated with the amount of antibodies production was carried out in patients with available quantitative anti-S1 IgG titers expressed as BAU/ml. All the analyses were performed using the statistical software SPSS v. 25. Overall, the most common hematological disease was acute myeloid leukemia (n = 112, 36%) followed by multiple myeloma (MM; n = 66, 16 .6%) and non-Hodgkin's lymphoma (NHL; (n = 63, 14.6%). ASCT recipients were significantly older, most of them being We performed a logistic regression univariate analysis of variables that could influence antibody production in allo-HSCT and ASCT recipients. Table 2 Twenty-six patients ( T A B L E 3 Logistic regression and median test analyses of anti-S1 IgG serostatus and titers after full vaccination Schedule in allo-HSCT recipients according to conditions potentially associated with antibody production 3.5 | Anti-S1 IgG antibody titers in allo-HSCT recipients To assess, in a homogeneous cohort, the magnitude of anti-S1 IgG titers at 3-6 weeks after full vaccination, we selected only the patients who were tested using a WHO standardized Abbott Architect SARS-CoV-2 IgG Quant II chemiluminescent microparticle immunoassay. There were 154 evaluable patients, including 142 allo-HSCT recipients and 12 ASCT. The median anti-S1 IgG titer was 109877.5 BAU/ml, (range 0-280 000; interquartile ranges 603.3-244757.57). We did not find statistically significant differences in the median anti-S1 IgG titers between allo-HSCT and ASCT (median allo-HSCT 115347.23 BAU/ml vs. median ASCT 3830.0 BAU/ml, p = .36). To evaluate the potential independent impact of variables shown to influence antibody detection in the univariate analysis, we performed a subanalysis only in allo-HSCT recipients. The clinical characteristics of the 142 recipients included in this subanalysis are summarized in Table S2 , and there were no significant differences with respect to the whole allo-HSCT cohort. The anti-S1 IgG detection rate was 80% (114/142 recipients). Univariate logistic regression analyses and median test results are shown in Table 3 . In multivariate analysis, the only factors significantly associated with lower median anti-S1 IgG titers were the type of donor and a lymphocyte count < 0.5 Â 10 9 /ml at vaccination ( Figure S3A ,B). We estimated the probability of having detectable SARS-CoV-2-reactive IgG antibodies according to the type of procedure and the presence of relevant conditions and/or several combinations of these conditions that may hamper antibody production (Table 4 ). In allo-HSCT recipients, the lowest rate of antibody detection occurred in recipients with active GvHD and lymphopenia < 0.5 Â 10 9 /ml (0%), followed by any immunosuppressive treatment and lymphopenia < 0.5 Â 10 9 /ml (25%), whereas the highest rate was observed in recipients without active GvHD and immunosuppressive drugs (82.8%). Finally, among ASCT recipients, those with MM showed a seropositivity rate of 91.2%, whereas in NHL, it was 60% and 100% in Hodgkin's disease. The lowest detection rate post-ASCT was observed in relapsed NHL patients under active treatment (40%) and in those under corticosteroid therapy (50%). In contrast, the highest probability of having detectable antibodies was observed in MM patients not receiving neither immunosuppressive nor corticosteroid treatment (100%, each). We report herein a real-life experience of COVID-19 vaccination and qualitative SARS-CoV-2-reactive IgG antibody monitoring in a large series of HSCT recipients from 14 hematology units in Spain. Vaccination was well tolerated (9% mild AEs) with an overall encouraging anti-S IgG detection rate of 79% (78% in allo-HSCT and 85% in ASCT recipients). We identified some potential predictive factors and estimated serological responses by these risk factors. Lymphopenia < 1 Â 10 9 /ml was the main factor related to lower probabilities of detectable antibodies in allo-HSCT recipients. In addition, active mounting antibody responses with any vaccine is challenging. 30 However, in our allo-HSCT series, recipients with active GvHD showed detectable antibodies in 80% of recipients with a lymphocyte count > 1 Â 10 9 /ml. GvHD (most of them with chronic forms) should not be regarded as futile. In contrast, our study confirms that the timing from transplant to vaccination was relevant, as seen with other vaccines in allo-HSCT recipients. 10 Vaccination more than 1 year after transplantation led to higher rates of treatment before ASCT and as a part of high-dose chemotherapy conditioning. Poor response to vaccination has been well described in patients treated with anti-CD20 moAb and lasting 6-12 months or more. 15, 18, 20 Based on the current data, SARS-CoV-2-reactive IgG antibody detection monitoring could be helpful in most allo-HSCT recipients since the prevaccine probability of serological response to a community-acquired infection is lower than in the general population, except for those with prior COVID-19 history (detection rate 92%). To assess the predictive factors of quantitative anti-S1 IgG antibody production, we performed a subanalysis in 142 allo-HSCT recipients. Again, we found lymphopenia (< 0.5 Â 10 9 /ml) as the main factor associated with lower antibody titers. However, we did not find any association with active GvHD, immunosuppressors, type of vaccine, corticosteroid therapy nor the timing of vaccination likely due to the small number of patients having these factors. Interestingly, however, we also found that type of donor was associated with the lower amount of antibody production. Recipients of allo-HSCT from HLAidentical sibling showed the highest median antibody titers followed by adult URD recipients, whereas recipients of haploidentical allo-HSCT had the lowest median antibody titers. These data may emphasize the critical role of HLA molecules in antigen presentation, T cell recognition, and antibody production. 37 The author(s) declare that they have no conflict of interests. Authors who were responsible for the conception and the design of the study: José Luis Piñana, Angel Cedillo, and Anna Sureda. 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