key: cord-0277659-qwrnvpx2 authors: Bergman, P.; Blennow, O.; Hansson, L.; Mielke, S.; Nowak, P.; Chen, P.; Soderdahl, G.; Osterborg, A.; Smith, C. I. E.; Wullimann, D.; Vesterbacka, J.; Lindgren, G.; Blixt, L.; Friman, G.; Borgstrom, E. W.; Nordlander, A.; Gomez, A. C.; Akber, M.; Valentini, D.; Norlin, A.-C.; Thalme, A.; Bogdanovic, G.; Muschiol, S.; Nilsson, P.; Hober, S.; Lore, K.; Sallberg Chen, M.; Buggert, M.; Ljunggren, H.-G.; Ljungman, P.; COVAXID collaborator group,; Aleman, S. title: Safety and efficacy of the mRNA BNT162b2 vaccine against SARS-CoV-2 in five groups of immunocompromised patients and healthy controls in a prospective open-label clinical trial date: 2021-09-12 journal: nan DOI: 10.1101/2021.09.07.21263206 sha: d4d4bac21fec5b3a114a50642d875df789d353bc doc_id: 277659 cord_uid: qwrnvpx2 Background: Patients with immunocompromised disorders have mainly been excluded from clinical trials of vaccination against COVID-19. Thus, the aim of this prospective clinical trial was to investigate the safety and efficacy after two doses of BNT162b2 mRNA vaccination in five selected groups of immunocompromised patients and healthy controls. Methods: 539 study subjects (449 patients and 90 controls) were included in the clinical trial. The patients had either primary (n=90), or secondary immunodeficiency disorders due to human immunodeficiency virus infection (n=90), allogeneic hematopoietic stem cell transplantation/chimeric antigen receptor T cell therapy (n=90), solid organ transplantation (SOT) (n=89), or chronic lymphocytic leukemia (CLL) (n=90). The primary endpoint was seroconversion rate two weeks after the second dose. The secondary endpoints were safety and documented SARS-CoV-2 infection. Findings: Adverse events were generally mild, but one case of fatal suspected unexpected serious adverse reaction occurred. 72.2% of the immunocompromised patients seroconverted compared to 100% of the controls (p=0.004). Lowest seroconversion rates were found in the SOT (43.4%) and CLL (63.3%) patient groups with observed negative impact of treatment with mycophenolate mofetil and ibrutinib, respectively. Interpretation: The results showed that the mRNA BNT162b2 vaccine was safe in immunocompromised patients. The rate of seroconversion was substantially lower than in healthy controls, with a wide range of rates and antibody titres among predefined patient groups and subgroups. This clinical trial highlights the need for additional vaccine doses in certain immunocompromised patient groups and/or subgroups to improve immunity. Coronavirus disease 2019 (COVID- 19) was declared a pandemic by the World Health Organization (WHO) in March 2020. Immunocompromised patients were recognized early on in the pandemic as a high-risk group for severe disease with high rates of mortality 1-3 . There are currently two approved mRNA vaccines, showing a good safety profile and high vaccine efficacy of 94-95% with regards to prevention of SARS-CoV-2 infection 4, 5 . Immunocompromised patients were not included in the pivotal trials. Thus, there is an unmet need for a clinical trial in which efficacy and safety data are prospectively evaluated in these vulnerable patient groups. The safety profile could be different due to elicitation of immune activation phenomena such as rejection of organ grafts or induction of graft-vs-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Emerging reports from cohort studies have also indicated poor antibody responses after COVID-19 vaccination in some immunocompromised patient groups [6] [7] [8] [9] [10] . The aim of this clinical trial was to investigate safety and efficacy defined as the rate of seroconversion after two doses of BNT162b2 mRNA vaccine in five selected groups of immunocompromised patients compared to healthy controls. We conducted an open-label, non-randomized prospective clinical trial, in which the safety and efficacy of two doses of the mRNA BNT162b2 (Comirnaty ® , Pfizer/BioNTech) being seronegative at study entry and who received two doses of vaccine ( Figure 1) . A PP (n=468) as well as a modified per protocol (mPP) population (n=466) were analyzed. The mPP excluded two patients who developed COVID-19 between study entry and day 35 (see Figure 1 ). The main secondary endpoint was safety and tolerability of the vaccine. This was analyzed on all patients receiving at least one dose of vaccine (safety population; intention to treat (ITT) population) (see Figure 1 ). An additional secondary endpoint was occurrence of SARS-CoV-2 infection with assessment of severity 11 (Supplementary Text). Reactogenicity was assessed by recording specific local (pain, erythema, or swelling at injection site) or systemic (fever, chill, headache, tiredness/fatigue, diarrhea, vomiting, new/worsened muscle-or joint pain) side effects as reported by patients in a paper diary for seven days following each vaccine dose. All reactogenicity events were graded as none/mild (grade 0-1), moderate (grade 2), severe (grade 3), life-threatening (grade 4), or death (grade 5) according to the Common Terminology Criteria for Adverse Events (CTCAE) (Supplementary Table 1 ). Other, non-reactogenicity associated adverse events (AE) were recorded until 14 days after administration of the second dose by patient interviews in conjunction with the second dose (day 21) and through a phone call two weeks following the 2 nd dose. Severe adverse events (SAE) and suspected, unexpected, serious adverse reactions (SUSAR) were assessed and recorded from the first vaccine dose to 6 weeks after the second dose, with exception of events related to the expected course of the main underlying disease. At the time of the study design, no information existed regarding the expected seroconversion rate of immunosuppressed individuals following vaccination with the mRNA BNT162b2 vaccine. Based on the initial BNT162b2 vaccine clinical trials results, we hypothesized that the proportion of seroconversion in healthy controls would be 99%. Choosing a sample size n=90 per group would give a power value of 81%, even with a conservatively low expected 10% difference in seroconversion in immunocompromised groups versus healthy controls. Analyses of the primary efficacy endpoint with seroconversion was performed on both the PP and the mPP populations, with estimation of the proportion of participants with seroconversion (95% confidence interval, CI). Comparisons of reactogenicity events between patient groups and controls were performed with Fisher's exact test. Proportions of seroconversion were compared in patient groups, or prespecified subgroups vs. controls, with estimation of CIs and p-values (Fisher's exact test). Logistic regression, univariable or multivariable, was used to analyze possible predictive factors for seroconversion failure. P values <0·05 were considered statistically significant. The statistical analyses were performed using R base (R Core Team, 2021). Additional details of statistical analyses are described in Supplementary Text. All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in Participants 781 individuals were screened for eligibility for the study between February 12 th and February 22 nd , 2021. Of these, 539 individuals were included in the trial (safety population; intention to treat (ITT)) ( Figure 1 ). Each of the five patient groups and the control group consisted of 90 patients, with the exception of the SOT group (89 patients). All 539 included patients received the first dose of vaccine between February 23 rd and March 30 th , 2021. Baseline characteristics of the ITT group is described in Table 1 . All but fourteen (2·6%) study subjects went on to the second dose ( Figure 1 ). Those that did not receive the second dose were study subjects diagnosed with COVID-19 (n=9) or that got side effects that prevented further vaccination (n=5) (Figure 1 ). Local and systemic reactogenicities, as reported by the study subjects in diaries, are presented in Supplementary Table 1. The proportions of patients and controls reporting reactogenicity events were not markedly different from each other in an overall comparison. However, a somewhat higher rate of systemic reactogenicity events was observed in the healthy control group than in the patient group (p<0.01) following the second dose, possibly due to some of the patient's immunosuppressed status. Adverse events: Other non-reactogenicity related AE, as reported by the study subjects by physical visits and telephone interviews are presented in Supplementary Table 2. A higher number of non-reactogenicity related AEs were registered in the patient groups compared to the controls regarding total numbers, grades 2-4 CTCAE, and these were possibly/probably related to the vaccine (Supplementary Table 2 ). Most AEs were from allogeneic HSCT/CAR All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted September 12, 2021. ; https://doi.org/10.1101/2021.09.07.21263206 doi: medRxiv preprint T cell treated patients (n = 50), followed by patients with PID (n = 36), and SOT patients (n = 26). The most frequently reported AEs were infections; all assessed as unlikely to be related to the vaccine. Notably, two patients having undergone HSCT had activation of GvHD with altered liver function tests that required treatment with corticosteroids and consequently did not proceed to the second dose. Two additional patients, among those who received two doses, developed chronic GVHD of the skin and signs of obliterative bronchiolitis with worsened respiratory dysfunction after discontinuing immunosuppression before the first dose of vaccine, respectively. Finally, three patients developed CTCAE grade 2 cytopenias (thrombocytopenia n=1; neutropenia n=2), which were self-resolving without intervention (Supplementary Table 2 ). Twenty-eight SAE were registered in a total of 24 patients during the study period (Table 2) . Five SAE were assessed as possibly being linked to the vaccination, including (i) one vasovagal reaction in a HIV patient (moderate), (ii) febrile neutropenia in a HSCT patient (moderate), (iii) rejection in a liver transplanted patient (severe), and (iv) syncope in another liver transplanted patient (moderate). In addition, a SUSAR occurred in the HSCT-group. Five months after an allogeneic HSCT with prior CD19 CAR T treatment, the patient developed fever, vomiting, signs of disorientation, and respiratory distress four days after the first vaccination. This led to hospitalization and subsequent referral to the intensive care unit with suspicion of an immunologically driven pneumonia (bronchiolitis obliterans organizing pneumonia). No second vaccine dose was given. The patient responded well to corticosteroids and could be discharged after three weeks. Unfortunately, the patient later developed progressive diffuse pulmonary infiltrates resistant to broad anti-infectious and immunosuppressive treatment, and subsequently required ventilator therapy. The patient died All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted September 12, 2021. two months after the first vaccination. An autopsy was performed revealing lung failure as the major cause of death. The case was assessed by the investigator and the sponsor to be likely related to the vaccination and has been reported as a SUSAR. Final results from both autopsy and additional immunological analyses are awaited and will be reported separately. Overall, the number of SAEs was highest in the SOT group and lowest in the people living with HIV (PLWH) group (below referred to as the HIV group). No SAE was observed in the healthy control group (Table 2) . The results of the PP analyses differed only marginally from the mPP analyses (Table 3 and Supplementary Table 3 ). Because of this, we chose to present the results from the mPP analyses. 466 study subjects (388 immunosuppressed patients in 5 groups and 78 healthy controls) were eligible for analyses ( Figure 1 ). Results in terms of seroconversion and antibody titres from spike-specific IgG measurements are displayed in Figure 2 (patient group analyses) and in Figure 3 (patient subgroup analyses) as well as in Supplementary Figure 1 (patients group analyses including study subjects with SARS-CoV-2 antibody/PCR positivity at baseline). 72·2% of the patients in the mPP group seroconverted at day 35, compared to 100% of the controls (p=0.004) ( Table 3 ). With exception of the HIV group, all patient groups showed a significantly higher likelihood for failure to seroconvert at day 35 compared to the control group. The highest seroconversion-failure rate was found in the SOT group, followed by the CLL group, PID group, HSCT group and the HIV group (Table 3 and Figure 2A ). Analyzing the different patient groups separately, the overall seroconversion rate in the SOT group was 43·4% (p<0.001 compared to controls). Analyzing the subgroups, patients All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted September 12, 2021. ; 12 receiving mycophenolate mofetil (MMF) had a significantly lower seroconversion rate than controls regardless of time after transplantation; 13·3% in patients <6 months after transplantation (p=0.01) and 10·0% in patients >6 months after transplantation (p<0.01). In contrast, the subgroup of patients not receiving MMF and vaccinated >6 months after transplantation had a seroconversion rate not differing significantly from controls (90·9% vs 100%, p=0.06) ( Table 4 and Figure 3A ). In multivariate analysis, MMF-treatment was an independent predictor for seroconversion failure ( Table 5 ). The overall seroconversion rate in the CLL group was 63·3% (p<0.01 compared to controls). Analyzing the subgroups, patients with the lowest seroconversion rate were found in the ongoing ibrutinib (a BTK inhibitor) treatment group (26·9%). The rate doubled in those who had previously been treated with ibrutinib (55·6%). Indolent and patients off long-term chemoimmunotherapy had seroconversion rates >80% (Table 4 and Figure 3A ). Treatment with ibrutinib had a negative impact on the likelihood for seroconversion in multivariate analysis. 16/18 patients (88·9%), who had previously (median 13 months; range 7 -29 months) been treated with anti-CD20 responded. Normal levels of IgG at baseline were positively correlated with seroconversion ( Table 5) . The overall seroconversion rate in the PID group was 73·3% (p<0.01 compared to controls). Analyzing the subgroups, patients with common variable immunodeficiency (CVID) had the lowest seroconversion rate (68·3%), followed by patients with monogenic PIDs (77·8%). Patients with low CD4-counts and other PIDs had almost normal seroconversion rates (90·9% and 100%, respectively). As expected, patients with X-linked agammaglobulinemia (XLA) failed to produce any spike specific IgG after vaccination (Table 4 and Figure 3A ). All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted September 12, 2021. ; The overall seroconversion rate in the HSCT group was 84·7% (p=0.02 compared to controls). Analyzing the subgroups, time after HSCT (<6 months and 6-12 months) significantly influenced the seroconversion compared to healthy controls (Table 4 and Figure 3B ). Univariate, but not multivariate analysis, identified severe chronic GvHD as a risk factor for failure to seroconvert (Table 5) . Two patients with CD19 CAR T cell treatment failed, as expected, to produce any spike-protein specific IgG after vaccination (Table 4 and Figure 3A ). Finally, the overall seroconversion rate in the HIV group was 98·7% (p =NS compared to controls), with no significant differences in the CD4 cell count subgroups (>300 CD4 cells/µl and <300 CD4 cells/µl, respectively) ( Table 4 and Figure 3A ). Additional results on SARS-CoV-2 antibody titres (U/ml) are depicted on a study group level Twenty-five study subjects (25/539, 4·6%) were found to be seropositive at baseline, among whom two (0·4%) were also RT-PCR positive for SARS-CoV-2. were diagnosed with COVID-19 between the first and second dose of vaccine. Among the All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in SOT patients showed the lowest overall seroconversion with only 43·4% responding. Receiving MMF as a part of the immunosuppressive treatment was strongly associated with low seroconversion, which is in line with previous studies 10, 12, 13 . A recently published report found that a third vaccine dose increased the seroconversion rate in SOT patients from 40% to 68% 14 . This, however, still leaves almost one third of SOT patients without a serological response. As the present results indicate, a possible strategy might be to temporarily discontinue MMF to increase the chance of a vaccine response. This intervention must be weighed against the risk of development of donor specific antibodies or even T-cell mediated rejection of the graft. The first reports on COVID-19 vaccination in CLL patients found that only 39·5% of included patients seroconverted 15 . The corresponding rate in our clinical trial was 63·3%. Seroconversion was generally low (26·9%) in patients with ongoing ibrutinib therapy, but nearly doubled in those who had stopped/paused this therapy, in line with previous reports All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in 15, 16 . In contrast, >80% of the patients who had indolent CLL or were long-term off anti-CD20 based chemoimmunotherapy responded to the vaccine. Previous anti-CD20 therapy has been associated with poor responses to vaccines. In the present study, however, most patients responded after a median time of 13 months between anti-CD20 therapy and vaccination. Hence, actions may be required, particularly in those who are on treatment with ibrutinib where temporary cessation of ibrutinib-treatment before vaccination could be warranted. With respect to patients with PID, a low seroconversion rate was found in patients with CVID. Interestingly, all but one of the patients with idiopathic CD4 cytopenia seroconverted. In addition, a patient with hypomorphic SCID due to a mutation affecting the Artemis gene and a patient with a CARD11-mutation did not respond to vaccination, supporting the importance of these genes for antibody responses 17, 18 . The results are in line with a previous study in which seroconversion was observed in 18/26 (69·2%) PID patients after vaccination with BNT162b2 8 . Overall, we observed that most PID-patients responded to vaccination and the number of AEs was low. In HSCT patients, the results are concordant with studies of other vaccines. Some of the present findings are also similar to other reports of COVID-19 vaccines in this patient group. Time after HSCT had a significant impact on the likelihood of seroconversion similar to findings in other studies [19] [20] [21] . However, it was observed that severity of chronic GvHD impacted negatively on seroconversion in univariate analysis. Seroconversion failure was furthermore found to be associated with ongoing second line treatments for chronic GvHD, such as ruxolitinib and photophoresis, and administration of anti-CD20 therapy given several months prior to vaccination. An effect of the severity of chronic GvHD has not been reported previously but is not unexpected considering what has been observed for other vaccines. None of the two assessable patients receiving CD19 CAR T cell therapy seroconverted, likely due to the persistent depletion of B cells after successful therapy. All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted September 12, 2021. ; https://doi.org/10.1101/2021.09.07.21263206 doi: medRxiv preprint during the study. In this respect, the present study was not powered to evaluate a potentially protective effect on the number and severity of COVID-19 cases. A particular strength of the present study is the clinical trial setting with careful prospective safety evaluation. In addition, the study comprises a relatively large participant number, with a priori defined monitoring and analyses of the data. The study clearly shows that not all patient groups have the same risk for poor response to COVID-19 vaccination. For example, HSCT patients at a late stage after transplantation and without chronic GvHD responded well to two doses of vaccine. It is unknown, however, whether the duration of immunity will be similar to healthy controls, which requires further studies with a longer follow-up time. In contrast, we also identified subgroups of patients responding poorly, or very poorly, to vaccination. Some of these risk factors have been previously identified, such as ibrutinib in CLL patients and the use of MMF in SOT patients and such patients might benefit from a 3 rd dose of vaccine. There are several limitations of this study. The trial had an open-label and non-randomized design. However, since the vaccine is approved and recommended by the Public Health Agency of Sweden, it was considered unethical to allocate patients to a non-treatment group. Furthermore, we did not pre-screen for SARS-CoV-2 antibodies. The 4·6% rate of seropositive cases at baseline was somewhat high, given the general recommendation of selfisolation for these patients. However, due to high prevalence of SARS-CoV-2 infection in the Stockholm region at the time of the study, the result should reflect the real-life situation. Finally, we did not include other immunological responses, such as T cell responses, in the predefined primary and secondary endpoints. There is a wide spectrum of immunosuppressive disorders and we studied only some of these. This study may, however, serve as a proof-ofconcept study to analyze the impact of specific immunosuppression on the seroconversion rate in some patient groups. All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted September 12, 2021. ; The results presented here show that many immunocompromised patients can respond to two doses of BNT162b2a vaccine against COVID-19. However, substantial proportions of these patients respond poorly and may therefore be in need of additional doses to boost the humoral immune response. Indeed, recent reports have shown that immunocompromised SOT-patients with negative antibodies after two doses of mRNA vaccine can respond to a third dose with production of specific antibodies 14, 29 . A third dose of COVID-19 vaccine has just (August 26, Authority. Similar recommendations have recently also been introduced by other national authorities such as the US CDC and the corresponding French Authority. In conclusion, this prospective clinical trial showed that the mRNA BNT162b2 vaccine is safe to administer to immunocompromised patients. However, the rate of seroconversion is substantially lower compared to healthy controls, with a wide range of seroconversion rates perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted September 12, 2021. ; honoraria for lectures and educational events, not related to this work, from Gilead, AbbVie, MSD, Biogen and Netdoktor, and reports grants from Knut and Alice Wallenberg Foundation for this study. Data will be submitted to European Union Drug Regulating Authorities Clinical Trials Laboratory parameters at baseline, median (range) IgG (g/L) Absolute lymphocyte count (x10 9 /L) Possible (n, %) 0 0% 1 (50%) 2 (40%) 3 2 (17%) 0% 5 Unlikely (n, %) 0 3 (100%) 0% 0% 10 (83%) 6 (100%) 19 Not related (n, %) 0 0% 1 (50%) 3 (60%) 0% 0% 4 Severe (n, %) 0 1 (33%) 1 (50%) 3 (60%) 4 (33%) 0 9 Moderate (n, %) 0 1 (33%) 1 (50%) 2 (40%) 8 (67%) 6 (100%) 18 Mild (n, %) 0 1 (33%) 0% 0% 0% 0% 1 Resolved 2 Yes (n, %) 0 3 (100%) 1 (50%) 5 (100%) 6 (50%) 5 (83%) 20 No (n, %) 0 0% 1 (50%) 0% 6 (50%) 1(17%) 8 Abbreviations: SAE: severe adverse reaction, PID: primary immunodeficiency, HIV: human immunodeficiency virus, HSCT: hematopoietic stem cell transplantation, SOT: solid organ transplantation, CLL: chronic lymphocytic leukemia. Footnotes: 1 Percentage was calculated as the proportion of patients with at least one SAE in the patient-group. 2 Percentage was calculated as the proportion of patients with at least one SAE divided by the total numbers of patients with at least one SAE. 3 One SUSAR occurred in this group. All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted September 12, 2021. ; https://doi.org/10.1101/2021.09.07.21263206 doi: medRxiv preprint Abbreviations: PID: primary immunodeficiency; CVID, common variable immunodeficiency; XLA, X-linked agammaglobulinemia, CD4-cyt: idiopathic CD4-cell lymphocytopenia, Monog. Dis: monogenic disorder, HIV: human immunodeficiency virus; CD4: CD4+ T-cells, HSCT, hematopoietic stem cell transplantation; CAR T, chimeric antigen receptor T-cells. Early, <6 months after transplantation; Interm, 6-12 months after transplantation; Late, >12 months after transplantation. SOT: solid organ transplantation; MMF, mycophenolate mofetil. CLL: chronic lymphocytic leukemia; Indol, indolent and not treated; Previous CD20-1b, previous treatment with BR/FCR bendamustine and rituximab / fludarabine, cyclophosphamide and rituximab; Ibru, ongoing ibrutinib treatment; Off ibru, off ibrutinib treatment for >2 months. CI: 95% confidence interval. Footnote: 1 P-values of the differences vs. healthy controls were calculated. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted September 12, 2021. ; https://doi.org/10.1101/2021.09.07.21263206 doi: medRxiv preprint N: no, IgG: immunoglobulin G, CD: cluster of differentiation, XLA: X-linked agammaglobulinemia, CVID: common variable immunodeficiency, GvHD: graft versus host disease, MMF: mycophenolate mofetil, ab: antibody Footnote: 1 Logistic regression, univariable and multivariable analyses in modified per protocol (mPP) population (n=466) were performed. The reference group for categorical variables of sex was women. For variables with categories of yes (Y) or no (N), "no" was set as reference group. All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted September 12, 2021 . perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted September 12, 2021. ; https://doi.org/10.1101/2021.09.07.21263206 doi: medRxiv preprint COVID-19 in immunocompromised populations: implications for prognosis and repurposing of immunotherapies Clinical characteristics and mortality of patients with hematologic malignancies and COVID-19: a systematic review The challenge of COVID-19 and hematopoietic cell transplantation; EBMT recommendations for management of hematopoietic cell transplant recipients, their donors, and patients undergoing CAR T-cell therapy Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine Impaired Humoral Immunity to SARS-CoV-2 Vaccination in Non-Hodgkin Lymphoma and CLL Patients Serological response to mRNA SARS-CoV-2 BNT162b2 vaccine in kidney transplant recipients depends on prior exposure to SARS-CoV-2 Immunogenicity of Pfizer-BioNTech COVID-19 vaccine in patients with inborn errors of immunity BNT162b2 COVID-19 vaccine is significantly less effective in patients with hematologic malignancies Immunogenicity of a Single Dose of SARS-CoV-2 Messenger RNA Vaccine in Solid Organ Transplant Recipients Antibody response to SARS-CoV-2 mRNA vaccine among kidney transplant recipients: a prospective cohort study Three Doses of an mRNA Covid-19 Vaccine in Solid-Organ Transplant Recipients Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia COVID-19 in patients with CLL: improved survival outcomes and update on management strategies Mechanistic understanding of the combined immunodeficiency in complete human CARD11 deficiency DCLRE1C (ARTEMIS) mutations causing phenotypes ranging from atypical severe combined immunodeficiency to mere antibody deficiency Safety and Immunogenicity of the BNT162b2 mRNA COVID-19 Vaccine in Patients after Allogeneic HCT or CD19-based CART therapy-A Single-Center Prospective Cohort Study Antibody response after second BNT162b2 dose in allogeneic HSCT recipients Safety and antibody response to the first dose of SARS-CoV-2 messenger RNA vaccine in persons with HIV. AIDS 2021. 23. Woldemeskel BA, Karaba AH, Garliss CC, et al. The BNT162b2 mRNA Vaccine Elicits Robust Humoral and Cellular Immune Responses in People Living with HIV-associated chronic immune activation Vaccinations for the HIV-Infected Adult: A Review of the Current Recommendations, Part I Poor immunogenicity of the H1N1 2009 vaccine in well controlled HIV-infected individuals Safety and Tolerability of SARS-CoV-2 Emergency-Use Authorized Vaccines Allogeneic Hematopoietic Stem Cell Transplant Recipients Comparable humoral response after two doses of adjuvanted influenza A/H1N1pdm2009 vaccine or natural infection in allogeneic stem cell transplant recipients Antibody Response After a Third Dose of the mRNA-1273 SARS-CoV-2 Vaccine in Kidney Transplant Recipients With Minimal Serologic Response to 2 Doses This study has been funded by the Knut and Alice Wallenberg Foundation, Nordstjernan AB, Region Stockholm (Clinical research position-, ALF-, and CIMED-grants), the Swedish Research Council, a graduate student fellowship from Karolinska Institutet. In addition, the Swedish patient organizations of Primary Immunodeficiencies (PIO) and Hematology (Swedish Blood Cancer Foundation) provided grants. Neither of funders had any role in study design, collection, analysis, interpretation of data or writing of the report.We thank all the participants enrolled in this study, and Karolinska University Hospital, the sponsor of this clinical trial for making this study feasible. We would like to thank all the research and clinical staff at Karolinska University Hospital, especially research/clinical nurses Linn Wursé, Cecilia Lång, Anna Löwhagen Welander, Susanne Hansen, Douglas 1. 18 Footnote: *all n=30 were on ibrutinib. 1 The different transplants in the SOT-group (n=89) were: 57 liver, 26 kidney, 6 kidney and pancreas.