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BackgroundAcetaminophen (APAP = paracetamol) may potentially impact vaccine-associated immune responses as the intake of APAP has been associated with a worse outcome in tumor patients receiving checkpoint inhibitors.[1]Different DMARD regimen have been shown to impair the humoral immune response to mRNA SARS-CoV-2 vaccines in patients with rheumatoid arthritis but the effect of paracetamol has not been explored thus far.ObjectivesTo analyse whether the intake of APAP may interfere with antiviral humoral immune responses following two doses of an anti-SARS-CoV-2 mRNA based vaccine in patients with rheumatoid arthritis (RA) on DMARD therapy.MethodsThe RECOVER trial (Rheumatoid Covid-19 Vaccine Immune Response) was a non-randomised, prospective observational control group trial and enrolled 77 RA patients on DMARD therapy and 21 healthy controls (HC). We performed a posthoc analysis of blood samples taken before the first vaccine dose (T0), two (T1) and three (T2) weeks after the first and second vaccine dose, and at 12 (T3) weeks. APAP intake was measured using ELISA. The antibody response (anti-S) to the receptor binding domain (RBD) within the SARS-CoV-2 S1 protein was measured with the Elecsys Anti-SARS-CoV-2-S (Roche Diagnostics GmbH) test. The neutralizing activity NT50 at week 12 was assessed using an HIV-based pseudovirus neutralization assay against Wuhan-Hu-1.ResultsBaseline characteristics of participants are detailed in Table 1. The immunogenicity analyses were based on 73 RA patients after exclusion of 4 patients with previously unnoticed SARS-CoV-2 infection (positive for anti-nucleoprotein at baseline). APAP was detected in serum samples from 34/73 (25%) RA patients and in 7/21 (33%) HC (least at one timepoint T0, T1 and/or T2). APAP intake in HC did not affect levels of anti-S at any timepoint and all HC developed potent neutralizing activity (NT50 ≥ 250) at week 12. RA patients, who tested positive for APAP at T1, showed comparable anti-S levels at T1, T2 and T3 compared to RA patients not exposed to APAP. The detection of APAP at T2 corresponded to lower anti-S levels at T2 (Figure 1 A, B). The detection of APAP at T2 was associated with a significantly lower SARS-CoV-2 neutralizing activity at week 12 compared to patients without perivaccination APAP exposure (p =0.04) (Figure 1 C).ConclusionA decrease of antiviral humoral immune responses was observed in RA patients (but not in HC) who were exposed to APAP at the time of the second mRNA vaccine dose compared to patients in whom APAP was not detected. Our data suggest that the use of paracetamol within the time period around vaccination may impair vaccine-induced immune responses in patients with an already higher risk for blunted immune responses.Reference[1]Bessede A et al. Ann Oncol 2022;33: 909-915Table 1.Baseline characteristics: RA patients and HC with/without APAP exposureRA APAP – n = 37RA APAP + n = 36p-valueHC APAP – n = 8HC APAP + n = 13p-valueAge (yrs), mean (± SD)62 (13)67 (10)0.07 (NS)45 (12)44 (14)0.90 (NS)Female sex, n (%)24 (65)19 (53)0.29 (NS)2 (25)5 (38)0.53 (NS)Vaccination type/schedulemRNA-1273, n (%)4 (11)8 (22.2)0.19 (NS)0 (0)0 (0)BNT162b2, n (%)33 (89)28 (77.8)0.19 (NS)8 (100)13 (100)RA disease characteristicsACPA ± RF, n (%)17/37 (46)19/36 (53)0.56 (NS)NANANARA disease duration (yrs ± SD)9.2 (9.8)10.2 (8.1)0.67 (NS)NANANADMARD therapycsDMARD-mono, n (%)13/37 (35)9/36 (25)0.35 (NS)NANANAbDMARD-mono/combo, n (%)16/37 (43)16/36 (44)0.92 (NS)NANANAtsDMARDs-mono/combo, n (%)8/37 (22)11/36 (31)0.38 (NS)NANANAPrednisone, n (%)15/37 (41)12/36 (33.3)0.52 (NS)NANANAMean daily dose prednisone (mg ± SD)4.6 ± 1.13.9 ± 2.30.39 (NS)NANANA* APAP = acetaminophenFigure 1.Acknowledgements:NIL.Disclosure of InterestsNone Declared.
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Background: SARS-CoV-2 infection leads to a broad range of clinical manifestations, from no symptoms to critical illness. Pre-stimulated innate defenses, rapid induction of SARS-CoV-2 responses and pre-existing crossreactive immunity to circulating human coronaviruses (HCoV) may early dampen SARS-CoV-2 infection, preventing symptomatic disease. Here we explore SARS-CoV-2 and HCoV antibody impact on asymptomatic infection in individuals first encountering SARS-CoV-2 in March 2020-March 2021 participating in a longitudinal pediatric cohort (n=2917) and a cross-sectional adult and children diagnostic cohort (n=882) in Switzerland. Method(s): Antibodies (Ab) to S1 of the four HCoV strains and SARS-CoV-2 antigens S1, RBD, S2 and N were determined in saliva (n=4993) and serum (n=7486) samples. Mucosal and systemic neutralization activity against wildtype SARS-CoV-2-Wuhan, and Alpha, Delta and Omicron (BA.2) variants of concerns (VoC) was assessed by pseudovirus neutralization in a subset of individuals. Result(s): Analysis of simultaneously sampled saliva and plasma revealed a strong correlation of mucosal and systemic SARS-CoV-2 anti-spike responses in recent infection. Notably, pre-existing high HCoV antibody response was significantly associated with higher systemic (IgG, IgA, and IgM, p< 0.001) and mucosal (IgG, p=0.03) SARS-CoV-2 responses following SARS-CoV-2 infection. Adjusting for age and sex, we found four saliva SARS-CoV-2 Ab parameters, namely total Ig S2, total Ig S1, IgA S2 and IgM S1 (p< 0.001, p< 0.001, p=0.02, p=0.01 respectively), inversely associated with salivary viral load highlighting the impact of mucosal Ab response on viral suppression. Saliva neutralization activity was modest but surprisingly broad, retaining same level activity against Wuhan, Alpha and Delta, but not Omicron BA.2, whereas plasma neutralization activity showed the typical decrease for all three VoCs compared to Wuhan. Most interestingly, asymptomatic individuals presented with higher IgG S2 antibody reactivity in saliva (p=0.03) and higher pre-existing HCoV-S1 IgG activity in plasma (HKU1, p=0.04) and saliva (total hCoV, p=0.02) suggesting immune factors that restrict disease severity. Conclusion(s): Focusing on a SARS-CoV-2 infection and vaccine naive population, our study reveals interdependencies of systemic and mucosal SARS-CoV-2 and HCoV immunity following primary SARS-CoV-2 infection and locates reactivities linked with reduced viral load and asymptomatic infection.
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Background: Despite favorable vaccine responses of people with HIV (PWH), susceptibility to SARS-CoV-2 (SCv2) infection and increased risk of COVID-19 in immunocompromised PWH continue to be of concern. Here, we searched the Swiss HIV Cohort Study (SHCS) with>9500 actively enrolled, optimally treated PWH to identify factors associated with SCv2 infection in the pre-and postvaccination area. Method(s): We utilized information on SCv2 events reported to the SHCS in 2020 -2021. To detect asymptomatic infection, we screened pre-pandemic (2019) and pandemic (2020-2021) bio-banked plasma for SCv2 antibodies (Ab). SCv2+ and matched SCv2- PWH were additionally screened for Abs to circulating human coronaviruses (HCoV). Data were compared to HIV negative (HIV-) controls. SCv2 data and >26 behavioral, immunologic and disease-parameters available in the SHCS data base were analyzed by logistic regression, conditional logistic regression, and Bayesian multivariate regression. Result(s): Considering information on the SCv2 status of 6270 SHCS participants, neither HIV-1 viral load nor CD4+ T cell levels were linked with increased SCv2 infection risk. COVID-19-linked hospitalization (87/982) and case fatality rates (8/982) were low, but slightly higher than in the general Swiss population when stratified by age. Compared to HIV-, PWH had lower SCv2 IgG responses (median effect size= -0.48, 95%-Credibility-Interval=[-0.7, -0.28]). Consistent with earlier findings, high HCoV Abs pre-pandemic (2019) were associated with a lower risk of a subsequent SCv2-infection and, in case or infection, with higher Ab responses. Examining behavioral factors unrelated to the HIV-status, people living in single-person households were less at risk of SCv2 infection (aOR= 0.77 [0.66,0.9]). We found a striking, highly significant protective effect of smoking on SCv2 infection risk (aOR= 0.46 [0.38,0.56], p=2.6*10-14) which was strongest in 2020 prior to vaccination and was even comparable to the effect of early vaccination in 2021. This impact of smoking was highly robust, occurred even in previous smokers and was highest for heavy smokers. Conclusion(s): Our unbiased cohort screen identified two controversially discussed factors, smoking and cross-protection by HCoV responses to be linked with reduced susceptibility to SCv2, validating their effect for the general population. Overall weaker SCv2 Ab responses in PWH are of concern and need to be monitored to ensure infection- and vaccine-mediated protection from severe disease.
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Background: Lower seroconversion rates have been reported in patients with rheumatic diseases receiving immunomodulatory therapies following a standard mRNA-based vaccine regimen. Data with regard to immunogenicity and safety of a 3rd vaccine dose in this patient population is limited1. Objectives: We aim to study immunogenicity, vaccine associated side effects and the occurrence of fares in RA patients unresponsive to a standard vaccine regimen eligible for a 3rd vaccine dose. Methods: RA patients who had a low or absent anti-S1 response after 12 (Cohort A) or 24 weeks (Cohort B) following a standard vaccination regimen received a 3rd vaccine dose. Temporary discontinuation of DMARD therapy was recommended. Serum samples were collected before, 2, 12, and 24 weeks after the 3rd vaccine dose. Quantitative measurement of anti-S was performed using the Roche Elecsys Anti-SARS-CoV-2 spike subunit assay. Neutralizing activity (NT50) against Wuhan WT and aasβ-, y-, and ô-variants was assessed by using a HIV-based pseudovirus system. Results: Baseline characteristics are shown in Table 1. 45/47 patients temporarily discontinued DMARD therapy: Mtx and JAKi were paused one 1 week before/restarted 2 weeks after the 3rd vaccine dose, bDMARDs were paused 2 weeks before/restarted 2 weeks after the 3rd dose. Local pain and/or systemic vaccine associated side effects following the 3rd vaccine dose were reported in 12/17 (71%) in Cohort A, and 10/29 (35%) patients in Cohort B (p = 0.018). Flares were defned as loss of low disease activity (LDA), subsequent to the 3rd vaccine dose and occurred in 17/47 (36%) patients (p = 0.0332) with comparable frequencies in both cohorts (41% Cohort A, 33% Cohort B (NS)). Low or absent anti-S titers were confrmed before the third vaccination (Cohort A: median 19.5 U/ml, IQR 0.47-57;cohort B: median 65.9 U/ml, IQR 22-154) (p = 0.0018). Two weeks after the 3rd dose, a rapid and signifcant increase in anti-S were observed in 12/17 (82%) and 25/28 (89%) patients (Cohort A: median 2500 U/ml, IQR 798-2500;Cohort B: median 2500 U/ml, IQR 2500-2500) (NS). High levels of anti-S were maintained in the majority of patients 55% (11/20) until week 12 in both cohorts (Figure 1). NT50 against Wuhan-WT and other variants was assessed in 21 patients 2 weeks after the 3rd vaccine dose revealing a low or absent NT50 against delta in 38% of patients despite a median anti-S response of 2500 U/ml (IQR 798-2500). 14/21 patients had peak anti-S titres of 2500 U/ml, of those 12/14 developed a strong NT50 response against the delta variant. Conclusion: Our data demonstrate that a 3rd vaccine dose, maybe complimented by temporary discontinuation of DMARD therapy, may lead to a rapid increase in anti-S antibodies when using a homologous vaccine and profound neutralizing activity in the majority of RA patients previously unresponsive to a standard two dose regimen. This seems to be independent of the interval to the previous standard vaccine regimen. As fares occurred in 36% of all patients, the necessity and length of DMARD discontinuation should be explored in more detail to balance between sustained control of disease activity and optimized vaccine induced immune responses.
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Background: Vaccines are highly effective in preventing COVID-19 associated hospitalization and deaths. Strong and persistent immune responses are critical to provide protection for patients with immunomodulatory therapies. Objectives: To assess humoral and cellular immune responses following 2 doses of an anti-SARS-CoV-2 mRNA based vaccine in rheumatoid arthritis (RA). Immune responses in patients treated with csDMARDs, bDMARDs (with the exception of rituximab) and JAK inhibitors were compared to healthy controls (HC) over 24 weeks. In addition, disease activity by CDAI and vaccine-induced side effects were prospectively monitored. Methods: The RECOVER trial (Rheumatoid Covid-19 Vaccine Immune Response) is a non-randomised, prospective observational control group trial and enrolled 77 RA patients on DMARD therapy and 21 HC. Clinical assessment and blood sampling was performed at baseline, 3 weeks after the 1st and 2 weeks after the 2nd vaccine dose and at week 12 and 24 after the 1st. Antibody response to the receptor binding domain (RBD) within the SARS-CoV-2 S1 protein was measured with the Elecsys Anti-SARS-CoV-2-S (Roche Diagnostics GmbH) test. The seroprofling assay ABCORA, which has been suggested as a surrogate for neutralization,1 was used to determine IgG, IgA and IgM responses to RBD, S1, S2 and N. The neutralizing activity NT50 at week 12 was assessed against Wuhan-Hu-1 pseudoviruses (HIV-based). IFN-y ELISpots were applied to detect spike-reactive T cell responses after in vitro stimulation with a spike peptide mix. Results: Baseline characteristics of participants are detailed in Table 1. Vaccination was well tolerated with no differences between RA patients and HC. At baseline, the majority of RA patients were in remission/LDA (57/77, 74%), this proportion decreased to 51% (39/77) after the second vaccine dose (p = 0.005). Treatment adjustments were required in 11/77 patients. The immunogenicity analyses were based on 73 RA patients after exclusion of 4 patients with previously unnoticed SARS-CoV-2 infection (positive for anti-nucleoprotein). In contrast to HC, anti-S titers were lower at all timepoints with signifcantly reduced titers observed in patients on abatacept and JAK inhibitors (Figure 1). Potent neutralizing activity (NT50 ≥ 250)) was detected in all HC at week 12, in contrast to 62% RA patients. NT50 correlated to the results based on the ABCORA assay. Peak anti-S titers (2 weeks after 2nd vaccine) were predictive of NT50 ≥ 250 at week 12 (p < 0.0001). In contrast to marked differences in the humoral immune responses, spike-protein specifc IFN-α secreting T cells were largely unaltered by different DMARD regimen. Conclusion: RA patients, in comparison with HC, revealed a slower kinetic and lower magnitude of humoral immune responses depending on the treatment regimen while T cell responses were largely maintained. Peak anti-S responses two weeks after the second vaccine were able to predict the development of potent neutralizing activity and should therefore be considered to individually tailor vaccination strategies.
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Background: Since January 2021, the two in Switzerland approved severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines tozinameran (Pfizer/Biontech) and elasomeran (Moderna) have been used to vaccinate the Swiss population. These vaccines were found to be safe in licensing trials with excellent efficacy of 95% and 94% in terms of preventing COVID-19 illness 14 days after the second vaccination. However, randomized evidence on the comparative effectiveness of both vaccines in immunocompromised patients is currently lacking. Methods: We conducted a parallel, two-arm (allocation 1:1) open-label, non-inferiority randomized clinical trial (RCT) nested into the Swiss HIV Cohort Study (SHCS) and the Swiss Transplant Cohort Study (STCS). Patients living with HIV and solid organ transplant recipients (i.e. lung and kidney) from these cohorts were randomized to receive either tozinameran or elasomeran. The primary endpoint was an antibody response to SARS-CoV-2 spike (S1) protein receptor binding domain using Elecsys® Anti-SARS-CoV-2 S assay from Roche (binary, cut-off ≥0.8 Units/ml) 12 weeks after first vaccination (8 weeks after second vaccination). Secondary outcomes were immune response measured with the Antibody CORonavirus Assay (ABCORA), clinical and safety outcomes. Results: A total of 430 patients were randomized and 412 were included in the intention-to-treat analysis (341 HIV patients and 71 solid organ transplant recipients). Antibody response was for elasomeran 92.1% (95% CI 88.4-95.8%;186/202) and for tozinameran 94.3% (95% CI 91.2-97.4%;198/210;difference:-2.2%;95% CI-7.1-2.7%), fulfilling non-inferiority of elasomeran. Overall, neutralization activity to SARS-CoV-2 Wuhan HU-1 strain was estimated to 96.5% (95% CI 94.5-98.4%) in HIV patients and 21.1% (95% CI 11.6-30.6%) in solid organ transplant recipients. 5 SARS-CoV-2 infections occurred (3 elasomeran;2 tozinameran) and 18 serious adverse event occurred (9 elasomeran;9 tozinameran). Conclusion: In immunocompromised patients the antibody response of elasomeran was comparable to tozinameran. People living with HIV had in general a sufficient immune response while a high proportion of transplant recipients had no immune response. Nearly 80% of patients with solid organ transplant have not developed neutralizing activity and need booster vaccination.
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Background: Neutralizing antibodies are recognized as a principal correlate for protection induced by SARS-CoV-2 vaccines and have been considered for antiviral treatment as an active component in convalescent plasma therapy (CPT) and as monoclonal antibody therapeutics. However, unless used at a very early stage of infection, antibody-based SARS-CoV-2 therapies have not achieved the substantial disease-modulating effect hoped for. Methods: Here, we conducted a proof-of-principle study of CPT based on a phase I trial in thirty hospitalized COVID-19 patients with a median interval between the onset of symptoms and the first transfusion of 9 days (IQR, 7-11.8 days). A comprehensive longitudinal monitoring of the virologic, serologic, and disease status of recipients in conjunction with detailed post-hoc seroprofiling of transfused convalescent plasma allowed deciphering of parameters on which plasma therapy efficacy depends. Results: In this study, CPT was safe as evidenced by the absence of transfusion-related adverse events. We also observed an overall low mortality (3.3%). Treatment with highly neutralizing plasma was significantly associated with faster virus clearance, as demonstrated by Kaplan-Meier analysis (p = 0.034) and confirmed in a parametric survival model including viral load and comorbidity (adjusted hazard ratio (HR) = 3.0 [95% confidence interval (CI) 1.1;8.1], p = 0.026) (Figure 1). Endogenous immunity had strong effects on virus control. Lack of endogenous neutralizing activity at baseline was associated with a higher risk of systemic viremia. The onset of endogenous neutralization had a noticeable effect on viral clearance but, importantly, even after adjusting for their endogenous neutralization status recipients benefitted from plasma therapy with high neutralizing antibodies (HR= 4.0 [95% CI 1.3;13], p = 0.017). Conclusion: In summary, our data demonstrate a clear impact of neutralizing antibody therapeutics on the rapid clearance of viremia and with this provide directions for improved efficacy evaluation of current and future SARS-CoV-2 therapies beyond antibody-based interventions. In particular, incorporating an assessment of the endogenous immune response and its dynamic interplay with viral production is critical for determining therapeutic effect.
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Introduction: Vaccines against SARS-CoV-2 have been approved rapidly. Pivotal studies were conducted in healthy volunteers. Data in allo- HCT patients (pts) are lacking. Here, we examined antibody (AB) titers to COVID-19 vaccination with BNT162b (Comirnaty®) or mRNA-1273 (Moderna Covid-19 Vaccine®) in allo-HCT pts. Methods: Serial AB titers (IgG, IgA, IgM: prior to;1m after dose 1;1, 3, 6m post 2. vaccine) against 4 SARS-CoV-2 antigens (receptor-binding domain, spike glycoprotein subunit S1/S2, and nucleocapsid protein) were recorded with a multiplex AntiBody CORonavirus Assay (ABCORA) in allo-HCT pts and healthy controls. Results: So far 99 pts (median age 55y (range 18y-74y)) have been enrolled. Currently, AB responses for the 1m after dose 1 and dose 2 are available for 74 and 57 pts, respectively. Pts were grouped into those (A) 3-6m post-HCT (n=14 after 1. dose, n=11 after 2. dose);(B) 6-12m post- HCT (n=11 after 1. dose, n=10 after 2. dose);and (C) >12m post-HCT (n=49 after 1. dose, n=36 after 2. dose). In addition, AB responses are available for n=32 healthy controls (median age 38y) after the 1. dose, and n=10 after 2. dose. There was a statistically significant difference of the S1 AB levels (IgG, IgA, IgM) between the 4 groups after both the 1. and the 2. dose (ANOVA p-value< 0.001 and 0.003, respectively, Fig.1). After the 1. dose, median values of sum of S1 signals were 0.97 (1Q-3Q=0.82-1.14) in (A), 0.92 (0.78-1.27) in (B), 2.35 (0.90-33.7) in (C);and 57.1 (14.6-69.7) in the healthy group. After the 2.dose, median values were 3.84 (1Q- 3Q=1.32-15.3) in (A), 20.9 (1.28-69.9) in (B), 118 (8.74-313) in (C);and 195 (150-238) in the healthy group. Values >9.3 are considered to represent protective immunity according to ancillary studies. Conclusion: Allo-HCT pts early post-HCT displayed only low/no AB formation to vaccination. Such knowledge is of critical importance to allo- HCT pts and transplant physicians to guide treatment decisions regarding re-vaccination and social behavior during this pandemic. Analyses on the impact of pharmacological immunosuppression and graft-vs-host disease on immune responses to the vaccine are underway. (Figure Presented).
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Background: Long-term data in allo-HCT patients after SARS-CoV-2 vaccination are lacking. We examined antibody (Ab) titers to the vaccination with BNT162b (BioNTech Pfizer) or mRNA-1273 (Moderna) Covid-19 vaccine in allo-HCT patients. Methods: Serial Ab titers (prior to;1m after 1. dose (T1);1m (T2), 3m (T3) post 2. dose) against SARS-CoV-2 antigens (receptor binding domain (RBD), spike glycoprotein subunit S1/S2, nucleocapsid) were recorded with the AntiBody CORonavirus Assay (ABCORA) in allo-HCT patients and healthy controls. Results: We enrolled 110 allo-HCT patients (median age 57y) and 86 healthy controls (median age 37y). Patients were grouped into: (A) 3-6m, (B) 6-12m and (C) >12m post-HCT. The sum of IgG, IgA and IgM S1 activities (cS1) >17 is considered to represent protective immunity. cS1 Ab levels were statistically different between the 4 groups both after the 1. and the 2. dose (ANOVA p-values<0.001, Fig.1) with the lowest antibody response in group A (S1 median value 0.959 at T1, 6.26 at T2, 1.24 at T3) and B (S1 median value 0.973 at T1, 4.76 at T2, 11.9 at T3) compared to group C (S1 median value 6.57 at T1, 179 at T2, 69.3 at T3) and healthy controls (S1 median value 54.9 at T1, 228 at T2, 91.1 at T3). Conclusion: Allo-HCT patients early post-HCT displayed only low or no Ab formation to vaccination with a decline in AB response after T2. We conclude that Ab response in allo-HCT patients should be measured regularly to guide treatment decisions regarding re-vaccination and social behavior.
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Background: Vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been approved rapidly. However, pivotal studies have been conducted in healthy volunteers, while recipients of allogeneic hematopoietic cell transplantations (allo-HCT) may have different dynamics and patterns of response to the vaccine and data in this cohort is lacking. Methods: Here, we examined longitudinal antibody (AB) titers to SARS-CoV-2 vaccination with BNT162b (Comirnaty ®) or mRNA-1273 (Moderna Covid-19 Vaccine ®) in allo-HCT recipients who had undergone allo-HCT >3months (m) ago and in healthy controls (hospital employers). Serial AB titers (prior to (T0);1m after 1 st dose (T1);1m (T2), 3m (T3), 6m (T4) post 2 nd dose) were measured with an in-house developed multiplex Antibody CORonavirus Assay (ABCORA) that measures SARS-CoV-2 IgG, IgA, and IgM reactivities against RBD (receptor binding domain), S1 (subunit 1 of the spike protein), S2 (subunit 2 of the spike protein) and N (nucleoprotein), thereby allowing to differentiate immunity after vaccination versus immunity after infection. As neutralization activity correlates well with S1 AB binding, the potency of the AB response was defined as the sum of S1 IgG, IgA and IgM reactivities (cumulative S1 (cS1)). Based on computational methods high neutralization potency was predicted above a cS1 threshold of 17. Results: We enrolled 114 allo-HCT patients (median age 57y (range 18y-74y)) between March 9th 2021 and May 31st 2021 at the University Hospital Zurich, Switzerland. Currently, AB responses at T1, T2, and T3 are available for 99, 95 and 89 patients, respectively. Patients were grouped into those (A) 3-6m post-HCT (T1: n=25 at, T2: n=23, T3: n=20);(B) 6-12m post-HCT (T1: n=13, T2: n=13, T3: n=12);and (C) >12m post-HCT (T1: n=61, T2: n=59, T3: n=57). In addition, AB responses are available for healthy controls (median age 35y (range 23y-64y)) (T1: n=75, T2: n=69, T3: n=48). There were 10 patients and 5 healthy subjects with a reported or detected SARS-CoV-2 infection. There was a statistically significant difference of cS1 AB levels between the 4 groups at T1, T2, and T3 (ANOVA p-values (p) <0.001, respectively, Fig 1) with the lowest AB response in group A (cS1 median value 0.957 at T1, 5.22 at T2, 1.90 at T3) and B (cS1 median value 0.973 at T1, 4.76 at T2, 11.9 at T3) compared to group C (cS1 median value 6.21 at T1, 199 at T2, 76.4 at T3) and healthy controls (cS1 median value 54.9 at T1, 228 at T2, 91.1 at T3). Using a multivariate linear regression analysis adjusted on age and gender, we found that patients in groups A and B had significantly lower cS1 levels than groups C and healthy subjects (p<0.001, p<0.001, p=0.034 of healthy versus groups A, B, C respectively at T2, and p<0.001, p=0.004, p=0.12 at T3), and that preinfected patients had higher cS1 levels at T2 and T3 respectively (p=0.003 and 0.006). The dynamics of the AB response were more diverse in allo-HCT recipients. In a multivariate linear regression analysis (Fig 2) assessing factors associated with humoral immune responses in allo-HCT recipients, we found consistently lower cS1 responses in patients early post-HCT (group A+B (p=0.002)) and higher cS1 levels in those who had been preinfected with SARS-CoV-2 (p=0.012). Patients under immunosuppressive treatment (IST) and those who had relapsed disease post-HCT showed significantly lower cS1 immune responses (p=0.028 and 0.005, respectively). The presence of moderate or severe chronic GVHD was not a statistically significant factor influencing AB levels. This may be explained by (i) the heterogeneity of the condition of chronic GVHD and low patient numbers;(ii) the late time point >12m post-HCT with generally higher AB levels. Consistent with other reports age >65y was also associated with lower cS1 responses (p=0.03). Conclusion: Allo-HCT recipients early post-transplant, those of older age, and those given IST displayed insufficient AB titers to the vaccine. Such knowledge is of critical importance to transplant recipients and th ir physicians to guide treatment decisions regarding re-vaccination, and social behavior during this pandemic. Monitoring AB development in all allo-HCT recipients and vulnerable patients with other immunocompromising conditions may be crucial to determine those at increased risk for infection and for the timing of booster vaccines. [Formula presented] Disclosures: Manz: CDR-Life Inc: Consultancy, Current holder of stock options in a privately-held company;University of Zurich: Patents & Royalties: CD117xCD3 TEA.