Background Vaccines against SARS-CoV-2 have been rapidly approved. While pivotal studies were conducted in healthy volunteers, little information is available on safety and efficacy of mRNA vaccines in immunocompromised patients, including recipients of allogeneic hematopoietic cell transplantations (allo-HCT). Objectives Here, we used a novel assay to analyze patient- and transplant-related factors and their influence on immune responses over an extended period of time (up to 6 months) to the SARS-CoV-2 vaccination in a large and homogenous group of allo-HCT recipients at a single center in Switzerland. Study Design We examined longitudinal antibody responses to SARS-CoV-2 vaccination with BNT162b2 (BioNTech/Pfizer) or mRNA-1273 (Moderna) in 110 allo-HCT recipients and 86 healthy controls. Seroprofiling recording IgG, IgA, and IgM reactivities against SARS-CoV-2 antigens (receptor-binding domain (RBD), spike glycoprotein subunits S1 and S2, and nucleocapsid protein (N)) was performed prior to vaccination, prior to the 2 nd dose, and 1, 3, and 6 months (m) after the 2 nd dose. Patients were stratified to three groups (A) 3-6m post HCT; (B) 6-12m post HCT; and (C) >12m post HCT. Results Individuals early post allo-HCT (3-6 and 6-12m post HCT) developed significantly lower antibody titers after vaccination compared to patients >12m post allo-HCT and healthy controls (p<0.001). Within the cohort of HCT recipients, patients >65 years (p=0.030), those under immunosuppression for prevention or treatment of graft-vs-host disease (GVHD) (p=0.033), and/or with relapsed disease (p=0.014) displayed poor humoral immune response to the vaccine. In contrast, the intensity of the conditioning regimen, underlying disease (myeloid/lymphoid/other), and presence of chronic GVHD had no impact on antibody levels. Antibody titers achieved the highest levels 1m after the 2 nd dose of the vaccine but substantially waned in all transplanted groups and healthy controls over time. Conclusions This analysis of long-term vaccine antibody response is of critical importance to allo-HCT recipients and transplant physicians to guide treatment decisions regarding re-vaccination and social behavior during the SARS-CoV-2 pandemic.

Background The use of short and uniform centrifugation schemes contributes significantly to the successful automation of laboratory procedures. It is however unclear if this is applicable to the hemostasis laboratory. Objectives This article assesses the accuracy of measurements obtained with a rapid, high-speed centrifugation scheme in a large set of hemostasis tests, covering the full spectrum of values obtained in clinical practice, and using meaningful statistical measures. Methods Two citrated plasma samples were obtained from consecutive patients of a tertiary hospital with suspected abnormal hemostasis tests and processed with two centrifugation schemes in parallel: 1,500 × g for 10 minutes and 3,137 × g for 7 minutes. The following tests were conducted: prothrombin time (n = 125), international normalized ratio (n = 146), activated partial thromboplastin time (n = 119), thrombin time (n = 105), fibrinogen (n = 125), factor (F)II (n = 69), FV (n = 64), FVII (n = 64), FX (n = 67), FVIII (n = 55), FIX (n = 37), FXI (n = 35), and FXIII (n = 20), D-dimer (n = 34), antithrombin (n = 31), anti-Xa activity (n = 30), von Willebrand antigen (n = 25), and von Willebrand activity (VWF:GPIbM; n = 27). Results A wide range of results were obtained in all tests. Spearman's rank correlation coefficient was at least 0.95 for all tests except FV, FIX, and FXI. The coverage probability π at a given deviation index κ of 15% was above 0.9 for all tests except FV, FVII, FX, FVIII, FIX, FXI, and VWF:GPIbM, suggesting a lack of agreement. Conclusion Our results suggest that high-speed centrifugation is applicable to the majority of routine hemostasis parameters. The coverage probability was more sensitive than Spearman's rank correlation to detect disagreement among centrifugation schemes.

Allogeneic haematopoietic cell transplantation (allo-HCT) recipients show impaired antibody (Ab) response to a standard two-dose vaccination against severe acute respiratory syndrome coronavirus-2 and currently a third dose is recommended as part of the primary vaccination regimen. By assessing Ab titres 1 month after a third mRNA vaccine dose in 74 allo-HCT recipients we show sufficient neutralisation activity in 77% of the patients. Discontinuation of immunosuppression before the third vaccine led to serological responses in 50% of low responders to two vaccinations. Identifying factors that might contribute to better vaccine responses in allo-HCT recipients is critical to optimise current vaccination strategies.

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 &gt;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) &gt;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) &lt;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&lt;0.001, p&lt;0.001, p=0.034 of healthy versus groups A, B, C respectively at T2, and p&lt;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 &gt;12m post-HCT with generally higher AB levels. Consistent with other reports age &gt;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 their 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. Figure 1 Figure 1. Disclosures Manz: CDR-Life Inc: Consultancy, Current holder of stock options in a privately-held company; University of Zurich: Patents & Royalties: CD117xCD3 TEA.