ABSTRACT
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.
ABSTRACT
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).
ABSTRACT
For patients with classical hairy cell leukemia (HCL) standard treatment options such as purine analogues (PA) achieve a durable response, but are associated with severe immunosuppression. In particular, PAs cause long-lasting depletion of CD4+-lymphocytes. The BRAF inhibitor vemu-rafenib is effective in HCL but its use in first line treatment is currently limited to select clinical situations such as active infection. There is a lack of clinical data on the impact of BRAF inhibitors on immune function or response to vaccines in HCL. Here, we report the use of vemurafenib in four patients with HCL during the coronavirus disease 2019 (COVID-19) pandemic with detailed immune monitoring during treatment. All patients responded to BRAFi with normalization of peripheral blood counts. None of the patients developed neutropenia or severe infection. We observed stable CD4+ and CD8+ T-lymphocyte counts while receiving vemurafenib (median treatment duration 131 days). Immunoglobulin levels were normal in all patients without decline. 3 out of 4 patients received the SARS-CoV-2 vaccination (Pfizer-BioNTech) during vemuraf-enib treatment. The IgG antibody levels against the spike-protein of SARS-CoV-2 were detectable in 3 out of 3 patients (2-12 weeks after the second vaccination). Our findings suggest that BRAF inhibitors have limited effect on cellular and humoral immune function. The findings may support the use of BRAF inhibitors during the current pandemic to avoid the potentially detrimental effects of PA and thus minimize COVID-19 related morbidity and mortality in patients without SARS-CoV-2 vaccination.
ABSTRACT
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.
ABSTRACT
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.