ABSTRACT
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.
ABSTRACT
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.
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
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.
ABSTRACT
Introduction: A- or presymptomatic SARS-CoV-2 infected individuals pose a potential threat for health care facilities due to the risk of secondary cases. To prevent unnoticed introduction of SARS-CoV-2, several institutions implemented universal admission screening. However, little is known on the yield of this approach in different epidemiological settings. Objectives: We aimed to describe the rate of asymptomatic SARSCoV- 2 infected patients identified in universal admission screening, and its correlation with the population incidence. Methods: Publicly available cantonal data were used to describe the population incidence. All patients admitted to the University Hospital Zurich, Switzerland, were tested for SARS-CoV-2 by polymerase chain reaction (PCR). SARS-CoV-2 positive patients were retrospectively categorized as symptomatic or asymptomatic at admission and history for prior COVID-19 assessed by medical chart review. For correlation analyses, we calculated the positivity rates per calendar week for the admission screening and incidence rates per calendar week and 100'000 inhabitants for the cantonal data. Results: In the canton of Zurich, median SARS-CoV-2 incidence was 34.3 infections per calendar week and 100'000 inhabitants (interquartile range: 9.9 to 250.2). A total of 21'512 admissions screenings were performed in a 44-week period between calendar week 18 2020 and calendar week 8 2021. SARS-CoV-2 PCR was positive in 647 (3.0%) individuals. In 89 (13.8%) individuals, the positive test result was considered as residual viral replication after recent COVID-19 and not reflecting contagiousness. 457 (70.6%) SARS-CoV-2 positive individuals presented with COVID-19 symptoms at admission, whereas 101 (15.6%) SARS-CoV-2 individuals did not show any COVID-19 symptoms. Both, the rate of SARS-CoV-2 positive individuals (r = 0.88, P < 0.001) and the rate of asymptomatic SARS-CoV-2 positive individuals (r = 0.84, P < 0.001) correlated with the population incidence (Figure). Conclusion: In line with prior studies, approximately 0.5% of all admission screenings were positive in asymptomatic individuals. A strong correlation of the rate of asymptomatic SARS-CoV-2 infected individuals with the population incidence was detected.