ABSTRACT
Background: We sought to determine immune and behavioral pre-infection correlates of protection against SARS-CoV-2 post-vaccine infections in a joint analysis of epidemiological and immunological cohort data. Methods: Serum and saliva samples from 176 BNT162b2-vaccinated adults in the Prospective Assessment of SARS-CoV-2 Seroconversion study were collected between October and December 2021 and assessed for serum and saliva levels of Wuhan-1 wild-type (WT) SARS-CoV-2 Spike (S)-specific IgG and IgA binding antibodies (bAb) using a multiplex microsphere-based immunoassay (MMIA). Serum samples were also assessed for WT receptor binding domain (RBD)-specific bAb by two commercial assays, BA.1 S-specific IgG bAb by MMIA, and neutralization activity against D614G, Delta (B.1.617.2), and Omicron BA.1 and BA.1.1 variants using a lentiviral pseudovirus neutralization assay. After the Fall 2021 visit, participants reported all positive PCR and/or antigen tests for SARS-CoV-2. Duration, severity, and type of symptoms, as well as risk exposures and adherence to precautionary measures, were assessed by questionnaires during the Spring 2022 visit. Results: Thirty-two participants (18.2%) developed symptomatic post-vaccination SARS-CoV-2 infections (PVI) between December 7, 2021 and April 1, 2022. Pre-infection WT (geometric mean (GM) of 3,863 vs 2,736 binding antibody unit [BAU]/ml, uninfected vs PVI, p=0.0098) and BA.1 (GM of 276.9 vs 179.9 arbitrary bAb unit [AU]/ml, uninfected vs PVI, p=0.04) anti-S IgG bAb levels measured by MMIA and neutralizing titers (NT) against BA.1 (GM titer [GMT] of 493.6 vs 286.2, uninfected vs PVI, p=0.0313) and BA.1.1 (GMT of 552.0 vs 302.5, uninfected vs PVI, p=0.021) were significantly higher in individuals that did not develop PVIs. WT anti-S bAb levels greater than 5,000 BAU/ml were associated with > 90% protection against symptomatic PVI. In individuals that developed PVI, WT anti-S IgG bAb levels correlated with lower disease severity scores ({rho}= -0.3859, p=0.032) and shorter duration of clinical disease ({rho}= -0.5273, p=0.0023). WT anti-RBD bAb levels measured by commercial assays correlated strongly with bAb levels measured by MMIA ({rho}=0.8239, p<0.0001 and {rho}=0.6929, p<0.0001, Roche and Siemens assays, respectively), but did not reach statistical significance for correlation with protection against PVI. Home risk score, but neither work nor home precautionary measures, correlated strongly with risk of PVI (mean score of 20.77 vs 47.33, uninfected vs PVI respectively, p<0.0001). Conclusions: Anti-S IgG bAb levels (directed against either WT or Omicron BA.1 subvariant) and NTs served as correlates of protection against symptomatic SARS-CoV-2 infection. Anti-S (WT) IgG bAb levels remained a significant correlate of protection against PVIs when adjusting for demography and risk behavior. Results of this study also suggest that commercial assays for anti-S bAb may need to be reformatted to enable detection of higher maximum values for use as predictors of increased susceptibility to SARS-CoV-2 infection.
Subject(s)
Severe Acute Respiratory Syndrome , COVID-19ABSTRACT
Background: Significant clinical similarities have been observed between the recently described Long-Haul COVID-19 (LHC) syndrome, Postural Orthostatic Tachycardia Syndrome (POTS) and Inappropriate Sinus Tachycardia (IST). Shared symptoms include light-headedness, palpitations, tremulousness, generalized weakness, blurred vision, chest pain, dyspnea, brain-fog, and fatigue. Ivabradine is a selective sinoatrial node blocker FDA-approved for management of tachycardia associated with stable angina and heart failure not fully managed by beta blockers. In our study we aim to identify risk factors underlying LHC, as well as the effectiveness of ivabradine in controlling heart rate dysregulations and POTS/IST related symptoms. Methods/Design: A detailed prospective phenotypic evaluation combined with multi-omic analysis of 200 LHC volunteers will be conducted to identify risk factors for autonomic dysfunction. A comparator group of 50 volunteers with documented COVID-19 but without LHC will be enrolled to better understand the risk factors for LHC and autonomic dysfunction. Those in the cohort who meet diagnostic criteria for POTS or IST will be included in a nested prospective, randomized, placebo-controlled trial to assess the impact of ivabradine on symptoms and heart rate, assessed non-invasively based on physiologic response and ambulatory electrocardiogram. Additionally, studies on catecholamine production, mast cell and basophil degranulation, inflammatory biomarkers, and indicators of metabolic dysfunction will be measured to potentially provide molecular classification and mechanistic insights. Discussion: Optimal therapies for dysautonomia, particularly associated with LHC, have yet to be defined. In the present study, ivabradine, one of numerous proposed interventions, will be systematically evaluated for therapeutic potential in LHC-associated POTS and IST. Additionally, this study will further refine the characteristics of the LHC-associated POTS/IST phenotype, genotype and transcriptional profile, including immunologic and multi-omic analysis of persistent immune activation and dysregulation. The study will also explore and identify potential endotheliopathy and abnormalities of the clotting cascade.
Subject(s)
Heart Failure , Primary Dysautonomias , Tachycardia, Sinus , Angina Pectoris , Dyspnea , Metabolic Diseases , Chest Pain , Postural Orthostatic Tachycardia Syndrome , Chronobiology Disorders , Vision Disorders , COVID-19 , Fatigue , TachycardiaABSTRACT
Background: Significant clinical similarities have been observed between the recently described ‘Long-Haul’ COVID-19 (LHC) syndrome, Postural Orthostatic Tachycardia Syndrome (POTS) and Inappropriate Sinus Tachycardia (IST). Shared symptoms include light-headedness, palpitations, tremulousness, generalized weakness, blurred vision, chest pain, dyspnea, “brain-fog”, and fatigue. Ivabradine is a selective sinoatrial node blocker FDA-approved for management of tachycardia associated with stable angina and heart failure not fully managed by beta blockers. In our study we aim to identify risk factors underlying LHC, as well as the effectiveness of ivabradine in controlling heart rate dysregulations and POTS/IST related symptoms. Methods/Design: A detailed prospective phenotypic evaluation combined with multi-omic analysis of 200 LHC volunteers will be conducted to identify risk factors for autonomic dysfunction. A comparator group of 50 volunteers with documented COVID-19 but without LHC will be enrolled to better understand the risk factors for LHC and autonomic dysfunction. Those in the cohort who meet diagnostic criteria for POTS or IST will be included in a nested prospective, randomized, placebo-controlled trial to assess the impact of ivabradine on symptoms and heart rate, assessed non-invasively based on physiologic response and ambulatory electrocardiogram. Additionally, studies on catecholamine production, mast cell and basophil degranulation, inflammatory biomarkers, and indicators of metabolic dysfunction will be measured to potentially provide molecular classification and mechanistic insights. Discussion: Optimal therapies for dysautonomia, particularly associated with LHC, have yet to be defined. In the present study, ivabradine, one of numerous proposed interventions, will be systematically evaluated for therapeutic potential in LHC-associated POTS and IST. Additionally, this study will further refine the characteristics of the LHC-associated POTS/IST phenotype, genotype and transcriptional profile, including immunologic and multi-omic analysis of persistent immune activation and dysregulation. The study will also explore and identify potential endotheliopathy and abnormalities of the clotting cascade. Trial registration:ClinicalTrials.gov, ID:NCT05481177 Registered on 29 July 2022.