The SARS-CoV-2 virus has infected to date 35 million and killed over 600,000 persons in the U.S. alone. Despite initial success of the vaccines, the emergence of increasingly more infectious variants such as the delta variant, coupled with vaccine hesitancy and insufficiently effective therapies, has resulted in a continued and deepening national and world-wide pandemic crisis. Moreover, a significant fraction of COVID-19 patients (~35%), even those who are initially asymptomatic, suffer long-term debilitating effects ("long-COVID"). Recent reports correlate the structure of specific SARS-CoV-2 induced antibodies with potentially lethal proinflammatory responses in acute COVID-19. Studies have also linked the antibody response to long-COVID. Moreover, the nature of the antibody response to vaccination correlates with breakthrough infections. Thus, the ability to rapidly perform high- resolution, highly multiplexed antibody response profiling can provide an essential tool, ultimately leading to more effective diagnostics, prognostics, vaccines and treatments for both acute and long-term disease. However, current antibody profiling methods produce a very limited view of the humoral repertoire. To address this unmet need, AmberGen proposes to further develop in Phase II its mass spectrometric bead-array technology for in-depth immune-profiling, termed PC-BAMS-IP. This will provide researchers with a new and powerful tool for high- resolution antibody profiling which unlike current technology facilitates 2-dimensions of multiplexing. This is accomplished using arrayed photocleavable mass-tag (PC-MT) encoded beads bearing viral antigens to bind serum antibodies, along with a range of PC-MT encoded probes to simultaneously measure the full breadth of bead-bound antibody types. Mass spectrometry imaging (MSI) of the bead-arrays facilitates the decoding of thousands of different PC-MTs, thereby revealing the full complexity of the antibody response and a means to correlate it with disease severity/outcome. Feasibility studies focused on SARS-CoV-2 demonstrate the ability of PC-BAMS-IP to perform simultaneous 2-dimensional antibody profiling of both the Fab traits (antigen binding function) and Fc traits (immune effector function). The proposed 2-year Phase II project will expand on this progress, including: i) design, synthesis and evaluation of 25 plug-and-play PC-MT encoded beads for SARS-CoV-2 antigen immobilization and 25 PC-MT probes to simultaneously query a range of Fc traits of the bead-bound serum antibodies; ii) initial validation of the PC-BAMS-IP assay using control and COVID-19 convalescent sera, including comparison to Luminex® xMAP® technology, the existing gold-standard for 1-dimensional multiplex antibody profiling; and iii) demonstrate that PC-BAMS-IP can distinguish severe and mild COVID-19. This work will be facilitated by our continued collaboration with leading experts including Prof. Cathy Costello (BU, world- renowned mass spectrometry expert), Dr. Jason Amsden (Duke University, mass spectrometric instrument development), Prof. Rahm Gummuluru (BU, Vice Chair of Microbiology, a leading virologist), and Prof. Plamen Ivanov (BU, Director, Keck Laboratory for Network Physiology, advanced statistical physics).
Public Health Relevance Statement: Narrative The COVID-19 pandemic caused by the SARS-CoV-2 virus has infected 35 million and killed over 600,000 persons in the U.S. and 4 million worldwide. Moreover, a significant fraction of patients, including many that are initially asymptomatic, often suffer from a diverse array of long-term debilitating effects. The objective of this project is to develop an urgently needed high-throughput, high-resolution, serological method to profile the antibodies produced by individuals in response to SARS-CoV-2 and other pathogens. This new 2D multiplexing capability, that goes well beyond simple antibody isotyping, will enable researchers to rapidly correlate subtle antibody characteristics with diverse manifestations of COVID-19 progression and will lead to improved diagnostics, prognostics and therapies for both acute and long-term disease.
Project Terms: Analysis of Variance; ANOVA; Variance Analyses; Antibodies; Epitopes; Antigenic Determinants; Binding Determinants; Antigens; immunogen; Viral Antigens; virus antigen; Biological Assay; Assay; Bioassay; Biologic Assays; Boston; Classification; Systematics; Cross Reactions; Disease; Disorder; Feasibility Studies; Fluorescence; glycosylation; Metabolic Glycosylation; Gold; Human; Modern Man; IgG1; Immobilization; orthopedic freezing; Immunoglobulin Isotypes; Laboratories; Methods; Microbiology; Persons; Noise; Patients; Physics; Physiology; Play; Reagent; Research; Investigators; Researchers; Research Personnel; ROC Analyses; receiver operating characteristic analyses; receiver operating characteristic curve; ROC Curve; medical college; school of medicine; medical schools; Sensitivity and Specificity; Cell Communication and Signaling; Cell Signaling; Intracellular Communication and Signaling; Signal Transduction Systems; Signaling; biological signal transduction; Signal Transduction; 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