Selective Detection and Ultrasensitive Quantification of SARS-CoV-2 IgG Antibodies in Clinical Plasma Samples Using Epitope-Modified Nanoplasmonic Biosensing Platforms

Monitoring the human immune response by assaying (detection and quantification) the antibody level against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is important in conducting epidemiological surveillance and immunization studies at a population level. Herein, we present the design and fabrication of a solid-state nanoplasmonic biosensing platform that is capable of quantifying SARS-CoV-2 neutralizing antibody IgG with a limit of detection as low as 30.0 attomolar (aM) and a wide dynamic range spanning seven orders of magnitude. Based on IgG binding constant determination for different biological motifs, we show that the covalent attachment of highly specific SARS-CoV-2 linear epitopes with an appropriate ratio, in contrast to using SARS-CoV-2 spike protein subunits as receptor molecules, to gold triangular nanoprisms (Au TNPs) results in a construction of a highly selective and more sensitive, label-free IgG biosensor. The biosensing platform displays specificity against other human antibodies and no cross reactivity against MERS-CoV antibodies. Furthermore, the nanoplasmonic biosensing platform can be assembled in a multi-well plate format to translate to a high-throughput assay that allowed us to conduct SARS-CoV-2 IgG assays of COVID-19 positive patient (n = 121) and healthy individual (n = 65) plasma samples. Most importantly, performing a blind test in an additional cohort of 30 patient plasma samples, our nanoplasmonic biosensing platform successfully identified COVID-19 positive samples with 90% specificity and 100% sensitivity. Very recent studies show that our selected epitopes are conserved in the highly mutated SARS-CoV-2 variant "Omicron"; therefore, the demonstrated high-throughput nanoplasmonic biosensing platform holds great promise for a highly specific serological assay for conducting large-scale COVID-19 testing and epidemiological studies and monitoring the immune response and durability of immunity as part of the global immunization programs.