Serological Markers of SARS-CoV-2 Reinfection
Sameed M. Siddiqui, Kathryn Bowman, Alex Zhu, Stephanie Fischinger, Samuel Beger, Jenny S. Maron, Yannic C. Bartsch, Caroline Atyeo, Matthew J. Gorman, Ahmad Yanis, Judd F. Hultquist, Ramón Lorenzo-Redondo, Egon A. Ozer, Lacy M. Simons, Rana Talj, Danielle A. Rankin, L. Chapman, Kyle Meade, Jordan Steinhart, Sean Mullane, Suzanne Siebert, Hendrik Streeck, Pardis C. Sabeti, Natasha Halasa, Elon R. Musk, Dan H. Barouch, Anil Menon, Eric J. Nilles, Douglas A. Lauffenburger, Galit Alter
Abstract
As public health and social distancing guidelines loosen in the setting of waning global natural and vaccine immunity, a deeper understanding of the immunological response to reexposure and reinfection to this highly contagious pathogen is necessary to maintain public health. Viral sequencing analysis provides a robust but unrealistic means to monitor reinfection globally. The identification of scalable pathogen-specific biomarkers of reexposure and reinfection, however, could significantly accelerate our capacity to monitor the spread of the virus through naive and experienced hosts, providing key insights into mechanisms of disease attenuation. Using a nonhuman primate model of controlled SARS-CoV-2 reexposure, we deeply probed the humoral immune response following rechallenge with various doses of viral inocula. We identified virus-specific humoral biomarkers of reinfection, with significant increases in antibody titer and function upon rechallenge across a range of humoral features, including IgG1 to the receptor binding domain of the spike protein of SARS-CoV-2 (RBD), IgG3 to the nucleocapsid protein (N), and FcγR2A receptor binding to anti-RBD antibodies. These features not only differentiated primary infection from reexposure and reinfection in monkeys but also were recapitulated in a sequencing-confirmed reinfection patient and in a cohort of putatively reinfected humans that evolved a PCR-positive test in spite of preexisting seropositivity. As such, this cross-species analysis using a controlled primate model and human cohorts reveals increases in antibody titers as promising cross-validated serological markers of reinfection and reexposure.