Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
Kathryn A. Bowman
Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA
Alex L. Zhu
Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA
Stephanie Fischinger
Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA
Samuel Beger
Space Exploration Technologies Corp., Hawthorne, California, USA
Jenny S. Maron
Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA
Yannic C. Bartsch
Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA
Caroline Atyeo
Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA
Matthew J. Gorman
Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA
Ahmad Yanis
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Judd F. Hultquist
Department of Medicine, Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
Ramon Lorenzo-Redondo
Department of Medicine, Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
Egon A. Ozer
Department of Medicine, Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
Lacy M. Simons
Department of Medicine, Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
Rana Talj
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Danielle A. Rankin
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Lindsay Chapman
Space Exploration Technologies Corp., Hawthorne, California, USA
Kyle Meade
Space Exploration Technologies Corp., Hawthorne, California, USA
Jordan Steinhart
Space Exploration Technologies Corp., Hawthorne, California, USA
Sean Mullane
Space Exploration Technologies Corp., Hawthorne, California, USA
Suzanne Siebert
Space Exploration Technologies Corp., Hawthorne, California, USA
Hendrik Streeck
Institute of Virology, University Hospital, University of Bonn, and German Center for Infection Research (DZIF), partner site Bonn-Cologne, Cologne, Germany
Pardis Sabeti
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
Natasha Halasa
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
Elon R. Musk
Space Exploration Technologies Corp., Hawthorne, California, USA
Dan H. Barouch
Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA
Anil S. Menon
Space Exploration Technologies Corp., Hawthorne, California, USA
Eric J. Nilles
Department of Medicine, Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
Douglas A. Lauffenburger
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
Galit Alter
Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA
ABSTRACT As public health guidelines throughout the world have relaxed in response to vaccination campaigns against SARS-CoV-2, it is likely that SARS-CoV-2 will remain endemic, fueled by the rise of more infectious SARS-CoV-2 variants. Moreover, in the setting of waning natural and vaccine immunity, reinfections have emerged across the globe, even among previously infected and vaccinated individuals. As such, the ability to detect reexposure to and reinfection by SARS-CoV-2 is a key component for global protection against this virus and, more importantly, against the potential emergence of vaccine escape mutations. Accordingly, there is a strong and continued need for the development and deployment of simple methods to detect emerging hot spots of reinfection to inform targeted pandemic response and containment, including targeted and specific deployment of vaccine booster campaigns. In this study, we identify simple, rapid immune biomarkers of reinfection in rhesus macaques, including IgG3 antibody levels against nucleocapsid and FcγR2A receptor binding activity of anti-RBD antibodies, that are recapitulated in human reinfection cases. As such, this cross-species analysis underscores the potential utility of simple antibody titers and function as price-effective and scalable markers of reinfection to provide increased resolution and resilience against new outbreaks. IMPORTANCE 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.
