TY - JOUR
T1 - Serological Markers of SARS-CoV-2 Reinfection
AU - Siddiqui, Sameed M.
AU - Bowman, Kathryn A.
AU - Zhu, Alex L.
AU - Fischinger, Stephanie
AU - Beger, Samuel
AU - Maron, Jenny S.
AU - Bartsch, Yannic C.
AU - Atyeo, Caroline
AU - Gorman, Matthew J.
AU - Yanis, Ahmad
AU - Hultquist, Judd F.
AU - Lorenzo-Redondo, Ramon
AU - Ozer, Egon A.
AU - Simons, Lacy M.
AU - Talj, Rana
AU - Rankin, Danielle A.
AU - Chapman, Lindsay
AU - Meade, Kyle
AU - Steinhart, Jordan
AU - Mullane, Sean
AU - Siebert, Suzanne
AU - Streeck, Hendrik
AU - Sabeti, Pardis
AU - Halasa, Natasha
AU - Musk, Elon R.
AU - Barouch, Dan H.
AU - Menon, Anil S.
AU - Nilles, Eric J.
AU - Lauffenburger, Douglas A.
AU - Alter, Galit
N1 - Publisher Copyright:
Copyright © 2022 Siddiqui et al.
PY - 2022/2/1
Y1 - 2022/2/1
N2 - 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 FcgR2A 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 FcgR2A 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.
AB - 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 FcgR2A 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 FcgR2A 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.
KW - Antibodies
KW - Biomarkers
KW - Diagnostics
KW - Humoral immunity
KW - Reinfection
KW - SARS-CoV-2
UR - http://www.scopus.com/inward/record.url?scp=85125923116&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85125923116&partnerID=8YFLogxK
U2 - 10.1128/MBIO.02141-21
DO - 10.1128/MBIO.02141-21
M3 - Article
C2 - 35073738
AN - SCOPUS:85125923116
SN - 2161-2129
VL - 13
JO - mBio
JF - mBio
IS - 1
M1 - e02141
ER -