Investigating the components of heterotypic immunity associated with protection against coronavirus related disease
OA Version
Citation
Abstract
A few highly pathogenic coronaviruses (CoVs) have emerged in the human population in the past twenty-five years and have impacted the world on a global scale. Several demographic and clinical factors are associated with protection against severe disease from these pathogenic human CoV infections. In the context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a recent infection with a “common cold” causing human endemic CoV (eCoV) is associated with protection against severe coronavirus disease 2019 (COVID-19). Yet, the cross-reactive immune components providing this heterotypic immunity between heterologous coronaviruses have not been fully elucidated. We hypothesize that heterotypic immune protection is not mediated by neutralizing antibodies (nAbs) because of the diversity in spike protein receptor binding domains within the CoV family, but by alternative adaptive immune factors that target more conserved CoV regions. To test this hypothesis, we identified individuals from Boston Medical Center (BMC) with prior infections or vaccinations to SARS-CoV-2 or the eCoVs (HCoV-229E, HCoV-HKU1, HCoV-NL63, and HCoV-OC43) and measured both homologous and heterologous CoV directed immune responses. First, in a study of risk factors of SARS-CoV-2 reinfection, SARS-CoV-2 antibody responses were similar between those with or without a SARS-CoV-2 reinfection and nAbs were not associated with long-term homotypic CoV protection. To explore heterotypic immunity, we classified individuals with or without a presumed or documented recent eCoV infection in a cohort of SARS-CoV-2 naïve individuals. Cross-reactive T cell and nAb responses against SARS-CoV-2 were similar between individuals regardless of recent eCoV infection history. Meanwhile, individuals with a presumed or documented recent eCoV infection had higher and correlative levels of Fc receptor (FcR) binding antibodies against eCoV spikes (S) and SARS-CoV-2 S2 subunit. Lastly to investigate the extent of coronavirus heterotypic immunity, we investigated immune components associated with SARS-CoV-2 mediated protection against subsequent symptomatic eCoV infections. Cross-reactive replication and transcription complex (RTC)-specific CD8+ T cells were associated with protection against symptomatic eCoV infections in individuals with a previous SARS-CoV-2 infection, while other eCoV-responsive T cells and nAbs were not predictive of heterotypic immune protection. In aggregate, nAbs were not associated with long-term protection against homologous or heterologous CoV infections and associated disease, but instead, antibody Fc effector functions and CD8+ T cells were associated with protective roles. These findings indicate that eliciting diverse immune functions along with nAbs in a future pan-CoV vaccine will be important to protect against disease from current and novel human CoVs.
Description
2025
License
Attribution 4.0 International