![]() The possibility that endemic coronaviruses may influence the dynamics of SARS-CoV-2 infection in a way seen among other endemic infections and emerging new variants or viruses should be considered ( 1, 2). It is generally assumed that humans are immunologically naive against SARS-CoV-2 and would show a primary immune response to the infection however, this could be an oversimplification. In addition to SARS-CoV-2, six human coronaviruses (hCoVs) are known: four seasonal coronaviruses (hCoV-229E, -NL63, -HKU1, and -OC43) which cause mild upper respiratory diseases, and the two most recently discovered viruses, SARS-CoV-1 and MERS-CoV, originating from recent zoonotic events. However, correlates of immunity to SARS-CoV-2 may be complicated by the existence of a pre-existing immunological memory to other human coronaviruses. Many public health responses to COVID-19 outbreaks are based on the assumption that the infection will result in a protective immune response of undefined duration. The duration and nature of immune responses to SARS-CoV-2 infection are not yet fully understood. The lack of pre-existing immunity is thought to be one reason for the rampant spread of the virus. The new SARS-CoV-2 pandemic has overwhelmed the world with its high contagiousness and range of severity, presenting from asymptomatic infection or mild symptoms to severe acute respiratory syndrome with severe morbidity and mortality. Here we discuss the potential of cross-reactive immunity to drive the immunopathogenesis of COVID-19 and its implications for current efforts to develop immune-based therapies and vaccines. Studies in non-human primates show that SARS-CoV-1 S-protein vaccine-induced antibodies are associated with acute lung injury in macaques challenged with SARS-CoV-1. There is also evidence that pre-existing T cell immunity to common cold coronaviruses can prime the response to SARS-CoV-2. Cross-reactive hCoV antibody responses have been detected in both SARS and COVID-19 patients. The early kinetics and magnitude of these responses are, in some cases, associated with worse clinical outcomes in SARS and COVID-19. The serological responses to both SARS-CoV-1 and SARS-CoV-2 virus have some unique characteristics that suggest cross-reactive priming by other human coronaviruses (hCoVs). 3Laboratory of Molecular Biology and Virology, Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.2Institute for Infection and Immunity, St George's, University of London, London, United Kingdom.Alberto Beretta 1*, Martin Cranage 2 and Donato Zipeto 3
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