Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) can cause the life-threatening acute respiratory disease called COVID-19 (Coronavirus Disease 2019) as well as debilitating multiorgan dysfunction that persists after the initial viral phase has resolved. Long COVID or Post-Acute Sequelae of COVID-19 (PASC) is manifested by a variety of symptoms, including fatigue, dyspnea, arthralgia, myalgia, heart palpitations, and memory issues sometimes affecting between 30% and 75% of recovering COVID-19 patients. However, little is known about the mechanisms causing Long COVID and there are no widely accepted treatments or therapeutics. After introducing the clinical aspects of acute COVID-19 and Long COVID in humans, we summarize the work in animals (mice, Syrian hamsters, ferrets, and nonhuman primates (NHPs)) to model human COVID-19. The virology, pathology, immune responses, and multiorgan involvement are explored. Additionally, any studies investigating time points longer than 14 days post infection (pi) are highlighted for insight into possible long-term disease characteristics. Finally, we discuss how the models can be leveraged for treatment evaluation, including pharmacological agents that are currently in human clinical trials for treating Long COVID. The establishment of a recognized Long COVID preclinical model representing the human condition would allow the identification of mechanisms causing disease as well as serve as a vehicle for evaluating potential therapeutics.

Coronaviruses are a significant threat to public health, animal welfare, and economic stability. SARS-CoV-2 and seasonal coronaviruses continue to cause disease and coronaviruses in the animal reservoir pose a constant spillover threat. Immunological imprinting is a term meant to represent the strong influence of the first viral infection on the outcome of subsequent related viral infections or vaccination, with “Original Antigenic Sin” having historically been applied to the potential negative effects of such imprinting. Little is known, however, about the imprinting potential between seasonal and severe coronaviruses of zoonotic origin and the regulation of cross-reactive responses, positive or negative, upon secondary or subsequent exposures. Here we adopted a step-wise experimental approach to examine the imprinting response and subsequent immune recall toward antigenically distinct coronaviruses at various distances using the Syrian hamster model. This approach enabled the experimental evaluation of cross-reactivity and cross-protection among coronaviruses which has not been previously done. Hamsters were imprinted with seasonal coronaviruses including alphacoronaviruses (HCoV-NL63, HCoV-229E) and betacoronaviruses (HCoV-OC43), or the original SARS-CoV-2 Wuhan virus (also a betacoronavirus). Seasonal CoV imprinting was followed by challenge with the original SARS-CoV-2 Wuhan virus representing distant imprinting-challenge combinations. Wuhan imprinting was followed by homologous Wuhan challenge or heterologous Beta or Omicron variants of concern to assess responses along a continuum of SARS-CoV-2 inter-relatedness. Weight loss and temperature as well as viral load, antibody induction, and host gene profiling for interferon responses, inflammation, and germinal center reactions were analyzed. Although imprinting with seasonal coronaviruses offered little protection against a SARS-CoV-2 Wuhan challenge in terms of viral replication and weight loss, NL63 imprinted animals mounted antigenic sin-like antibody responses while T cell gene signatures were noted in OC43 imprinted animals. The more similar imprinting-challenge regimens led to minimal or no viral replication. Subtle differences in the host responses were noted between Omicron and Beta challenges, suggesting Omicron to be more antigenically distant from Wuhan than the Beta variant. Host gene expression profiling analysis indicated interferon responses and germinal center reactions to be induced during more similar imprinting-challenge combinations while inflammation and antiviral response suppression were signatures in antigenically distant viral challenges. This work is the first characterization and analysis of seasonal coronavirus infection in animals and the subsequent effects on secondary SARS-CoV-2 infection. These results are important for calculating the antigenic distance between coronaviruses and for determining positive or negative cross-reactive signatures. As we begin to construct a matrix of protection, these data may inform the design of pan-coronavirus vaccines and the components needed in a multivalent platform to protect against antigenically distinct groups of coronaviruses while mitigating the risk of negative interference.