Upper respiratory infection drives clinical signs and inflammatory responses in heterologous challenge of SARS-CoV-2 variants of concern

During the COVID-19 pandemic, three variants of concern (VOC) of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) emerged globally with increasingly greater ability to evade the immune response and enhanced transmissibility. A critical question we have faced with each new VOC is how well the vaccine based on the ancestral strain will protect. Given vaccine hesitancy, it is also important to address how prior live infections may protect against new variants. To address this later question, K18-hACE2 mice were infected with a low, partially lethal dose of WA1/2020 (WA1), the prototype strain on which the mRNA vaccines are based. On 24 days post-infection (dpi), surviving mice were challenged with WA1, Alpha or Delta. Nasal turbinates and lungs showed active replication on 1- and 3-days post-challenge (dpc) in Alpha- and Delta-, but not WA1- challenge groups. The rate of recovery of Alpha- and Delta-challenged mice lagged behind WA1 with mice showing weight loss despite a greatly dampened proinflammatory response in the lung. In contrast, nasal turbinates had a heightened proinflammatory response for Alpha- and Delta- but not WA1-challenged groups. Inflammatory responses were limited to the upper respiratory tract. Despite this, we did not observe significant difference among the groups in fold change in the neutralizing titer. In summary, infection with a low dose of SARS-CoV-2 confers protection from challenge, but mice in the heterologous challenge group differed in having greater weight loss, viral replication, and a heightened proinflammatory response in the upper respiratory tract. Mice were intranasally infected with SARS-CoV-2 WA1/2020 isolate and challenged with either WA1/2020 or the VOCs, Alpha, or Delta 24 days post-infection. Nasal turbinates and lung samples were collected 1 and 3 days post-infection and post-challenge.