Immunoglobulin evolution of pre-existing and newly generated human memory B cell responses to Coronaviruses spike proteins

The recent emergence of the coronavirus disease 2019 (COVID-19) pandemic has caused a great threat to humanity. The infectious agent, the SARS-CoV-2, causes mild symptoms in most cases but can also cause severe complications in some patients. Risk factors associated with severe illness include host-related factors such as older age, underlying co-morbidities and uncontrolled immune response. Virus-related factors such as within-host virus diversity could also trigger an aggressive immune response, and conversely cause severe symptoms. Therefore, understanding the immune response to SARS-CoV-2 infection is critical to understand variabilities in disease outcomes as well as to support the ongoing development of effective therapies. Former studies on SARS-CoV-1 and MERS-CoV indicated the importance of humoral immune response as a major defense system against CoV. Further, human B-cell-derived recombinant monoclonal antibodies have been proven effective against several respiratory viral infections including CoV. However, little is known about B cells and antigen receptors stimulated by SARS-CoV-2 infection. To date, there are very few studies characterizing B cell response to SARS-CoV-2 infection. One of these studies (Mathew et al. 2020) reported the B cells activation in some COVID-19 patients, while others did not experience any response. Additional two studies carried out by Galson (UK) and Nielsen (USA) also reported changes in human B cell compartment with a stereotypical naive immune response that was consistent across COVID-19 patients. However, no information was provided regarding disease outcome in either studies. Of note, the diversity of generated B cell repertoire could also be affected by the previous exposure to other coronaviruses. Therefore, infection with SARS-CoV-2 may result in the production of non-neutralizing antibodies which may form complexes with the SARS-CoV-2 or virus-activated complement components, thereby triggering inflammation, cytokine storm and hence the poor outcome of the disease. Another factor that might affect B cell repertoire diversity is the quasispecies nature of coronaviruses. Those viruses exist as a cloud of closely related viruses and hence is expected to elicit more diverse B cell response to encounter virus diversity. Our analysis of SARS-CoV-2 viruses from severe and mild cases revealed significantly higher diversity among severe cases. It is crucial to drive a deeper understanding of the nature and role of humoral immunity during SARS-CoV-2 infection and to identify potential therapeutic antibodies to SARS-CoV-2. To do so, analysis of B cell receptor (BCR) repertoire from COVID-19 patients at various stages of their immune response is necessary. Currently, there are many vaccine approaches that are mainly targeting the spike (S) glycoprotein - a viral surface protein which mediates virus entry by binding to host receptor. The antibody response to such vaccines will be polyclonal in nature and will likely include both neutralizing and non-neutralizing antibodies. Therefore, studies exploring the dynamics and the mechanisms of the humoral immune response in COVID-19 patients are necessary to guide the ongoing vaccine development -which is expected to be ready in a year- and therapeutic monoclonal antibodies. This will help us better identify B cells clones that will confer long-lasting protective antibody responses and prevent reinfection, as seen with other viral infections. Moreover, analysis of elicited antibodies may reveal the presence of broadly-neutralizing antibodies that can cross-react with other coronaviruses, similar to those found in influenza. At present, available immunological studies lack information about (1) the role of B cells in SARS-CoV-2 infection; (2) B cell repertoire in patients with variable clinical outcomes and of age groups; (3) the long-term evolution and survival of generated memory B cell responses in recovered patients; and (4) the difference of humoral immune response to the spike protein between infected and vaccinated individuals. In this study, we hypothesize that B cell repertoire differ in patients with variable disease outcomes, in various age groups of patients, and in those infected versus those that are vaccinated. We also propose that the quasispecies nature of coronaviruses would trigger higher diversity in B cell repertoire.