Longitudinal analyses after COVID-19 recovery or prolonged infection reveal unique immunological signatures after repeated vaccinations

Background To strategically develop preventive and therapeutic measures against coronavirus disease 2019 and its causative virus, SARS-CoV-2, it is critical to fully characterize immune response and sustained immune activation following viral infection and vaccination. However, the mechanisms controlling intrapersonal variation in antibody titers against SARS-CoV-2 antigens remain unclear. To gain further insights into how we can optimize therapeutic and preventive care, we performed a robust molecular and cellular investigation of immune responses in infected, recovered, and vaccinated individuals. Methods We evaluated the expression of 29 cytokines and assessed their correlation with neutralizing potency. We further investigated memory B-cell response in patients infected with the original SARS-CoV-2 strain or other variants of concern, and in vaccinated individuals. Results Correlation analyses showed that the relationship between neutralizing activity and cytokine expression differed according to disease severity and viral strain. Furthermore, long-term longitudinal analyses revealed that post-vaccination neutralizing potential was more strongly associated with various cytokine expression levels in recovered patients than in naïve individuals. Notably, we found a similar distribution of virus-specific antibody gene families in triple-vaccinated individuals and a patient with COVID-19 pneumonia for one year. Conclusion Our results showed that distinct immune responses occur depending on the viral strain suggesting that therapeutic options should be selected on a case-by-case basis. Furthermore, longitudinal analyses revealed biomarker candidates that correlated with repeated vaccination that may be applicable to therapies regulating specific immune responses and novel monoclonal antibodies. Funding This work was supported by the Institutional Funds, YOKOYAMA Foundation for Clinical Pharmacology (#YRY-2121), and the Japan Society for the Promotion of Science (JSPS)/ Ministry of Education, Culture, Sports, Science, and Technology (MEXT) KAKENHI; Grant-in-Aid for Early-Career Scientists (#21K15888).