Influenza A H1N1–mediated pre-existing immunity to SARS-CoV-2 predicts COVID-19 outbreak dynamics

Background Susceptibility to SARS-CoV-2 infections is highly variable, ranging from asymptomatic and mild infections in most, to deadly outcome in few. This individual difference in susceptibility and outcome could be mediated by a cross protective pre-immunity, but the nature of this pre-immunity has remained elusive. Methods Antibody epitope sequence similarities and cross-reactive T cell peptides were searched for between SARS-CoV-2 and other pathogens. We established an ELISA test, a Luminex Multiplex bead array assay and a T cell assay to test for presence of identified peptide specific immunity in blood from SARS-CoV-2 positive and negative individuals. Mathematical modelling tested if SARS-CoV-2 outbreak dynamics could be predicted. Findings We found that peptide specific antibodies induced by influenza A H1N1 (flu) strains cross react with the most critical receptor binding motif of the SARS-CoV-2 spike protein that interacts with the ACE2 receptor. About 55–73% of COVID-19 negative blood donors in Stockholm had detectable antibodies to this peptide, NGVEGF, in the early pre-vaccination phase of the pandemic, and seasonal flu vaccination trended to enhance SARS-CoV-2 antibody and T cell immunity to this peptide. Twelve identified flu/SARS-CoV-2 cross-reactive T cell peptides could mediate protection against SARS-CoV-2 in 40–71% of individuals, depending on their HLA type. Mathematical modelling taking pre-immunity into account could fully predict pre-omicron SARS-CoV-2 outbreaks. Interpretation The presence of a specific cross-immunity between Influenza A H1N1 strains and SARS-CoV-2 provides mechanistic explanations to the epidemiological observations that influenza vaccination protects people against SARS-CoV-2 infection.