Abstract Viral respiratory infections are responsible for major morbidity and mortality in early life. Infants account for a significant proportion of influenza hospitalizations and are considered a top high-risk group. In addition to the acute morbidity, initial immune responses to influenza shape/imprint the immune system and affect subsequent responses to influenza infections and vaccinations, which tend to induce humoral responses skewed towards epitopes present in the first influenza antigen encountered. In contrast, SARS-CoV-2 infection in infants is generally mild and less severe than in older individuals. This is remarkable and suggests that there are unique features on how the infant immune system responds to SARS-CoV-2, compared to its responses against other respiratory viruses, that can be leveraged to improve our understanding of early life immunity. On the basis of these observations, we hypothesize that early life viral respiratory infections elicit virus-specific immune responses that lead to distinct immune developmental trajectories. To address this hypothesis, we will compare three longitudinal cohorts: i) infants infected with SARS-CoV-2; ii) infants infected with influenza virus; and as reference iii) healthy infants with none of those two infections. After acute infection children will be followed longitudinally for three years and immune responses assessed in the context of influenza and COVID- 19 vaccinations. We designed two integrated research projects, supported by three cores. Project 1 will define: 1) the differences of blood transcriptional immune signatures in infants with SARS-CoV-2 versus infants with influenza infection; 2) the magnitude, immunodominance pattern and breath of the antibody responses to influenza virus and evolution of antibody responses to SARS-CoV-2; and 3) perform high-throughput longitudinal evaluation of B cell responses to influenza and SARS-CoV-2. Project 2 will: 1) Assess the blood cell composition, transcriptome and epigenome in response to influenza and SARS-CoV-2 infection occurring in the first six months of life at the single cell level; and 2) Characterize the PBMC phenotype/cell composition, transcriptome and epigenome in response to vaccination against influenza and SARS-CoV-2.

Narrative Influenza viruses cause severe disease in infants. In contrast, SARS-CoV-2 infection in infants is generally mild and less severe. This is remarkable and offers a unique opportunity to study how the infant immune system responds to these two viral infections.