Project 1

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 the acute infections, children will be followed longitudinally for three years and immune responses assessed in the context of influenza and COVID-19 vaccinations. We designed the following specific aims: Aim 1. Define the differences of blood transcriptional immune signatures in infants with SARS-CoV-2 versus infants with influenza infection. We will assess the differences in immune signatures between: i) the two acute viral infections SARS-CoV-2 versus influenza in infants; ii) primary acute infection versus primary vaccination, and iii) between initial (primary responses) and subsequent vaccinations (recall responses). Will correlate immune signatures with antibody profiles and B cell responses. Aim 2. Define the magnitude, immunodominance pattern and breath of the antibody responses to influenza virus and evolution of antibody responses to SARS-CoV-2. First, we will define the evolution of the antibody responses to influenza virus in infants upon initial infection and subsequent vaccination(s). Second, we will define the antibody responses to SARS-CoV-2 in infants upon initial infection and subsequent vaccination(s). Additionally, we will compare primary immune responses to infection versus vaccination with each of the two viruses. Aim 3. High-throughput longitudinal evaluation of B cell responses to influenza and SARS-CoV-2. We will perform high-throughput single cell assays using the 10xGenomics drop-seq platform to perform multi-variate analyses of single B cells at the level of the variable gene repertoire, cell-surface phenotype, transcriptome, and Ig specificity.