Severe disease is not essential for a high neutralizing antibody response post-SARS-CoV-2 infection

Neutralizing antibody responses correlate with protection from SARS-CoV-2 infection, yet higher neutralizing responses associate with more severe disease. Whether people without severe disease can also develop strong neutralizing responses to infection, and the pathways involved, is less clear. We performed a proteomic analysis on sera from 71 individuals infected with ancestral SARS-CoV-2, enrolled during the first South African infection wave. We determined disease severity by whether participants required supplemental oxygen and measured neutralizing antibody levels at convalescence. High neutralizing antibodies were associated with high disease severity, yet 40% of participants with lower disease severity had neutralizing antibody levels comparable to those with severe disease. We found 130 differentially expressed proteins between high and low neutralizers and 40 between people with high versus low disease severity. Five proteins overlapped, including furin, a protease which enhances SARS-CoV-2 infection. High neutralizers with non-severe disease had similar levels of differentially expressed neutralization response proteins to high neutralizers with severe disease, yet similar levels of differentially expressed disease severity proteins to participants with non-severe disease. Furthermore, we could reasonably predict who developed a strong neutralizing response based on a single protein, HSPA8, involved in clathrin pit uncoating. These results indicate that a strong antibody response does not always require severe disease and may involve different pathways.