The Impact of Prior Viral Exposures on SARS-CoV-2 Immunity

A new analysis in the Journal of Experimental Medicine found that prior infection with common‑cold coronaviruses augments antibody responses to SARS‑CoV‑2 by concentrating activity on the conserved S2 region of the spike protein. That S2‑focused immunity could justify vaccine strategies aimed at broader, cross‑coronavirus protection.

The investigators stratified participants by serologic evidence of prior endemic coronavirus exposure. They measured antibody binding and neutralization breadth directed at the S2 subunit, a conserved mechanistic target across coronavirus subfamilies. In some donors, S2‑binding antibodies demonstrated measurable neutralizing activity, though typically weaker than S1/RBD‑directed responses.

The expanded breadth appears to come from antibodies targeting conserved S2 epitopes shared across embecoviruses and may derive from memory B cells primed by earlier OC43‑like infections. In patients with more severe disease, anti‑S2 responses were broader and in some cases functionally neutralizing, whereas those with milder illness tended to make weaker or non‑neutralizing anti‑S2 antibodies.

Together, these observations suggest preexisting, S2‑focused immunity could modulate the clinical phenotype of SARS‑CoV‑2 infection and may influence progression from mild to severe disease.

S2 therefore emerges as a pragmatic antigenic candidate for next‑generation pan‑coronavirus immunogens. A priming strategy that uses OC43 S2 protein sequences or mosaic S2 constructs provides a rationale for expanded neutralization breadth and potential durability compared with current spike‑focused vaccines.