Immune Pressure From Plasma From Immunocompromised and Healthy Individuals Drives Differential SARS-CoV-2 Evolution and Escape Mutation Emergence.

Immunocompromised individuals with prolonged SARS-CoV-2 infections are recognized reservoirs for viral evolution and the emergence of immune escape variants. We investigated intra-host evolutionary dynamics of SARS-CoV-2 under distinct immune pressures exerted by plasma from kidney transplant recipients (KTRs). Wild-type (WT) SARS-CoV-2 (B.6.6) and Omicron subvariants (BA.5.2 and XBB.1.5.57) were serially passaged in the presence of convalescent plasma. KTR plasma exerted selective pressure on the spike protein without compromising replicative capacity, thereby facilitating viral diversification and the subsequent fixation of immune escape mutations. Three notable mutations, T95I (B.6.6), A879V (XBB.1.5.57) and I1114F (BA.5.2), were identified under KTR plasma pressure. When engineered into the WT spike, T95I, A879V, and I1114F conferred reductions in neutralization titers (1.5-fold, 6.0-fold, and 2.9-fold, respectively) against plasma from vaccine-boosted individuals. A879V also modestly reduced viral binding and entry in both WT and Omicron backgrounds, suggesting a possible trade-off between immune escape and viral fitness. These findings highlight the potential of antigenically distinct variants to emerge in immunocompromised hosts and the need for enhanced genomic surveillance in this population to preempt variant spread.