Anti-receptor-binding domain IgG responses after SARS-CoV-2 infection in outpatients treated with ensitrelvir

Ensitrelvir, a SARS-CoV-2 3C-like protease inhibitor, achieves rapid viral clearance. Whether early viral suppression attenuates humoral immune responses induced by SARS-CoV-2 infection remains unclear. During the KP.3 epidemic in Japan, we conducted a prospective study at 10 outpatient clinics comparing post-infection antibody responses in patients with mild COVID-19 treated with ensitrelvir and those untreated. KP.3-specific anti-spike receptor-binding domain (RBD) IgG titers were measured at baseline and 28 days. Data from 54 patients (30 treated and 24 untreated) were analyzed, with some baseline characteristics differing between groups. The post-treatment geometric mean titers (GMTs) were lower in the ensitrelvir group than in the untreated group (3,652 [95% CI, 2,849-4,682] vs. 5,816 [3,887-8,702] AU/mL; p = 0.040), although the difference was within twofold and the geometric mean fold increases were comparable between groups (12.51 [95% CI, 8.22-19.04] vs. 12.15 [7.33-20.17]; p = 0.928). In multivariable analysis, ensitrelvir use was independently associated with lower titers (β = -0.77; 95% CI, -1.33 to -0.22; p = 0.008), whereas in the propensity score-matched analysis, the between-group difference remained within twofold and was no longer statistically significant (p = 0.111). Substantial antibody increases were observed in both groups, with no statistically significant difference (9.61 vs. 14.8; p = 0.382), although a between-group difference cannot be excluded given the limited sample size. These results suggest that ensitrelvir may not meaningfully impair humoral immune responses to SARS-CoV-2 infection; however, the findings should be interpreted cautiously in light of baseline imbalances between treatment groups and potential residual confounding.