Journal of Biomedical Science · Published 2026-07-22 · DOI 10.1186/s12929-026-01276-5
Chiaho Shih, You-Zhen Liao, Che-Yu Hsu, Ying-Chen Tsai, Ming-Yen Lin, Hsin-Ying Clair Chiou, Wen-Hui Kuan, Chih-Hsu Chang, An-Ting Liou, Yu-Chi Chou, Jih-Jin Tsai, Ping-Chang Lin, Ming-Lung Yu, Wan-Long Chuang, Jia-Jung Lee, Jer-Ming Chang, Shang-Jyh Hwang, Justin Shih, Wen-Chun Hung, Ming-Feng Hou, Inn-Wen Chong, Yuh-Jyh Jong, Jung-San Chang
Abstract Background Individuals with asymptomatic SARS-CoV-2 infection can unknowingly transmit the virus, yet identifying such subclinical infections in post-vaccinated populations remains challenging. Methods We conducted a longitudinal study of 129 infection-naïve vaccine recipients immunized with various combinations of SARS-CoV-2 spike (S) protein vaccine platforms. Sera were collected before the first dose (v1), at 2 weeks (v7) and 6 months (v8) after the third dose. Taiwan’s first major COVID-19 outbreak occurred between v7 and v8. We measured anti-nucleocapsid (anti-N) and anti-S IgG antibody titers by ELISA and assessed virus-neutralizing activity using live virus and pseudovirus assays. Results By developing an iterative serial screening method, we identified asymptomatic breakthrough (post-vaccination) infections among unconfirmed cases. Our v7-v8 paired cohort resolved into three distinct groups: confirmed cases (21%), asymptomatic breakthrough infections (17%), and uninfected subjects (62%). In normalized v8 sera, confirmed cases exhibited an anti-S+++ (high) /anti-N+++ (high) phenotype, while uninfected subjects showed an anti-S+ (low)/anti-N+(baseline) phenotype. Statistical analysis validated a distinct asymptomatic group characterized by an antibody profile anti-S++ (intermediate) /anti-N+ (baseline). Conclusions This approach may enable more accurate estimates of vaccine efficacy and infection prevalence. In a spike-vaccinated population, anti-N antibody is more a potential specific marker for COVID-19 symptomatic disease than an ideal marker for SARS-CoV-2 infection. To our knowledge, this is the first preliminary report of identification of asymptomatic breakthrough infection from a well-vaccinated population using self-matched longitudinal pairs of serum samples.
Abstract from DOAJ. Public domain (CC0 1.0).
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Shih, C., Liao, Y., Hsu, C., et al. (2026). Hidden asymptomatic breakthrough infection in a proof-of-concept longitudinal study on SARS-CoV-2 vaccine recipients. Journal of Biomedical Science. https://doi.org/10.1186/s12929-026-01276-5