Blinded two-year longitudinal evaluation of SARS-CoV-2 antigenemia in long COVID

OBJECTIVES: SARS-CoV-2 antigens have been detected in plasma months after acute infection, but their long-term dynamics and clinical relevance remain unclear. We aimed to assess the persistence and clinical specificity of plasma SARS-CoV-2 antigenemia over 2 years after acute infection. METHODS: We conducted a 2-year longitudinal study involving 425 adults who developed Long COVID (n = 167) or fully recovered from acute COVID-19 (n = 148), and uninfected controls (n = 110). Plasma samples were collected at 6-12 months and 18-24 months after infection. SARS-CoV-2 spike, S1 subunit, and nucleocapsid antigens were quantified using the ultrasensitive Simoa® platform blinded for clinical features. SARS-CoV-2 specific humoral responses, including neutralizing antibodies, were also assessed. RESULTS: At 6-12 months, SARS-CoV-2 antigenemia (any antigen) was detected in 31% of individuals with Long COVID, in 20% of those fully recovered and in 5.4% of uninfected controls. By 18-24 months, positivity declined to 3.5%, 0%, and 1.5%, respectively. Full spike was the most frequent antigen detected, whereas S1 was rarely observed and nucleocapsid was absent in recovered participants. Antigenemia was not associated with number or type of persistent symptoms, antibody titres, including neutralizing capacity, or vaccination status. CONCLUSIONS: SARS-CoV-2 antigens circulate in plasma up to 1 year after infection in a minority of individuals, regardless of whether they develop Long COVID or not, and become rarely detectable later on. Therefore, current evidence does not support its use to guide clinical monitoring or treatment decisions in Long COVID.