Beyond seropositivity: SARS-CoV-2 IgG responses in high-risk COVID-19 patients

Background: Understanding the clinical relevance of anti-Spike IgG antibodies in the Omicron era remains crucial for optimizing the management of vulnerable patients with COVID-19. This study aimed to evaluate the relationships between humoral immunity, virological features, and host factors in high-risk individuals infected during the Delta-Omicron transition. Methods: We investigated 120 high-risk patients with early COVID-19 in Italy, with sampling performed shortly after symptom onset. Humoral immunity was assessed using a quantitative anti-Spike IgG assay and an ACE2–RBD receptor-binding inhibition assay. Plasma viral load (RNAemia) and viral variant typing were performed. Multivariable regression models were used to explore associations among immune markers, virological characteristics, vaccination status, age, and comorbidities. Results: At baseline, 67.5% (81/120) of patients were IgG-seropositive and were older than seronegative individuals. Anti-Spike IgG titers correlated strongly with wild-type RBD–ACE2 binding inhibition overall (r = 0.80), with a stronger correlation in Delta infections (r = 0.91) than Omicron infections (r = 0.64). Higher IgG titers showed a trend towards lower viral load in Delta but not in Omicron infections. Omicron infection was independently associated with significantly higher RNAemia. Among seropositive patients, vaccination was associated with lower IgG titers but higher ACE2-RBD inhibition capacity. Increasing age correlated positively with IgG titers, while the number of risk factors correlated negatively. RNAemia was frequent but was not associated with long-COVID. Conclusion: These findings highlight variant-specific limitations of anti-Spike IgG as a universal marker of protection and support the need for integrated serological and virological assessment to guide antiviral and monoclonal antibody strategies in vulnerable populations.