Correlates of Protection Against Symptomatic COVID-19: The CORSER 5 Case-Control Study.

Background: Establishing correlates of protection often requires large cohorts. A rapid and adaptable case-control study design can be used to identify antibody correlates of protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in serum and saliva.
Methods: We designed a case-control study to compare antibody levels between cases of SARS-CoV-2 infection within 5 days of symptom onset and uninfected controls. Controls were matched on age, number of coronavirus disease 2019 vaccine doses, time since last dose, and past episodes of infection. We quantified anti-SARS-CoV-2 and seasonal coronavirus immunoglobulin (Ig) G in serum and saliva at inclusion, 1 month, and 6 months.
Results: We included 90 cases and 62 controls between February and September 2022. A boost and decay pattern of serum antibodies was observed in cases at 1 and 6 months, respectively, but not in controls. Anti-SARS-CoV-2 antibody levels were significantly higher in controls at inclusion both in serum (particularly antinucleocapsid IgG: 4.14 times higher compared with cases; 95% CI, 2.46-6.96) and saliva (particularly antispike for Delta variant IgG: 4.89 times higher compared with cases; 95% CI, 2.91-9.89). Saliva antibodies generally outperformed serum antibodies for case/control differentiation.
Conclusions: In this case-control study, we provided evidence of correlates of protection of anti-SARS-CoV-2 IgG in saliva and serum, with saliva antibodies often outperforming serum. The finding that antibodies in saliva are a better correlate of protection than antibodies in serum may inform vaccine development by highlighting the importance of robust induction of mucosal immune responses. This study design may be used during future epidemics for the prompt assessment of correlates of protection.
Competing Interests: Potential conflicts of interest. All authors report that they have no conflicts of interest.
(© The Author(s) 2025. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)