Serological Predictors of Protection from Infection Upon Household Exposure to SARS-CoV-2

Correlates of protection against symptomatic and severe breakthrough SARS-CoV-2 infections are well characterized. However, correlates of protection against virus transmission are poorly defined due to a lack of evidence in well-designed prospective clinical trials. We studied a Croatian cohort of individuals with documented household exposure to SARS-CoV-2 in late 2022/early 2023. Sera were acquired at the time of the COVID-19 diagnosis of the index case and before symptom onset of the test case. Samples were comprehensively analyzed for predictors of protection against virus transmission. PCR-negative participants at day 0 were recalled 14 days later and re-tested by PCR and IgM ELISA to identify any virus transmission, including asymptomatic ones. Out of nearly 200 tested serological parameters, several serological features differed between the participants that became PCR-positive during the study period and those that remained PCR-negative, although none remained significant after correction for multiple testing in the full cohort. Titers of variant-specific neutralizing antibody showed the biggest difference and were higher in the uninfected subgroup. Since recent antigenic exposure may confound results, we identified the recipients exhibiting IgM seroconversion and censored them from the study. This refinement clearly separated infected and uninfected individuals by variant-specific neutralization titers and IgA1 responses to BA4/5 RBD, which remained significant after correction. Therefore, our data indicate that high IgA1 and neutralizing titers may be predictive serum correlates of protection against SARS-CoV-2 transmission in intense contacts among household members, but only if variant-specific antigen is used in serological assays.