Qualitative Changes in the SARS-CoV-2 Antibody Response in the Post-Infection Phase Impact the estimates of infections in Population-Based Seroprevalence Studies

Fenwick, C.; Croxatto, A.; Coste, A. T.; Pojer, F.; Andre, C.; Pellaton, C.; Farina, A.; Campos, J.; Hacker, D.; Lau, K.; Bosch, B. J.; Gonseth Nussle, S.; Bochud, M.; D'Acremont Genton, V.; Trono, D.; Greub, G.; Pantaleo, G.

In the present study, we have determined SARS-CoV-2-specific antibody responses in a cohort of 96 individuals during the acute phase of infection and in a cohort of 578 individuals enrolled in a seroprevalence population study in Switzerland including three groups, i.e. subjects with previous RT-PCR confirmed SARS-CoV-2 infections (n=90), positive patient contact (n=177) and random selected subjects (n=311). Six serological assays detecting predominantly IgG antibodies targeting either the Spike (S) and/or the nucleocapsid (N) proteins were used including also a Luminex based assay using an S protein in its native trimeric form. Antibody responses against the S and/or the N proteins were equally sensitive in the acute infection phase although differences in sensitivity (range 83 to 97% 16-33 days post-initial symptoms) were observed between the different assays and the Luminex S protein trimer assay was the most sensitive. Interestingly, antibody responses against the N protein appear to wane in the post-infection phase of the infection while those against the S protein persist over time, as indicated by the drop in sensitivity of the assays targeting the N protein (sensitivity range 71-77%). Assays detecting anti-N IgG antibodies may substantially underestimate the proportion of SARS-CoV-2 infections in the groups of patient positive contacts, i.e. 10.9 to 32.2% reduction (P<0.05-<0.0001) and in the random selected general population, i.e. up to 45% reduction (P<0.05). The overall reduction in seroprevalence for the total cohort ranged from 9.4 to 31% (P<0.0009-<0.0001). Of note, the assay using the S protein in its native trimer form was more sensitive as compared to those using monomeric S proteins. These results indicate that assays targeting the S protein, ideally the trimeric form, should be implemented as reference test to estimate SARS-CoV-2 infections in seroprevalence population studies.