Performance of SARS COV-2 IgG Anti-N as an Independent Marker of Exposure to SARS COV-2 in an Unvaccinated West African Population

Determination of previous SARS-COV-2 infection is hampered by the absence of a standardized test. The marker used to assess previous exposure is IgG antibody to the nucleocapsid (IgG anti-N), although it is known to wane quickly from peripheral blood. The accuracies of seven antibody tests (virus neutralization test, IgG anti-N, IgG anti-spike [anti-S], IgG anti-receptor binding domain [anti-RBD], IgG anti-N + anti-RBD, IgG anti-N + anti-S, and IgG anti-S + anti-RBD), either singly or in combination, were evaluated on 502 cryopreserved serum samples collected before the COVID-19 vaccination rollout in Kumasi, Ghana. The accuracy of each index test was measured using a composite reference standard based on a combination of neutralization test and IgG anti-N antibody tests. According to the composite reference, 262 participants were previously exposed; the most sensitive test was the virus neutralization test, with 95.4% sensitivity (95% CI: 93.6-97.3), followed by 79.0% for IgG anti-N + anti-S (95% CI: 76.3-83.3). The most specific tests were virus neutralization and IgG anti-N, both with 100% specificity. Viral neutralization and IgG anti-N + anti-S were the overall most accurate tests, with specificity/sensitivity of 100/95.2% and 79.0/92.1%, respectively. Our findings indicate that IgG anti-N alone is an inadequate marker of prior exposure to SARS COV-2 in this population. Virus neutralization assay appears to be the most accurate assay in discerning prior infection. A combination of IgG anti-N and IgG anti-S is also accurate and suited for assessment of SARS COV-2 exposure in low-resource settings.