Natural Antibodies and Severe Acute Respiratory Syndrome Coronavirus 2–Specific Antibodies in Healthy Asymptomatic Individuals

To theEditor—Reports in this journal [1, 2] and others [3] have concluded with varying degrees of certainty that detection of specific immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike and coat proteins in plasma of asymptomatic healthy individuals might be indicative of prior infection. They suggest that these data are consistent with there being individuals infected in late 2019 (September–December) and early 2020, prior to the main 2020 epidemic outbreaks. Data in Apolone et al [3], referring to detection of IgG and IgM antibodies in (a small number of) asymptomatic individuals in Italy as early as September 2019, would date the appearance of coronavirus disease 2019 (COVID-19) to a time that contradicts other molecular analyses, dating the earliest rapid evolution of the virus to “the period between mid-October and mid-November 2019 as the plausible interval when the first case of SARS-CoV-2 emerged in Hubei province, China” [4]. How valid are these conclusions based on serology? In our opinion, all such claims are equivocal. In our collective experience [5–7], naturally arising antibodies at high titers (neutralizing antibodies [NAbs]; reviewed in Holodick et al [8]) are often detected in random patterns like this [1–3] in two main ways: Through continuous endogenous self-antigen stimulation and clonal selection by antigenic epitopes exposed to the normal immune system on “buried” or “masked” self-components as they age and become effete—most are B cells secreting IgM expressing germline encoded variable (V) regions [8]. How such V element specificities become germline encoded in NAbs has been considered again recently by us [9]. Some, like the well-known anti-phosphorylcholine specificity, play demonstrable roles in both protective immunity to exogenous pathogens such as Streptococcus pneumoniae and also in internal disposal of effete apoptotic cells and oxidized lipids in cardiovascular repair [8]; and Through the chance cross-stimulation and clonal selection by environmental and cross-reactive antigens on other pathogens—many of these NAbs could be both long-lived IgG and shorter half-life high-turnover IgM. In this regard the more conservative report based on IgG antibodies in a very small number of positive detections (7 of 24 079 study participants in the United States) by Althoff et al [2] is more representative of the “norm” than Apolone et al [3], who reported 111 positives out of 959 study participants in Italy. We think it most likely that the data from Apolone et al reflect “background” levels of natural IgM antibodies and some lower-frequency, cross-reactive, exogenous induced long-lived IgG. The Italian study shows a random incidence pattern across the country supporting the hypothesis conclusion that they are NAbs arising spontaneously,without prior SARS CoV-2 infection, in asymptomatic humans. While this alternative conclusion is not mentioned by these authors, we concede they may have tacitly understood this to be the case. We predict the existence of a predominantly IgM antibody reactivity pattern with lower-level IgG, as reported in Apolone et al [3] and including Basavaraju et al [1], for almost any randomly chosen antigen in plasma or serum of normal, healthy “asymptomatic” individuals.

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