Serology testing can provide information on the degree of infection in different geographical locations and ethnicities. Using sero-assays also helps estimate how much of the population is uninfected, allowing public health officials to plan future health care needs. Serologic assays are critical tools for determining the prevalence of infection and immune responses to the virus and vaccines ( Amanat et al., 2020 Long et al., 2020 Stadlbauer et al., 2020). Protein target expression determines cross-reactivity, with N being more conserved across coronaviruses than S, and within S, S2 and RBD are more conserved than S1 ( Amanat and Krammer, 2020 Huang et al., 2021 Jaimes et al., 2020 Krammer and Simon, 2020). Multiple forms of S protein-full length (S1 + S2) or partial (S1 domain or receptor-binding domain )-are used as antigens for immunological assessment. S protein is essential for viral entry and is present on the viral surface, whereas N protein is the most abundantly expressed immunodominant protein that interacts with RNA. The two primary antigenic targets of the SARS-CoV-2 virus against which antibodies are detected are Spike glycoprotein (S) and nucleocapsid phosphoprotein (N). Thus, a detailed parallel comparison of the humoral and cellular immunity induced after SARS-CoV-2 infection in asymptomatic versus symptomatic individuals is needed ( Amanat and Krammer, 2020 Sette and Crotty, 2021 Vabret et al., 2020). However, it is equally important to determine the degree of infection prevalent in the broader community and establish any unique phenotypes associated with asymptomatic individuals that render them less susceptible to disease. Clinical research is focused on understanding the mechanisms underlying viral infection and measures to reduce disease severity ( Felsenstein et al., 2020 Lega et al., 2020 Ye et al., 2020). The new coronavirus (severe acute respiratory syndrome coronavirus 2 ) outbreak has spread to dangerous levels with a high level of morbidity in the United States and has created an urgent national health emergency ( Ciotti et al., 2019 Hu et al., 2021).

Furthermore, IgG antibody responses against S and RBD may correlate with high inhibition of ACE2 binding in individuals tested for SARS-CoV-2 infection or post vaccination. Our study shows that healthy individuals can mount robust immune responses against SARS-CoV-2 without symptoms. SARS-CoV-2 symptomatic patients had decreased antibody responses, ACE2 binding inhibition, and antibody cross-reactivity. We also analyzed samples from 94 SARS-CoV-2 patients and compared them with those of asymptomatic individuals. Of these 3%, individuals with the highest anti-S or anti-RBD IgG level showed a strong correlation with inhibition of ACE2 binding and cross-reactivity against non-SARS-CoV-2 coronavirus S-proteins. To understand protective immunity against COVID-19, we screened over 60,000 asymptomatic individuals in the Southeastern United States for IgG antibody positivity against the viral Spike protein, and approximately 3% were positive. The SARS-CoV-2 viral pandemic has induced a global health crisis, which requires more in-depth investigation into immunological responses to develop effective treatments and vaccines.

Spike protein antibody levels