Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) still poses a challenge for biomedicine and public health. To advance the development of effective diagnostic, prognostic, and preventive interventions, our study focused on high‐throughput antibody binding epitope mapping of the SARS‐CoV‐2 spike RBD protein by IgA, IgM and IgG antibodies in saliva and sera of different cohorts from healthy uninfected individuals to SARS‐CoV‐2‐infected unvaccinated and vaccinated asymptomatic, recovered, nonsevere, and severe patients. Identified candidate diagnostic (455‐LFRKSNLKPFERD‐467), prognostic (395‐VYADSFVIRGDEV‐407‐C‐KLH, 332‐ITNLCPFGEV‐342‐C‐KLH, 352‐AWNRKRI‐358‐C‐KLH, 524‐VCGPKKSTNLVKN‐536‐KLH), and protective (MKLLE‐487‐NCYFPLQSYGFQPTNGVG‐504‐GGGGS‐446‐GGNYNYLYRLFRKSNLKPFERD‐467) epitopes were validated with sera from prevaccine and postvaccine cohorts. The results identified neutralizing epitopes and support that antibody recognition of linear B‐cell epitopes in RBD protein is associated with antibody isotype and disease symptomatology. The findings in asymptomatic individuals suggest a role for anti‐RBD antibodies in the protective response against SARS‐CoV‐2. The possibility of translating results into diagnostic interventions for the early diagnosis of asymptomatic individuals and prognosis of disease severity provides new tools for COVID‐19 surveillance and evaluation of risks in hospitalized patients. These results, together with other approaches, may contribute to the development of new vaccines for the control of COVID‐19 and other coronavirus‐related diseases using a quantum vaccinomics approach through the combination of protective epitopes. Recognition of linear B‐cell epitopes in SARS‐CoV‐2 Spike protein is associated with antibody isotype and disease symptomatology. Antibody isotype mapping identified reactive immunodominant epitopes in infected individuals from asymptomatic to severe cases. These results may translate into diagnostic and prognostic interventions for COVID‐19 surveillance and development of new vaccines.