Several serology tests for diagnoses of SARS-CoV-2 infection are currently in use which primarily assess Spike (S), and on occasion Nucleocapsid (N) antibodies. Most vaccines in use are Spike focused and inactivated whole virion vaccines are in limited use. Serology to detect infection is dependent on the retention of specific responses which have waning over time, contain antigenic changes, and specificity is dependent on low cross-reactivity with existing antibody responses. We have defined the antibody landscape of the SARS-CoV-2 response after infection. We evaluated the anti-SARS-CoV-2 antibody profiles to 15 antigens by cloning and expressing open reading frames (ORFs) in mammalian cells and screened antibody responses from COVID-19 patients using the Luciferase Immunoprecipitation System (LIPS). We assessed responses in patient plasma and a large set of pre-pandemic samples to define cut-offs, and calculated assay sensitivity and specificity. The LIPS technique allowed us to detect antibody responses in COVID-19 patients to 11 of the 15 SARS-CoV-2 antigens, identifying novel immunogenic targets. We found that antigens ORF3b and ORF8 allow detection of antibody early in infection in a specific manner and revealed the immunodominance of the N antigen in COVID-19 patients. Antibodies that target non surface proteins can mediate Fc receptor functions, we therefore assessed ORF8-specific antibodies in patients for FcR binding to mediate cellular cytotoxicity and phagocytosis function. Furthermore, the incorporation of non-structural proteins in inactivated vaccines was assessed by comparison of antibodies from mRNA BNT162b2 versus Coronavac vaccinees. These studies provide novel insights for SARS-CoV-2 replication, immunogenicity to identify key targets for specific diagnostics for breakthrough infections.