Streptococcus pyogenes (Strep A) causes illness ranging from superficial skin and throat infections through to life‑threatening invasive disease. Untreated Strep A infections can also lead to the immune sequalae acute rheumatic fever (ARF), which can progress to permanent rheumatic heart disease. These diseases cause significant morbidity and mortality globally and remain prevalent in underserved Indigenous and Pacific populations in Australia and New Zealand. ARF develops several weeks after a Strep A infection and serological tests are therefore crucial to the diagnosis of the disease. We have developed a series of multiplex bead-based assays that quantify serum antibody responses to Strep A antigens with utility in clinical diagnostics and vaccine development. While there are several Strep A vaccines candidates in development, none have reached licensure. Our initial triplex assay comprising antigens traditionally utilised in clinical streptococcal serology (streptolysin-O and DNaseB), as well as the novel antigen SpnA, highlighted immunokinetic difference between antigens that improved the sensitivity of ARF diagnosis. Expanding this assay to an 8-plex format encompassing leading Strep A vaccine antigens (Spy0843, SCPA, SpyCEP, SpyAD, Group A carbohydrate) has enabled antibody profiling in a range of Strep A disease states. This revealed the magnitude and breadth of antibodies in ARF is significantly elevated compared to precursor skin and throat infections, giving rise to a distinct serological profile and providing insights into disease pathogenesis. Finally, our most recently developed assays move beyond conserved Strep A antigens to include type‑specific antigens (M‑proteins and T-antigens). This has facilitated investigation of antibody features associated with functional immune responses (opsonophagocytosis) in children with Strep A pharyngitis. Defining the antibody-correlates of Strep A killing has important implications for understanding vaccine-induced immunity, and our systems serology analysis suggests a combination of distinct antibody features are involved.