Acute Rheumatic Fever (ARF) is a serious post-infectious sequela of Streptococcus A (Strep A) and a major cause of health inequity in Aotearoa New Zealand, with unacceptably high rates among Māori and Pacific children. Pathogenesis remains poorly understood but repeated Strep A infections are thought to prime the immune system and contribute to a loss of tolerance and autoimmune responses. We have previously mapped Strep A exposures using an array of strain type (M-type) specific peptides and revealed ARF patients had serological evidence of significantly more exposures than matched controls1. Here, the same methodology was applied to three siblings: Child A, the index case diagnosed with ARF; a healthy sibling (child B), and child C who was a healthy sibling but developed ARF six months later. Child C had seven M-type reactivities initially, which increased to nine at ARF presentation. In contrast, child B only had serological evidence of two prior Strep A exposures. Antibodies to two M-types in child C, also present in child A, belonging to the E2 cluster-type were new or boosted at ARF presentation suggesting an E2 cluster strain triggered ARF in these siblings. Inflammatory markers and cytokines (C-reactive protein, IL-6 and TNFalpha) were elevated upon ARF diagnosis compared with pre-disease samples from child C and the healthy sibling. This study presents unique insights into Strep A exposure within a family unit and further supports the role for multiple Strep A infections in ARF pathogenesis.