Induction of an immune response that can prevent re-infection is the basis behind all vaccines. But induction of a protective immune response against many of the RNA viruses that circulate with large genetic diversity has been problematic. We studied, in a rare prospective cohort, 15 subjects that were naturally followed through multiple infections of hepatitis c virus (HCV), the B cell and antibody characteristics that correlated with protection against chronic re-infection. HCV will develop chronic disease in 75% of patients and so we were able to compare individuals that were able to clear their second infection to those that developed a second or third chronic infection. We performed ELISAs, pseudoparticle and cell culture derived assays to measure autologous binding and neutralising breadth and also phenotyped and single cell RNA sequencing on B cells sorted for HCV envelope specificity. We found that the breadth of the antibody response did not necessarily protect from chronic re-infection, with evidence of antigenic sin from the conservation of the epitope hierarchy and clonal recall. However, a higher ratio of IgD+ to IgG+ HCV E2 positive cells and also a less ‘activated’ transcriptomic profile did associate with protection from chronic disease. Understanding what constitutes a protective response for highly variable RNA viruses is extremely important for both vaccine design and also for evaluating vaccine efficacy.