Hepatitis C virus (HCV) is an insidious blood-borne pathogen that has infected ~3% of the world’s population. In the 75% of infected individuals that develop chronic infection, significant morbidity arises due to ongoing liver inflammation, and severe sequela if left untreated. Treatment rates have now reached 95% clearance rates, which has lead to the hope that the global burden of HCV disease can be significantly reduced. Although, a vaccine is still a priority to prevent ongoing transmission. However, the complex nature of HCV infection in regards to its asymptomatic state in early infection and its varied infection outcomes has made it difficult to understand the immune response required to protect against HCV infection. In a unique cohort of 14 recently HCV infected individuals, we have taken a systems biology approach to understand why some individuals naturally clear the infection, while others do not. By applying advanced next generation sequencing technology to sequence the virus and advanced immune assays including 14 colour flow and single cell technology, we have begun to piece together the early evolutionary pathway of the virus and how hosts that successfully clear the infection generate early neutralising antibody (nAb) responses that prevent ongoing evolution of the virus, while others have delayed nAb responses but early and strong CD8+ T cell responses that drive virus evolution and establish chronic infection. Understanding how the hosts’ immune repertoire and the antigenicity of the virus drive these different pathways has become the next step to explore towards designing the optimal vaccine that will confer protection against a very complex virus.