The dynamics underlying severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) re-infection remain poorly understood. We identified a small cluster of individuals with two episodes of 2019 coronavirus disease (COVID-19) in March and late May of 2020. In the first episode, individuals presented an enhanced innate response compared to healthy individuals, but neutralizing humoral immunity was not fully achieved. The second episode was associated with different SARS-CoV-2 strains, higher viral loads, and clinical symptoms. The identification that some individuals with mild COVID-19 may have controlled SARS-CoV-2 replication without developing detectable humoral immunity raises the possibility that re-infection is more frequent than supposed, but weakly documented.