Acute lymphoblastic leukaemia (ALL) is the most common type of cancer in children, accounting for approximately 25% of childhood cancer cases. As a result of effective treatments over the past decades, paediatric ALL mortality has been greatly reduced. Chemotherapy, however, has a range of harmful side effects including the loss of protective antibodies against vaccine-preventable diseases. Since ALL survivors have an increased risk of health problems including organ insufficiencies, acquired vaccine-preventable infections subsequent to clinical remission could become life threatening to these individuals. This review will summarize clinical findings regarding defective humoral immunity in ALL survivors, identify current knowledge gaps and highlight mechanisms related to deficiencies in the B-cell compartment important for serological memory. Further, we illuminate the emerging evidence for a relationship between chemotherapy and gut microbiota, which could play an important role in vaccine responses and the shaping of a young immune system subjected to maturation and recovery.