Streptococcus pneumoniae (the pneumococcus) is an important paediatric pathogen that causes a range of respiratory tract diseases and commonly resides in the nasopharynx of young children. Over 90 pneumococcal serotypes exist, each defined by their immunologically distinct capsular polysaccharide antigen. Current pneumococcal conjugate vaccines induce protection against only 10-13 serotypes. The pneumococcal whole cell vaccine (WCV) induces immunity against non-capsular antigens, and protects mice against nasopharyngeal colonisation via antibody-independent, TH17 mechanisms when administered before infectious challenge. In high disease-burden settings infants are exposed to pneumococci soon after birth.Therefore, this project investigated the effect of WCV on colonisation when administered after established colonisation (“therapeutic” vaccination). Infant mice were colonised with pneumococcal strain EF3030 (serotype 19F) before subcutaneous immunisation with WCV or adjuvant-only control. Therapeutic WCV significantly reduced the density of pneumococcal colonisation in a dose dependent manner by 4.3-fold (one dose, p<0.0001) and 8.6-fold (two doses, p=0.014) compared to therapeutic adjuvant (Mann-Whitney). This reduction was dependent on non-capsular antibodies: therapeutic WCV did not affect colonisation in antibody-deficient μMT-/- mice compared to therapeutic adjuvant, and levels of serum IgG specific for the WCV antigen (p=0.003) and pneumococcal proteins PspA (p=0.004), CbpA (p=0.022) and PiaA (p=0.028) were inversely correlated with colonisation density in wild type mice (Spearman’s correlation). No associations between systemic, local or splenic IL-17A responses and colonisation density were observed. In addition, shedding of pneumococci from the upper respiratory tract of mice was reduced after each WCV dose (p<0.0001, Mann-Whitney). This project has demonstrated that therapeutic WCV immunisation effectively reduces pneumococcal colonisation and has identified a novel role for non-capsular antibodies in controlling colonisation density. Given that WCV reduces colonisation density and shedding, it is likely that WCV could reduce pneumococcal transmission and contribute to herd protection. These data support further investigation of WCV in high disease-burden settings where children are more likely to carry pneumococci at the time of vaccination.