In Malawi’s first CHIM clinical trial, 204 adults were randomized to receive PCV13 or placebo before intranasal inoculation with Streptococcus pneumoniae serotype 6B. This landmark study demonstrated that PCV13 reduced experimental carriage by 62%, confirming the feasibility and utility of the CHIM in a high carriage setting. Analysis of vaccine-induced antibody levels, showed a weak correlation with protection, indicating limitations of serum IgG as a correlate. In addition, pre-existing natural carriage, particularly of serotype 3, was associated with increased susceptibility to experimental carriage and reduced vaccine efficacy. These findings highlight the need to optimize vaccines for high pneumococcal carriage settings.