Cross-reactivity within the pneumococcal immune response was examined in this study. Significant cross-reactivity between serotypes 9V, 15B and 19A was identified in infant post-immunization serum that could not be effectively titrated during specific IgG measurements. Pre-absorption using serotype 9V inhibited this cross-reactivity and normalized titratability in the WHO ELISA for serotypes 15B and 19A. However, this did not affect functional avid IgG and was associated with fewer pneumococcal conjugate vaccine (PCV) doses, suggesting that cross-reactive antibodies were of low avidity. The results in this study have important implications for assessment of vaccine immunogenicity.