The 23-valent pneumococcal polysaccharide (Ps) vaccine offer protection against vaccine serotypes, but its cross-protection against vaccine-related serotypes is variable. We have demonstrated that the functional antibodies to serotype 15B are specific to the O-acetylated 15B-Ps and that they have low cross-reactivity with serotype 15C. Demonstration of functionally cross-reactive antibodies to vaccine-related serotypes is important for surveillance and vaccine development.