Conjugate vaccines against Streptococcus pneumoniae have significantly reduced diseases caused by serotypes included in those vaccines; however, there is still need for vaccines that confer serotype-independent protection. In the current study, we have constructed a library of conserved surface proteins from S. pneumoniae and screened for IL-17A and IL-22 production in human immune cells obtained from adenoidal/tonsillar tissue of children and IL-17A production from splenocytes from mice that were immunized with a killed whole cell vaccine or previously exposed to pneumococcus. A positive correlation was found between rankings of proteins from human IL-17A and IL-22 screens, but not between human and mouse screens. All proteins were tested for protection against colonization, from which we identified protective antigens that are IL-17A dependent. We found that the likelihood of finding a protective antigen is significantly higher from groups of proteins ranked in the top 50% of all three screens than for groups of proteins ranked in the bottom 50% of all three. The results thus confirmed the value of such screens to identify Th17 antigens. Further, these experiments have evaluated and compared the breadth of human and mouse Th17 responses to pneumococcal colonization and enabled the identification of potential vaccine candidates based on immunological responses in mouse and human cells. Copyright 2018 American Society for Microbiology.