Compositions and methods for determining immunologically cross-reactive molecules comprising a cross-reactive antigenic determinant are provided, in particular for determining proteins comprising cross-reactive antigenic determinants, in particular for determining proteins that are cross-reactive based on serological screens using sequential immunological challenges to an animal, including determining cross-reactive H. parasuis proteins. Also provided are compositions, vaccines, and kits using the molecules for diagnostics and methods for preventing or treating a disease, disorder, condition, or symptoms thereof associated with infectious agents, in particular infectious microorganisms, in particular for preventing or treating a disease, disorder, condition, or symptom thereof associated with H. parasuis infection.