Provided are compositions and methods for prophylaxis and/or therapy of C. difficile infection, and for inhibiting dissemination of C. difficile spores. The compositions contain C. difficile proteins, including distinct proteins and fusions of C. difficile CD 1067, BclA1, SleC, CotA, Spl7, FliC, FliD, CD toxin A, CD toxin B, and combinations thereof. The methods include prophylaxis and/or therapy of C. difficile infection by administering to a subject in need a composition that includes the C. difficile protein(s).