Abstract: Non-human IFNL3 polypeptides and their uses thereof are provided. Exemplary embodiments provide IFNL3 polypeptides which include one or more amino acid substitutions, additions, or deletions with natural or non-naturally encoded amino acids, and/or linkage or fusion to other biologically active molecules including other IFNL3 polypeptides, as well as PK enhancing moieties (PKEMs). Additionally, use of said IFNL3 polypeptides for innate immune system stimulation, as a vaccine adjuvant, as well as treatment or prevention of diseases such as viral and bacterial infections, and inflammation, is also provided.