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Scabies is a highly contagious disease caused by Sarcoptes scabiei which burrows into stratum corneum of host's skin. In this study, after optimizing vaccination schedule, a vaccination trial is comprised of three test groups of rabbits (n = 10/group) by immunization with (1) rSsCLP5; (2) rSsCLP12; or (3) a mixture of rSsCLP5 and rSsCLP12, three biological replicates groups (n = 10/group) and three control groups (n = 10/group). Levels of specific IgG, total IgE and cytokines in sera were detected and histopathologically analyzed as indicators of vaccine effects. The results showed that 85% (17/20) of rabbits exhibited no detectable skin lesions of S. scabiei infestation in mixed protein groups compared to single protein groups with 75% (15/20) and 70% (14/20), respectively. Moreover, the deworming rates of mixed groups are increased by 10%–20% compared with that of single groups. Each of six groups immunized with rSsCLP displayed significant increases of specific IgG, total IgE, IL-10, and TNF-α. The degree of skin damage in test groups also significantly lower than that of control groups. Thus, purified rSsCLP5 and rSsCLP12 subunit cocktail vaccine induced robust immune protection and could significantly decrease mite populations to reduce the direct transmission between rabbits. [ABSTRACT FROM AUTHOR]