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Weak antibody responses to protein antigens after oral immunization remain a serious problem. Yeasts have a rigid cell wall and are inherently resistant to harsh conditions, suggesting that recombinant antigens made in yeast could have a greater chance of making contact with the immune cells of the gastrointestinal (GI) tract in intact form. We compared antibody responses to oral immunization with purified recombinant antigen, used in the conventional manner, and responses to whole recombinant yeast producing the antigen intracellularly. Recombinant capsid protein (CP) of red-spotted grouper necrosis virus (RGNNV) was used as model antigen and Saccharomyces cerevisiae as host. The purified CP was obtained from the S. cerevisiae producing the RGNNV CP. Whole recombinant yeast producing RGNNV CP provoked 9–27 times higher anti-RGNNV CP IgG titres than purified RGNNV CP. Moreover, sera from mice immunized with the recombinant yeast had neutralizing activity against RGNNV, while those from mice immunized with purified CP did not. These results show that whole recombinant yeast is a promising platform for antigen delivery by oral immunization.Provoking sufficient antibody responses by oral immunization has been an enormous challenge because of the harsh conditions of the gastrointestinal (GI) tract. Immunization strategies using purified antigen to make oral vaccines are incapable of commercialization because excessive amount of antigen is required to provoke antibody responses. Therefore, resolving the problems concerning the cost and effectiveness of oral vaccines is a high priority. Our results suggest that recombinant yeast has great potential for inducing antigen-specific immune responses by oral immunization. We believe that oral immunization using recombinant yeast can be a breakthrough technology.