Orally Antigen-Engineered Yeast Vaccine Elicits Robust Intestinal Mucosal Immunity

Mucosal immunity plays a pivotal role in safeguarding against significant global infectious diseases caused by mucosal pathogens. The development of mucosal vaccines has been limited by the poor efficiency of antigen display and the risk of adjuvants. Here, we report an engineered yeast vaccine integrating a well-displayed antigen with an intrinsic adjuvant for the development of innate and adaptive immunity to the intestinal mucosa. Compared with antigen-secretory yeast, antigen-anchored yeast significantly activated gut dendritic cells (DCs) and promoted follicular helper T (Tfh) cell differentiation, thereby amplifying the immune response by the interaction with Tfh-B cells. Consequently, oral vaccination of SARS-CoV-2 receptor-binding domain (RBD)-anchored yeast triggered stronger RBD-specific IgA-neutralizing effects, providing potential adaptive protections. Given its corresponding impact on the functionality of both innate and adaptive mucosal responses, the proposed RBD-anchored yeast outperformed RBD-anchored bacteria and biomimetic nanovaccine in the production of RBD-specific IgA and IgG. Together, these results revealed how antigen-displaying patterns could be modulated to elicit intestinal mucosal immunity and demonstrated the translational potential of antigen-displayed yeast for effective mucosal protection.