The norovirus causes acute and incapacitating gastroenteritis, characterized by vomiting and diarrhea. A recombinant GII. 4 P domain particle (Pd) vaccine adjuvanted with flagellin, Vibrio vulnificus FlaB, was recently shown to promote both humoral and cell-mediated immune responses efficiently. For a study, researchers discovered that sublingual (SL) vaccination resulted in larger fecal secretory IgA (SIgA) responses, whereas intranasal (IN) immunization resulted in higher amplitudes of humoral and cellular immune responses in the systemic compartment. Researchers reasoned that combining the IN and SL pathways would result in more strong and prolonged SIgA responses in the gut. They attempted combinatorial prime-boost immunization using both the IN and SL approaches in this investigation. IN priming and SL boosting with the Pd+FlaB vaccination resulted in the largest SIgA responses in feces and increased Pd-specific memory B cells and plasma cells in the spleen and bone marrow, respectively. 

Notably, combined IN prime and SL boost immunization generated the highest long-lasting SIgA response in feces, which lasted for more than 3 months. The IN prime and SL boost combination significantly increased gut-homing B cell and follicular helper T cell responses in mesenteric lymph nodes (mLNs). Pd-specific IFN, IL-2, IL-4, and IL-5 cytokine responses in the systemic immune compartment required IN priming. 

The combination of IN prime and SL boost was the most effective in inducing balanced long-lasting immune responses against the norovirus antigen in enteric and systemic compartments. These findings implied that distinct prime-boost immunization approaches could be used to train immune responses in specific mucosal compartments.