More robust gut immune responses induced by combining intranasal and sublingual routes for prime-boost immunization

Abstract

Norovirus causes acute and debilitating gastroenteritis, characterized by vomiting and diarrhea. We recently reported a recombinant GII. 4 P domain particle (Pd) vaccine adjuvanted with a flagellin, Vibrio vulnificus FlaB, effectively promoting both humoral and cell-mediated immune responses. In the previous study, we found that sublingual (SL) immunization induced higher fecal secretory IgA (SIgA) responses while intranasal (IN) route provided higher amplitude of humoral and cellular immune responses in the systemic compartment. We hypothesized that the combination of IN and SL routes should induce more potent and sustained SIgA responses in the gut. In this study, we have tried combinatorial prime-boost immunization employing both IN and SL routes. The IN priming and SL boosting with the Pd+FlaB vaccine enhanced highest SIgA responses in feces, accompanying increased Pd-specific memory B cells and plasma cells in spleen and bone marrow, respectively. Notably, the strongest long-lasting SIgA response in feces was induced by combined IN prime and SL boost vaccination, which was sustained for more than 3 months. Significantly enhanced gut-homing B cell and follicular helper T cell responses in mesenteric lymph nodes (mLNs) were observed in the IN prime and SL boost combination. IN priming was a requisite for the robust induction of Pd-specific IFNγ, IL-2, IL-4 and IL-5 cytokine responses in the systemic immune compartment. Collectively, the IN prime and SL boost combination was the best option for inducing balanced long-lasting immune responses against the norovirus antigen in both enteric and systemic compartments. These results suggest that immune responses in specific mucosal compartments may be programmed by employing different prime-boost immunization routes.

A Fusion Protein of Derp2 Allergen and Flagellin Suppresses Experimental Allergic Asthma

“…When we treated the sensitized mice with the same dose of Derp2 + FlaB or Derp2-FlaB fusion protein via the sublingual route, we did not observe an obvious inhibitory effect on airway inflammation (data not shown). Flagellin exhibits effective mucosal adjuvant activity: immunization through the intranasal and sublingual routes induces considerable systemic and local antibody responses 83435. However, as the intranasal route is superior to the sublingual route in inducing systemic immune responses, the administration route may affect the immunomodulatory threshold of flagellin in inducing the suppressive immunomodulation of airway inflammation.…”

Human Norovirus: Experimental Models of Infection

“…HuNoV VLPs assemble spontaneously after the expression of either VP1, or VP1 and VP2. The immunogenicity of HuNoV VLPs in BALB/c mice upon oral [ 28 , 29 ], intradermal [ 29 , 30 ], intramuscular [ 31 ], intranasal [ 31 , 32 , 33 , 34 ], and sublingual [ 32 ] administration have been studied. The immune responses following intranasal administration of HuNoV VLPs to guinea pigs have also been evaluated [ 34 , 35 ].…”

Sublingual Boosting with a Novel Mucoadhesive Thermogelling Hydrogel Following Parenteral CAF01 Priming as a Strategy Against Chlamydia trachomatis

“…These results are consistent with previous studies that describe the boosting effect of the sublingual route. [ 14,40,41 ] Animals vaccinated parenterally with CAF01/CTH522 had significantly higher serum IgG responses than mice immunized exclusively by the sublingual route ( p < 0.05) ( Figure 3A–D). Although the group boosted with OGEL/CTH522 produced the highest IgA and IgG mean titers in vaginal secretions, which is one of the vaccination targets against sexual diseases, this enhancement was not statistically significant compared to animals only vaccinated with CAF01/CTH522.…”