Parenteral
vaccinations are not able to elicit effective systemic
and gastrointestinal immune protection simultaneously because the
lymphocytes are typically restricted to primed tissues. Although all-trans retinoic acid (atRA) was reported
to trigger the gut-homing of immunocytes, the bioavailability and
systemic immune responses remain limited for use in robust enteric
vaccinations. Here, we show that co-delivery of atRA, CpG oligodeoxynucleotides (CpG), and antigens via engineered polymer/lipid nanoparticles (PLNPs) could exploit the
amplifying function of draining lymph nodes (DLNs) for potent gut
tropism and immune activations. After intramuscular injection, forming
an immune-potentiated environment at the injection site, the PLNPs
induced the designated transfer of primed dendritic cells (DCs) to
the DLNs instead of the gastrointestinal tissues. Within the DLNs,
the immune-potentiated environment markedly amplified the antigen
presentation and homing receptor switch among immunocytes, which simultaneously
stimulated the preferential dissipation of activated lymphocytes in
the peripheral and gastrointestinal tissues, that is, exerted a DLN-amplifying
effect. Compared with current atRA-containing formulations,
the PLNPs not only boosted potent IgG secretions and T cell activations
in the peripheral tissue but also provoked robust T cell homing and
antigen-specific IgA levels in the gastrointestinal tracts in both
ovalbumin and EV71 vaccinations. These data indicate that exploiting
DLN amplification can stimulate potent systemic and gastrointestinal
responses for more efficient enteric vaccinations.
Vaccines based on live attenuated Chlamydia elementary bodies (EBs) can cause disease in vaccinated animals and the comparably safer inactivated whole EBs are only marginally protective. Recent studies show that a vaccine formulation comprising UV-inactivated EBs (EB) and appropriate mucosal delivery systems and/or adjuvants induced significant protective immunity. We tested the hypothesis that intranasal delivery of UV-inactivated C. psittaci EB formulated in Vibrio cholerae ghosts (VCG)-chitosan nanoparticles will induce protective immunity against intranasal challenge in SPF chickens. We first compared the impact of VCG and CpG adjuvants on protective immunity following IN mucosal and IM systemic delivery of EB formulated in chitosan hydrogel/microspheres. Immunologic analysis revealed that IN immunization in the presence of VCG induced higher levels of IFN-γ response than IM delivery or the CpG adjuvanted groups. Also, vaccine efficacy evaluation showed enhanced pharyngeal bacterial clearance and protection against lung lesions with the VCG adjuvanted vaccine formulation, thereby establishing the superior adjuvanticity of VCG over CpG. We next evaluated the impact of different concentrations of VCG on protective immunity following IN mucosal immunization. Interestingly, the adjuvanticity of VCG was concentration-dependent, since protective immunity induced following IN mucosal immunization showed dose-dependent immune responses and protection. These studies reveal that formulation of inactivated chlamydial antigens with adjuvants, such as VCG and chitosan increases their ability to induce protective immune responses against challenge.
Emulsions are one of the most often used vaccine adjuvant formulations. Although they promote high humoral immunity, the induced cellular immunity is often poor, which restrict their application. To enhance the cellular immunity, some researchers have prepared mixed formulations by adding particles into the aqueous phase of emulsions. However, the particle preparation process usually involves the addition and removal of organic reagents, which is environmentally unfriendly and cumbersome. Moreover, the obtained vaccine adjuvant only induces limited cell‐mediated immunity and humoral immunity compared with emulsion‐adjuvanted vaccines. Herein, we developed a green and simple method for fabricating a novel nanoparticles‐in‐emulsions (NPE) formulation. Firstly, a temperature‐sensitive hydrogel was used to prepare particles by self‐solidification without additional crosslinking reagents. Secondly, the white oil was used as organic phase to avoid the particle washing procedures and organic solvent residues. Moreover, the effect of NPE as vaccine adjuvant was evaluated by using two veterinary vaccines as model antigens. NPE showed advantages than the conventional vaccine formulations in inducing both humoral and cellular immunity. This work provides a facile and broadly applicable approach for preparing nanoparticles‐in‐emulsions formulation, and presents an effective adjuvant for enhancing immunity against infectious diseases.
Chitosan with pH sensitivity and
biocompatibility was
selected
to prepare chitosan nanoparticle-stabilized Pickering emulsion (CSPE).
The flexibility of CSPE enables stress deformation when in contact
with cell membranes, thereby mimicking the deformability of natural
pathogens and facilitating their efficient uptake by cells. In the
acidic environment of lysosomes, the amino groups of chitosan molecules
are protonated, and the water solubility increases. CSPE transforms
from particle-stabilized to polymer chain-stabilized, its subsequent
swelling and proton accumulation lead to lysosome rupture. The experimental
results evaluating CSPE as an adjuvant shows that CSPE could efficiently
load antigens, promote endocytosis and antigen cross-presentation,
recruit antigen-presenting cells at the injection site, boost T-cell
activation, and enhance both humoral and cellular immune responses.
In the prophylactic and therapeutic tumor models of E.G7-OVA lymphoma
and B16-MUC1 melanoma, CSPE significantly inhibited tumor growth and
prolonged the survival of mice. In summary, antigenic lysosomal escape
resulted from the chitosan molecular state transition is the key to
the enhancement of cellular immunity by CSPE, and CSPE is a promising
vaccine adjuvant.
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