Abstract
Vaccine adjuvants that can induce not only antigen-specific antibody responses but also Th1-type immune responses and CD8+ cytotoxic T lymphocyte responses are needed for the development of vaccines against infectious diseases and cancer. Of many available adjuvants, oligodeoxynucleotides (ODNs) with unmethylated cytosine-phosphate-guanine (CpG) motifs are the most promising for inducing the necessary immune responses, and these adjuvants are currently under clinical trials in humans. However, the development of novel delivery vehicles that enhance the adjuvant effects of CpG ODNs, subsequently increasing the production of cytokines such as type-I interferons (IFNs), is highly desirable. In this study, we demonstrate the potential of pH-responsive biodegradable carbonate apatite (CA) nanoparticles as CpG ODN delivery vehicles that can enhance the production of type-I IFNs (such as IFN-α) relative to that induced by CpG ODNs and can augment the adjuvant effects of CpG ODNs in vivo. In contrast to CpG ODNs, CA nanoparticles containing CpG ODNs (designated CA-CpG) induced significant IFN-α production by mouse dendritic cells and human peripheral blood mononuclear cells in vitro; and production of interleukin-12, and IFN-γ was higher in CA-CpG-treated groups than in CpG ODNs groups. In addition, treatment with CA-CpG resulted in higher cytokine production in draining lymph nodes than did treatment with CpG ODNs in vivo. Furthermore, vaccination with CA-CpG plus an antigen, such as ovalbumin or influenza virus hemagglutinin, resulted in higher antigen-specific antibody responses and CD8+ cytotoxic T lymphocyte responses in vivo, in an interleukin-12- and type-I IFN-dependent manner, than did vaccination with the antigen plus CpG ODNs; in addition, the efficacy of the vaccine against influenza virus was higher with CA-CpG as the adjuvant than with CpG ODNs as the adjuvant. These data show the potential of CA nanoparticles to serve as CpG ODN delivery vehicles that increase the production of cytokines, especially IFN-α, induced by CpG ODNs and thus augment the efficacy of CpG ODNs as adjuvants. We expect that the strategy reported herein will facilitate the design and development of novel adjuvant delivery vehicles for vaccines.
Highlights
As the recent Ebola virus outbreak and past worldwide influenza pandemics have demonstrated, infectious diseases are a serious global health problem [1]
We evaluated the usefulness of carbonate apatite (CA) nanoparticles as CpG ODN delivery vehicles
We found that the amount of K-type CpG ODNs used to generate CA-CpG affected the efficiency with which the K-type CpG ODNs was encapsulated in CA-CpG (Figure 1A)
Summary
As the recent Ebola virus outbreak and past worldwide influenza pandemics have demonstrated, infectious diseases are a serious global health problem [1]. There are various types of vaccines, including attenuated live vaccines, inactivated whole vaccines, and protein- or peptidebased subunit vaccines [3,4,5], and they all have various advantages and disadvantages. Protein- or peptide-based subunit vaccines are much safer than attenuated live vaccines and inactivated whole vaccines; when used alone, subunit vaccines evoke only weak adaptive immunity. Alum induces strong Th2-type immune responses, it cannot induce Th1-type immune responses or CD8+ cytotoxic T lymphocyte (CTL) responses, which are necessary for vaccines against infectious diseases such as influenza virus, hepatitis C, and malaria as well as for cancer vaccines designed to eliminate infected or malignant cells [8]. The development of adjuvants that can induce Th1-type immune responses and CD8+ CTL responses is necessary
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