A unique nanoparticulate TLR9 agonist enables a HA split vaccine to confer FcγR-mediated protection against heterologous lethal influenza virus infection

Abstract

The development of a universal influenza vaccine that can provide a robust and long-lasting protection against a broader range of influenza virus strains is a global public health priority. One approach to improve vaccine efficacy is to use an adjuvant to boost immune responses to the target antigens; nevertheless, the role of adjuvants in the context of influenza vaccines is not fully understood. We have previously developed the K3-schizophyllan (SPG) adjuvant, which is composed of nanoparticulated oligodeoxynucleotides K3, a TLR9 agonist, with SPG, a non-agonistic β-glucan ligand of Dectin-1. In this study, K3-SPG given with conventional influenza hemagglutinin (HA) split vaccine (K3-SPG HA) conferred protection against antigenically mismatched heterologous virus challenge. While K3-SPG HA elicited robust cross-reactive HA-specific IgG2c and CD8 T-cell responses, CD8 T-cell depletion had no impact on this cross-protection. In contrast, K3-SPG HA was not able to confer protection against heterologous virus challenge in FcRγ-deficient mice. Our results indicated that FcγR-mediated antibody responses induced by the HA antigen and K3-SPG adjuvant were important for potent protection against antigenically mismatched influenza virus infection. Thus, we demonstrated that the K3-SPG-adjuvanted vaccine strategy broadens protective immunity against influenza and provides a basis for the development of next-generation influenza vaccines.

Murine Cross-Reactive Nonneutralizing Polyclonal IgG1 Antibodies Induced by Influenza Vaccine Inhibit the Cross-Protective Effect of IgG2 against Heterologous Virus in Mice

“…Consistent with previous reports (17,18), we showed that CpG ODN, as an adjuvant, has the potential to protect against heterologous virus challenge (Fig. 3c to f).…”

“…Furthermore, CD8 ϩ T cells induced by whole inactivated influenza virus vaccine are important for cross-protection (21,22). However, in the present study, consistent with another report (17), CD4 ϩ or CD8 ϩ T cells did not contribute to cross-protection in the SV plus CpG ODN-immunized group (Fig. 4a and b), even though CpG ODN is one of the most effective adjuvants at inducing Th1-type immune responses and CD8 ϩ cytotoxic T lymphocytes responses (13).…”

“…In addition, CpG ODN-based new adjuvants with improved adjuvanticity and safety have been developed. For example, conjugation of CpG ODN with a nonagonistic ␤-glucan ligand of Dectin-1 enhanced adjuvant activity (43), and Yamamoto et al showed that this adjuvant, when used with influenza vaccine, provided cross-protection against a heterologous strain (17). In addition, recent studies have revealed a novel mechanism for the production of antigen-specific IgG2 in mice (44,45).…”

“…We speculated that the selective production of PR8-specific IgG2 by SV plus CpG ODN played an important role in the cross-protection against heterologous virus challenge. However, in addition to the cross-reactive antibody response, we thought that cellular immune responses might also play an important role in cross-protection, because CpG ODN can induce CD8 ϩ cytotoxic T lymphocytes (16,17). To determine the contribution of T cells to the immune response as effector cells for cross-protection against PR8 challenge in SV plus CpG ODN-immunized mice, we depleted the CD4 ϩ or CD8 ϩ T cells in SV plus CpG ODN-immunized mice before and during PR8 challenge by using anti-CD4-or anti-CD8-specific antibodies ( Fig.…”

Lipid Nanoparticles Potentiate CpG-Oligodeoxynucleotide-Based Vaccine for Influenza Virus

“…In contrast, after influenza infection, not only antibodies but also CD8 + T cells play crucial roles in cross-protection (56). However, Yamamoto et al (57) showed that CD8 + T cells do not contribute to cross-protection in the immunization of mice with SV modified with CpG ODN, although SV modified with CpG ODN induces a strong cross-reactive CD8 + T cell response.…”