Polycationic HA/CpG Nanoparticles Induce Cross-Protective Influenza Immunity in Mice

Abstract

The intranasal (i.n.) route is an ideal vaccination approach for infectious respiratory diseases like influenza. Polycationic polyethylenimine (PEI) could form nanoscale complexes with negatively charged viral glycoproteins. Here we fabricated PEI-hemagglutinin (HA) and PEI-HA/CpG nanoparticles and investigated their immune responses and protective efficacies with an i.n. vaccination regimen in mice. Our results revealed that the nanoparticles significantly enhanced HA immunogenicity, providing heterologous cross-protection. The conserved HA stalk region induced substantial antibodies in the nanoparticle immunization groups. In contrast to the Th2-biased, IgG1-dominant antibody response generated by PEI-HA nanoparticles, PEI-HA/CpG nanoparticles generated more robust and balanced IgG1/IgG2a antibody responses with augmented neutralization activity and Fc-mediated antibody-dependent cellular cytotoxicity (ADCC). PEI-HA/CpG nanoparticles also induced enhanced local and systemic cellular immune responses. These immune responses did not decay over six months of observation postimmunization. PEI and CpG synergized these comprehensive immune responses. Thus, the PEI-HA/CpG nanoparticle is a potential cross-protective influenza vaccine candidate. Polycationic PEI nanoplatforms merit future development into mucosal vaccine systems.

Recent Advances in Inhaled Nanoformulations of Vaccines and Therapeutics Targeting Respiratory Viral Infections

“…A sustained release profile accounting for approximately 20% drug release at 2 h indicated that the drugs were released slowly from the liposomal DPI in the lungs, thus could offer the opportunity to reduce the need of frequent dosing [ 76 ]. In addition, various nanoparticle-based strategies have been designed to tackle influenza infection, including the use of a nanoparticle as carrier of the vaccine, genes and drugs [ 5 , 77 – 80 ]. In addition, nanoparticles with anti-influenza properties are also under development [ 79 , 81 ] (Fig.…”

“…Notably, owing to a lack of IFN-γ cytokine induction, the protective cellular responses such as cytotoxic T-lymphocyte activation are not induced with PEI. Therefore, the incorporation of unmethylated cytosine-guanine rich oligonucleotide motifs (CpG) onto PEI-HA might trigger the TLR-9 signalling pathway, thus inducing a balanced Th1/Th2 immune response [ 77 ]. Compared to the PEI-HA nanoparticle, the intranasal vaccination of PEI-HA/CpG nanoparticles led to a more balanced Th1/Th2 response with the generation of an IgG1 and IgG2a antibody as well as enhanced neutralising action and Fc-mediated antibody-dependent cellular cytotoxicity (ADCC) [ 77 ].…”

“…Therefore, the incorporation of unmethylated cytosine-guanine rich oligonucleotide motifs (CpG) onto PEI-HA might trigger the TLR-9 signalling pathway, thus inducing a balanced Th1/Th2 immune response [ 77 ]. Compared to the PEI-HA nanoparticle, the intranasal vaccination of PEI-HA/CpG nanoparticles led to a more balanced Th1/Th2 response with the generation of an IgG1 and IgG2a antibody as well as enhanced neutralising action and Fc-mediated antibody-dependent cellular cytotoxicity (ADCC) [ 77 ]. In addition, the cross-protective immunity lasted over 6 months in mice vaccinated with intranasal PEI-HA/CpG nanoparticle [ 77 ].…”

“…Compared to the PEI-HA nanoparticle, the intranasal vaccination of PEI-HA/CpG nanoparticles led to a more balanced Th1/Th2 response with the generation of an IgG1 and IgG2a antibody as well as enhanced neutralising action and Fc-mediated antibody-dependent cellular cytotoxicity (ADCC) [ 77 ]. In addition, the cross-protective immunity lasted over 6 months in mice vaccinated with intranasal PEI-HA/CpG nanoparticle [ 77 ]. In another approach, an intranasal vaccination strategy has been developed to target the highly conserved influenza nucleoprotein (NP) using self-assembly nanolipoprotein particle (NLP) as the carrier [ 84 ].…”

Molecular Bottlebrushes for Immunostimulatory CpG ODN Delivery: Relationship among Cation Density, Complex Formation Ability, and Cytotoxicity

“…Independent studies by Kobiyama et al and Nishikawa et al have shown that nanoparticulation of CpG ODNs enhances dramatically their immunostimulatory activity. In addition, many other studies have demonstrated nanoparticulated CpG ODNs, − indicating the rising interest in incorporating CpG ODNs into nanoparticles.…”