Demonstration of<scp>d</scp>-Octaarginine-Linked Polymers as Promising Adjuvants for Mucosal Vaccination through Influenza Virus Challenge

Miyata, Koichiro; Mohri, Kunihiko; Egawa, Tomomi; Endo, Rikito; Morimoto, Naoki; Ochiai, Kyohei; Hiwatari, Ken‐ichiro; Tsubaki, Kazufumi; Tobita, Etsuo; Uto, Takuhiro; Baba, Masanori; Sakuma, Shinji

doi:10.1021/acs.bioconjchem.6b00283

Cited by 10 publications

(29 citation statements)

References 27 publications

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“…IgA secreted on the nasal mucosa in mice inoculated with a mixture of inactivated H1N1 A/Puerto Rio/8/34 (PRI) influenza viruses and D-octaarginine-linked polymers cross-reacted to recombinant HA (rHA) proteins of not only antigenically-drifted variants within a subtype of the inoculated strains but also virus strains categorized into different subtypes such as H3N2 and H5N1. 15,16) A similar result was obtained when antigens were substituted with inactivated H1N1 A/New Caledonia/20/99 IVR116 influenza viruses. Our latest infection experiments using mouse-adapted PRI viruses revealed that mice immunized with inactivated PRI viruses in the presence of D-octaarginine-linked polymers were perfectly protected from homologous virus infection; however, those immunized with the antigen alone were infected with the PRI viruses.…”

supporting

confidence: 62%

“…9,13,14) We have separately found that there is another potential of D-octaarginine-linked PNVA-co-AA as an adjuvant for mucosal vaccination. [15][16][17] Mucosal vaccination is one of the most effective and adaptive immunization strategies for protecting hosts against infectious pathogens that invade epithelial cells on the mucosa such as influenza viruses. [18][19][20][21][22] Both humoral responses: immunoglobulin G (IgG) and immunoglobulin A (IgA), are observed in the blood and on the mucosa, respectively, in hosts immunized mucosally with antigens.…”

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confidence: 99%

“…Mucosal IgA induced in the presence of D-octaarginine-linked PNVA-co-AA possessed a broad spectrum of heterosubtype immunity against influenza virus infection. 16,17) However, it is unclear if the current level of IgA induction is sufficient for the heterosubtypic cross-protection. Our previous study revealed that IgA cross-reactivity to heterologous virus strains was more clearly observed as IgA reactivity to homologous virus strains elevated.…”

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confidence: 99%

“…Our previous study revealed that IgA cross-reactivity to heterologous virus strains was more clearly observed as IgA reactivity to homologous virus strains elevated. 16) In the present study, we evaluated effects of chemical structures of oligoarginines conjugated to PNVA-co-AA on IgA induction.…”

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confidence: 99%

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Effects of the Chemical Structures of Oligoarginines Conjugated to Biocompatible Polymers as a Mucosal Adjuvant on Antibody Induction in Nasal Cavities

Mohri

Miyata

Egawa

et al. 2018

CHEMICAL & PHARMACEUTICAL BULLETIN

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We have been investigating the potential of oligoarginine-linked polymers as an adjuvant for mucosal vaccination that induces immunoglobulin G (IgG) in systemic circulation and immunoglobulin A (IgA) secreted on the mucosa. Our latest infection experiments demonstrated that mice immunized nasally with a mixture of inactivated influenza viruses and poly(N-vinylacetamide-co-acrylic acid) (PNVA-co-AA) modified with D-octaarginine were perfectly protected from homologous virus infection. On the contrary, virus infection was observed in mice immunized with the antigen alone. This difference was presumably due to insignificant induction of secreted IgA on the nasal mucosa in the latter mice. Since it was unclear whether the current induction level was sufficient for heterologous virus infection, we evaluated the effects of the chemical structures of oligoarginines conjugated to PNVA-co-AA on induction of intranasal IgA. The number and optical activity of the arginine residues and the degree of modification with oligoarginines in the polymer backbone were listed as a factor that would influence IgA induction. Mouse experiments revealed that maximization of the modification resulted in an increase in adjuvant activities of oligoarginine-linked polymers most effectively. Glycine segments inserted between oligoarginines and the polymer backbone were a prerequisite for the maximization. The highest IgA level was observed when antigens were coadministered with diglycine-D-octaarginine-linked PNVA-co-AA.

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confidence: 62%

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confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Effects of the Chemical Structures of Oligoarginines Conjugated to Biocompatible Polymers as a Mucosal Adjuvant on Antibody Induction in Nasal Cavities

Mohri

Miyata

Egawa

et al. 2018

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…Therefore, polymers that are able to induce a DAMP response similar to an adjuvant whilst delivering antiviral siRNAs may be beneficial in acute antiviral treatment [134,135]. This approach is currently being investigated for polymer-peptide-based vaccines and mRNA and pDNA vaccines against a range of viruses [136][137][138][139][140][141][142][143].…”

Section: Safety and Immune System Activation And Potential Adjuvant Ementioning

confidence: 99%

Polymers in the Delivery of siRNA for the Treatment of Virus Infections

2017

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Viral diseases remain a major cause of death worldwide. Despite advances in vaccine and antiviral drug technology, each year over three million people die from a range of viral infections. Predominant viruses include human immunodeficiency virus, hepatitis viruses, and gastrointestinal and respiratory viruses. Now more than ever, robust, easily mobilised and cost-effective antiviral strategies are needed to combat both known and emerging disease threats. RNA interference and small interfering (si)RNAs were initially hailed as a "magic bullet", due to their ability to inhibit the synthesis of any protein via the degradation of its complementary messenger RNA sequence. Of particular interest was the potential for attenuating viral mRNAs contributing to the pathogenesis of disease that were not able to be targeted by vaccines or antiviral drugs. However, it was soon discovered that delivery of active siRNA molecules to the infection site in vivo was considerably more difficult than anticipated, due to a number of physiological barriers in the body. This spurred a new wave of investigation into nucleic acid delivery vehicles which could facilitate safe, targeted and effective administration of the siRNA as therapy. Amongst these, cationic polymer delivery vehicles have emerged as a promising candidate as they are low-cost and easy to produce at an industrial scale, and bind to the siRNA by non-specific electrostatic interactions. These nanoparticles (NPs) can be functionally designed to target the infection site, improve uptake in infected cells, release the siRNA inside the endosome and facilitate delivery into the cell cytoplasm. They may also have the added benefit of acting as adjuvants. This chapter provides a background around problems associated with the translation of siRNA as antiviral treatments, reviews the progress made in nucleic acid therapeutics and discusses current methods and progress in overcoming these challenges. It also addresses the importance of combining physicochemical characterisation of the NPs with in vitro and in vivo data.

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