Overview and Outlook of Toll-like Receptor ligand–antigen Conjugate Vaccines

Fujita, Yoshio; Taguchi, Hiroaki

doi:10.4155/tde.12.52

Cited by 45 publications

(42 citation statements)

References 117 publications

(127 reference statements)

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“…In this study, the histological analysis and the serum total IgE assay support the advantages of ⌬A146Ply over CT as an pneumococcal vaccine adjuvant. TLR agonists, including Pam3/2Cys, lipid A, flagellin, imidazoquinolines and CpG motifs, are important mucosal adjuvants (33,41). Of these, flagellin, a TLR5 agonist, has been tested as an adjuvant against bacterial infections in animals, and human clinical trials are under way (33,42,43).…”

Section: Discussionmentioning

confidence: 99%

Mucosal Immunization with Recombinant Fusion Protein DnaJ-ΔA146Ply Enhances Cross-Protective Immunity against Streptococcus pneumoniae Infection in Mice via Interleukin 17A

et al. 2014

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Pneumolysin (Ply) and its variants are protective against pneumococcal infections in animal models, and as a Toll-like receptor 4 agonist, pneumolysin has been reported to be a mucosal adjuvant. DnaJ has been approved as a useful candidate vaccine protein; we therefore designed novel fusion proteins of DnaJ with a form of Ply that has a deletion of A146 (⌬A146Ply-DnaJ [the C terminus of ⌬A146Ply connected with the N terminus of DnaJ] and DnaJ-⌬A146Ply [the C terminus of DnaJ connected with the N terminus of ⌬A146Ply]) to test whether they are protective against focal and lethal pneumococcal infections and their potential protective mechanisms. The purified proteins were used to intranasally immunize the animals without additional adjuvant. Immunization with DnaJ-⌬A146Ply or DnaJ plus ⌬A146Ply (Ply with a single deletion of A146) could significantly reduce S. pneumoniae colonization in the nasopharynx and lung relative with DnaJ alone. Additionally, we observed the best protection for DnaJ⌬A146Ply-immunized mice after challenge with lethal doses of S. pneumoniae strains, which was comparable to that achieved by PPV23. Mice immunized with DnaJ-⌬A146Ply produced significantly higher levels of anti-DnaJ IgG in serum and secretory IgA (sIgA) in saliva than those immunized with DnaJ alone. The production of IL-17A was also striking in DnaJ-⌬A146Ply-immunized mice. IL-17A knockout (KO) mice did not benefit from DnaJ-⌬A146Ply immunization in colonization experiments, and sIgA production was impaired in IL-17A KO mice. Collectively, our results indicate a mucosal adjuvant potential for ⌬A146Ply and that, without additional adjuvant, DnaJ-⌬A146Ply fusion protein exhibits extensive immune stimulation and is effective against pneumococcal challenges, properties which are partially attributed to the IL-17A-mediated immune responses.

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Section: Discussionmentioning

confidence: 99%

Mucosal Immunization with Recombinant Fusion Protein DnaJ-ΔA146Ply Enhances Cross-Protective Immunity against Streptococcus pneumoniae Infection in Mice via Interleukin 17A

et al. 2014

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“…pathogen-associated molecular patterns or danger/damage associated molecular patterns and play a key role in innate immune responses [1,2]. When a host immune system is exposed to pathogens, antigens are captured by antigen presenting cells (APCs) and then processed and presented via the major histocompatibility complex to T cells through T cell receptors.…”

Section: Introductionmentioning

confidence: 99%

Salmonella flagellin is a potent carrier–adjuvant for peptide conjugate to induce peptide-specific antibody response in mice

Qian

Guo

et al. 2015

Vaccine

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“…Significant effort has been expended towards harnessing the power of TLR agonists for adjuvants with promising results in adults (for review see (28)). An increasing body of work supports direct conjugation of a TLR agonist to an antigen or synthesis as a fusion protein as mechanisms to improve responses following vaccination (for review see (29)). TLR agonists that have been employed in this way include Pam2Cys, Pam3Cys, MPL, flagellin, imidazoquinolines, and CpG.…”

Section: Introductionmentioning

confidence: 99%

A Novel R848-Conjugated Inactivated Influenza Virus Vaccine Is Efficacious and Safe in a Neonate Nonhuman Primate Model

Holbrook

Kim

Blevins

et al. 2016

The Journal of Immunology

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Influenza virus infection of neonates poses a major health concern, often resulting in severe disease and hospitalization. At present, vaccines for this at-risk population are lacking. Thus, development of an effective vaccine is an urgent need. Here we have used an innovative nonhuman primate neonate challenge model to test the efficacy of a novel TLR 7/8 agonist (R848) conjugated influenza virus vaccine. The use of the intact virus represents a step forward in conjugate vaccine design as it provides multiple antigenic targets allowing for elicitation of a broad immune response. Our results show that this vaccine induces high level virus-specific antibody and cell mediated responses in neonates that result in increased virus clearance and reduced lung pathology following challenge compared to the non-adjuvanted virus vaccine. Surprisingly, the addition of a second TLR agonist (flagellin) did not enhance vaccine protection, suggesting combinations of TLR that provide increased efficacy must be determined empirically. These data support further exploration of this new conjugate influenza vaccine approach as a platform for use in the at-risk neonate population.

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Overview and Outlook of Toll-like Receptor ligand–antigen Conjugate Vaccines

Cited by 45 publications

References 117 publications

Mucosal Immunization with Recombinant Fusion Protein DnaJ-ΔA146Ply Enhances Cross-Protective Immunity against Streptococcus pneumoniae Infection in Mice via Interleukin 17A

Mucosal Immunization with Recombinant Fusion Protein DnaJ-ΔA146Ply Enhances Cross-Protective Immunity against Streptococcus pneumoniae Infection in Mice via Interleukin 17A

Salmonella flagellin is a potent carrier–adjuvant for peptide conjugate to induce peptide-specific antibody response in mice

A Novel R848-Conjugated Inactivated Influenza Virus Vaccine Is Efficacious and Safe in a Neonate Nonhuman Primate Model

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