Engagement of TLR signaling as adjuvant: Towards smarter vaccine and beyond

Lahiri, Amit; Das, Priyanka; Chakravortty, Dipshikha

doi:10.1016/j.vaccine.2008.09.045

Cited by 123 publications

(101 citation statements)

References 83 publications

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“…As a result, activation of a class of innate pathogen receptors called pattern recognition receptors is a central feature of many adjuvant systems (26). This can be readily appreciated in prior studies, which demonstrated that TLR activators, such as LPS, and NOD-like receptor activators, such as aluminum hydroxide, are effective immune adjuvants (15,17,20,(27)(28)(29).…”

Section: Discussionmentioning

confidence: 99%

Chitin Particles Are Multifaceted Immune Adjuvants

Silva¹,

Pochard²,

Lee³

et al. 2010

Am J Respir Crit Care Med

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Rationale: Chitin is a ubiquitous polysaccharide in fungi, insects, allergens, and parasites that is released at sites of infection. Its role in the generation of tissue inflammation, however, is not fully understood. Objectives: We hypothesized that chitin is an important adjuvant for adaptive immunity. Methods: Mice were injected with a solution of ovalbumin and chitin. Measurements and Main Results: We used in vivo and ex vivo/in vitro approaches to characterize the ability of chitin fragments to foster adaptive immune responses against ovalbumin and compared these responses to those induced by aluminum hydroxide (alum). In vivo, ovalbumin challenge caused an eosinophil-rich pulmonary inflammatory response, Th2 cytokine elaboration, IgE induction, and mucus metaplasia in mice that had been sensitized with ovalbumin plus chitin or ovalbumin plus alum. Toll-like receptor-2, MyD88, and IL-17A played critical roles in the chitin-induced responses, and MyD88 and IL-17A played critical roles in the alum-induced responses. In vitro, CD4 1 T cells from mice sensitized with ovalbumin plus chitin were incubated with ovalbumin-stimulated bone marrowderived dendritic cells. In these experiments, CD4 1 T-cell proliferation, IL-5, IL-13, IFN-g, and IL-17A production were appreciated. Tolllike receptor-2, MyD88, and IL-17A played critical roles in these in vitro adjuvant properties of chitin. TLR-2 was required for cell proliferation, whereas IL-17 and TLR-2 were required for cytokine elaboration. IL-17A also inhibited the generation of adaptive Th1 responses.Conclusions: These studies demonstrate that chitin is a potent multifaceted adjuvant that induces adaptive Th2, Th1, and Th17 immune responses. They also demonstrate that the adjuvant properties of chitin are mediated by a pathway(s) that involves and is regulated by TLR-2, MyD88, and IL-17A.

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Section: Discussionmentioning

confidence: 99%

Chitin Particles Are Multifaceted Immune Adjuvants

Silva¹,

Pochard²,

Lee³

et al. 2010

Am J Respir Crit Care Med

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“…It was discovered in the late 1980s that conjugation of Pam3CSS (tripalmitoyl Cys-SerSer) or Pam2CSS (di-O-acylated palmitoyl Cys-Ser-Ser) to peptides derived from bacterial or viral proteins could convert the immunologically inactive peptides into potent vaccines that provided long-lasting protection against bacterial or viral infections in animal models. This effect was enabled by induction of neutralizing antibodies (28,29) and by in vivo priming of epitope-specific cytotoxic T cells and memory T cells (30)(31)(32). Since antibodies to the lipid moieties are not generated in vivo, the immune-enhancing effect of the lipids is believed to be similar to that of a conventional adjuvant, and thus, bacterial lipoprotein/lipopeptidecontaining vaccines are recognized as one category of selfadjuvanting vaccines (21)(22)(23)33).…”

Section: Immune-enhancing Effects Of the N-terminal Lipids Of Rlp2086mentioning

confidence: 99%

“…It was perceived in early days that the lipids simply anchor the lipoproteins/lipopeptides to the surface membrane of immune cells to facilitate the internalization. Recent research suggested that the lipid moieties interact with various TLRs, a type of membranebound pattern recognition receptors (PRRs), to drive the endocytosis of the lipoproteins by antigen-presenting cells (34) and induce various immune responses (21,22,32). PRR is a key component of the innate immune system to identify pathogen-associated molecular patterns (PAMPs) (35).…”

Section: Immune-enhancing Effects Of the N-terminal Lipids Of Rlp2086mentioning

confidence: 99%

The Dual Role of Lipids of the Lipoproteins in Trumenba, a Self-Adjuvanting Vaccine Against Meningococcal Meningitis B Disease

Luo

Friese

Runnels

et al. 2016

AAPS J

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ABSTRACT.Trumenba (bivalent rLP2086) is a vaccine licensed for the prevention of meningococcal meningitis disease caused by Neisseria meningitidis serogroup B (NmB) in individuals 10-25 years of age in the USA. The vaccine is composed of two factor H binding protein (fHbp) variants that were recombinantly expressed in Escherichia coli as native lipoproteins: rLP2086-A05 and rLP2086-B01. The vaccine was shown to induce potent bactericidal antibodies against a broad range of NmB isolates expressing fHbp that were different in sequence from the fHbp vaccine antigens. Here, we describe the characterization of the vaccine antigens including the elucidation of their structure which is characterized by two distinct motifs, the polypeptide domain and the N-terminal lipid moiety. In the vaccine formulation, the lipoproteins self-associate to form micelles driven by the hydrophobicity of the lipids and limited by the size of the folded polypeptides. The micelles help to increase the structural stability of the lipoproteins in the absence of bacterial cell walls. Analysis of the lipoproteins in Toll-like receptor (TLR) activation assays revealed their TLR2 agonist activity. This activity was lost with removal of the O-linked fatty acids, similar to removal of all lipids, demonstrating that this moiety plays an adjuvant role in immune activation. The thorough understanding of the structure and function of each moiety of the lipoproteins, as well as their relationship, lays the foundation for identifying critical parameters to guide vaccine development and manufacture.

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“…Individual TLR have distinct pathogen-associated motif specificities, with TLR4 recognizing LPS (1), TLR2 binding bacterial lipopeptides (2), while TLR3 and TLR9 bind viral and bacterial nucleic acids, respectively (3)(4)(5). The use of noninfectious TLR agonists as vaccine adjuvants is a promising approach to generate pathogen-specific adaptive responses (6,7); however, the ability of specific TLR engagement to promote primary and secondary immune responses is not clearly resolved.…”

Section: Tlr2 Engagement On Dendritic Cells Promotes Highmentioning

confidence: 99%

TLR2 Engagement on Dendritic Cells Promotes High Frequency Effector and Memory CD4 T Cell Responses

Chandran

Verhoeven

Teijaro

et al. 2009

The Journal of Immunology

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Ligation of TLR by distinct pathogen components provides essential signals for T cell priming, although how individual TLR engagement affects primary and memory T cell responses is not well defined. In this study, we demonstrate distinct effects of TLR2 vs TLR4 engagement on primary and memory CD4 T cell responses due to differential effects on APC. Priming of influenza hemagglutinin (HA)-specific naive CD4 T cells with HA peptide and the TLR2 agonist Pam3CysK in vivo resulted in a high frequency of activated HA-specific CD4 T cells that predominantly produced IL-2 and IL-17, whereas priming with HA peptide and the TLR4 agonist LPS yielded a lower frequency of HA-specific CD4 T cells and predominant IFN-γ producers. TLR2 agonist priming depended on TLR2 expression by APC, as wild-type CD4 T cells did not expand in response to peptide and Pam3CysK in TLR2-deficient hosts. TLR2-mediated priming also led to an increased frequency of Ag-specific memory CD4 T cells compared with TLR4 priming and mediated enhanced secondary responses to influenza challenge. Our results show that TLR engagement on APC influences both primary and secondary CD4 T cell responses, and suggest that long-term functional capacities of T cells are set by innate signals during early phases of an infection.

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Engagement of TLR signaling as adjuvant: Towards smarter vaccine and beyond

Cited by 123 publications

References 83 publications

Chitin Particles Are Multifaceted Immune Adjuvants

Chitin Particles Are Multifaceted Immune Adjuvants

The Dual Role of Lipids of the Lipoproteins in Trumenba, a Self-Adjuvanting Vaccine Against Meningococcal Meningitis B Disease

TLR2 Engagement on Dendritic Cells Promotes High Frequency Effector and Memory CD4 T Cell Responses

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