Protective Humoral Immunity Elicited by a Needle-Free Malaria Vaccine Comprised of a Chimeric Plasmodium falciparum Circumsporozoite Protein and a Toll-Like Receptor 5 Agonist, Flagellin

Carapau, Daniel; Mitchell, Robert A.; Nacer, Adéla; Shaw, Alan; Othoro, Caroline; Frevert, Ute; Nardin, Elizabeth

doi:10.1128/iai.00263-13

Cited by 29 publications

(17 citation statements)

References 68 publications

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“…Previous studies have reported that inbreed mice immunized with T1BT* constructs have in their serum IgG subtypes associated with both Th1 and Th2 cellular responses [59], [91]. We found that DR4 transgenic mice immunized with T1BT*-Y initially have respectively stronger Th2–associated IgG1 and Th1-associated IgG2/b response than T1BT* immunized mice.…”

Section: Discussionsupporting

confidence: 52%

An Unstable Th Epitope of P. falciparum Fosters Central Memory T Cells and Anti-CS Antibody Responses

et al. 2014

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Malaria is transmitted by Plasmodium-infected anopheles mosquitoes. Widespread resistance of mosquitoes to insecticides and resistance of parasites to drugs highlight the urgent need for malaria vaccines. The most advanced malaria vaccines target sporozoites, the infective form of the parasite. A major target of the antibody response to sporozoites are the repeat epitopes of the circumsporozoite (CS) protein, which span almost one half of the protein. Antibodies to these repeats can neutralize sporozoite infectivity. Generation of protective antibody responses to the CS protein (anti-CS Ab) requires help by CD4 T cells. A CD4 T cell epitope from the CS protein designated T* was previously identified by screening T cells from volunteers immunized with irradiated P. falciparum sporozoites. The T* sequence spans twenty amino acids that contains multiple T cell epitopes restricted by various HLA alleles. Subunit malaria vaccines including T* are highly immunogenic in rodents, non-human primates and humans. In this study we characterized a highly conserved HLA-DRβ1*04:01 (DR4) restricted T cell epitope (QNT-5) located at the C-terminus of T*. We found that a peptide containing QNT-5 was able to elicit long-term anti-CS Ab responses and prime CD4 T cells in HLA-DR4 transgenic mice despite forming relatively unstable MHC-peptide complexes highly susceptible to HLA-DM editing. We attempted to improve the immunogenicity of QNT-5 by replacing the P1 anchor position with an optimal tyrosine residue. The modified peptide QNT-Y formed stable MHC-peptide complexes highly resistant to HLA-DM editing. Contrary to expectations, a linear peptide containing QNT-Y elicited almost 10-fold lower long-term antibody and IFN-γ responses compared to the linear peptide containing the wild type QNT-5 sequence. Some possibilities regarding why QNT-5 is more effective than QNT-Y in inducing long-term T cell and anti-CS Ab when used as vaccine are discussed.

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Section: Discussionsupporting

confidence: 52%

An Unstable Th Epitope of P. falciparum Fosters Central Memory T Cells and Anti-CS Antibody Responses

et al. 2014

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“…The TLR5 agonist flagellin has been proven as an effective mucosal adjuvant, in addition to its systemic adjuvant activity [5], when administered via the i.n. route [6,7], which can prominently increase a protective IgA response [8,9]. However, the mechanism by which flagellin drives a mucosal immune response when acting as an i.n.…”

Section: Introductionmentioning

confidence: 99%

Frontline Science: Nasal epithelial GM-CSF contributes to TLR5-mediated modulation of airway dendritic cells and subsequent IgA response

Cao

Zhang

Yang

et al. 2017

Journal of Leukocyte Biology

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Flagellin, as a TLR5 agonist, is an established mucosal adjuvant for enhancing mucosal IgA responses by i.n. immunization. Nasal epithelial cells (NECs) are the first sentinel cells to be exposed to antigen and adjuvant in i.n. immunization, and it is suggested that they play an important role in the mucosal adjuvant activity of flagellin. However, the molecular mechanism leading to modulation and the response by flagellin-activated NECs remain unknown. We aimed to identify the soluble mediator(s) from flagellin-activated NECs that modulate the functions of airway dendritic cells (DCs) and enhance subsequent IgA response. In vitro studies showed that compared with the TLR4 agonist LPS, flagellin directly triggered slight up-regulation of CD80 on airway DCs but was insufficient to affect CD86 expression and DC-mediated IgA response. With the use of an in vitro system for culturing mouse primary NECs (mNECs), we demonstrated that flagellin-activated mNECs could functionally modulate airway DCs, which manifested as significant up-regulation of CD80/CD86 and enhancement of IgA production. The functional modulation of airway DCs was dependent on TLR5 activation of mNECs rather than direct TLR5 activation of airway DCs. With the use of cytokine array and antibody-blocking assays, we further identified that GM-CSF, a cytokine secreted from TLR5-activated mNECs, contributes to the activation of mNECs to airway DCs and subsequent IgA enhancement. In vivo blocking experiments confirmed that GM-CSF is an important factor in recombinant flagellin derived from (FliC)-induced airway DC activation and antigen-specific IgA enhancement. Our data directly demonstrate that nasal epithelial GM-CSF contributes to TLR5-mediated modulation of airway DCs and a subsequent IgA response.

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“…Thus, it remains unclear what amino acid regions from the hypervariable domains mitigate this third unknown pathway and whether this attribute is shared by other flagellin molecules or limited to close relatives of FliC. Nempont and colleagues (30) described three different FliC deletions D204-292, D191-352, and D174-400 that had reduced immunogenicity, although the most severely attenuated mutants were the D191-352 and D174-400 deletions, suggesting that the D2 domain may be the most critical for MyD88-independent IgG1 anti-flagellin responses (33,41). Future studies using flagellin from L. monocytogenes and S. adelaide to define the precise structures on D2/D3 that are required to enhance Ab production will be helpful to understand FliC's biological activity and also for vaccine development.…”

Section: Immunohorizonsmentioning

confidence: 99%

“…The D2 and the D3 domains (D2/D3) of FliC are largely exposed on the outer surface of the flagellar filament, and are the regions of the protein that are recognized by serotype specific Abs during natural Salmonella infections (28,29). Although most studies have implicated the TLR5 recognition site of FliC as the critical component of flagellin's adjuvancy and immunogenicity, there are additional reports that suggest the D2/D3 domain of flagellin is a contributing factor (30)(31)(32)(33). Thus, there is precedence for anti-flagellin Ab responses being influenced by structures other than the well-characterized TLR5 (D1) and Naip5/6 (D0) recognition sites.…”

Section: Introductionmentioning

confidence: 99%

FliC’s Hypervariable D3 Domain Is Required for Robust Anti-Flagellin Primary Antibody Responses

López-Yglesias

Zhao

et al. 2019

ImmunoHorizons

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Bacterial flagellin is a well-known agonist of the innate immune system that induces proinflammatory responses through the TLR5 and Naip5/6 recognition pathways. Several clinical trials investigating flagellin fusion proteins have demonstrated promising results for inducing protective immunity toward influenza virus, which has been largely attributed to flagellin's ability to activate TLR5. Our laboratory previously demonstrated that the Salmonella enterica serovar Typhimurium flagellin protein, FliC, induces Ab responses in mice through a third pathway that is independent of TLR5, Casp1/11, and MyD88. In this study, we further define the structural features of FliC that contribute to this unknown third pathway. By destroying the Naip5/6 and TLR5 recognition sites, we demonstrate that neither were required for the TLR5-, inflammasome-and MyD88-independent Ab responses toward FliC. In contrast, deletion of FliC's D3 or D0/D1 domains eliminated primary anti-flagellin Ab responses. For optimal primary and secondary anti-flagellin Ab responses we show that TLR5, inflammasome recognition, and the D3 domain of FliC are essential for flagellin's robust immunogenicity. Our data demonstrate that the D3 domain of FliC influences immunogenicity independent of the known innate recognition sites in the D0/D1 domains to augment Ab production. Our results suggest full-length FliC is critical for optimal immunogenicity and Ab responses in flagellin-based vaccines. ImmunoHorizons, 2019, 3: 422-432.

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Protective Humoral Immunity Elicited by a Needle-Free Malaria Vaccine Comprised of a Chimeric Plasmodium falciparum Circumsporozoite Protein and a Toll-Like Receptor 5 Agonist, Flagellin

Cited by 29 publications

References 68 publications

An Unstable Th Epitope of P. falciparum Fosters Central Memory T Cells and Anti-CS Antibody Responses

An Unstable Th Epitope of P. falciparum Fosters Central Memory T Cells and Anti-CS Antibody Responses

Frontline Science: Nasal epithelial GM-CSF contributes to TLR5-mediated modulation of airway dendritic cells and subsequent IgA response

FliC’s Hypervariable D3 Domain Is Required for Robust Anti-Flagellin Primary Antibody Responses

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