CD8+ T cell adjuvant effects of Salmonella FliCd flagellin in live vaccine vectors or as purified protein

Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1374, São Paulo, SP 05008-000, Brazil.
Vaccine (Impact Factor: 3.62). 11/2009; 28(5):1373-82. DOI: 10.1016/j.vaccine.2009.11.003
Source: PubMed


Salmonella flagellin, the flagellum structural subunit, has received particular interest as a vaccine adjuvant conferring enhanced immunogenity to soluble proteins or peptides, both for activation of antibody and cellular immune responses. In the present study, we evaluated the Salmonella enterica FliCd flagellin as a T cell vaccine adjuvant using as model the 9-mer (SYVPSAEQI) synthetic H2(d)-restricted CD8(+) T cell-specific epitope (CS(280-288)) derived from the Plasmodium yoelii circumsporozoite (CS) protein. The FliCd adjuvant effects were determined under two different conditions: (i) as recombinant flagella, expressed by orally delivered live S. Dublin vaccine strains expressing the target CS(280-288) peptide fused at the central hypervariable domain, and (ii) as purified protein in acellular vaccines in which flagellin was administered to mice either as a recombinant protein fused or admixed with the target CS(280-288) peptide. The results showed that CS(280-288)-specific cytotoxic CD8(+) T cells were primed when BALB/c mice were orally inoculated with the expressing the CS(280-288) epitope S. Dublin vaccine strain. In contrast, mice immunized with purified FliCd admixed with the CS(280-288) peptide and, to a lesser extent, fused with the target peptide developed specific cytotoxic CD8(+) T cell responses without the need of a heterologous booster immunization. The CD8(+) T cell adjuvant effects of flagellin, either fused or not with the target peptide, correlated with the in vivo activation of CD11c(+) dendritic cells. Taken together, the present results demonstrate that Salmonella flagellins are flexible adjuvant and induce adaptative immune responses when administered by different routes or vaccine formulations.


Available from: Mauricio Rodrigues, Nov 24, 2014
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    • "Besides, immunization with P. falciparum PfMSP119 fused to flagellin induced high antibody levels that efficiently inhibited the in vitro parasite growth [182]. Moreover, the CS280-288 protein (CD8+ T cell epitope from the CSP) from P. yoelii induced CS-specific CD8+ T cell responses when combined with flagellin and in the absence of any conventional adjuvant [183]. "
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    ABSTRACT: There is no malaria vaccine currently available, and the most advanced candidate has recently reported a modest 30% efficacy against clinical malaria. Although many efforts have been dedicated to achieve this goal, the research was mainly directed to identify antigenic targets. Nevertheless, the latest progresses on understanding how immune system works and the data recovered from vaccination studies have conferred to the vaccine formulation its deserved relevance. Additionally to the antigen nature, the manner in which it is presented (delivery adjuvants) as well as the immunostimulatory effect of the formulation components (immunostimulants) modulates the immune response elicited. Protective immunity against malaria requires the induction of humoral, antibody-dependent cellular inhibition (ADCI) and effector and memory cell responses. This review summarizes the status of adjuvants that have been or are being employed in the malaria vaccine development, focusing on the pharmaceutical and immunological aspects, as well as on their immunization outcomings at clinical and preclinical stages.
    04/2013; 2013(24):282913. DOI:10.1155/2013/282913
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    • "In addition, an increasing number of studies have demonstrated the adjuvant effects of flagellin [11], [12], [13], [14], [15], [16], including its ability to promote cytokine production through generalized recruitment of T and B lymphocytes and to activate dendritic cells and T lymphocytes through the Toll-like receptor (TLR) signaling pathway by the receptor TLR5 [14], [17]. In the mouse model, studies have also found that stimulation with flagellin resulted in substantial activation of murine bone marrow-derived dendritic cells (BMDCs) [18], [19], [20], [21]. "
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    PLoS ONE 10/2012; 7(10):e47724. DOI:10.1371/journal.pone.0047724 · 3.23 Impact Factor
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    • "The flagellin adjuvant effects were determined with two vaccine formulations: (i) attenuated S. Dublin strains administered orally expressing hybrid flagella composed of the flagellin-CS fusion protein and (ii) purified flagellins administered s.c. to mice either as hybrid flagellin or native flagellin mixed with synthetic CS280–288 peptide. Both formulations induced CS-specific CD8+ T-cell responses in the absence of any conventional adjuvant, as measured by ELISPOT [87]. These results suggest that Salmonella flagellins are promising soluble adjuvants for synthetic peptides in regard to the activation of specific cytotoxic T cell responses. "
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    ABSTRACT: In the past 25 years, the development of an effective malaria vaccine has become one of the biggest riddles in the biomedical sciences. Experimental data using animal infection models demonstrated that it is possible to induce protective immunity against different stages of malaria parasites. Nonetheless, the vast body of knowledge has generated disappointments when submitted to clinical conditions and presently a single antigen formulation has progressed to the point where it may be translated into a human vaccine. In parallel, new means to increase the protective effects of antigens in general have been pursued and depicted, such as the use of bacterial flagellins as carriers/adjuvants. Flagellins activate pathways in the innate immune system of both mice and humans. The recent report of the first Phase I clinical trial of a vaccine containing a Salmonella flagellin as carrier/adjuvant may fuel the use of these proteins in vaccine formulations. Herein, we review the studies on the use of recombinant flagellins as vaccine adjuvants with malarial antigens in the light of the current state of the art of malaria vaccine development. The available information indicates that bacterial flagellins should be seriously considered for malaria vaccine formulations to the development of effective human vaccines.
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