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Heterologous prime–boost regimen adenovector 35-circumsporozoite protein vaccine/recombinant Bacillus Calmette-Guérin expressing the Plasmodium falciparum circumsporozoite induces enhanced long-term memory immunity in BALB/c mice
Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
Stockholms universitet, Naturvetenskapliga fakulteten, Wenner-Grens institut, Avdelningen för immunologi.
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(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Naturvetenskap
Identifikatorer
URN: urn:nbn:se:su:diva-72299OAI: oai:DiVA.org:su-72299DiVA, id: diva2:491735
Tillgänglig från: 2012-02-07 Skapad: 2012-02-07 Senast uppdaterad: 2012-02-07Bibliografiskt granskad
Ingår i avhandling
1. Novel immunization strategies and interethnic differences in response to malaria infection
Öppna denna publikation i ny flik eller fönster >>Novel immunization strategies and interethnic differences in response to malaria infection
2012 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

A better understanding of the role of antigen-presenting cells (APCs) in host resistance to malaria is essential to unravel the complex interactions between the host and the parasite. This would improve the design of malaria vaccines.

Mycobacterium bovis Bacillus Calmette-Guérin (BCG) has been utilized as a vector to deliver vaccine candidate antigens. We assessed the immunogenicity of a recombinant BCG-expressing (BCG-CS) circumsporozoite protein (CSp) as a malaria vaccine candidate. Immunization of BALB/c mice with BCG-CS augmented the numbers of dendritic cells (DCs) in draining lymph nodes and in the spleen. The activation markers MHC-class-II, CD40, CD80, and CD86 on DCs were significantly upregulated by BCG-CS as compared to wild-type BCG (wt-BCG). In vitro stimulation of bone marrow-derived DCs and macrophages with BCG-CS induced IL-12 and TNF-α production. BCG-CS induced higher phagocytic activity in macrophages as compared to wt-BCG. Finally, BCG-CS induced CSp-specific antibodies and IFN-γ-producing memory cells. Taken together, we found that BCG-CS is highly efficient in activating innate immune responses and could effectively prime the adaptive immune system.

Heterologous prime–boost approaches using vectors are optimal strategies to improve a broad and prolonged immunogenicity of malaria vaccines. We have demonstrated in BALB/c mice that priming with a replication-defective human adenovirus serotype 35 (Ad35) vector encoding CSp (Ad35-CS), followed by boosting with BCG-CS, maintained antibody responses and significantly increased levels of long-lived plasma cells (LLPC) and IFN-g-producing cells in response to CSp peptides. The increased number of IFN-g-producing cells induced by the combination of Ad35-CS/BCG-CS and the sustained type 1 antibody profile, together with high levels of LLPCs, may be essential for the development of long-term protective immunity against liver-stage parasites.

Fulani and Dogon, two sympatric ethnic groups living in northeastern Mali, are characterized by a marked difference in the susceptibility to P. falciparum malaria. We investigated whether APCs obtained from Fulani and Dogon children exhibited differences in terms of activation status and toll-like receptor (TLR) responses during malaria infection. We observed decreased activation of APCs and markedly suppressed TLR responses in Dogon children as compared to Fulani. These findings suggest that APCs and TLR signaling may be of importance for the protective immunity against malaria observed in the Fulani.

In conclusion, this thesis provides new insights that could facilitate a rational design of novel vaccines against malaria. Furthermore, the results elicit some immunological bases of the APC activation underlying the differences in host susceptibility to malaria infections.

Ort, förlag, år, upplaga, sidor
Stockholm: The Wenner-Gren Institute, Stockholm University, 2012. s. 93
Nyckelord
Malaria, Immunization, Ethnic groups, vaccines
Nationell ämneskategori
Immunologi
Forskningsämne
immunologi
Identifikatorer
urn:nbn:se:su:diva-72288 (URN)978-91-7447-450-3 (ISBN)
Disputation
2012-03-15, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 12, Stockholm, 10:00 (Engelska)
Opponent
Handledare
Anmärkning
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 1: In Press. Paper 2: Manuscript.Tillgänglig från: 2012-02-22 Skapad: 2012-02-06 Senast uppdaterad: 2012-02-08Bibliografiskt granskad

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Arama, CharlesFernández, C.Troye-Blomberg, Marita
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