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Vaccine development strategies applied to the Plasmodium falciparum malaria antigen 332
Stockholm University, Faculty of Science, The Wenner-Gren Institute .
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Malaria is one of the major infectious diseases in the world with regard to mortality and morbidity, and the development of a vaccine against the malaria parasite Plasmodium falciparum is considered of high priority. The aim of the work presented in this thesis was to develop and characterize recombinant vaccine constructs based on the P. falciparum asexual blood-stage antigen Pf332. We have studied the humoral responses in mice elicited by various types of constructs, including naked DNA plasmids, naked mRNA, alphavirus, and peptides. Immunological memory was successfully induced against the repetitive EB200 fragment of Pf332, although the antibody titers were generally low and the highest titers were unexpectedly obtained with a conventional DNA plasmid. In another study, we also demonstrated the ability to circumvent genetically restricted immune responses in mice against two malaria epitopes, one of them derived from Pf332, by inclusion of universal T-cell epitopes into multiple antigen peptide constructs. However, the overall variability of the responses stressed the importance of including several epitopes in a future malaria vaccine. Further, the recent completion of sequencing of Pf332 enabled us to identify and characterize the immunogenic properties of a non-repeat fragment of the Pf332, termed C231. Our analyses of C231 showed that antibodies raised against the recombinant protein possess an in vitro parasite inhibitory capacity similar to that of antibodies against recombinant EB200. Furthermore, the recognition of C231 by antibodies in sera from individuals naturally primed to P. falciparum, correlated well with that previously observed for the corresponding sera and EB200. When analyzing the IgG subclass distribution of anti-C231 antibodies, we noted a bias towards IgG2 and IgG3 relative to IgG1, differing from the subclass profiles of IgG binding crude P. falciparum antigen, which were dominated by IgG1. Taken together, the work presented herein is likely to facilitate further studies on Pf332 as a potential target for protective immune responses, and amounts to a small step towards the realization of a malaria vaccine.

Place, publisher, year, edition, pages
Stockholm: Wenner-Grens institut för experimentell biologi , 2006. , 67 p.
Keyword [en]
malaria, sub-unit vaccines, immunogenicity, antibody response, antigen Pf332
National Category
Immunology
Identifiers
URN: urn:nbn:se:su:diva-1263ISBN: 91-7155-231-6 (print)OAI: oai:DiVA.org:su-1263DiVA: diva2:189733
Public defence
2006-10-13, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 8 C, Stockholm, 10:00
Opponent
Supervisors
Available from: 2006-09-21 Created: 2006-09-21 Last updated: 2011-08-22Bibliographically approved
List of papers
1. Comparative immunization study using RNA and DNA constructs encoding a part of the Plasmodium falciparum antigen Pf332
Open this publication in new window or tab >>Comparative immunization study using RNA and DNA constructs encoding a part of the Plasmodium falciparum antigen Pf332
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2001 In: Scandinavian Journal of Immunology, ISSN 0300-9475, Vol. 54, no 1-2, 117-24 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-22913 (URN)
Note
Part of urn:nbn:se:su:diva-1263Available from: 2006-09-21 Created: 2006-09-21Bibliographically approved
2. Differential antibody responses to Plasmodium falciparum-derived B-cell epitopes induced by diepitope multiple antigen peptides (MAP) containing different T-cell epitopes
Open this publication in new window or tab >>Differential antibody responses to Plasmodium falciparum-derived B-cell epitopes induced by diepitope multiple antigen peptides (MAP) containing different T-cell epitopes
2004 In: Vaccine, ISSN 0264-410X, Vol. 23, no 3, 343-52 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-22914 (URN)
Note
Part of urn:nbn:se:su:diva-1263Available from: 2006-09-21 Created: 2006-09-21Bibliographically approved
3. Characterization of the antigenic properties of Pf332-C231, a fragment of a non-repeat region of the Plasmodium falciparum antigen Pf332
Open this publication in new window or tab >>Characterization of the antigenic properties of Pf332-C231, a fragment of a non-repeat region of the Plasmodium falciparum antigen Pf332
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Article in journal (Refereed) Submitted
Identifiers
urn:nbn:se:su:diva-22915 (URN)
Note
Part of urn:nbn:se:su:diva-1263Available from: 2006-09-21 Created: 2006-09-21Bibliographically approved
4. Antibody responses to a C-terminal fragment of the Plasmodium falciparum blood-stage antigen Pf332 in Senegalese individuals naturally primed to the parasite
Open this publication in new window or tab >>Antibody responses to a C-terminal fragment of the Plasmodium falciparum blood-stage antigen Pf332 in Senegalese individuals naturally primed to the parasite
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2008 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 152, no 1, 64-71 p.Article in journal (Refereed) Published
Abstract [en]

Previous studies have shown that antibodies from humans exposed continuously to malaria recognize the Plasmodium falciparum asexual blood-stage antigen Pf332. Here we analysed the antibody responses to a C-terminal fragment of Pf332, designated C231, in individuals from Senegal, by measuring the serum levels of immunoglobulin M (IgM), IgG class and subclass and IgE antibodies. IgG antibody reactivity with crude P. falciparum antigen was detected in all the donors, while many of the children lacked or had low levels of such antibodies against C231. The antibody levels increased significantly with age for both crude P. falciparum antigen and C231, and in the older age groups most of the donors displayed antibodies to C231. This was also true for IgM, IgE and IgG subclass reactivity against C231. Moreover, the ratio of IgG1/IgG2 was considerably lower for C231 than for crude P. falciparum antigen, and in age groups 10–14 and 15–19 years the levels of IgG2 against C231 even exceeded that of IgG1. The IgG2/IgG3 ratios suggest that C231 gives similar levels of IgG2 and IgG3, except for children aged 4–9 years, where IgG3 was higher. Raw IgM, IgG class and subclass and IgE antibody levels to C231 tended to be higher in those who did not experience a malaria attack, but following linear multivariate analysis the trends were not significant.

Keyword
antibody responses, antigen/epitopes, immunoglobulins, Plasmodium spp
National Category
Immunology
Research subject
Immunology
Identifiers
urn:nbn:se:su:diva-15992 (URN)10.1111/j.1365-2249.2008.03607.x (DOI)000253757700010 ()18279441 (PubMedID)
Available from: 2008-12-12 Created: 2008-12-12 Last updated: 2011-08-22Bibliographically approved

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