Immunological investigations to re-engineer a Plasmodium falciparum blood-stage human malaria vaccine

Date
2012-05
Authors
Pusic, Kae Myriam
Journal Title
Journal ISSN
Volume Title
Publisher
[Honolulu] : [University of Hawaii at Manoa], [May 2012]
Abstract
Despite decades of intensive research, malaria remains one of the most prevalent and devastating infectious diseases in the developing world. There is dire need for an effective malaria vaccine. The Merozoite Surface Protein of P. falciparum, MSP1-42, is one of the leading candidates for a blood-stage malaria vaccine. However, clinical trials of MSP1-42 show no efficacy. Here, we provide in vivo evidence that T cell epitope regions at the N-termjnus of MSP1-42 (MSP1-33) provide functional help in inducing antibodies to the C-terminal protective fragment (MSP1-19). We further demonstrated that these T cell epitopes positively or negatively influenced antibody responses directed towards MSP1-19. Differential recognition of these regions by humans may play a critical role in natural immunity to MSP1-4;, and may also be a critical determinant of vaccine efficacy. This study provides the rational basis to re-engineer more efficacious MSP1-42 vaccines by selective inclusion and exclusion of MSP1-33 specific T cell epitopes. Another major obstacle in the development of a subunit recombinant MSP1-42 malaria vaccine is the availability of safe and effective adjuvants that can potentiate a robust protective immune response. Currently, the adjuvant formulations suitable for clinical testing are very limited. Alternate strategies to enhance vaccine immunogenicity need to be explored and developed. One such strategy is the use of particle-mediated delivery systems such as nanoparticles. Here, we demonstrated the use of inorganic nanoparticles (<15nm) as a potent vaccine delivery platform to enhance the immunogenicity of the recombinant malaria vaccine antigen without additional adjuvants. Results showed that the inorganic nanoparticle delivery platform was as effective in enhancing immunogenicity as the malaria antigen administered with a clinically acceptable adjuvant. Moreover, the malaria vaccine/nanoparticle formulation induced parasite inhibitory antibodies in more than one animal species. Preliminary toxicity studies showed no significant deviations from normal clinical values. We also investigated the effects of nanoparticle uptake by dendritic cell and macrophages and showed that targeting to these antigen presenting cells may be one of the principle modes of action in enhancing vaccine induced immune responses. Our results indicate that the inorganic nanoparticles is a viable vaccine delivery platform for further clinical development.
Description
Ph.D. University of Hawaii at Manoa 2012.
Includes bibliographical references.
Keywords
malaria, vaccine, adjuvant
Citation
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