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Project Title
Antibody functionality in GMZ2 immunized individuals and the interaction between GMZ2 induced antibodies and host genetic factors in relation to the risk of malaria

Introduction
Malaria is one of the world’s most serious infectious diseases causing an estimated 584 000 deaths a year most of which occurs in Africa [1]. Current interve..... Read more

Dassah Sylvester
PHD Candidate

 
Executive Summary
Malaria is one of the world’s most serious infectious diseases causing an estimated 584 000 deaths a year most of which occurs in Africa [1]. Current intervention measures have contributed in reducing malaria morbidity and mortality, but long term sustainability is not guaranteed. A potent vaccine is therefore in dire need of since vaccine has yielded much success in the eradication of several infectious diseases that had plagued the world in history. Several candidate malaria vaccines are at various stages of clinical trial but none has yet been proven successful.
Natural immunity to malaria is developed slowly as a function of continual exposure to the parasite and the immunity acquired is thought to reflect gradual acquisition of effective immune cells and antibodies directed against malaria polymorphic and variable P. falciparum blood stage antigens [3 - 6]. This supports the long standing evidence that human antibodies have a crucial protective role to clinical malaria especially those of the cytophilic subclasses (IgG1 and IgG3) [7 -10]. An effective mechanism in areas of intense disease requires the involvement of blood cells which has been demonstrated in experimental Antibody Dependent Cellular Inhibition (ADCI) assay [12 - 14]. Two molecules (MSP3 and GLURP) have been identified as among the most effective targets of human antibodies and these two proteins were shown to have a complementary effect that provides a rationale for combining these two antigens in a hybrid vaccine formulation like GMZ2 (Soe et al., 2004). GMZ2 (GLURP-MSP3 bivalent vaccine) is a recombinant hybrid protein between Glutamate Rich protein and Merozoite Surface Protein 3 expressed in Lactococcus. Lactis. GMZ2 is adjuvanted with aluminum hydroxide (GMZ2/Al(OH)3) and the formulation has now been tested in a multi-centre Phase IIb efficacy trial involving children living in Burkina Faso, Gabon, Ghana, and Uganda. One of the explorative objectives was to assess the biological activity of antibodies elicited by vaccination in the ADCI assay. The study will use samples from the GMZ2 efficacy trial to investigate mechanisms of GMZ2-vaccine mediated immunity in relation to the outcome of Pf infection. This study will generate data on the effectiveness of antibodies induced by individuals immunized with GMZ2 vaccine at the phase IIb clinical trial stage in an endemic area as the vaccine development progresses. It will also offer us a unique opportunity to investigate at firsthand how gene polymorphism (e.g. FCGR3B polymorphism) effect modification of malaria specific antibodies [21] influences the outcome of a typical malaria vaccine trial. The development of an effective malaria vaccine may  i) come from candidate vaccines already undergoing preliminary clinical trials at various stages, ii) require selection of entirely new antigens from the P. falciparum proteome or iii) require new insights into host-parasite interactions. Each of these possibilities depends on basic epidemiological data. The development of an effective malaria vaccine is being impeded by the complexity of the Plasmodium life cycle. Selection of promising candidate vaccine antigens therefore require identification of specific immune responses which are associated with acquired immunity to malaria. In this study samples from the GMZ2 phase IIb clinical trial will be analyzed to assess the functionality of vaccine induced antibodies, quantity and quality of antibodies. In addition, the interaction between these vaccine induced antibodies and host genetic factors in relation to the risk of malaria in GMZ2 immunized children will be investigated.
 
     Objective
    To assess antibody functionality in GMZ2 immunized individuals and the interaction between GMZ2 induced antibodies and host genetic factors in relation to the risk of malaria
    • To assess the capacity of antibodies in GMZ2 immunized children to inhibit P. falciparum growth in the absence or presence of monocytes by the in vitro GIA and ADCI assay respectively.
    • To evaluate IgG and IgG1-4 subclass responses to the GMZ2 vaccine antigens in relation to the risk of malaria.
    • To assess the impact of antibodies against other GMZ2 unrelated antigens (including GLURP-R2, AMA1, MSP3 and MSP1) on the overall risk of malaria in the vaccine trial cohort.
    • To assess the interaction between  polymorphisms in key immune response genes (ITGB2, FCGR2A, FCGR2B, FCGR3A, FCGR3B, IGHG3) and malaria specific antibodies in relation to the risk of malaria.
 




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