Experimental infection and protection against ... - TI Pharma

18 Chapter 1
Malaria immunity
Central to the hampering vaccine development is our limited understanding of
precisely what constitutes immunity to Pf malaria. In areas of natural exposure,
clinical immunity to malaria slowly develops in repeatedly exposed humans. In
such populations, immunity to severe disease develops in early childhood,
whereas immunity to mild disease is not typically acquired until late adolescence
[53, 54] (Figure 4). Immunity is never sterile and the cumulative incidence of
parasitemia may approach 100% in adults [55]. Instead, natural acquired
immunity appears to be directed at the control of parasite replication and
limited parasite clearance.
Both humoral and cellular mechanisms contribute to the immunological
responses to Pf parasites, depending on the stage of the life cycle. Although
antibodies can inhibit the invasion of parasites into hepatocytes [56], rodent
studies suggest that pre-erythrocytic immunity is dependent mainly upon
cascades of cellular and cytokine interactions [57, 58]. CD8+ T cells have been
implicated as the principal effector cells, and IFN-γ as a critical effector molecule
[59, 60].
Given the absence of antigen processing in erythrocytes, immunity to blood
stage malaria parasites is primarily conferred by humoral immune responses
[61], although T-cells may be able to also limit blood stage parasite growth by
enhancing phagocytosis by macrophages [62]. The importance of antibodies in
blood stage parasite inhibition was originally demonstrated by passive transfer
experiments [63, 64], whereby the transfer of antibodies from exposed
volunteers suppressed parasitemia in Pf patients. Antibodies may act
independently in inhibiting parasite growth, as shown by in vitro parasite growth
inhibition assays (GIA) [65], or they may assist the cellular killing of parasites, an
in vitro phenomenon called antibody-dependent cell-mediated cytotoxicity [66].
Ideally, immunological assays should be able to predict the efficacy of malaria
vaccines. Unfortunately, immune correlates of protection are lacking and thus
malaria vaccine development depends on a trial-and-error approach [12].
Controlled malaria infections
A controlled malaria infection provides the opportunity of obtaining preliminary
efficacy data for a vaccine candidate in a selected small group of malaria naïve
volunteers and act as the key tool for downstream selection of vaccine