Interferon-γ, a valuable surrogate marker of Plasmodium falciparum pre-erythrocytic stages protective immunity

Abstract

Immunity against the pre-erythrocytic stages of malaria is the most promising, as it is strong and fully sterilizing. Yet, the underlying immune effectors against the human Plasmodium falciparum pre-erythrocytic stages remain surprisingly poorly known and have been little explored, which in turn prevents any rational vaccine progress. Evidence that has been gathered in vitro and in vivo, in higher primates and in humans, is reviewed here, emphasizing the significant role of IFN-γ, either as a critical immune mediator or at least as a valuable surrogate marker of protection. One may hope that these results will trigger investigations in volunteers immunized either by optimally irradiated or over-irradiated sporozoites, to quickly delineate better surrogates of protection, which are essential for the development of a successful malaria vaccine.

Figure 1

IFN-γ is associated with protection induced by LSA3 in Aotus monkeys. Specific IFN-γ responses were studied in nine Aotus immunized either by LSA3 recombinant proteins [53] or by long peptides [54]. Monkeys were challenged with P. falciparum sporozoites from Santa lucia strain and the IFN-γ responses were evaluated in protected, non-protected and control animals immunized with the GST or ASO2 adjuvant alone. After immunization, the production of IFN-γ was assessed either ex-vivo by ELISpot or by ELISA after 40 h of in vitro re-stimulation with LSA3 peptides (squares) or Rc proteins (circles), as described in detail in [53] and [55].

Figure 2

IFN-γ is associated with protection induced by LSA3 in chimpanzees. Summary of specific IFN-γ responses in eighteen chimpanzees immunized either by LSA3 recombinant proteins or by Peptides/Lipopeptides. Chimpanzees were challenged once or twice (*) with P. falciparum sporozoites. After immunization, the IFN-γ producing T cell responses were compared in protected versus non-protected animals. Chimpanzees that received adjuvant alone or saline alone (vehicle) were used as controls. The production of IFN-γ was assessed after in vitro stimulation with LSA3 peptides (squares) or Rc proteins (circles) using either ELISA (A), as described [55] or ex-vivo ELISpot (B) as described [53,56].