Immunity to Liver Stage Malaria: Considerations for Vaccine Design

Abstract

Malaria is the world's deadliest parasitic disease and effective control measures are a public health priority. Most deaths in humans from malaria are caused by one species of the protozoa, Plasmodium falciparum. An efficacious and cost-effective vaccine against this parasite is considered a holy grail of modern molecular medicine. A vaccine that targets liver stage parasites would prevent infection from reaching the blood and causing clinical disease. Among known P. falciparum antigens, liver stage antigen-1 (LSA-1) is the only protein expressed exclusively by infected hepatocytes. Several independent studies in humans have consistently related immune responses to LSA-1 with resistance to infection or disease, providing a powerful rationale for the development of liver stage vaccines. Investigations by ourselves and others aim to dissect the mechanism of cellular immunity to LSA-1 and to evaluate in different delivery systems epitopes associated with protection as components of a multiantigen malaria vaccine. The first clinical trials are already being conducted, the results of which are eagerly awaited.

Phase I Safety and Immunogenicity Trial of Plasmodium vivax CS Derived Long Synthetic Peptides Adjuvanted with Montanide ISA 720 or Montanide ISA 51

“…Sera and cells from these individuals recognize proteins expressed on the sporozoites and the parasite liver forms [5][6][7][8][9] that have been incriminated in this protection and therefore have been proposed as malaria vaccine candidates. 10,11 Among them, the circumsporozoite (CS) protein that is abundantly expressed on the sporozoite surface has been shown to be involved in the process of parasite invasion to the hepatocyte 12,13 and its immunological blockage prevents the development of malaria infection. 6,7,14 The RTS-S vaccine based on a construct of the Plasmodium falciparum CS protein and the S antigen of human hepatitis B virus has proven to be immunogenic and partially protective in phase II studies conducted with human malaria-naive volunteers [15][16][17][18] and in adults and children from malaria-endemic areas of Africa.…”

Tomatine Adjuvantation of Protective Immunity to a Major Pre-erythrocytic Vaccine Candidate of Malaria is Mediated viaCD8+T Cell Release of IFN-γ

“…One such antigen that has been studied extensively is the immunodominant circumsporozoite (CS) protein that is the major surface protein of sporozoites, the hepatocyte-invasive stage of the Plasmodium life cycle [12]. Passive transfer of a CTL clone recognizing P .…”

Usefulness of the recombinant liver stage antigen-3 for an early serodiagnosis of Plasmodium falciparum infection

“…During this incubation period, the parasites express liver stagespecific antigens, including LSA-1 and LSA-3. These preerythrocyte antigens evoked specific humoral and cellular immune responses in the hosts and have been recognized as candidates for vaccine (Aidoo et al, 2000;Daubersies et al, 2000;Joshi et al, 2000;Kurtis et al, 2001;Perlaza et al, 2001;Sauzet et al, 2001;Taylor-Robinson, 2003). In this consideration, the liver stage-specific antigen could also be a good diagnostic candidate for early diagnosis of malaria.…”

“…Specific humoral, cellular, and cytokine immune responses to LSA-1 and LSA-3 are well documented, with epitopes identified that correlate with the antibody production, proliferative T-cell responses, or cytokine induction (Aidoo et al, 2000;Joshi et al, 2000;Perlaza et al, 2001). Both preerythrocyte antigens have been considered to be vaccine candidates against P. falciparum due to their antigenic and protection-inducing immunogenic properties Kurtis et al, 2001;Sauzet et al, 2001;Taylor-Robinson, 2003). In the present study, we evaluated the usefulness of P. falciparum LSA-3 as a serodiagnostic antigen for a more rapid diagnosis of falciparum malaria than using the currently available diagnostic tools.…”