Experimental infection and protection against ... - TI Pharma

Introduction 15
The division of antigen expression according to parasite life-cycle stages,
although useful, may be a simplification of reality since many antigens are
shared between stages [17-19].
Pre-erythrocytic vaccine candidates
The development of pre-erythrocytic vaccines started with the observation by
Ruth Nussenzweig that vaccination of mice with irradiated sporozoites results in
protection from sporozoite challenge. [20]. Following this observation, the
exploration of sporozoite antigens lead to the identification of the
circumsporozoite protein (CS), which was capable of inducing immunity in mice
[21]. Further development of this antigen, particularly by the Walter Reed Army
Institute of Research in the United States, has resulted in the most advanced
vaccine candidate so far: GlaxoSmithKline's RTS,S vaccine. This candidate
consists of a Hepatitis B surface antigen fused to the Pf circumsporozoite
protein, adjuvanted by GlaxoSmithKline's proprietary adjuvant AS01 containing
the immunostimulants MPL and QS21 in liposomes. It is currently in phase III
clinical development and has consistently shown 30-60% clinical protection [22-
27].
Other promising pre-erythrocytic antigens include thrombospondin-related
adhesion protein (TRAP) and liver stage antigen 1 and 3 (LSA). Cytokine
responses to LSA-1 were associated with parasitemia and clinical malaria in
endemic human populations and the antigen is safe and immunogenic in
primates and humans [28-30]. Unfortunately, a phase IIa efficacy trial with the
AS01/AS02 adjuvanted recombinant LSA1 product did not show any protection
or delay in prepatent period [31]. The vaccine candidate LSA-3 was safe and
immunogenic in humans, but did not protect malaria naïve volunteers in a
controlled human malaria infection trial (Nieman et al. manuscript in
preparation). A vaccine based on multiple T- and B-cell epitopes, amongst which
LSA-1 and LSA-3, fused to the TRAP antigen protected malaria-naïve subjects
against subsequent challenge with infectious mosquitoes, when administered as
a heterologous prime-boost schedule whereby the plasmid DNA vaccine is
boosted by a viral-vectored vaccine [32], but did not show any efficacy in field
trials in both adult and children [33, 34].
The most successful immunization strategy so far, however, was directly derived
from the irradiated sporozoites used in the murine models of Ruth Nussenzweig.
Infected, laboratory-reared Anopheles stephensi mosquitoes were irradiated and