n A synthetic dodecapeptide (Asn-Ala-Asn-Pro) 3 conjugated to the tetanus toxoid. This
represents the part of the epitope of P. falciparumCS protein.
n A non-conjugated recombinant polypeptide made up of a stretch of 32 P. falciparum
CS repeat units [(Asn-Ala-Asn-Pro) 15 (Asn-Val-Asp-Pro) 2 ] fused to a stretch of 32
amino-acid residues.Both vaccines only induced low levels of antibodies in most of the volunteers. To
induce higher levels of antibodies, P. falciparumCS repeats were inserted into the
hepatitis surface antigen (HBsAg) and the vaccine was adsorbed onto alum (an adjuvant)
before being inoculated into volunteers. All of the volunteers developed antibodies to
the P. falciparumCS repeats but the infection was still able to develop into the disease
stage in many of the volunteers. A similar trial was carried out using P. vivax, another
species of Plasmodiumthat infects humans, but the CS protein turned out to be poorly
immunogenic in a trial involving 30 human volunteers.n 10.6.2 CELL-MEDIATED IMMUNITY
Analysis of the immune response to malaria has shown that in addition to the production
of antibodies the CD8+T cells (T cytotoxic cells) are activated. Cells not exposed to the
malaria parasites can be extracted from body fluids from non-infected humans or mice
and kept alive in culture cells. In culture, the cells can be exposed to specific circum-
sporozoite (CS) antigen extracted from cultured sporozoites. Non-infected mice were
protected against strains of mouse malaria when injected with cytotoxic lymphocytes (CTLs)
primed against the CS antigen. The target for the primed cytotoxic lymphocytes was found
to be infected liver cells (hepatocytes). The cell adhesion molecules in the vicinity of the
infected liver cells were activated and attracted primed CTLs, which led to the destruc-
tion of intrahepatocytic parasites. There is experimental evidence indicating that protection
involved both cytotoxic lymphocytes and neutralising antibodies.
Vaccines that contain synthetic circumsporozoite peptides that may stimulate CTL
activity to induce protection against malaria are now being prepared for trials.n 10.6. 3BLOOD STAGE VACCINES
The parasites that invade the hepatocytes undergo a multiplicative phase, known as
schizogony, which results in the production of numerous merozoites. The merozoites exit
from the liver into the circulating blood and invade erythrocytes. Once inside an ery-
throcyte, the merozoite undergoes a development phase and grows into a trophozoite
which has a very distinctive shape and is known as the ‘signet ring’ stage. Erythrocytes
infected with this stage of P. falciparumcan be maintained by in vitro culture and a para-
site antigen, referred to as ring infected erythrocyte surface antigen (RESA) and
identified as PF155/ring antigen, has been extracted from such cultures.
Infected erythrocytes have deposits of the antigen, a non-polymorphic 155 kDa
polypeptide, on their surface membrane. The molecular structure of the antigen
P155/RESA has at the carboxyl terminal region two tandemly repeated sequences (5 copies
of Glu-Asn-Val-Glu-His-Asp-Ala and 30 copies of Glu-Glu-Asn-Val). These two regions
of the antigen (the epitopes) react with receptor sites on human B and T cells.
Antibodies raised against the PF155/RESA antigens have been shown in vitro to be
able to block the merozoites of P. falciparumfrom invading erythrocytes. Partial protec-
tion was achieved in monkeys by passive transfer of IgG antibodies specific to either the
(Glu-Glu-Asn-Val) 2 or the Glu-Glu-Asn-Val-Glu-His-Asp-Ala repeats.
Trials are being conducted using vaccine containing synthetic PF155/RESA antigens.PARASITOLOGY