Malaria by Shazleen Farhana Bt Khairul Azam, C11109868

Infection remains the main cause of morbidity and mortality in man,

particularly in underdeveloped areas where it is associated with poverty and
overcrowding. In the developed world increasing prosperity, universal
immunization and antibiotics have reduced the prevalence of infectious disease.
However, antibiotic-resistant strains of microorganisms and diseases such as
human immunodeficiency virus (HIV) infection, variant Creutz feldt-Jakob disease
(vCJD), and severe acute respiratory syndrome (SARS) have emerged. There is
increased global mobility, both enforced (as a result of war, civil unrest, and
natural disaster), and voluntary (for tourism and economic benefit). This has
aided the spread of infectious disease and allowed previously localized
pathogens such as SARS and West Nile virus to establish themselves world-wide.
An increase in the movement of livestock and animals has enabled the spread of
zoonotic diseases like monkeypox, while changes in farming and food-processing
methods have contributed to an increasein the incidence of food and waterborne diseases. Deteriorating social conditions in the inner city areas of our
major conurbations have facilitated the resurgence of tuberculosis and other
infections. Prisons and refugee camps, where large numbers of people are forced
to live in close proximity, often under poor conditions, are providing a breeding
ground for devastating epidemics of infectious disease. There are new concerns
about the deliberate release of infectious agents such as smallpox or anthrax by
terrorist groups or national governments.
In the developing world successes such as the eradication of smallpox
have been balanced or outweighed by the new plagues. Infectious diseases
cause nearly 25% of all human deaths (Table 2.1). Two billion people - one-third
of the world's population - are infected with tuberculosis, 500 million people
catch malaria every year, and 200 million are infected with schistosomiasis.
Infections are often multiple, and there is synergy both between different
infections, and between infection and other factors such as malnutrition. Many of
the infectious diseases affecting developing countries are preventable or
treatable, but continue to thrive owing to lack of money and political will.
Immunity to Malaria; Pathogenesis and Clinical Manifestations
Malaria is a disease caused by a protozoan parasite (Plasmodium) that infects
more than 100 million people and causes 1 to 2 million deaths annually. Malaria,

especially that caused by infection with Plasmodium falciparum, continues to be

one of the most widespread and prevalent diseases today. Infection is initiated
when sporozoites are inoculated into the blood stream by the bite of an infected
mosquito (Anopheles). The sporozoites rapidly disappear from the blood and
invade the parenchymal cells of the liver. In the hepatocytes, sporozoites
develop into merozoites by a multiple-fission process termed schizogony. One to
2 weeks after infection, the infected hepatocytes burst and release thousands of
merozoites, thereby initiating the erythrocytic stage of the life cycle. The
merozoites invade red blood cells by a process that involves multiple
ligandreceptor interactions, such as binding of the P. falciparum protein EBA-175
to glycophorin A on erythrocytes. Merozoites develop sequentially into ring
forms, trophozoites, and schizonts, each of which expresses both shared and
unique antigens. The erythrocytic cycle continues when schizont-infected red
blood cells burst and release merozoites that invade other erythrocytes. Sexual
stage gametocytes develop in some cells and are taken up by mosquitoes during
a blood meal, after which they fertilize and develop into oocysts. Immature
sporozoites develop in the mosquitoes within 2 weeks and travel to the salivary
glands, where they mature and become infective.
The clinical features of malaria caused by the four species of Plasmodium that
infect humans include fever spikes, anemia, and splenomegaly. Many pathologic
manifestations of malaria may be due to the activation of T cells and
macrophages and production of TNF. The development of cerebral malaria in a
murine model is prevented by depletion of CD4 + T lymphocytes or by injection of
neutralizing anti-TNF antibody.
The immune response to malaria is complex and stage specific; that is,
immunization with antigens derived from sporozoites, merozoites, or
gametocytes protects only against the particular stage. On the basis of this
observation, it is postulated that a vaccine consisting of combined immunogenic
epitopes from each of these stages should stimulate more effective immunity
than a vaccine that incorporates antigens from only one stage. The best
characterized malaria vaccines are directed against sporozoites. Because of the
stage-specific nature of sporozoite antigens, such vaccines must provide
sterilizing immunity to be effective. Protective immunity may be induced in
humans by injection of radiation-inactivated sporozoites. This type of protection
is partially mediated by antibodies that inhibit sporozoite invasion of liver cells in

vitro. Such antibodies recognize the circumsporozoite (CS) protein, which

mediates the binding of parasites to liver cells. The CS protein contains a central
region of about 40 tandem repeats of the sequence Asn-Ala-Asn-Pro (NANP),
which makes up the immunodominant B cell epitope of the protein. Anti-(NANP)n
antibodies neutralize sporozoite infectivity, but such antibodies provide only
partial protection against infection. The antibody response to CS protein is
dependent on helper T cells. Most CS-specific helper T cells recognize epitopes
outside the NANP region, and some of these T cell epitopes correspond to the
most variable residues of the CS protein, which suggests that variation of the
antigens of the surface coat may have arisen in response to selective pressures
imposed by specific T cell responses.
CD8+ T cells play an important role in immunity to the hepatic stages of
infection. If sporozoite-immunized mice are depleted of CD8 + T cells by injection
of anti-CD8 antibodies, they are unable to resist a challenge infection. The
protective effects of CD8+ T cells may be mediated by direct killing of sporozoiteinfected hepatocytes or indirectly by the secretion of IFN- and activation of
hepatocytes to produce nitric oxide and other agents that kill parasites. IL-12
induces resistance to sporozoite challenge in rodents and nonhuman primates,
presumably by stimulating IFN- production. Conversely, resistance of
Plasmodium berghei sporozoite-immunized mice to a challenge infection is
abrogated by treatment with anti-IFN- antibodies.
The sexual blood stage of malaria is an important target for vaccine
development. The major goal of this form of immunization is to kill infected
erythrocytes or to block merozoite invasion of new red cells. Although infected
individuals mount strong immune responses against blood stage antigens during
natural malaria infections, most of these responses do not appear to affect
parasite survival or to result in the selection of new antigenic variants.
Nevertheless, some merozoite proteins may be good vaccine candidates. Of
particular interest is the major merozoite surface antigen MSP-1, which contains
a highly conserved carboxyl terminal region. Immunization with recombinant
DNA-derived carboxyl terminal peptides has been shown to confer significant
protection against malaria in rodents and has shown promising results in primate
trials with human malaria parasite strains. The resistance induced by MSP-1
vaccination appears to involve antibody-dependent mechanisms.

Transmission-blocking vaccines are being developed to act on stages of the

parasite life cycle that are found in mosquitoes. Such vaccines provide no
protection for an immunized individual but act to reduce the number of parasites
available for development in the mosquito vector. One such vaccine is an
antigen, Pfs25, that is located on the surface of zygotes and ookinetes and is
involved in parasite invasion of mosquito gut epithelium. In individuals
immunized against this parasite antigen, the antibodies that develop are
ingested by the mosquito during a blood meal and block the ability of the
parasite to infect and mature in the mosquito. These parasite stages are found
only in the mosquito vector and are not exposed to host immune responses.
Therefore, the antigens expressed in the mosquito do not undergo the high rates
of variation that are typical of immunodominant parasite antigens in the
vertebrate host.