SECTION THREE: Vaccines in development and new vaccine strategies
53
Malaria vaccines
Human malaria is caused by five species of the protozoan
Plasmodium: Plasmodium falciparum, Plasmodium vivax,
Plasmodium ovale, Plasmodium malariae, and Plasmodium
knowlesi. The life cycle and parasite-host interaction of each
species determines the severity and pathogenesis of clinical
disease.1,2 P. falciparum has the highest case fatality rate, espe-
cially in young children. The ability of P. vivax to develop
dormant intrahepatocytic hypnozoites results in clinical relapses
and has the greatest geographic distribution.3 Malaria occurs
where the environment supports competent Anopheles mos-
quito vectors with access to malaria-infected hosts.3,4 Until the
early 1900s, malaria was endemic across every continent except
Antarctica. Malaria was controlled in the United States, Europe,
and Australia by the 1950s using insecticides and environmen-
tal strategies.1 A multifaceted strategy including environmental
control, insecticides, bed nets, and chemotherapy has been
successful over the past decade, with some countries reporting
a dramatic fall in malaria incidence.5 Nevertheless, a safe and
effective vaccine remains an essential missing tool in the fight
to control and eventually eliminate malaria.
Background
All species of malaria have a complex life cycle that begins
in humans when the female Anopheles mosquito deposits
sporozoites subcutaneously during a blood meal. The sporo-
zoites enter the bloodstream and lymphatics and in minutes
to hours migrate to the liver and invade hepatocytes to form
schizonts. Within the intracellular environment, each schiz-
ont develops over 6 to 16 days to contain tens of thousands of
merozoites. The P. vivax hypnozoites may remain quiescent
in the liver for months to years before emerging into the cir-
culation. Once merozoites erupt from hepatocytic schizonts
and invade circulating red blood cells (RBCs), symptoms of
clinical disease become apparent. Over 24 to 48 hours, each
merozoite develops into 8 to 10 new merozoites that rupture
through the erythrocyte membrane and infect other RBCs.
Some parasites develop into sexual-stage gametocytes, which,
if taken up by an Anopheles during a blood meal, develop
into male or female gametes, undergo fertilization to form
ookinetes, and penetrate the gut epithelium to form oocysts.
Sporozoites develop during the next 2 to 3 weeks, emerge from
the oocysts, and localize to the salivary glands, where they
become infectious for humans.
Systemic signs and symptoms characteristic of malaria
include episodic fever, malaise, headache, photophobia, muscle
aches, anorexia, nausea, and vomiting.6 The signs and symp-
toms seem to coincide with the synchronized lysis of RBCs
W. Ripley Ballou
Joe Cohen
by erythrocytic schizonts releasing malarial toxins along with
new merozoites. Severe disease occurs most frequently with
P. falciparum because of its ability to multiply in infected eryth-
rocytes, leading to massive destruction of RBCs, and because
mature schizont-infected RBCs can cytoadhere and obstruct
capillary walls.2,6 Clinical sequelae (such as acute renal failure,
severe anemia, hypoglycemia, cerebral malaria, and pulmonary
edema) occur most commonly in populations that are relatively
immunonaïve, such as children and travelers.7 Pregnant women
and the developing fetus are at special risk for severe disease,
indicating a unique mechanism of pathogenesis.8 Coinfection
with HIV seems to predispose to more severe disease, especially
in children and malaria-naïve adults.9
Epidemiology and burden of disease
Quantification of the clinical burden of malaria is imprecise
and is impacted by variable access to diagnosis and treatment,
species prevalence, case definition, and, in many malaria-
endemic settings, low specificity of diagnosis.10,11 It is thought
that there are 170 to 300 million clinical cases per year glob-
ally, about 25% of which are caused by P. vivax. Estimates of
annual malaria-attributable deaths in 2009 varied from 0.7 to
1 million,12 with the majority of deaths occurring in children in
sub-Saharan Africa infected with P. falciparum. P. knowlesi was
recognized in 2008 by the World Health Organization (WHO)
as the fifth human Plasmodium species potentially leading to
fatal outcome.13 Tourism and economic development in south-
ern and Southeast Asia will likely lead to a further increase in
cases among locals and travelers.
The number of malaria cases diagnosed within the United
States has been stable at approximately 1,000 to 1,500 per year
for the past decade, with the vast majority of cases reported by
travelers and military personnel overseas. The United States
has a very small number of congenital, blood-transfusion, and
locally acquired cases.14 Cases of imported malaria in Europe
increased steadily for several decades, but the incidence has
been consistently falling since 2000.15
Vaccinology
Multiple lines of evidence suggest that a malaria vac-
cine for humans is feasible. Immunization of humans with
radiation-attenuated sporozoites confers sterile protection in
roughly 90% of naïve volunteers who are challenged within
12 months.16–18 Because this model requires each volunteer to
be bitten by approximately 1,000 irradiated, malaria-infected