REVIEW
© 2008 Nature Publishing Group http://www.nature.com/natureimmunology
Immunity to malaria: more questions than
answers
Jean Langhorne1, Francis M Ndungu1, Anne-Marit Sponaas1 & Kevin Marsh2
Malaria is one of the main health problems facing developing countries today. At present, preventative and treatment strategies
are continuously hampered by the issues of the ever-emerging parasite resistance to newly introduced drugs, considerable costs
and logistical problems. The main hope for changing this situation would be the development of effective malaria vaccines.
An important part of this process is understanding the mechanisms of naturally acquired immunity to malaria. This review will
highlight key aspects of immunity to malaria, about which surprisingly little is known and which will prove critical in the search
for effective malaria vaccines.
Malaria, caused by infection with protozoan parasites of the genus important body of literature was generated by the use of induced
Plasmodium, is a major global heath problem and is responsible for malaria in the treatment of neurosyphilis in the early twentieth cen-
the deaths of over a million people annually, mainly children in sub- tury. Those studies have informed the paradigm of how humans
Saharan Africa1. There has been an understandable push to develop respond to malaria, and re-analysis of the data has provided new
effective antimalaria vaccines. However, it has not been matched by insights into the immune response3. At present, induced malaria
a similar level of investment in understanding basic aspects of the in volunteers forms an important aspect of testing of some malaria
immune response to this parasite. vaccines and offers the opportunity of detailed studies of possible
In this review we highlight key aspects of acquired immunity in protective mechanisms4.
humans and critically review work, particularly in mouse models, on After an infected mosquito bites through the skin, sporozoites
two main issues: what is the function of the immune response in patho- rapidly move from the dermis to the liver, where they go through
genesis, and why is immunity apparently short-lived. Understanding an asymptomatic stage of rapid division before the parasite reenters
these aspects may allow the delineation of pathological versus protec- the bloodstream (Fig. 1a). In the blood, exponential expansion of
tive responses and determine the nature of long-term immunity and parasite populations leads to febrile illness. Typically, acute infection
thus provide more effective immunological interventions. is controlled and chronic infection is established at reasonably low
parasite density, with intermittent episodes of fever associated with
Immunity to malaria in humans peaks of higher parasitemia5. Such peaks are of progressively lower
Humans with no previous experience of malaria almost invariably density until the infection is eliminated, usually after many months.
become ill on their first exposure to the parasite. They develop a febrile There is relatively rapid acquisition of immunity to the homologous
illness, which may become severe and, in a proportion of cases, may parasite, demonstrated as more rapid control of successive infections
lead to death. In malaria-endemic areas, young children are particularly at lower parasite densities and less-severe or even absent clinical ill-
susceptible, and it has been estimated that a quarter of all childhood ness. Although less profound in terms of parasitological indices, there
deaths are due to malaria2. However, with exposure, older children is also evidence of early acquisition of heterologous immunity, par-
and adults develop essentially complete protection from severe ill- ticularly in terms of clinical symptoms6.
ness and death, although sterile immunity is probably never achieved. Immunity to malaria in an endemic area is seen as both lower
Although vaccines may not be limited to mimicking natural immunity, prevalence of ‘parasitization’ with age and lower rates of disease
as clear a picture as possible of the mechanisms of such immunity is (Fig. 1b). However, the timing of changes in the rates of parasitiza-
an important starting point. tion, mild disease and severe disease are different. Although it could
The picture of human immunity to malaria has been provided be argued that these all reflect the same underlying process, immunity
by two main sources: deliberately induced malaria in nonimmune to severe malaria is essentially fully established at a time when there
people, and natural history studies in endemic populations. An are no changes in the rates of mild febrile disease and when parasite
rates in the population are still increasing, which suggests that there
1Division of Parasitology, National Institute for Medical Research, London NW7 may be distinct mechanisms underlying these different expressions
1AA, UK. 2Kenya Medical Research Institute–Wellcome Trust Collaborative of immunity. The picture that emerges from human studies is that
Project, Kilifi, Kenya. immunity to malaria infection is relatively slow to develop and incom-
Correspondence should be addressed to J.L. (email: jlangho@nimr.mrc.ac.uk). plete, although immunity to death is acquired more quickly and may
Published online 18 June 2008; doi:10.1038/ni.f.205 be important after a single episode7.
NATURE IMMUNOLOGY VOLUME 9 NUMBER 7 JULY 2008 725
, REVIEW
a Human malaria Rodent malaria
Figure 1 The life cycle of the malaria parasite Plasmodium
P. falciparum P. yoelii falciparum and acquisition of immunity in an area of endemic
P. vivax P. berghei transmission. (a) Possible immune mechanisms at various stages
P. ovale P. chabaudi of the plasmodium life cycle in the mammalian host. Top left and
P. malariae P. vinckei
right, various plasmodia that infect humans and experimental
Antibody rodent models. Sporozoites are injected through the dermis
CD4+ T cells
γδ-T cells
by a female anopheles mosquito, enter the bloodstream (pink
Antibody
Macrophages shaded area, left) and migrate to the liver, then enter hepatocytes
ROI-NO (brown shaded area) and undergo an amplification phase lasting
between 2 and 9 days. Merozoites released after rupture of the
infected hepatocyte invade RBCs and initiate the asexual cycle
© 2008 Nature Publishing Group http://www.nature.com/natureimmunology
in RBCs (pink shaded area, right); each cycle of invasion and
replication is between approximately 24 and 72 hours, depending
on the species of plasmodium. Sexual stages (male and female
gametocytes) are formed during the erythrocytic cycle; this stage
CD8+ T cells continues the life cycle in the mosquito after a blood meal.
(CD4+ T cells) Parasite stages in the liver are clinically silent. Fever and severe
NK cells malaria are associated with the parasite cycle in the blood, as
NKT cells
γδ-T cells well as adherence of infected RBCs to blood vessel endothelium
Fever
Antibody Cerebal malaria and to each other (rosetting; inset in gray). Numbers indicate
Respiratory distress effector mechanisms thought to be effective against plasmodium
Amemia
in the mammalian host and in blocking transmission to the
b Hypoglycemia
mosquito: 1, antibodies to sporozoites neutralize sporozoites
and/or block invasion of hepatocytes; 2, IFN-γ and CD8+ T cells
(CD4+ dependent), natural killer (NK) cells, natural killer T
(NKT) and γδ T cells kill intrahepatic parasites; 3, antibodies to
merozoites opsonize merozoites for uptake and/or inhibit invasion
of RBCs; 4, antibodies to infected RBCs surface opsonize infected
100
Severe malaria RBCs for phagocytosis and/or block the adhesion of infected
Mild malaria
RBCs to endothelium; TNF and IFN-γ activate macrophages to
90
phagocytose and/or kill infected RBCs and merozoites; antibodies
Asymptomatic infection
80 to glycosylphosphatidylinositol neutralize parasite toxins and
Percent of maximum
70
prevent the induction of excessive inflammation; 5, antibodies
to infected RBCs prevent the sequestration of gametocytes,
60 which prevents the sequestration and maturation of gametocytes;
50
and 6, antibody and complement taken up in the blood meal
mediate the lysis of gametocytes and prevent fertilization and
40
further development of the parasite in the mosquito. ROI, reactive
30 oxygen intermediate; NO, nitrous oxide. (b) Population indices
of immunity in an endemic area of P. falciparum transmission
20
(adapted from ref. 96). Change over time of various indices of
10 malaria in a population living in an endemic area of P. falciparum
transmission: asymptomatic infection (pink), mild disease (febrile
0
0 10 20 30 40 50 episodes caused by malaria; blue) and severe or life-threatening
Age (years)
disease (green). The data are normalized and are presented as the
percent of maximum cases for each population index.
Mechanisms of immunity key in blood-stage immunity. In mouse models, B cells and antibodies
Immune attack could theoretically be directed at any point in the life are important in eliminating parasites13, with some contribution from
cycle from the time of entry of the sporozoite (Fig. 1a). However, longi- ‘parasiticidal’ mediators released from macrophages or similar cells
tudinal studies in exposed populations suggest that immune responses of the innate system and probably activated by T cells14. Most infor-
to the pre-erythrocytic stages probably have limited involvement8. mation on the function of human immune responses to blood-stage
Certainly when the liver stage is bypassed by direct injection of blood- parasites has been provided by longitudinal studies in endemic popula-
stage parasites, immune adults are still able to limit parasite popula- tions, supported by classical passive-transfer experiments15,16.
tion expansion and avoid symptoms9. This is in contrast to deliberate The mechanisms by which antibody is effective include blockade
immunization with either whole irradiated sporozoites10 or vaccines of the invasion of RBCs by merozoites17, antibody-dependent cellular
based on pre-erythrocytic antigens, which can induce considerable killing mediated by cytophilic antibodies18 and binding of antibody
immunity and indeed form the basis of the most advanced malaria to parasite-induced molecules on the RBC surface, leading to greater
vaccine available at present11. The mechanism by which these vac- clearance of infected RBCs19. However, the relative importance of each
cines may act is indicated by studies in mice in which elimination of of these mechanisms is still a matter of debate. Some human studies
pre-erythrocytic parasites requires mainly CD8+ effector cells produc- point to an important function for antibody-dependent cellular kill-
ing interferon-γ (IFN-γ) that kill parasites in infected hepatocytes12. ing20, and work with mice expressing a human Fcγ receptor (FcγR)
Antibodies to the sporozoites are thought to have a lesser function. supports this view21. However, the few studies of mouse models lacking
For erythrocytic stages, potential targets for an immune response are FcγR or complement suggest that parasite can be eliminated with-
free merozoites or intraerythrocytic parasites. Given that HLA class I or out opsonization22,23. Perhaps the ‘take-home’ message is that there
II molecules are absent from the surface of the parasite or the infected is no single measure of a protective antibody response for a complex
red blood cell (RBC), it is usually assumed that humoral responses are pathogen.
726 VOLUME 9 NUMBER 7 JULY 2008 NATURE IMMUNOLOGY
