Progress in the development of recombinant and synthetic blood-stage malaria vaccines
Malaria Vaccine Development Unit, NIAID, NIH, Twin Brook I, 5640 Fishers Lane, Rockville, MD 20852, USA
* Author for correspondence (e-mail: smahanty{at}niaid.nih.gov)
Accepted 7 August 2003
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Summary |
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Key words: malaria, vaccine, blood stage, recombinant antigen, Plasmodium falciparum, clinical trials, antigenic polymorphism
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Introduction |
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Successful vaccination against the malaria parasite entails overcoming
special hurdles, because the parasite can establish a chronic infection within
an immunocompetent host. Although repeated natural infections confer immunity
against severe disease, this immunity is normally species/strain specific,
dependent on continuous boosting by regular infections, and usually
short-lived. Thus the vaccine is required to generate `super-natural'
immunity. Additionally, different stages of the parasite express a different
repertoire of antigens, and many proteins of the parasite exhibit remarkable
polymorphisms. Host genetic determinants, for example, specific polymorphisms
in immune response genes (Hill,
1999; Troye-Blomberg,
2002
), may profoundly influence the immunity towards individual
antigens
Despite these challenges, there are several lines of evidence supporting
the feasibility of a vaccine: the age-related acquisition of immunity against
severe clinical malaria in endemic regions
(Bull et al., 1998;
Bull and Marsh, 2002
); the
ability of passively transferred antibodies from immune adults to protect
against natural and challenge infections with P. falciparum
(Bouharoun-Tayoun et al.,
1990
; Cohen et al.,
1961
; McGregor,
1964
); induction of protective immunity with defined antigens in
animal models (reviewed in Kumar et al.,
2002
); in experimental models, the ability of adoptive transfer of
B cells from immune donors into B cell-deficient mice to clear parasites
(von der Honarvar et al.,
1996
); and the demonstrated reduction of parasite density in the
only Phase 2b trial to date, that of a recombinant asexual blood-stage vaccine
(Genton et al., 2002
;
Saul et al., 1999
).
Blood-stage vaccines against Plasmodium falciparum are aimed at preventing complications of disease, such as cerebral malaria or anemia. Both P. falciparum and P. vivax can cause severe anemia, but only P. falciparum causes the many complications of cerebral malaria, hypoglycaemia, metabolic acidosis and respiratory distress. P. falciparum is responsible for the great majority of deaths and, for this reason, most effort has been devoted to P. falciparum vaccines. Therefore, we have limited this discussion to these vaccines.
Many strategies have been tested, including recombinant proteins, synthetic peptides, DNA with or without prime-boost strategies, and progress made in some of these areas are reviewed in other articles in this issue. In this review we focus on progress made in the development of P. falciparum blood-stage antigens in the form of recombinant or synthetic protein vaccines.
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Immunology and pathogenesis of the asexual blood stages of P. falciparum |
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The location of these receptors within organelles provides some protection
to the parasite from antibody-mediated neutralization, since exposure to
antibody occurs only between release from one RBC and invasion of another.
This provides a short window of opportunity for antibodies to bind and
neutralize merozoites. Once inside RBC, some parasite molecules make their way
to the RBC surface, while others remain in membranous vacuoles within the cell
(Miller et al., 2002). Since
the RBC lacks Class I and Class II major histocompatibility complex (MHC)
antigens, the blood-stage parasites are also protected from effector T-cell
responses, which are dependent on Class I and II antigen-presentation
pathways. Only after rupture of the RBC at the ring stage are the antigens
internal to the parasite directly exposed to antibodies.
Immunity against blood-stage antigens is thought to involve both antibodies
and T cells although, in humans, better evidence exists for antibody-mediated
immunity (Good et al., 1998).
Epidemiological studies in malaria-endemic regions support the notion that
antibody responses to blood-stage parasites contribute to naturally acquired
immunity. Sera from humans living in hyperendemic regions contain antibodies
that prevent red cell invasion by targeting antigens on merozoites
(Bull and Marsh, 2002
). Direct
evidence for a protective function of antibodies comes from passive transfer
of purified immunoglobulins from `naturally immune' individuals into partially
immune children, which was found to produce rapid clearance of parasites in
recipient children even when the antibodies did not block growth in
vitro (McGregor, 1964
).
These sera undoubtedly contained high levels of antibodies against the variant
RBC surface antigen, PfEMP1, which would not kill in vitro, but would
prevent sequestration of mature parasites in vivo, resulting in their
splenic destruction. These results are consistent with the observed effects of
anti-PfEMP1 antibodies induced in Aotus monkeys challenged with
P. falciparum (Baruch et al.,
1996
). In humans, sera from immune individuals have high titers of
antibodies against erythrocyte membrane protein 1 (PfEMP1) in addition to
other surface and internal merozoite antigens, so investigators have
speculated that PfEMP1 is a target for antibody-mediated immunity
(Miller et al., 2002
).
Different domains of this erythrocyte surface-expressed antigen mediate
cytoadherence of parasitized RBC through interactions with specific receptors,
for example, CD36 (on endothelial cell surfaces) and chondroitin sulfate A (on
placental syncytiotrophoblasts) (Miller et
al., 2002
). PfEMP1 is encoded by the large and diverse
var gene family, which plays a key role in clonal antigenic
variation. Immune pressure results quickly in the emergence of parasites
expressing different variant genes. However, recent studies indicate that some
functional domains of the molecule may induce a degree of cross-variant
immunity (Baruch et al.,
1997
).
In addition to the direct effect of human antibody on parasites, in
vitro incubation of infected erythrocytes with IgG from immune human
donors and monocytes from a naïve donor kills the parasite within the
RBC. This antibody-dependent cellular inhibition (ADCI) associated killing of
the parasite is mediated by transferable soluble factors in macrophage
supernatants (Bouharoun-Tayoun et al.,
1995). Cytophilic antibodies to merozoite antigens have been
implicated in vitro in assays with human macrophages and in
vivo in SCID mice (Badell et al.,
2000
). ADCI may provide an alternative or complementary strategy
for antibody-mediated parasite clearance following vaccination.
Independent of antibody, T-cell lines and clones can adoptively transfer
protection, suggesting that CD4 T cells can control blood-stage parasites
(Amante and Good, 1997;
Brake et al., 1988
). Studies
in animal models have also implicated T-cell-mediated (or
antibody-independent) mechanisms in immunity against blood-stage malaria
parasites (for a review, see Wipasa et
al., 2002
). These studies have shown that clones
(Brake et al., 1988
) and
polyclonal populations of T cells (Amante
and Good, 1997
) can adoptively transfer protection, apparently in
the absence antibodies, suggesting that CD4 T cells can control blood-stage
parasites. Speculation continues about the mechanisms underlying the CD4
T-cell-mediated control of parasites. Cytokines and other direct effector
mechanisms like nitric oxide and
T cells have been implicated
in parasite clearance by a number of studies
(Hirunpetcharat et al., 1999
;
Seixas et al., 2002
). However,
conclusions from rodent studies should be extended to human malaria
cautiously, because there are clear differences in the relative importance of
antibodies and T-cell effector function for parasite clearance between
different rodent malaria species and hosts. While most of the evidence for
involvement of T cells has come from murine studies, recent data from humans
showing that repeated low grade infection induces sterile immunity in the
absence of detectable antibodies suggests that T-cell-mediated protection also
operates in humans (Pombo et al.,
2002
).
Recent investigations have yielded new insights into the role of T cells
and innate immunity in clearance of blood-stage parasites
(Perlmann and Troye-Blomberg,
2002). Evidence comes from experiments demonstrating that
infection with some parasite species in rodents can lead to anergy and
apoptosis of parasite-specific CD4 T cells (but not cells of other
specificities) (Xu et al.,
2002
). This could be an additional parasite strategy to inhibit
host immunity. Other mechanisms of immune impairment by the malaria parasite
have also been described, such as inhibition of dendritic cell maturation and
activation by the parasite (Urban et al.,
2001
).
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Vaccine candidates currently under development |
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Among the recombinant blood-stage antigens that have been proposed for
development as candidate vaccines, the leading asexual (erythrocyte) stage
antigens, merozoite surface protein 1 and apical membrane antigen 1 (AMA1) are
expressed in all species of Plasmodium, with homologues in rodent and
simian parasites, thus making it possible to test these vaccines in animal
models, although the models are often imperfect representations of human
infections (Anders and Saul,
2000). Several other candidate antigens that are expressed during
the erythrocytic stage of P. falciparum have also been tested in
animal models (rodent or non-human primates challenged after immunization with
asexual blood-stage parasites) and a number of these are at various stages of
development as vaccine antigens, either alone or as components of
multi-antigen vaccines (Table
1).
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Clinical trials of recombinant vaccines against asexual blood-stage malaria |
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A phase I trial of a vaccine based on MSP119 (FVO and 3D7
strains of P. falciparum) fused to CD4 T-cell epitopes from tetanus
toxoid concluded that the vaccines were immunogenic but had a sufficiently
high rate of adverse reactions to warrant alternative formulations
(Keitel et al., 1999).
MSP142 formulated in ASO2 went into phase I trials in the US and
Kenya (Heppner et al., 2001
;
Lee et al., 2002
;
Stoute et al., 1998
) and
E. coli-produced MSP142 and RTS,S combined with
MSP142, in the United States
(Gordon et al., 1995
). Other
phase I and II trials are planned for vaccines based on the C terminus of
MSP1. An AMA1 vaccine comprising two allelic forms (clones 3D7 and FVO) is in
phase I testing. A chimeric molecule that includes MSP119 and AMA1
is likely to be tested soon in China (reviewed in
Genton and Corradin, 2002
).
Thus, it is likely that several recombinant blood-stage vaccines will undergo
safety and immunogenicity studies in malaria-endemic regions within the next
year.
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Challenges for the development of recombinant blood-stage vaccines |
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Formulations and immunogenicity of malaria vaccines
The short time of exposure of the merozoites to antibodies between release
from one infected RBC and attachment/entry into another means that very high
antibody levels are necessary to block entry
(Saul, 1987), levels that may
not be achieved with alum. Therefore, considerable effort is being devoted to
the testing and development of new adjuvants for asexual blood-stage antigens
(Daly and Long, 1996
;
Hui and Hashimoto, 1998
). The
adjuvant formulation has two functions: enhancing the delivery of antigens to
the immune system, e.g. by generating a depot of antigen and direct
antigen-independent stimulation, often through pattern-recognition receptors,
such as Toll receptors (Cox and Coulter,
1997
).
Substances that have been used as adjuvants include aluminium salts,
water-in-oil emulsions, oil-in-water emulsions, immune-stimulating complexes
(ISCOMs), liposomes, saponin, bacterial toxins and recombinant cytokines.
However, there is considerable variability in the immune-enhancing effects of
a given adjuvant, depending on the antigen and experimental model. Thus, it is
difficult to predict the efficacy of an adjuvant in humans based on
experimental animal models. Furthermore, the incidence of severe or serious
adverse reactions to an adjuvant is unpredictable - often the most immunogenic
adjuvants are also the most reactogenic, limiting the choice of acceptable
antigen-adjuvant combinations (Daly and
Long, 1996; Gordon,
1993
). Ideally, therefore, many combinations should be tested in
human phase I trials. The choice of adjuvants available for use in humans
include alum, MF59, Montanide ISA720, Montanide ISA51 in combination with MPL,
QS21 and CpG as immunostimulators. However, the only adjuvants with a track
record in humans are alum and MF59. ASO2 that was used in the RTS,S vaccine
(Bojang et al., 2001
), an
MF59-like oil-in-water adjuvant containing MPL and QS21, is also being used
with MSP1.
There is a dire need for a single-platform formulation, usable with a number of antigens, because the immunogenicity of each antigen in humans is strongly influenced by the formulation used. However, when an antigen formulated with a new adjuvant goes to field trials, a difficult choice often has to be made between enhanced immunogenicity and the risk of late adverse reactions, because the late appearance of serious reactions can stop a promising vaccine program. The identification of appropriate formulations with low risks of adverse reactions, important as it is now, will become vitally important when multiple antigens are deployed in multistage combination vaccines.
Antigenic polymorphism and development of vaccines
An attractive approach in dealing with the problem of antigenic variation
is to include multiple antigens in the vaccine. Multivalency in the design of
blood-stage vaccines offers several advantages. First, each antigen may induce
protection independent of the others included in the vaccine. The additive
effect of the immunity induced by each component may result in substantial
immunity, even if each antigen is insufficient on its own. Second, mixtures of
antigens will help induce immunity in genetically heterogeneous populations
(e.g. because of polymorphisms in HLA, or other genetic traits); this is
particularly true for genetically restricted T-cell responses. Third,
combining antigens may facilitate the development of a single vaccine that
protects against more than one species of malaria. Additionally, the emergence
of parasites that escape vaccine-induced immunity is much less likely with a
multivalent vaccine than with a single-component vaccine. However, mixtures of
antigen carry the risk of interference between antigens. Mixtures may also
increase the likelihood of local reactogenicity, which may increase as the
amount of antigen in the vaccine increases.
ADCI may provide a means of generating cross-strain protection, since
macrophages activated by the antibodies to one variant may be able to kill
parasites in RBC infected by other strains or variants, thus providing
density-dependent control of mixed infections, provided the key antigens from
at least one isolate in the mixture are recognized by the appropriate
antibody. Additionally, since the concentration of IgG required for ADCI may
be lower than those needed for blockade of merozoite invasion, this mechanism
of parasite inhibition may still be useful for antigens that are not highly
immunogenic. Merozoite antigens that have been demonstrated to have ADCI
activity include MSP3 (Oeuvray et al.,
1994b), SERA (Aoki et al.,
2002
) and GLURP (Theisen et
al., 2001
). Since ADCI, once initiated, appears not to be strictly
dependent on continuing antigen-antibody interactions, parasite killing
via ADCI can continue after merozoite invasion and entry into the
RBC, and is not restricted to a small time-window in the same manner as direct
antibody-mediated blockade of invasion. The exploitation of ADCI-mediated
clearance of the parasite may be a useful strategy for vaccines against blood
stages.
Antibody-independent mechanisms may also be useful for blood-stage
vaccines. Rodent studies showed that CD4 T cells can control parasite growth
in an antibody-independent manner
(Hirunpetcharat et al., 1999;
Weidanz et al., 1988
), and
human T cells demonstrate parasite growth inhibition in vitro by
production of nitric oxide and other small reactive molecules
(Good and Doolan, 1999
). In
humans, repeated infections with low doses of blood-stage parasites followed
by drug cure resulted in resistance to re-challenge, despite the lack of
development of antibodies against the parasite or RBC surface
(Pombo et al., 2002
). This
suggests that T cells may also play a role in resistance against malaria in
humans, as has been observed in mouse malaria with P.
chaubaudi/P. vinckei
(Hirunpetcharat et al., 1999
;
Xu et al., 2002
). However,
there are practical hurdles to cross before vaccines relying on T-cell
mechanisms can be developed. For example, selection of epitopes is not
straightforward since animal models may lack the correct T-cell host
specificities. Furthermore, the T-cell responses generated in the mouse models
are proinflammatory, often leading to death of the mice from immunopathology,
and this needs to be resolved before human trials could commence.
The need for more clinical trials
The large number of blood-stage antigens identified for development and the
timely selection of antigens for multicomponent vaccines requires testing of
multiple formulations in phase I and phase II trials. Since the first
multicomponent vaccine with a blood-stage antigen, SPf66
(Patarroyo et al., 1988), 13
more human phase II trials have been published, 11 using SPf66
(Greenwood and Alonso, 2002
).
The numbers of human clinical trials ongoing at present are too few to allow
rapid progress in the selection of the best antigens. The capacity for testing
vaccines in endemic regions is being expanded by efforts such as the
development of the African Malaria Vaccine Testing Network/African Malaria
Network and programs for training African scientists in clinical trials.
However, progress will become limited by resources, and several fundamental
issues pertinent to clinical trials remain unresolved. These include
identification of clinical and laboratory measures of malaria-specific
morbidity and of clinical protection, the need for better infrastructure to
conduct these studies, and the necessity of large study populations (thousands
of subjects in phase III trials) when assessing the impact of these vaccines
on population-level morbidity and mortality
(Kwiatkowski and Marsh, 1997
).
Factorial and clustered designs may help in reducing the operational
difficulties of large study groups and thereby aid the feasibility of clinical
trials (Greenwood and Alonso,
2002
), but the continuing investment of national and international
funding agencies will be critical for the malaria research community to
overcome these challenges.
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