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Current Molecular Medicine
ISSN: 1566-5240
Current Molecular Medicine
Volume 6, Number 2, March 2006
Contents
Fighting Malaria in the 21st Century
Executive Editor: Pedro L. Alonso
Editorial Pp. 135
Malaria: Burden of Disease Pp. 137-140
C. Guinovart, M.M. Navia, M. Tanner and P.L. Alonso
[Abstract]
Severe Malaria: Metabolic Complications
Pp. 141-153
T. Planche and S. Krishna
[Abstract]
Severe Malarial Anaemia Pp. 155-168
C. Casals-Pascual, D.J. Weatherall, and D.J. Roberts
[Abstract]
Immune Response to Pre-Erythrocytic Stages of
Malaria Parasites Pp. 169-185
D.L. Doolan and N. Martinez-Alier
[Abstract]
Immune Responses to Asexual Blood-Stages of Malaria Parasites
Pp. 187-203
S.S. Yazdani, P. Mukherjee, V.S. Chauhan and C.E.
Chitnis
[Abstract]
Clinical Immunity to Malaria Pp. 205-221
L. Schofield and I. Mueller
[Abstract]
Sexual-Stage Antibody Responses to P. falciparum
in Endemic Populations Pp. 223-229
J.T. Bousema, C.J. Drakeley and R.W. Sauerwein
[Abstract]
Malaria Vaccine Development: Progress and Challenges
Pp. 231-245
Z.H. Reed, M. Friede and M.P. Kieny
[Abstract]
Malarial Parasites vs. Antimalarials: Never-Ending
Rumble in the Jungle Pp. 247-251
B. Mordmüller and P.G. Kremsner
[Abstract]
Current Issues for Anti-Malarial Drugs to Control
P. falciparum Malaria Pp. 253-260
D. Schellenberg, S. Abdulla and C. Roper
[Abstract]
Prevention of Malaria Using ITNs: Potential for Achieving
the Millenium Development Goals Pp. 261-267
F. Binka and P. Akweongo
[Abstract]
Malaria During Pregnancy Pp. 269-273
C. Menendez
[Abstract]
Abstracts
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Editorial
The global malaria situation is a desperate one, and in some
circumstances becoming worse, particularly in sub-Saharan
Africa. The reasons for this are multiple and run the gamut
from the emergence of widespread resistance to available,
affordable, and once highly effective drugs; the breakdown
and inadequacy of health systems; and the lack of financial,
human, and institutional resources for anti-malaria efforts.
Controlling malaria is essential to global efforts to reduce
poverty, minimize childhood mortality, and strengthen the
most vulnerable societies. Despite many words of commitment,
the world is failing to meet this challenge.
The realization that world malaria eradication was beyond
reach, off at the time available tools and logistic and technical
capacities, led to the era of control and to a certain skepticism
and abandonment of energies and momentum. Over two decades,
malaria control programmes were abandoned throughout much
of sub-Saharan Africa, leading to a massive resurgence of
the disease. Since that time, global and regional groupings
of political leaders and health ministers have repeatedly
called for greater action against malaria, and new institutions
have been created to strengthen malaria control efforts, such
as the Roll Back Malaria initiative and the Global Fund to
Fight AIDS, Tuberculosis and Malaria (GFATM) (WHO 2000).
But 100 years beyond Laveran described plasmodium species
and Ross confirmed that they were transmitted by female anopheline
mosquitoes, malaria remains not only a leading cause of morbidity
and mortality worldwide but also a scientific challenge. Although
the areas where transmission takes place have reduced, and
they are by now confined to the inter tropical areas, the
number of people living at risk has grown to about 3 billion,
and is expected to go on increasing.
This issue highlights the emerging scientific opportunities
to improve our understanding and help us create new tools
for the future control of malaria. Hopes for such new tools
emerge from vast new data and information about the genomes
of the three organisms that interact in an ancient and intricate
dance to produce malaria – the human, the parasite and
the mosquito vector. Together with modern immunonology and
molecular biology we should better understand the pathophysiology
of this interaction and the acquisition of immunity.
The challenge of malaria is for the multiple sectors and
communities that must be involved to move beyond targets and
calls for action by designing programs that best impact malaria
now; by mobilizing more resources while, at the same time,
assuring that programmatic and intervention options that are
better suited to the realities of inadequate resources evolve.
That requires a difficult balance between passion and practicality.
The world needs to raise new resources, while the public health
community finds better ways to assure that, whatever resources
are available, have their maximal impact. We need to deploy
current tools while we also invest in the creation of new
tools whose effectiveness, affordability and delivery are
designed to deal with resource and structural inadequacies
that, while we may strive to have them go away, won’t,
at least in the near term. In short, the scientific and public
health communities must work with developing countries and
donors, within the current inadequacies of both available
interventions and available resources to act now while improving
both the tools and the resources. In doing all of this, we
must also remain humble and retain the lessons of the past
that leave little space for content:
“The history of special antimalarial campaigns
is chiefly a record of exaggerated expectations followed sooner
or later by disappointment and abandonment of the work. This
record of failures and disappointed hopes makes it clear that
the only prospect of real progress lies in renewed activity
in the continuous study of the disease in all its aspects”.
Malaria Commission (1927) Principles and Methods of Antimalarial
Measures in Europe. 2nd General Report of the Malaria Commission
of the League of Nations, Geneva.
This same Commission insisted: “that the fight against
malaria must be waged not as a separate and isolated task
but as part of a general social, economic and sanitary campaign
by an enlightened public health service and to secure continuity
of action and unity of purpose”.
League of Nations: Second General Report of the Malaria Commission
(1927).
With new tools, improved financing mechanisms, political
support and improved understanding of the parasite and its
relation with the human host, the world has a unique opportunity
to improve the unacceptable global burden of malaria.
Pedro L. Alonso
Centre de Salut Internacional
Hospital Clínic/IDIBAPS/Universitat de Barcelona
Barcelona
Spain
E-mail: palonso@clinic.ub.es
[Back to top]
Malaria: Burden of Disease
C. Guinovart, M.M. Navia, M. Tanner and P.L. Alonso
Despite more than 100 years since Laveran described plasmodium
species and Ross confirmed that they were transmitted by female
anopheline mosquitoes, malaria remains a leading cause of
morbidity and mortality worldwide. Although the areas where
transmission takes place have reduced, and they are by now
confined to the inter tropical areas, the number of people
living at risk has grown to about 3 billion, and is expected
to go on increasing. Not only does malaria cause around 500
million cases every year, and between 1 and 3 million deaths,
but it also carries a huge burden that impairs the economic
and social development of large parts of the planet. The failed
attempt to eradicate malaria gave way to the control policy
that was followed by a huge resurgence of malaria during the
late 70s and 80s. Together with the emergence and spread of
resistance to chloroquine and the weak health infrastructure
in many of the endemic countries, particularly in Africa,
the malaria situation worsened worldwide. The last decade
of the 20th century was witness to the international
community becoming increasingly aware of the unacceptable
situation that the burden of malaria represented to large
parts of the world. Renewed efforts to describe the problem,
design and evaluate new control strategies, design and develop
new drugs, better understand the biology of the parasite and
the immunity it induces in the human host, develop candidate
vaccines, together with new financial support constitute renewed
hope that may lead to new trends in global health.
[Back to top]
Severe Malaria: Metabolic Complications
T. Planche and S. Krishna
Metabolic complications of severe malaria are some of the
most important and potentially treatable manifestations of
this deadly disease. The commonest metabolic complications
(lactic acidosis and hypoglycaemia) arise from increased host
anaerobic metabolism probably due to a mismatch between tissue
oxygen supply and requirement. Optimising treatments for these
complications should be guided by detailed understanding of
their underlying pathophysiology, and may help to reduce the
intolerably high case fatality rate of severe malaria.
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Severe Malarial Anaemia
C. Casals-Pascual, D.J. Weatherall, and D.J. Roberts
This review describes the importance of severe malarial anaemia
as a public health problem, and the clinical and pathophysiological
aspects of this syndrome. The review also highlights the recent
advances in our understanding of the epidemiological, clinical,
cellular and molecular aspects of severe malarial anaemia.
[Back to top]
Immune Response to Pre-Erythrocytic Stages of Malaria
Parasites
D.L. Doolan and N. Martinez-Alier
Immunization with radiation-attenuated Plasmodium
spp. sporozoites induces sterile protective immunity against
parasite challenge. This immunity is targeted primarily against
the intrahepatic parasite and appears to be sustained long
term even in the absence of sporozoite exposure. It is mediated
by multifactorial mechanisms, including T cells directed against
parasite antigens expressed in the liver stage of the parasite
life cycle and antibodies directed against sporozoite surface
proteins. In rodent models, CD8+ T cells have been
implicated as the principal effector cells, and IFN-γ
as a critical effector molecule. IL-4 secreting CD4+
T cells are required for induction of the CD8v T cell responses,
and Th1 CD4+ T cells provide help for optimal CD8+
T cell effector activity. Components of the innate immune
system, including gamma-delta T cells, natural killer cells
and natural killer T cells, also play a role. The precise
nature of pre-erythrocytic stage immunity in humans, including
the contribution of these immune responses to the age-dependent
immunity naturally acquired by residents of malaria endemic
areas, is still poorly defined. The importance of immune effector
targets at the pre-erythrocytic stage of the parasite life
cycle is highlighted by the fact that infection-blocking immunity
in humans rarely, if ever, occurs under natural conditions.
Herein, we review our current understanding of the molecular
and cellular aspects of pre-erythrocytic stage immunity.
[Back to top]
Immune Responses to Asexual Blood-Stages of Malaria Parasites
S.S. Yazdani, P. Mukherjee, V.S. Chauhan and C.E.
Chitnis
The blood stage of the malaria parasite’s life cycle
is responsible for all the clinical symptoms of malaria. The
development of clinical disease is dependent on the interplay
of the infecting parasite with the immune status and genetic
background of the host. Following repeated exposure to malaria
parasites, individuals residing in endemic areas develop immunity.
Naturally acquired immunity provides protection against clinical
disease, especially severe malaria and death from malaria,
although sterilizing immunity is never achieved. Given the
absence of antigen processing in erythrocytes, immunity to
blood stage malaria parasites is primarily conferred by humoral
immune responses. Cellular and innate immune responses play
a role in controlling parasite growth but may also contribute
to malaria pathology. Here, we analyze the natural humoral
immune responses acquired by individuals residing in P.
falciparum endemic areas and review their role in providing
protection against malaria. In addition, we review the dual
potential of cellular and innate immune responses to control
parasite multiplication and promote pathology.
[Back to top]
Clinical Immunity to Malaria
L. Schofield and I. Mueller
Under appropriate conditions of transmission intensity, functional
immunity to malaria appears to be acquired in distinct stages.
The first phase reduces the likelihood of severe or fatal
disease; the second phase limits the clinical impact of ‘mild’
malaria; and the third provides partial but incomplete protection
against pathogen burden [1, 2]. These findings suggest clinical
immunity to mortality and morbidity is acquired earlier, with
greater ease, and via distinct mechanisms as compared to anti-parasite
immunity, which is more difficult to achieve, takes longer
and is only ever partially efficacious. The implications of
this view are significant in that current vaccination strategies
aim predominantly to achieve anti-parasite immunity, although
imparting clinical immunity is the public health objective.
Despite enormous relevance for global public health, the mechanisms
governing these processes remain obscure. Four candidate mechanisms
might mediate clinical immunity, namely immunity to cytoadherence
determinants, tolerance to toxins, acquired immunity to toxins,
and immunoregulation. This review addresses the targets and
determinants of clinical immunity, and considers the implications
for vaccine development.
[Back to top]
Sexual-Stage Antibody Responses to P. falciparum
in Endemic Populations
J.T. Bousema, C.J. Drakeley and R.W. Sauerwein
Gametocytes and sporogonic stages are responsible for the
spread of disease and drug resistance in the population. Sexual
stage immunity affects the infectiousness of gametocytes to
mosquitoes. Specific antibodies including anti-Pfs48/45 and
anti-Pfs230 antibodies are found in individuals with limited
prior exposure to malaria. Sexual stage antibodies are rapidly
acquired after infection and are relatively prevalent in gametocytaemic
individuals. Functional transmission reducing activity (TRA)
is found after primary infections and in young children and
appears to depend on recent rather than cumulative exposure
to gametocytes. Exposure to gametocytes decreases with age
most likely as a consequence of the acquisition of asexual-stage
immunity that controls asexual parasite density and consequently
gametocytaemia. This results in lower exposure to the antigenic
load of gametocytes in semi-immune individuals. Since sexual
stage immunity is probably short-lived in the absence of gametocytes,
we hypothesize that sexual stage immunity will wane, resulting
in low antibody and TRA prevalences in clinically semi-immune
carriers.
[Back to top]
Malaria Vaccine Development: Progress and Challenges
Z.H. Reed, M. Friede and M.P. Kieny
A safe and effective malaria vaccine would contribute greatly
to the control and prevention of the disease. Although a review
of global activity in malaria vaccine development does reflect
significant activity, progress has remained slow. This article
discusses the current vaccine candidates, with emphasis on
those in the clinic, and explains the numerous challenges
to making and evaluating malaria vaccines, which have resulted
in only a few approaches being adopted and repeatedly evaluated.
Against a parasite with more than 5200 genes, the lack of
definitive knowledge regarding the nature of protective immunity
and absence of reliable surrogates of protection are among
the key challenges to a rational evaluation and prioritization
of candidate vaccines. Pursuing the current R&D strategies
may not result in the availability of a vaccine with characteristics
suitable to impact significantly on disease morbidity in developing
countries. Therefore, it is critical that the main challenges
to malaria vaccine development be unambiguously identified
and collectively addressed.
[Back to top]
Malarial Parasites vs. Antimalarials: Never-Ending
Rumble in the Jungle
B. Mordmüller and P.G. Kremsner
Development of resistance is an increasing problem for antimalarial
chemotherapy because resistance against most available drugs
has developed in the majority of world-wide parasite populations.
Therefore, several strategies to counteract resistance-development
are in place. From the pharmaceutical side, identification
of new targets and compounds, development of structural relatives
of known antimalarials, and fixed combination therapy are
pursued. On the other hand, clinical studies focus on novel
regimens, distribution schemes and drug combinations. A third
possibility to diminish progression of resistance is the application
of evolutionary concepts to design new strategies for validation,
monitoring and interference with the selection-process that
leads to the spread of multidrug-resistance. Since the pharmacologic
and clinical side of antimalarial chemotherapy is covered
by recent reviews we refer to the newest developments only
and lay our focus on determinants of selection for drug resistance
in human malaria.
[Back to top]
Current Issues for Anti-Malarial Drugs to
Control P. falciparum Malaria
D. Schellenberg, S. Abdulla and C. Roper
Successful malaria control depends heavily on efficacious
anti-malarial drugs for the treatment of malaria. Artesunate-containing
Combination Treatments (ACT) are increasingly recommended
as first line malaria treatment in endemic countries, but
implementation of this recommendation is limited by the small
number of available and affordable co-formulated anti-malarial
drugs. In recent years Intermittent Preventive Treatment has
been recommended for malaria control in pregnancy and has
been shown to be of potential public health importance in
the prevention of malaria and anaemia in children. The use
of drugs for malaria treatment or prevention is associated
with the development of resistance and recent advances in
molecular biology facilitate the evaluation of the impact
on drug resistance of new drug-based strategies. This review
concentrates on the challenges surrounding the use of ACT,
the current understanding of IPT in infants and the use of
molecular approaches to enhance our understanding of the effects
of interventions on the spread of drug resistance.
[Back to top]
Prevention of Malaria Using ITNs: Potential for Achieving
the Millenium Development Goals
F. Binka and P. Akweongo
The use of insecticide treated nets is effective in reducing
all cause malaria mortality and morbidity between 17 and 43%
in children under five years and provides protection to pregnant
women who are most susceptible to malaria. ITNs (Insecticide
Treated Nets) are easy to use and require less technical and
capital outlay to implement compared with other vector control
methods. They are cost-effective, which has led to widespread
implementation of ITNs by countries on a large scale. ITN
use has however been limited due to the cost outlay households
require to make towards the purchase of nets, households’
inability to associate the effectiveness of the net with the
insecticide leading to low re-treatment rates in most settings
and the seasonality associated with the spread of malaria.
This chapter provides a review of research on ITN, strategies
of improving the availability and effectiveness of the nets
and a comparison of ITNs and other malaria preventive methods.
The review highlights inequity in ITN use among various socio-economic
groups with the poorest being the least to benefit from ITNs
even where they are highly subsidized. It discusses the break
through in the production of PermaNet® to resolve the
problem of low re-treatment of nets.
[Back to top]
Malaria During Pregnancy Pp. 269-273
C. Menendez
Each year approximately 50 million women living in malaria
endemic areas become pregnant and are at risk of the adverse
health impact of malaria. Approximately half of them live
in sub-Saharan Africa and most of them in areas of intense
falciparum transmission. The increased susceptibility to malaria
of pregnant women has long been recognized. Although some
progress has been accomplished in recent years, resulting
in the identification of intermittent preventive treatment
(IPTp) and insecticide treated nets (ITNs) as key strategies
to control malaria in pregnancy in Africa, much work needs
to be done to control malaria effectively in this high at
risk group. There are still many gaps in knowledge that need
to be addressed: from the biological mechanism (s) that explains
the increased susceptibility during pregnancy, the most effective
control measures in different transmission areas and the best
drugs for case management.
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