Current Molecular Medicine - Volume 6, Issue 2, 2006

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.

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.

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.

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.

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 CD8+ 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 preerythrocytic stage immunity.

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.

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.

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.

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.

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 multidrugresistance. 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.

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.

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 costeffective, 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.

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.