A review of malaria vaccine clinical projects based on the WHO rainbow table

Development and Phase 3 testing of the most advanced malaria vaccine, RTS,S/AS01, indicates that malaria vaccine R&D is moving into a new phase. Field trials of several research malaria vaccines have also confirmed that it is possible to impact the host-parasite relationship through vaccine-induced immune responses to multiple antigenic targets using different platforms. Other approaches have been appropriately tested but turned out to be disappointing after clinical evaluation. As the malaria community considers the potential role of a first-generation malaria vaccine in malaria control efforts, it is an apposite time to carefully document terminated and ongoing malaria vaccine research projects so that lessons learned can be applied to increase the chances of success for second-generation malaria vaccines over the next 10 years. The most comprehensive resource of malaria vaccine projects is a spreadsheet compiled by WHO thanks to the input from funding agencies, sponsors and investigators worldwide. This spreadsheet, available from WHO's website, is known as "the rainbow table". By summarizing the published and some unpublished information available for each project on the rainbow table, the most comprehensive review of malaria vaccine projects to be published in the last several years is provided below.     

Malaria during pregnancy: a priority area of malaria research and control

More than 2000 million people live in areas where malaria transmission occurs and are therefore at risk of being infected. It follows that 1000 million people are exposed to the risks of malaria when pregnant. Although the special features of malaria during pregnancy have been recognized for nearly a century(1), it is only recently that it is being considered as a priority for malaria research and control, as discussed here by Clara Menendez.     

A research agenda for malaria eradication: drugs

Antimalarial drugs will be essential tools at all stages of malaria elimination along the path towards eradication, including the early control or "attack" phase to drive down transmission and the later stages of maintaining interruption of transmission, preventing reintroduction of malaria, and eliminating the last residual foci of infection. Drugs will continue to be used to treat acute malaria illness and prevent complications in vulnerable groups, but better drugs are needed for elimination-specific indications such as mass treatment, curing asymptomatic infections, curing relapsing liver stages, and preventing transmission. The ideal malaria eradication drug is a coformulated drug combination suitable for mass administration that can be administered in a single encounter at infrequent intervals and that results in radical cure of all life cycle stages of all five malaria species infecting humans. Short of this optimal goal, highly desirable drugs might have limitations such as targeting only one or two parasite species, the priorities being Plasmodium falciparum and Plasmodium vivax. The malaria research agenda for eradication should include research aimed at developing such drugs and research to develop situation-specific strategies for using both current and future drugs to interrupt malaria transmission.     

Prevalence of Malaria in Pregnant Women in Lagos, South-West Nigeria

Prevalence rates reported for malaria in pregnancy in Nigeria vary considerably. The accuracy of results of malaria diagnosis is dependent on training, experience, and motivation of the microscopist as well as the laboratory facility available. Results of training programmes on malaria microscopy have shown low levels of sensitivity and specificity of those involved in malaria diagnosis routinely and for research. This study was done to ascertain the true prevalence of malaria in pregnancy in Lagos, South-West Nigeria. A total of 1,084 pregnant women were recruited into this study. Blood smears stained with Giemsa were used for malaria diagnosis by light microscopy. Malaria infection during pregnancy presents mostly as asymptomatic infection. The prevalence of malaria in this population was 7.7% (95% confidence interval; 6.2-9.4%). Factors identified to increase the risk of malaria infection include young maternal age (< 20 years), and gravidity (primigravida). In conclusion, this study exposes the over-diagnosis of malaria in pregnancy and the need for training and retraining of laboratory staffs as well as establishing the malaria diagnosis quality assurance programme to ensure the accuracy of malaria microscopy results at all levels.     

Regime shifts and heterogeneous trends in malaria time series from Western Kenya Highlands

Large malaria epidemics in the East African highlands during the mid and late 1990s kindled a stream of research on the role that global warming might have on malaria transmission. Most of the inferences using temporal information have been derived from a malaria incidence time series from Kericho. Here, we report a detailed analysis of 5 monthly time series, between 15 and 41 years long, from West Kenya encompassing an altitudinal gradient along Lake Victoria basin. We found decreasing, but heterogeneous, malaria trends since the late 1980s at low altitudes (<1600 m), and the early 2000s at high altitudes (>1600 m). Regime shifts were present in 3 of the series and were synchronous in the 2 time series from high altitudes. At low altitude, regime shifts were associated with a shift from increasing to decreasing malaria transmission, as well as a decrease in variability. At higher altitudes, regime shifts reflected an increase in malaria transmission variability. The heterogeneity in malaria trends probably reflects the multitude of factors that can drive malaria transmission and highlights the need for both spatially and temporally fine-grained data to make sound inferences about the impacts of climate change and control/elimination interventions on malaria transmission.     

The Multilateral Initiative on Malaria: co-ordination and co-operation in international malaria research

The Multilateral Initiative on Malaria (MIM) is an international alliance of organisations and individuals. It aims to maximise the impact of scientific research against malaria, through strengthening research capacity in Africa, promoting global collaboration and co-ordination, and increasing available resources. Since its establishment in 1997, the initiative has generated a remarkable level of enthusiasm and activity. Many new scientific partnerships have been established, enabled by enhanced communications and novel funding mechanisms. Dovetailing of research activities with control programmes is also improving. The challenges posed by malaria remain great, however, and in order to achieve a sustainable impact it will be crucial for the research community to capitalise on what has been achieved to date and to maintain the momentum for action well into the next millennium. This article is a personal view contributed by the Wellcome Trust as the nominated co-ordinator for MIM during 1998 and a leading international funder of malaria research. It aims to explain how the novel malaria initiative operates, to summarise some of its key outcomes, and to set out the perspectives for the future.     

A research agenda for malaria eradication: vaccines

Vaccines could be a crucial component of efforts to eradicate malaria. Current attempts to develop malaria vaccines are primarily focused on Plasmodium falciparum and are directed towards reducing morbidity and mortality. Continued support for these efforts is essential, but if malaria vaccines are to be used as part of a repertoire of tools for elimination or eradication of malaria, they will need to have an impact on malaria transmission. We introduce the concept of "vaccines that interrupt malaria transmission" (VIMT), which includes not only "classical" transmission-blocking vaccines that target the sexual and mosquito stages but also pre-erythrocytic and asexual stage vaccines that have an effect on transmission. VIMT may also include vaccines that target the vector to disrupt parasite development in the mosquito. Importantly, if eradication is to be achieved, malaria vaccine development efforts will need to target other malaria parasite species, especially Plasmodium vivax, where novel therapeutic vaccines against hypnozoites or preventive vaccines with effect against multiple stages could have enormous impact. A target product profile (TPP) for VIMT is proposed and a research agenda to address current knowledge gaps and develop tools necessary for design and development of VIMT is presented.     

Malaria in pregnancy and the endemicity spectrum: what can we learn?

The increased susceptibility of pregnant women to malaria infection has long been recognized, but the magnitude of the disease burden in this particular group, together with the pathophysiology of maternal malaria and the specific difficulties in treatment, have only recently been the focus of research. Most research on maternal malaria has derived from sub-Saharan Africa where transmission is high, whereas most of the studies on the treatment of malaria and the effect of non-falciparum species has been conducted in low-transmission areas of Asia. In this paper, we attempt to improve our understanding of the disease and its mechanisms from observed differences and similarities between contrasting areas of transmission, and to identify priorities for future research.     

Cell-mediated immunity in protection and pathology of malaria

The stimulation of protective immunity against malaria is the goal of many research groups. But trials with antigens that stimulate antibodies have yet to fulfil these expectations, and it is increasingly recognized that non-antibody-mediated immunity is also important in immunity to malaria - especially through mediators such as gamma interferon, tumour necrosis factor and reactive forms of oxygen. However, the host can suffer if this type of immune response is too exuberant, and in this review, Ian Clark argues that much of what is recognized as clinical malaria is caused in this way. He suggests that only when discussed in these terms can malaria illness and pathology be seen as a coherent, predictable entity instead of a sea of unconnected surprises. Moreover, these ideas have important implications for vaccine development that, although requiring more basic work, must not be neglected.     

Laboratory models for research in vivo and in vitro on malaria parasites of mammals: Current status

In research aimed at developing strategies for the eradication of human malaria, various species of rodent, avian and non-human primate plasmodia are used as laboratory models. Here Barend Mons and Robert Sinden attempt to summarize the most common laboratory models for mammalian malaria, and to shed some light on their applicability to different aspects of malaria research.     

Engaging the community in research: lessons learned from the malaria vaccine trial

When staff of the Papua New Guinea Institute of Medical Research first went into Wosera in 1979, to try and interest the community into participating in malaria research, the traditional warning sign of crossed bamboo sticks constantly blocked their path as they tried to enter the villages. In 2003, the site is a thriving research centre, with many projects under its belt, a successfully executed malaria vaccine trial to its credit, and approximately 13000 people from 29 villages currently participating in demographic surveillance and various research projects. It has been a long road from community suspicion to sustainable community participation, and the field workers have learned many important lessons along the way that can be applicable to research programs in other disease-endemic areas.     

A research agenda for malaria eradication: cross-cutting issues for eradication

Discipline-specific Malaria Eradication Research Agenda (malERA) Consultative Groups have recognized several cross-cutting issues that must be addressed to prevent repetition of some of the mistakes of past malaria elimination campaigns in future programs. Integrated research is required to develop a decision-making framework for the switch from malaria control to elimination. Similarly, a strong economic case is needed for the very long-term financial support that is essential for elimination. Another cross-cutting priority is the development of improved measures of intensity of transmission, especially at low and nonrandom levels. Because sustained malaria elimination is dependent on a functioning health system, a further key cross-cutting research question is to determine how inputs for malaria can strengthen health systems, information systems, and overall health outcomes. Implementation of elimination programs must also be accompanied by capacity building and training to allow the assessment of the impact of new combinations of interventions, new roles for different individuals, and the operational research that is needed to facilitate program expansion. Finally, because community engagement, knowledge management, communication, political, and multisectoral support are critical but poorly understood success factors for malaria elimination, integrated research into these issues is vital.     

Malaria and social health determinants: a new heuristic framework from the perspective of Latin American social medicine

Traditionally, malaria research and study have followed the positivist scientific paradigm and its biomedical conception of disease. From this perspective, diverse control actions and strategies have been designed. However, despite a century of scientific experience and the depth and thoroughness achieved in the knowledge of malaria, this has not been translated into a constant and progressive decrease of its epidemiological burden. This essay argues for the need for a change in malaria conception, reconfiguring it as a process of biological and social character, where the geno-phenotypical possibilities of the host-parasite relationship and of the diseases clinical expression are articulated with the historic and social dynamics of the spaces in which they occur. In addition, it proposes rethinking the epidemiological research of this entity on the basis of the visualization of the dynamic, heterogeneous, dialectic and complex character of biosocial organizations that constitute the reality of malaria (from the social structure to the genetic and phenotypic level of parasite individuals, vectors and humans). To achieve this, it is suggested that: 1) the Latin American perspective on the social determinants of health be adopted; 2) new analytical categories (for instance, malaria social territory) and new investigation tools (matrices of critical processes of social determination) be incorporated, and 3) the conventional epidemiological categories of infectious diseases such as the transmission and infectiousness be reinterpreted.     

State of the art of the production of the antimalarial compound artemisinin in plants

For more than three centuries we have relied on the extracts of the bark of Cinchona species to treat malaria. Now, it seems we may be changing to the leaves of a Chinese weed, Artemisia annua, and its active compound artemisinin. Artemisinin-derived drugs have been proved particularly effective treatments for severe malaria, even for multi-drug-resistant malaria. However, this promising antimalarial compound remains expensive and is hardly available on a global scale. Therefore, many research groups have directed their investigations toward the enhancement of artemisinin production in A. annua cell cultures or whole plants in order to overproduce artemisinin or one of its precursors. This article provides a brief review of the state of art of the different aspects in A. annua research.     

T cell-derived IL-10 and its impact on the regulation of host responses during malaria

Despite intense research, malaria still is the one of the most devastating diseases killing more people than any other parasitic infection. In an attempt to control the infection, the host immune system produces a potent pro-inflammatory response. However, this response is also associated with complications, such as severe anaemia, hypoglycaemia and cerebral malaria. This pronounced production of pro-inflammatory cytokines response is a common feature of malaria caused by parasites infecting humans as well as rodents and primates. A balance between pro- and anti-inflammatory responses may be fundamental to the elimination of the parasite without inducing excessive host pathology. IL-10 is a key cytokine that has been shown to have an important regulatory function in establishing this balance in malaria. Here we discuss which cells can produce IL-10 during infection, and present an overview of the evidence showing that T-cell derived IL-10 plays an important role in regulating malaria pathology. Many different subsets of T cells can produce IL-10, however, evidence is accumulating that it is effector Th1 CD4(+) T cells which provide the crucial source that down-regulates inflammatory pathology during blood-stage malaria infections.     

Limburger cheese as an attractant for the malaria mosquito Anopheles gambiae s.s

In the process of bloodfeeding, female Anopheles can transmit malaria parasites to humans. At night, while searching for blood, these insects respond to visual, physical and chemical properties of humans. Current research concentrates on the identification of kairomones, which guide mosquitoes to humans. Earlier observations on the biting behaviour of Anopheles gambiae s.s. on humans have now resulted in the discovery of a remarkable attractant for this important malaria vector, and it is thought that this will accelerate the development of odour-baited traps for malaria mosquito surveillance and control in sub-Saharan Africa, as discussed here by Bart Knols and Ruurd De Jong.     

Implementation of malaria control

Global trends of infant and child mortality have decreased over the last 30 years, while the proportion of malaria deaths has progressively increased due to the deteriorating situation in sub-Saharan Africa. The Global Malaria Control Strategy promoted by WHO has encountered several obstacles to its implementation. Early diagnosis and prompt treatment can reduce malaria mortality, but there is still low investment on safe and effective modalities of care delivery at the periphery, where most of the malaria burden exists. Selective vector control (indoor residual spraying and insecticide-treated nets) plays a significant role outside Africa, but its wider use is limited by cost/affordability problems and operational issues (supply, delivery and logistics). Alternative methods such as environmental management and biological control are cost-effective only under very specific epidemiological situations. In most countries forecasting, early detection and containment of malaria epidemics is deficient, and there is separation between the research and control communities, particularly in Africa. Involvement of the internal agencies, strategic investments in capacity building and institutional networking are needed to strengthen capacity for malaria and research in the countries. The major responsibility is to guide the expenditure made by the communities (which far out-weigh the limited share of national health budgets) towards the most cost-effective approaches to reduce malaria mortality and morbidity.     

Application of Geographical Information Systems and Remote Sensing technologies for assessing and monitoring malaria risk

Despite over 30 years of scientific research, algorithm development and multitudes of publications relating Remote Sensing (RS) information with the spatial and temporal distribution of malaria, it is only in recent years that operational products have been adopted by malaria control decision-makers. The time is ripe for the wealth of research knowledge and products from developed countries be made available to the decision-makers in malarious regions of the globe where this information is urgently needed. This paper reviews the capability of RS to provide useful information for operational malaria early warning systems. It also reviews the requirements for monitoring the major components influencing emergence of malaria and provides examples of applications that have been made. Discussion of the issues that have impeded implementation on a global scale and how those barriers are disappearing with recent economic, technological and political developments are explored; and help pave the way for implementation of an integrated Malaria Early Warning System framework using RS technologies.     

Molecular approaches to malaria: seeking the whole picture

This year, Australia hosted its first major international conference on malaria - Molecular Approaches to Malaria in Lorne, Victoria, 2-5 February 2000 (MAM2000). The worldwide research effort toward a better understanding of the pathogenesis and control of malaria in the post-genomic era was discussed and debated by over 250 researchers from 18 countries during four days packed with molecular biology, cell biology, genomics, vaccines and pathogenic mechanisms. This special malaria edition of Parasitology Today is an attempt to capture and summarize the quality and breadth of work presented at the conference and place this in the context of the current global malaria research effort; eight of the nine Reviews in this issue have been written by session chairs or presenters at MAM2000.     

Synergism/complementarity of recombinant adenoviral vectors and other vaccination platforms during induction of protective immunity against malaria

The lack of immunogenicity of most malaria antigens and the complex immune responses required for achieving protective immunity against this infectious disease have traditionally hampered the development of an efficient human malaria vaccine. The current boom in development of recombinant viral vectors and their use in prime-boost protocols that result in enhanced immune outcomes have increased the number of malaria vaccine candidates that access pre-clinical and clinical trials. In the frontline, adenoviruses and poxviruses seem to be giving the best immunization results in experimental animals and their mutual combination, or their combination with recombinant proteins (formulated in adjuvants and given in sequence or being given as protein/virus admixtures), has been shown to reach unprecedented levels of anti-malaria immunity that predictably will be somehow reproduced in the human setting. However, all this optimism was previously seen in the malaria vaccine development field without many real applicable results to date. We describe here the current state-of-the-art in the field of recombinant adenovirus research for malaria vaccine development, in particular referring to their use in combination with other immunogens in heterologous prime-boost protocols, while trying to simultaneously show our contributions and point of view on this subject.