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 By summarizing the published and some unpublished information available for each project on the rainbow table, the most comprehensive review of malaria vaccine projects to be published in the last several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.     

Environmental Management for Malaria Control: Knowledge and Practices in Mvomero,Tanzania

Environmental conditions play an important role in the transmission of malaria; therefore, regulating these conditions can help to reduce disease burden. Environmental management practices for disease control can be implemented at the community level to complement other malaria control methods. This study assesses current knowledge and practices related to mosquito ecology and environmental management for malaria control in a rural, agricultural region of Tanzania. Household surveys were conducted with 408 randomly selected respondents from 10 villages and qualitative data were collected through focus group discussions and in-depth interviews. Results show that respondents are well aware of the links between mosquitoes, the environment, and malaria. Most respondents stated that cleaning the environment around the home, clearing vegetation around the home, or draining stagnant water can reduce mosquito populations, and 63% of respondents reported performing at least one of these techniques to protect themselves from malaria. It is clear that many respondents believe that these environmental management practices are effective malaria control methods, but the actual efficacy of these techniques for controlling populations of vectors or reducing malaria prevalence in the varying ecological habitats in Mvomero is unknown. Further research should be conducted to determine the effects of different environmental management practices on both mosquito populations and malaria transmission in this region, and increased participation in effective techniques should be promoted.     

Capacity strengthening in malaria research: the Gates Malaria Partnership

The Gates Malaria Partnership (GMP) includes five African and four European partner institutions. Its research programme has five priority areas involving an extensive range of field-based studies. GMP research has contributed significantly to the development of new research consortia investigating strategies for improving means of malaria control, and has already had an impact on policy and practice. A substantial investment in innovative training activities in malaria has enhanced knowledge and practice of malaria control at all levels from policy making to local community involvement. Capacity development, notably through a PhD programme, has been an underlying feature of all aspects of the programme.     

The United States Army and malaria control in World War II

The United States Army faced difficult malaria control problems both at home and abroad during World War II. This challenge forced the Army to develop new tools and strategies for use in malarious areas where fighting was occurring. Due to the severe malaria problems being faced in some combat areas and the need to solve these problems quickly, intensive malaria research and operational programs were developed and implemented. With these concerted efforts and the simultaneous development of new control technologies, malaria was successfully controlled in most locations. In order to accomplish this high level of control both in the US and overseas, the Army developed a very organized approach to the malaria problem and implemented it in an effective manner. The creation of new technical solutions was also strongly emphasized and out of this effort came the development of effective antimalaria drugs to replace quinine, of new insecticides and of more effective systems for delivering these insecticides. Some of the major new tools which came out of this research were DDT and drugs such as Atabrine and chloroquine. The availability of Atabrine and DDT revolutionized malaria control throughout the world. The knowledge and experience gained through the use of these new tools by the US Army and other agencies in World War II provided the basis for a new optimism regarding malaria control which then led to the development of the global malaria eradication strategy in the post-war years.     

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.     

How Well Are Malaria Maps Used to Design and Finance Malaria Control in Africa?

Introduction

Rational decision making on malaria control depends on an understanding of the epidemiological risks and control measures. National Malaria Control Programmes across Africa have access to a range of state-of-the-art malaria risk mapping products that might serve their decision-making needs. The use of cartography in planning malaria control has never been methodically reviewed.

Materials and Methods

An audit of the risk maps used by NMCPs in 47 malaria endemic countries in Africa was undertaken by examining the most recent national malaria strategies, monitoring and evaluation plans, malaria programme reviews and applications submitted to the Global Fund. The types of maps presented and how they have been used to define priorities for investment and control was investigated.

Results

91% of endemic countries in Africa have defined malaria risk at sub-national levels using at least one risk map. The range of risk maps varies from maps based on suitability of climate for transmission; predicted malaria seasons and temperature/altitude limitations, to representations of clinical data and modelled parasite prevalence. The choice of maps is influenced by the source of the information. Maps developed using national data through in-country research partnerships have greater utility than more readily accessible web-based options developed without inputs from national control programmes. Although almost all countries have stratification maps, only a few use them to guide decisions on the selection of interventions allocation of resources for malaria control.

Conclusion

The way information on the epidemiology of malaria is presented and used needs to be addressed to ensure evidence-based added value in planning control. The science on modelled impact of interventions must be integrated into new mapping products to allow a translation of risk into rational decision making for malaria control. As overseas and domestic funding diminishes, strategic planning will be necessary to guide appropriate financing for malaria control.     

An exploratory study of community factors relevant for participatory malaria control on Rusinga Island, western Kenya

Background

Capacity strengthening of rural communities, and the various actors that support them, is needed to enable them to lead their own malaria control programmes. Here the existing capacity of a rural community in western Kenya was evaluated in preparation for a larger intervention.

Methods

Focus group discussions and semi-structured individual interviews were carried out in 1,451 households to determine (1) demographics of respondent and household; (2) socio-economic status of the household; (3) knowledge and beliefs about malaria (symptoms, prevention methods, mosquito life cycle); (4) typical practices used for malaria prevention; (5) the treatment-seeking behaviour and household expenditure for malaria treatment; and (6) the willingness to prepare and implement community-based vector control.

Results

Malaria was considered a major threat to life but relevant knowledge was a chimera of scientific knowledge and traditional beliefs, which combined with socio-economic circumstances, leads to ineffective malaria prevention. The actual malaria prevention behaviour practiced by community members differed significantly from methods known to the respondents. Beside bednet use, the major interventions implemented were bush clearing and various hygienic measures, even though these are ineffective for malaria prevention. Encouragingly, most respondents believed malaria could be controlled and were willing to contribute to a community-based malaria control program but felt they needed outside assistance.

Conclusion

Culturally sensitive but evidence-based education interventions, utilizing participatory tools, are urgently required which consider traditional beliefs and enable understanding of causal connections between mosquito ecology, parasite transmission and the diagnosis, treatment and prevention of disease. Community-based organizations and schools need to be equipped with knowledge through partnerships with national and international research and tertiary education institutions so that evidence-based research can be applied at the grassroots level.     

The IPTi Consortium: research for policy and action

The results of a randomized controlled trial in Tanzania suggest that intermittent preventive treatment in infants (IPTi), delivered through the Expanded Program on Immunization, might be a useful approach to controlling malaria in countries where it is endemic. An international consortium of research collaborations, involving the World Health Organization and United Nation's Children's Fund, is now evaluating IPTi in a range of different settings to generate robust and compelling evidence to guide policy. This review summarizes the available information on IPTi and presents the consortium's approach to determining whether IPTi might be a valuable additional strategy in programs to control malaria.     

Systems immunology of human malaria

Plasmodium falciparum malaria remains a global public health threat. Optimism that a highly effective malaria vaccine can be developed stems in part from the observation that humans can acquire immunity to malaria through experimental and natural P. falciparum infection. Recent advances in systems immunology could accelerate efforts to unravel the mechanisms of acquired immunity to malaria. Here, we review the tools of systems immunology, their current limitations in the context of human malaria research, and the human 'models' of malaria immunity to which these tools can be applied.     

A strain theory of malaria transmission

Does the fact that the risk o f getting malaria is high in most endemic areas mean that it will be impossible to control through vaccination? Not if malaria is composed of several mildly transmissible strains, and what we are measuring as the high risk is the probability of being infected by any one of the several strains circulating independently within the same area. In this article, Sunetra Gupta and Karen Day discuss a strain theory of malaria transmission that fits both recent serological and molecular observations and more conventional epidemiological data on age distributions of infection and disease. Their analyses suggest that the transmissibility of malaria has been grossly overestimated, and that the control of malaria through vaccination may be far easier than previously assumed.     

Control to elimination: implications for malaria research

Recent reports indicate that a high level of malaria control can be achieved with existing control tools once their use has been scaled up. This has led to renewed interest in the possibility of malaria elimination, an approach that is now supported by several influential organisations. An increasing focus on elimination requires a review of priorities within the malaria research agenda. The development of drugs and vaccines with a strong transmission-blocking potential becomes increasingly important. Novel approaches to surveillance will be necessary to ensure that once elimination has been achieved, it is not threatened by a rapid reintroduction of malaria from neighbouring areas.     

Malaria vaccines: if at first you don't succeed..

The Roll Back Malaria campaign vowed to halve the global burden of malaria in ten years but, midway into that campaign, few new malaria control tools have been introduced, and many established methods appear to be failing with effective chemotherapy being perhaps the most problematic. It has been repeatedly argued that the discovery and implementation of a safe and effective vaccine against malaria is a major priority in the control of the disease. Indeed, many malaria control experts believe that sustainable reductions in malaria control will be nigh on impossible in the absence of such a vaccine. While most would agree that we are still some way from being able to introduce a vaccine, steady progress is being made. We review here some new approaches and developments in vaccine research that were discussed at the Molecular Approaches to Malaria conference held 1-5 February 2004 in Lorne, Australia.     

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.     

Combating malaria vectors in Africa: current directions of research

Vector control remains an important component of malaria control, particularly in Africa where most infant deaths occur. Among the different methods, insecticide-treated bednets seem to be a suitable way to reduce morbidity and child mortality in endemic areas. To facilitate their large-scale use and to investigate alternative vector control methods, the authors propose these current directions of research that are already being explored in Africa through a collaborating network involving several African countries: (1) vector genetics, (2) insecticide resistance and (3) vector control strategies.     

From predicting mosquito habitat to malaria seasons using remotely sensed data: practice, problems and perspectives

Remote sensing techniques are becoming increasingly important for identifying mosquito habitats, investigating malaria epidemiology and assisting malaria control. Here, Simon Hay, Bob Snow and David Rogers review the development of these techniques, from aerial photographic identification of mosquito larval habitats on the local scale through to the space-based survey of malaria risk over continental areas using increasingly sophisticated airborne and satellite-sensor technology. They indicate that previous constraints to uptake are becoming less relevant and suggest how future delays in the use of remotely sensed data in malaria control might be avoided.     

The last and the next hundred years of malariology

The founding fathers of malariology combined scientific originality, perseverance in research, strong characters, breadth of interest and social concern. A hundred years later research and understanding has made immense progress but the world still bears a huge burden of malaria. For the next century research requires both more specialism and a holistic range if it is to be used in control, requiring multidisciplinary team work. Environmental changes and interventions produce a dynamic and changing pattern of malaria, not the static one of the past. From the original parasite life cycle, research has analysed a series of other cycles at electron microscope, biochemical and genome levels on decreasing size scales and quantitative epidemiological cycles for control. Recent additions to these concepts have been stage-specific antigens, cycles of disease rather than parasites alone, considering populations of parasites rather than just cases, and also genetic variation in each component of the parasite-human host-vector triad. In this volume there emerges for the first time a coherent overall picture of the biomedical aspects of basic malariology as the interacting population genetics of malaria parasites, anophelines and people. This provides a coherent model for the new century dealing with the great biological malaria problems of drug resistance, vaccine development, insecticidal and net control and can feed, with socio-economic work, into the gathering renewal of control efforts. New work on large-scale changes of malaria in space and time enables us to be precise about effects of local and global environmental changes to predict epidemics. Future research will be as much about linking these different scales of understanding as control will be about linking different levels of the health system. The grim situation in poor holoendemic countries also requires practical support of the type that the founders of malariology were involved in. A coherent understanding needs to feed into the new control efforts, from Roll Back Malaria onwards, for the next century.     

An Open Source Business Model for Malaria

Greater investment is required in developing new drugs and vaccines against malaria in order to eradicate malaria. These precious funds must be carefully managed to achieve the greatest impact. We evaluate existing efforts to discover and develop new drugs and vaccines for malaria to determine how best malaria R&D can benefit from an enhanced open source approach and how such a business model may operate. We assess research articles, patents, clinical trials and conducted a smaller survey among malaria researchers. Our results demonstrate that the public and philanthropic sectors are financing and performing the majority of malaria drug/vaccine discovery and development, but are then restricting access through patents, ‘closed’ publications and hidden away physical specimens. This makes little sense since it is also the public and philanthropic sector that purchases the drugs and vaccines. We recommend that a more “open source” approach is taken by making the entire value chain more efficient through greater transparency which may lead to more extensive collaborations. This can, for example, be achieved by empowering an existing organization like the Medicines for Malaria Venture (MMV) to act as a clearing house for malaria-related data. The malaria researchers that we surveyed indicated that they would utilize such registry data to increase collaboration. Finally, we question the utility of publicly or philanthropically funded patents for malaria medicines, where little to no profits are available. Malaria R&D benefits from a publicly and philanthropically funded architecture, which starts with academic research institutions, product development partnerships, commercialization assistance through UNITAID and finally procurement through mechanisms like The Global Fund to Fight AIDS, Tuberculosis and Malaria and the U.S.’ President’s Malaria Initiative. We believe that a fresh look should be taken at the cost/benefit of patents particularly related to new malaria medicines and consider alternative incentives, like WHO prequalification.     

Control of Vector-Borne Disease by Genetic Manipulation of Insect Populations: Technological Requirements and Research Priorities

The possibility of controlling vector-borne disease through the development and release of transgenic insect vectors has recently gained popular support and is being actively pursued by a number of research laboratories around the world. Several technical problems must be solved before such a strategy could be implemented: genes encoding refractory traits (traits that render the insect unable to transmit the pathogen) must be identified, a transformation system for important vector species has to be developed, and a strategy to spread the refractory trait into natural vector populations must be designed. Recent advances in this field of research make it seem likely that this technology will be available in the near future.
In this paper we review recent progress in this area as well as argue that care should be taken in selecting the most appropriate disease system with which to first attempt this form of intervention. Much attention is currently being given to the application of this technology to the control of malaria, transmitted by Anopheles gambiae in Africa. While malaria is undoubtedly the most important vector-borne disease in the world and its control should remain an important goal, we maintain that the complex epidemiology of malaria together with the intense transmission rates in Africa may make it unsuitable for the first application of this technology. Diseases such as African trypanosomiasis, transmitted by the tsetse fly, or unstable malaria in India may provide more appropriate initial targets to evaluate the potential of this form of intervention.     

Helminth-infected patients with malaria: a low profile transmission hub?

The scale-up of malaria control efforts in recent years, coupled with major investments in malaria research, has produced impressive public health impact in a number of countries and has led to the development of new tools and strategies aimed at further consolidating malaria control goals. As a result, there is a growing need for the malaria policy setting process to rapidly review increasing amounts of evidence. The World Health Organization Global Malaria Programme, in keeping with its mandate to set evidence-informed policies for malaria control, has convened the Malaria Policy Advisory Committee as a mechanism to increase the timeliness, transparency, independence and relevance of its recommendations to World Health Organization member states in relation to malaria control and elimination. The Malaria Policy Advisory Committee, composed of 15 world-renowned malaria experts, will meet in full twice a year, with the inaugural meeting scheduled for 31 January to 2 February 2012 in Geneva. Policy recommendations, and the evidence to support them, will be published within two months of every meeting as part of an open access Malaria Journal thematic series. This article is a prelude to that series and provides the global malaria community with the background and overview of the Committee and its terms of reference.     

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.