Malaria vaccine development: progress and challenges

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.     

Towards a blood-stage vaccine for malaria: are we following all the leads?

Although the malaria parasite was discovered more than 120 years ago, it is only during the past 20 years, following the cloning of malaria genes, that we have been able to think rationally about vaccine design and development. Effective vaccines for malaria could interrupt the life cycle of the parasite at different stages in the human host or in the mosquito. The purpose of this review is to outline the challenges we face in developing a vaccine that will limit growth of the parasite during the stage within red blood cells--the stage responsible for all the symptoms and pathology of malaria. More than 15 vaccine trials have either been completed or are in progress, and many more are planned. Success in current trials could lead to a vaccine capable of saving more than 2 million lives per year.     

A whole parasite vaccine to control the blood stages of Plasmodium: the case for lateral thinking

Now, 27 years following the cloning of malaria antigens with the promise of the rapid development of a malaria vaccine, we face significant obstacles that are belatedly being addressed. Poor immunogenicity of subunit vaccine antigens and significant antigenic diversity of target epitopes represent major hurdles for which there are no clear strategies for a way forward within the current paradigm. Thus, a different paradigm - a vaccine that uses the whole organism - is now being examined. Although most advances in this approach relate to a vaccine for the pre-erythrocytic stages (sporozoites, liver stages), this opinion paper will outline the possibilities of developing a whole parasite vaccine for the blood stage and address some of the challenges for this strategy, which are entirely different to the challenges for a subunit vaccine. It is the view of the author that both vaccine paradigms should be pursued, but that success will come more quickly using the paranormal approach of exposing individuals to ultra-low doses of whole attenuated or killed parasites.     

Development of humanized mouse models to study human malaria parasite infection

Malaria is a disease caused by infection with Plasmodium parasites that are transmitted by mosquito bite. Five different species of Plasmodium infect humans with severe disease, but human malaria is primarily caused by Plasmodium falciparum. The burden of malaria on the developing world is enormous, and a fully protective vaccine is still elusive. One of the biggest challenges in the quest for the development of new antimalarial drugs and vaccines is the lack of accessible animal models to study P. falciparum infection because the parasite is restricted to the great apes and human hosts. Here, we review the current state of research in this field and provide an outlook of the development of humanized small animal models to study P. falciparum infection that will accelerate fundamental research into human parasite biology and could accelerate drug and vaccine design in the future.     

Veterinary endectocides for malaria control and elimination: prospects and challenges

Residual transmission is the persistence of malaria transmission after scale-up of appropriate vector control tools and is one of the key challenges for malaria elimination today. Although long associated with outdoor biting, other mosquito behaviours such as partly feeding upon animals contribute greatly to sustaining transmission. Peri-domestic livestock can be used as decoy to protect humans from blood-seeking vectors but this approach often leads to an increased malaria risk in a phenomenon known as zoopotentiation. Treating the said livestock with drugs capable of killing intestinal parasites as well as mosquitoes that feed upon them has the potential to tackle malaria through a previously unexplored mechanism. The advantages and challenges associated with this approach are briefly discussed here. Numerous references are purposely provided.This article is part of the theme issue ‘Novel control strategies for mosquito-borne diseases’.     

Systemwide Initiative on Malaria and Agriculture: AnInnovative Framework for Research and Capacity Building

The Systemwide Initiative on Malaria and Agriculture (SIMA) is an initiative of international agricultural research centers to promote research and capacity building on the links between malaria and agriculture and to validate innovative interventions that would strengthen and complement existing malaria-control strategies in clearly defined settings. Knowledge regarding the nature and dynamics of agroecosystems is particularly needed for the purpose of developing appropriate farmer-managed preventive measures against malaria. SIMA research aims to make use of new and existing information on biomedical and socioeconomic determinants of malaria risks in formulating and evaluating the feasibility of integrated strategies. The initiative is especially interested and proactive in promoting and facilitating transdisciplinary and participatory research in relation to malaria. The convening institute for SIMA is the International Water Management Institute at its Africa Regional Office in Pretoria, South Africa. This article outlines SIMAs objectives and scope of activities and also highlights achievements, challenges, and opportunities for future collaboration.     

Do molecules matter more than morphology? Promises and pitfalls in parasites

Systematics involves resolving both the taxonomy and phylogenetic placement of organisms. We review the advantages and disadvantages of the two kinds of information commonly used for such inferences--morphological and molecular data--as applied to the systematics of metazoan parasites generally, with special attention to the malaria parasites. The problems that potentially confound the use of morphology in parasites include challenges to consistent specimen preservation, plasticity of features depending on hosts or other environmental factors, and morphological convergence. Molecular characters such as DNA sequences present an alternative data source and are particularly useful when not all the parasite's life stages are present or when parasitaemia is low. Nonetheless, molecular data can bring challenges that include troublesome DNA isolation, paralogous gene copies, difficulty in developing molecular markers, and preferential amplification in mixed species infections. Given the differential benefits and shortcomings of both molecular and morphological characters, both should be implemented in parasite taxonomy and phylogenetics.     

Iron and malaria

Iron deficiency is common in the developing world; consequently, programmes of presumptive therapy and mass supplementation have been introduced in several countries. In this article Stephen Oppenheimer suggests caution, as recent evidence suggests that these practices may actually increase the likelihood of the subject developing patent malaria in endemic areas. This may be especially significant in infants, who are less likely to be immune to malaria, and in pregnant women, who are often routinely given iron supplements and in whom malaria may damage the foetus.     

Controlling malaria transmission with genetically-engineered, Plasmodium-resistant mosquitoes: milestones in a model system

We are developing transgenic mosquitoes resistant to malaria parasites to test the hypothesis that genetically-engineered mosquitoes can be used to block the transmission of the parasites. We are developing and testing many of the necessary methodologies with the avian malaria parasite, Plasmodium gallinaceum, and its laboratory vector, Aedes aegypti, in anticipation of engaging the technical challenges presented by the malaria parasite, P. falciparum, and its major African vector, Anopheles gambiae. Transformation technology will be used to insert into the mosquito a synthetic gene for resistance to P. gallinaceum. The resistance gene will consist of a promoter of a mosquito gene controlling the expression of an effector protein that interferes with parasite development and/or infectivity. Mosquito genes whose promoter sequences are capable of sex- and tissue-specific expression of exogenous coding sequences have been identified, and stable transformation of the mosquito has been developed. We now are developing the expressed effector portion of the synthetic gene that will interfere with the transmission of the parasites. Mouse monoclonal antibodies that recognize the circumsporozoite protein of P. gallinaceum block sporozoite invasion of mosquito salivary glands, as well as abrogate the infectivity of sporozoites to a vertebrate host, the chicken, Gallus gallus, and block sporozoite invasion and development in susceptible cell lines in vitro. Using the genes encoding these antibodies, we propose to clone and express single-chain antibody constructs (scFv) that will serve as the effector portion of the gene that interferes with transmission of P. gallinaceum sporozoites.     

Plasmodium vivax transmission-blocking vaccines: Progress,challenges and innovation

Existing control measures have significantly reduced malaria morbidity and mortality in the last two decades, although these reductions are now stalling. Significant efforts have been undertaken to develop malaria vaccines. Recently, extensive progress in malaria vaccine development has been made for Plasmodium falciparum. To date, only the RTS,S/AS01 vaccine has been tested in Phase 3 clinical trials and is now under implementation, despite modest efficacy. Therefore, the development of a malaria transmission-blocking vaccine (TBV) will be essential for malaria elimination. Only a limited number of TBVs have reached pre-clinical or clinical development with several major challenges impeding their development, including low immunogenicity in humans. TBV development efforts against P. vivax, the second major cause of malaria morbidity, lag far behind those for P. falciparum. In this review we summarize the latest progress, challenges and innovations in P. vivax TBV research and discuss how to accelerate its development.     

Diagnosis of malaria: challenges for clinicians in endemic and non-endemic regions

Malaria is a leading cause of morbidity and mortality worldwide. Prompt diagnosis and treatment are critical factors in reducing morbidity and mortality, as delayed treatment of malaria increases the risk of death. Microscopy has long been the standard of malaria diagnosis, but newer diagnostic tests now offer advantages in certain settings. Malaria diagnosis is complicated by the fact that acquired immunity to malaria can result in asymptomatic infections. In a symptomatic (febrile) patient, no existing malaria diagnostic test can distinguish malarial illness from parasitemia with concomitant fever of another cause. In this review we discuss the available malaria diagnostic tests, appropriate applications for each, and the challenges of malaria diagnosis in both endemic and non-endemic settings.     

Current issues for anti-malarial drugs to control P. falciparum 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.     

Vaccination: the present and the future

Vaccines have undoubtedly saved the lives of millions, and along with improved sanitation, they remain one of the cornerstones of modern medicine. Many diseases that were once widespread are now eradicated, but vaccine programs face ongoing challenges. Safety concerns as well as limited funding have led to pockets of reduced vaccine coverage around the world - including in developed countries. Chronic and recurrent diseases such as human immunodeficiency virus (HIV), tuberculosis, and malaria remain without effective vaccines. This review will briefly describe vaccines and the two major issues faced by modern vaccination programs: insufficient vaccine coverage and developing effective vaccines for chronic and recurrent diseases.     

Helicases - feasible antimalarial drug target for Plasmodium falciparum

Of the four Plasmodium species that cause human malaria, Plasmodium falciparum is responsible for the most severe form of the disease and this parasite is developing resistance to the major antimalarial drugs. Therefore, in order to control malaria it is necessary to identify new drug targets. One feasible target might be helicases, which are important unwinding enzymes and required for almost all the nucleic acid metabolism in the malaria parasite.     

Malaria vaccines: triumphs or tribulations?

A safe and effective malaria vaccine will greatly facilitate efforts to control the global spread of malaria. This paper discusses the conceptual framework for developing malaria vaccines and some of the difficulties that the various approaches face. It emphasizes the role of pre-erythrocytic malaria vaccines, which are designed to protect against malaria infection, rather than simply prevent clinical disease. It describes recent encouraging results in human subjects with the RTS,S vaccine, a promising pre-erythrocytic malaria vaccine candidate.     

Towards a vaccine against pregnancy-associated malaria

The consequences of pregnancy-associated malaria on pregnant women (anaemia), their babies (birth weight reduction), and infants (increased morbidity and mortality) are well documented. Field observations during the last decade have underlined the key role of the interactions between P. falciparum variable surface antigens expressed on infected erythrocytes and a novel receptor: chondroitin sulfate A (CSA) for the placental sequestration of infected erythrocytes. Identification of a distinct P. folciparum erythrocyte membrane protein 1 (PfEMP1) variant, VAR2CSA, as the dominant variant surface antigen and as a clinically important target for protective immune response to pregnancyassociated malaria has raised hope for developing a new preventive strategy based on inducing these immune responses by vaccination. However, despite particular structure and interclonal conservation of VAR2CSA among other PfEMP1, significant challenges still exist concerning the development of a VAR2CSA-based vaccine with profound efficacy.     

Can plant biotechnology help break the HIV–malaria link?

The population of sub-Saharan Africa is at risk from multiple, poverty-related endemic diseases. HIV and malaria are the most prevalent, but they disproportionately affect different groups of people, i.e. HIV predominantly affects sexually-active adults whereas malaria has a greater impact on children and pregnant women. Nevertheless, there is a significant geographical and epidemiological overlap which results in bidirectional and synergistic interactions with important consequences for public health. The immunosuppressive effects of HIV increase the risk of infection when individuals are exposed to malaria parasites and also the severity of malaria symptoms. Similarly, acute malaria can induce a temporary increase in the HIV viral load. HIV is associated with a wide range of opportunistic infections that can be misdiagnosed as malaria, resulting in the wasteful misuse of antimalarial drugs and a failure to address the genuine cause of the disease. There is also a cumulative risk of toxicity when antiretroviral and antimalarial drugs are given to the same patients. Synergistic approaches involving the control of malaria as a strategy to fight HIV/AIDS and vice versa are therefore needed in co-endemic areas. Plant biotechnology has emerged as a promising approach to tackle poverty-related diseases because plant-derived drugs and vaccines can be produced inexpensively in developing countries and may be distributed using agricultural infrastructure without the need for a cold chain. Here we explore some of the potential contributions of plant biotechnology and its integration into broader multidisciplinary public health programs to combat the two diseases in developing countries.     

Malaria in India: Challenges and opportunities

India contributes about 70% of malaria in the South East Asian Region of WHO. Although annually India reports about two million cases and 1000 deaths attributable to malaria, there is an increasing trend in the proportion of Plasmodium falciparum as the agent. There exists heterogeneity and variability in the risk of malaria transmission between and within the states of the country as many ecotypes/paradigms of malaria have been recognized. The pattern of clinical presentation of severe malaria has also changed and while multi-organ failure is more frequently observed in falciparum malaria, there are reports of vivax malaria presenting with severe manifestations. The high burden populations are ethnic tribes living in the forested pockets of the states like Orissa, Jharkhand, Madhya Pradesh, Chhattisgarh and the North Eastern states which contribute bulk of morbidity and mortality due to malaria in the country. Drug resistance, insecticide resistance, lack of knowledge of actual disease burden along with new paradigms of malaria pose a challenge for malaria control in the country. Considering the existing gaps in reported and estimated morbidity and mortality, need for estimation of true burden of malaria has been stressed. Administrative, financial, technical and operational challenges faced by the national programme have been elucidated. Approaches and priorities that may be helpful in tackling serious issues confronting malaria programme have been outlined.     

Genome-informed contributions to malaria therapies: feeding somewhere down the (pipe)line

Whole-genome sequences of Plasmodium spp. have helped redefine malaria research, including initiatives that seek to develop drugs, vaccines, and other antimalarial therapies. The problems caused by malaria were brought to the public's attention once more on World Malaria Day (April 25). Unfortunately, the current impact of genome-informed research is not as great as might have been hoped, and the reasons for this and continuing challenges are discussed.     

Progress towards the development of malaria vaccines

The misery and suffering caused worldwide by infection with the malaria parasite, especially Plasmodium falciparum, has been well documented. Although no licensed vaccine against malaria currently exists, progress has accelerated in recent years towards the goal of developing one. Although the complexity of the malaria parasite has made the malaria vaccine development process tenuous, advances in science and in the vaccine development process as well as increases in funding are encouraging. These advances, coupled with the results of the recent clinical trial of the vaccine candidate RTS,S, have added new vigor to the idea that a malaria vaccine is not only possible but probable.