Part II: The Global Strategy
2. Control: Overcoming Malaria
4. The Malaria Research Agenda: A. Research and Development for New and Improved Tools
New and improved tools are needed to control and eliminate malaria. This chapter will discuss current and future interventions, identifying what is working well today, and what may be needed for the scale-up, sustained control and elimination stages.
R&D in the Control Stage
The purpose of scaling up and sustaining control is to rapidly bring down burden of disease through high, compliant, and sustained coverage of key preventive and curative interventions. When used appropriately, current interventions offer significant protection against malaria infection; however, gaps in existing interventions still hamper progress in these stages. Research is needed for vector control, treatment, diagnosis, and vaccines.
Opportunities to improve vector control. Vector control interventions can make a significant impact on morbidity and mortality today. However, several opportunities to improve on existing interventions might be addressed by research and development.
- Costs and challenges of Indoor Residual Spraying (IRS): While IRS can be a very effective form of vector control, it is cumbersome to apply and requires strong systems to execute correctly. Vast improvements in the application equipment, which has not changed in 50 years, are necessary to improve execution and protective impact. The ‘final step’ in IRS, the actual application of the insecticide to the wall, is entirely dependent on the spray operator’s diligence in maintaining the correct pump pressure, distance to the surface and speed of application. The difficulty of this job is compounded by personal protective equipment (masks, coveralls, gloves, etc.), the heat, salary and other factors. Additionally, cost is a challenge, which ranges from US$ 7.50 to more than US$ 20 per household per round, and high, perennial transmission areas may require multiple applications per year. Longer-lasting IRS formulations may ease this challenge by enabling less frequent sprayings.
- Distribution and practicality of long-lasting insecticidal nets (LLINs): The bulkiness of nets makes distribution a challenge. Even when LLINs are distributed, utilization rates may be low for several reasons: aesthetics, discomfort sleeping under net due to high temperature and reduced air flow, lack of awareness of proper use and/or the benefits associated with reduced biting and infection by mosquitoes and lack of a bed or adequate household structure to accommodate use of a net. Additionally, there are limited suitable active ingredients that are safe for use in settings with significant human contact.
- Delaying resistance to pesticides: Resistance to pesticides is a significant threat to current interventions. Resistance to DDT and pyrethroids is already emerging, although the extent in many parts of the world is not known. There is evidence that this becomes even more dangerous in later stages of control when decreasing transmission potentially facilitates faster emergence. Implementation of specific R&D strategies to discover new active ingredients (detailed below) and monitoring technologies could delay the emergence and potential impact of resistance for all products, as well as improve the ability to respond to resistance.
- New chemistries and targets for killing vectors: As there are only four active ingredient classes suitable for vector control, research that includes the development of new chemistries, targets and a wider range of classes could help pre-empt or combat resistance. Unfortunately, R&D surrounding pesticides brings particular challenges. Developing a new active ingredient requires an investment of more than US$ 175 million over 12 years.[85]Interviews with topic experts. The public health market for pesticides is very small compared to that of the agriculture market, and therefore receives much less investment and research focus. While public health has benefited previously from agriculture, as all previous ingredients are offshoots from agriculture, crop trends such as genetically modified seeds and systemic pesticides are limiting the future pipeline of pesticides which may have public health benefits.
- Larvicides for use in multiple settings and inexpensive biologics: Biologics are expensive (2-3 times more expensive than traditional insecticides), while larviciding is not feasible in many high burden areas due to the large number of breeding sites. Research is needed to develop opportunities for less expensive biologics and more operational research indicating where larviciding may be feasible (or applications where larviciding can be feasible in regions previously thought inappropriate).
- Novel mechanisms for killing vectors: Consumer products such as sprays, repellants and coils are being purchased and used by private buyers primarily for nuisance-abatement. However, current evidence shows that these products are not effective against malaria control. Additionally, there is potential for greater impact through other evidence-based barriers to biting, such as spatial repellents, novel toxins and others. Housing modification interventions such as screening could also be evaluated further. Merging nuisance-abatement and anti-malarial properties into combination products will likely enable pull-through from buyers and increased impact on transmission.
- Control methods and personal protection measures for outdoor biting vectors The major forms of vector control today, IRS and LLINs, are almost ineffective at addressing outdoor-biting vectors. While other impregnated materials (e.g. blankets, insecticide-treated hammocks and nets for hammock) are more promising in these environments, there is still a gap in tools which effectively target these vectors.
Status of the Research. Many researchers are working to increase the breadth and depth of the vector control pipeline, mostly in the pesticide category. For example, the Innovative Vector Control Consortium (IVCC) brings researchers together to develop new and improved products to control transmission of vector-born diseases.[86]See Innovative Vector Control Consortium website.
Click for source Several products aimed at addressing two of the opportunities outlined above, targeting resistance and improving IRS, include:
- Two new formulations for LLINs to reduce reliance on pyrethroids;
- Tools to monitor pesticide resistance in Africa, to launch in early 2009; and
- Five new formulations for longer-lasting IRS to launch in the near term.
The current vector control pipeline is detailed in Figure II.11. Only programs in the public domain are illustrated (IVCC, Bill & Melinda Gates Foundation, National Institutes of Health, etc). While some private developments are active, they are not shown for reasons of intellectual property protection and confidentiality.
Figure II.11: Current vector control pipeline and opportunities
Note: Only programmes in the public domain are illustrated (IVCC BMGF, NIH etc sponsored). While some private developments are active they cannot be shown for reasons of IP protection and confidentiality
Source: Innovative Vector Control Consortium
Proposed Recommendations. R&D opportunities for improving vector control include:
- New chemistries and targets for killing vectors (including development of new active ingredient classes to stave resistance);
- Research into safe, longer-lasting, insecticides for IRS and LLINs;
- Development of less expensive but still highly effective pesticides and biologics;
- Interventions targeting outdoor-biting vectors; and
- New mechanisms for application and use, such as new tools for spraying or fogging, consumer products with evidence-based efficacy, and other impregnated materials (curtains, wall-paper, mosquito-proofing).[87]Information taken from presentation by Guillet P at the 2008 WHO Informal Consultation on Global Malaria Control and Elimination, 2008; Lines J, Whitty CJM, Hanson, K. Prospects for Eradication and Elimination of Malaria: A Technical Briefing for DFID. December 2007; Interviews with topic experts.
Opportunities to improve treatment. Effective treatment is an essential part of Malaria Control Programs. The only drugs recommended currently by WHO for the treatment of uncomplicated P. falciparum malaria are artemisinin-based combination therapies (ACTs). (The drug combinations include artemether-lumefantrine, artesunate + amodiaquine, artesunate + mefloquine, artesunate + sulphadoxine–pyrimethamine). Chloroquine and primaquine are recommended for uncomplicated P. vivax. Opportunities that might be addressed with research and development include the following:
- Reducing the costs of treatments. While ACTs are highly effective against P. falciparum, price is a significant barrier to widespread uptake. At costs ranging from 50 cents to more than US$ 5 depending on the manufacturer,[88]Board on Global Health (BGH). Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance, 2004.
Click for source more work is needed to bring the cost of treatment for all ACTs down to an affordable level for both public sector purchase and individual access. Active ingredients with lower cost of goods for treatment of P. falciparum malaria are needed. - Increasing compliance with drug regimens. Unusual dosing regimens of some earlier ACTs are cited as barriers to compliance which not only lead to treatment failures but could potentially increase drug resistance. Three ACTs now have once daily dosing: Amodiaquine Artesunate, Dihydroartemisinin – Piperaquine and Pyronaridine – Artesunate.[89]Their brand names are Coarsucam, Eurartesim and Pyramax, respectively. A single-dose cure would be even more advantageous, and this is part of the optimal target product profile for any novel P. falciparum therapy.
- Improving the shelf life of ACTs. ACTs have a relatively short (~2 year) shelf life, which is particularly challenging in developing world settings. Currently one drug in the pipeline, Pyronaridine-artesunate, is addressing this gap, and is projected to have a 3-year shelf life. Other non-ACT combinations will need to be developed with an ultimate objective of a 5-year shelf life.
- Treatments for small children and expectant mothers. New formulations and dosages for the treatment of small children (less than 12 months) and expectant mothers are needed. A deepened understanding of the pharmacokinetics of medicines is key, since metabolism in these patient groups is very hard to predict. In addition, new medicines are needed for intermittent preventive treatments of infants and of expectant mothers.
Status of the research. Several companies and organizations, including the Medicines for Malaria Venture (MMV), are investing to increase the breadth and depth of the drug pipeline to address the gaps. The current drug pipeline is detailed in Figure II.12. Key products in the pipeline include five late-stage ACTs; each use different companion drugs in order to reduce selection pressure and help minimize risk of resistance development. Another product is Tafenoquine, which is being developed as a radical cure for P. vivax. Artemisinin products for severe malaria are also in development, and include suppositories and intravenous formulations. Intermittent preventive treatment is being pioneered with non-artemisinin combinations (Azithromycin-Chloroquine) as well as those which contain artemisinin (Eurartesim: Dihydroartemesinin Piperaquine). The early stage pipeline contains a wide variety of drugs targeting new mechanisms, which although higher risk from a development viewpoint, will ensure as wide a protection as is possible against the emergence of resistance.
Figure II.12: Current drug pipeline
Source: Medicines for Malaria Venture
Challenges. Effective treatment of all populations, especially infants and expectant mothers is a priority. Given the relative lack of pharmacovigilance, accurate monitoring and reporting of safety and adverse event profiles are essential.
- Risk of emergence to artemisinin. Potential emergence of resistance to artemisinin is one of the major dangers to treatment effectiveness. Historically, resistance to anti-malarial drugs has emerged to all drugs used for treatment. Patients with delayed parasite-clearance times have already been detected, and it is only a matter of time before artemisinin-resistant strains will emerge. To combat this, a robust pipeline of new medicines is needed, including non-artemisinin-based combinations with novel mechanisms of action. Ideally, a radically new treatment should be ready for launch into the community every 5 years. More artemisinin combinations and perhaps “combinations of combinations”, though costly, may be necessary to slow emergence and build-up of resistance.[90]Interviews with topic experts. Separate drugs specifically tailored for IPT and mass drug administration (MDA) should also decrease pressure on the drugs that are used for standard case management. Diversifying the number of tools used may enable the renewed use of drugs previously lost to resistance (e.g. chloroquine, SP), especially where clinically synergistic effects (such as with Azithromycin and chloroquine) are seen.
- New interventions for certain populations. Another challenge is that ACTs cannot be used by pregnant women in the first trimester. Other options which can be used in all stages of pregnancy should be developed and evaluated. These studies will take considerable time to minimize risk to mother and unborn child, but also to optimize the dose based on an understanding of pharmacokinetics. In pediatrics, treatments for use in infants of less than 12 months need to be optimized to ensure correct dosing. Treatments also need to take account of variations in nutritional status of the child. Additionally, two aspects of the immune status need to be allowed for – firstly, the immune status of the patients can be modified by co-infections (such as HIV/AIDS), and then, increasingly with vaccination post-launch. Given that vaccination is only estimated to protect a percentage of the population, careful study of the therapy for breakthrough infections will be needed.
- New approaches to intermittent preventive treatment. This work needs to proceed along two lines. First are the clinical studies to test the hypothesis of intermittent preventive treatment with combinations of medicines which already exist. Looking longer term, new medicines are needed with the appropriately long half lives for such IPT regimes. Given the propensity of long half-life drugs to induce resistance, new medicines with unprecedented mechanisms will be a priority.
- Interventions for patients with severe malaria. More interventions are also needed for patients with severe malaria. Nearing completion of development, rectal artesunate will be for patients too ill to take oral medications and too far from health facilities to receive an injection.[91]Gomes A. Rectal artemisinins for malaria: a review of efficacy and safety from individual patient data in clinical studies. BMC Infectious Diseases, 2008, 8:39.
Click for source A temporary solution until patients reach a hospital, it has been shown to clear parasites faster than parenteral quinine. - Implementation studies of new medicines. Given the challenges of health care in malaria-endemic countries, it is important to have studies on the implementation of new medicines within the local healthcare systems. Here, important data on compliance and uptake can be gathered, along with accurate data on safety and adverse events. See Section II – Chapter 4C: Operational and Implementation Research.
Recommendations.R&D opportunities for improving treatment include:
- Development of drugs with improved stability and a longer shelf life, dosing regimens that promote compliance (e.g. single dose for uncomplicated malaria), and lower price;
- New, improved interventions for patients with severe malaria;
- New curative and preventive treatments for under-served populations at high risk of the disease (e.g. infants, children, pregnant women, immune-compromised patients); and
- New drugs which pre-empt emergence and impact of resistance.
Opportunities to improve diagnosis. Improved case management requires accurate diagnosis, either through microscopy or rapid diagnostic tests (RDTs). RDTs can be used for populations at risk for P. falciparum and P. vivax in all malarious areas today, and are especially suitable for areas with little or no infrastructure. Over 100 RDTs from 50 different manufacturers exist today. However, several performance and quality issues surrounding some RDTs should be addressed in order to gain the full benefit from their use.[92]P. Ringwald. Antimalaria Medicines and Diagnostics: Strengths and Limitations. Presented at the WHO Informal Consultation on Malaria Control and Elimination, 2008.
- Improved reliability of diagnostics. The sensitivity and stability of RDTs are often inconsistent and sometimes unreliable. Field microscopy has also been demonstrated to be of poor quality in many endemic areas. Consequently, there is considerable evidence that health care providers do not use the results of diagnostic tests, even when they have them. RDTs with improved effectiveness, sensitivity and stability are needed in order to increase trust within the health care sector (both of patients and providers) and improve case management. This will be even more important as the proportion of malaria cases among all febrile illness declines.[93]Frost L. MRDTs: Global Scaling up and Introduction of new diagnostic method for malaria. Harvard School of Public Health.
- Quality assurance: Quality assurance systems are often inadequate or non-existent. Systems for both microscopy and RDTs need to be strengthened in order to improve the accuracy of, and confidence in diagnosis for case management and for monitoring of disease burden. There are currently quality tests under development, specifically designed for use by community health care workers in low-resource environments. Launch is expected in 2009, and the priority will be ensuring rapid scale-up and use of these to confirm the effectiveness of batches of RDTs.
- Diagnostics for identifying different risk factors. Lastly, some experts recommend development of diagnostics to identify at-risk groups (e.g. G6PD deficiency) where drugs may do more harm than good.
- Lower cost RDTs: The cost of RDTs, which is similar to that of a treatment course, is also cited as a barrier to use, and often leads to presumptive treatment. More affordable yet still highly accurate tests will be needed to facilitate widespread diagnosis.
Proposed Recommendations. The key R&D opportunities for improving diagnostics are:
- Low cost, consistently accurate RDTs for both P. falciparum and P. vivax and
- Quality assurance systems for RDTs and microscopy.
Vaccine opportunities. Effective malaria vaccines would be useful in the sustained control stage to reduce morbidity and mortality.[94]Lines J, Whitty CJM, Hanson, K. Prospects for Eradication and Elimination of Malaria: A Technical Briefing for DFID. December 2007. From 2005 to 2006, more than 230 experts representing 100 organizations participated in the Malaria Vaccine Technology Roadmap Process.[95]This effort was called for by the Malaria Vaccine Advisory Committee to the WHO, coordinated by the WHO Initiative for Vaccine Research (IVR) and sponsored by the Bill and Melinda Gates Foundation, PATH Malaria Vaccine Initiative (MVI), and the Wellcome Trust. This collaboration led to two stated goals: by 2015, to develop and license a first-generation P. falciparum malaria vaccine with a protective efficacy against severe disease and death of more than 50% and which lasts longer than one year; and by 2025, to develop and license a malaria vaccine with a protective efficacy against clinical disease of more than 80% and which lasts longer than four years.
Status of the Research. The new tools at the disposal of the malaria vaccine research community, combined with the decoding of the P. falciparum, P. vivax and other experimentally relevant animal model parasite genomes (e.g. P. knowlesi and rodent malaria parasites) and the infusion of significant financial resources, are making possible new advances in malaria vaccine development. Categories of vaccines under development include those which prevent, delay or diminish infection, those which interrupt transmission and those which decrease anemia and other severe symptoms in persons infected with parasites. The most clinically advanced vaccine candidate, RTS,S, has been shown to be safe and efficacious when administered to children aged one to four years, reducing infection, mild and severe disease over an 18-month period. More recently, it has been shown to be safe in young infants, reducing infection by 65% over a three-month follow-up period and episodes of clinical malaria by 35% percent over a six-month follow-up period starting after the first dose.
Worldwide, there are about 40 P. falciparum candidate malaria vaccines or vaccine components in the pipeline[96]The Malaria Product Pipeline: Planning For the Future. The George Institute for International Health, September 2007.
Click for source and only a few for P. vivax. Only one vaccine for P. vivax (the Duffy Binding Protein, Region II) is heading towards clinical trials. Experience with vaccine development, in general, shows that perhaps one in ten will make it through the development process and into use. As yet, however, it is not known whether this success rate will hold true for malaria vaccines. The overall vaccine portfolio is characterized by a legacy of blood-stage candidates, more recent pre-erythrocytic candidates and reflects the entry of new platforms (such as viruses) into the pipeline.
Challenges. While considerable progress has been made in malaria vaccine development, developers will need to overcome significant challenges to arrive at a vaccine with at least 80% efficacy, the 2025 goal described above.[97]Interviews with personnel from the Center of Disease Control (CDC), National Institute of Allergy and Infectious Disease (NAID) and National Institutes of Health (NIH). First, no human vaccine has ever been developed against a parasite: all vaccines currently in use target either viruses or bacteria. Second, the malaria parasite is extremely complex, which may require unique approaches to target the different stages in its lifecycle. Third, the ability of the pathogen to quickly mutate and evade the immune system makes it a more challenging target. Fourth, evasion of even a few pathogens from a vaccine has the potential to cause serious illness, especially in malaria-naïve individuals.
To address these challenges, new antigens, platforms and adjuvants, are needed[98]Malkin E, Dubovsky F, Moree M. Progress towards the development
of malaria vaccines. Trends in Parasitology, 22, 2006.
Click for source as well as additional assays and other evaluation technologies to inform decision-making. Figure II.13 provides a simple illustration of the four areas of research seen as crucial to developing a vaccine of at least 80 percent efficacy by 2025.
Figure II.13: Areas of research for vaccines
Source: Malaria Vaccine Initiative
- Antigens. Antigen discovery remains a crucial area of research within the malaria vaccine field, given the limited number of antigens — whether blood-stage or pre-erythrocytic — currently under development and the strong likelihood that a more effective, next-generation vaccine will need to combine vaccine components and approaches.
- Platforms. Viruses, bacteria, virosomes, and nanoparticles are among the platforms or delivery vehicles under exploration in the malaria vaccine R&D field. As with antigens, platforms may be used in combinations to induce a larger number of more robust specific responses including increased breadth, magnitude, and duration of induced immunity.
- Assays and evaluation technologies. Enhancing methods for in vivo and in vitro assessment of candidate vaccines is another critical need in malaria vaccine R&D. Investments to develop and refine evaluation tools, such as in vitro assays and human as well as non-human primate challenge models, and the support of reference and service centers, are needed to capitalize on the prospective value that can be generated from the comparative assessment of candidate vaccines. Success in this area would yield a significant return over the long-term by providing robust data to inform development decision-making and reduce development investment risk.
As necessary scientific advances are being made, vaccine access strategies should be addressed. Cost and cost effectiveness will be key to enabling broad population access to the vaccine. Additionally, effective distribution strategies (e.g. including a vaccine within existing Expanded Program for Immunization (EPI) schedule or alternative distribution systems) and proactively dealing with potential cold chain and scalability issues will be important. Regarding EPI, operational research should be conducted on inclusion of a partially protective malaria vaccine into the program, and its impact on mothers’ perceptions of the EPI program and vaccines in general when mothers are accustomed to completely preventive vaccines. (See Section II – Chapter 4C: Operational and Implementation Research)
Proposed Recommendations. R&D opportunities for vaccine development include:
- A "next-generation," highly-efficacious vaccine that combines vaccine approaches and targets P. falciparum; and
- Vaccine access strategies that address policy and regulatory challenges, introduction and roll-out, advocacy and communications, and ongoing distribution.
R&D for Elimination/Eradication
Most experts believe elimination is not possible in high transmission areas with today’s tools. In order to facilitate a consensus-driven approach to address tools needed specifically for elimination and eradication, the Bill and Melinda Gates Foundation hosted “The Consultation on R&D for Malaria Eradication” in March 2008. The meeting engaged an ad hoc group of experts across all malaria interventions to develop a framework for considering R&D issues and to lay out a process to organize these efforts. The outcome of the future consultation process will be strategies and target product profiles needed to achieve the goal of eradication, focusing on the following seven themes: drugs, vaccines, vector control, modeling, M&E/surveillance, integration strategies, and health systems/operational research/diagnostics. Although the priorities are still to be developed, some of the preliminary questions and hypotheses regarding the tools needed are listed below.
Opportunities to improve vector control. In addition to the gaps in control listed previously, there are opportunities to improve vector control.
- Increased emphasis on Integrated Vector Management (IVM): As defined by WHO, IVM is a “rational decision-making process for the optimal use of resources for vector control” across all vector-borne diseases including malaria.[99]Position Statement on Integrated Vector Management. Geneva, World Health Organization, 2008.
Important attributes of IVM include employing the most cost-effective methods for a particular setting, leveraging inter-sector approaches (e.g. involving health, agriculture, transportation and other government sectors) and ensuring effective decision-making processes at all levels. Unfortunately, stakeholders often are not able to take such a comprehensive, holistic view. This limited approach then results in the use of interventions and approaches which may not be effective for a particular transmission setting.
While these concepts are important during the initial control stages, they also fit well within the elimination stage. IVM relies on sustaining and consolidating the public health achievements achieved during the scale-up stage through an inter-sector approach, which are key components of elimination programs. - Larval source and environmental management: Historically, environmental management was the key to elimination in many environments, including the U.S., and is key to the elimination programs of several low- to moderate-transmission countries including the United Arab Emirates and Oman. In Africa, however, the ecology of the malaria vectors, especially the ubiquity of breeding sites, their relatively long flight range, and high vectorial capacity make them extremely difficult to control through larval source management. While recent projects in urban Dar es Salaam and the African highlands are encouraging, more work is needed before this can be considered on par with LLINs and IRS.[100]Michael MacDonald, USAID, personal communication, 2008.
Proposed Recommendations. The key opportunity for improving vector control for elimination is:
- Additional research into applications of larviciding and environmental management in various transmission settings.
Opportunities to improve treatment. Treatment becomes even more important when regions strive for elimination, as areas change from high- to low-transmission settings and as incidence and, consequently, natural immunity decline. Some of the key research questions and needs involving treatment relate to drugs which interrupt (and sustain the interruption of) transmission and those targeting asymptomatic reservoirs of disease.
- Interventions which interrupt transmission. With elimination as a goal, new strategies to interrupt transmission from humans to mosquitoes will be essential. New medicines which target the gametocyte stages will be especially important in reducing transmission in areas where there is already a partial immune reaction to the parasite. Given that these patients will be asymptomatic, then particular attention has to be paid to the safety profile. Currently, primaquine and tafenoquine (in development) kill gametocytes more effectively, but carry a risk of haemolysis[101]Destruction or dissolution of red blood cells with subsequent release of hemoglobin. which can be dangerous if populations have a prevalence of G6PD deficiency, as is common in malaria-endemic populations.[102]Lines J, Whitty CJM, Hanson, K. Prospects for Eradication and Elimination of Malaria: A Technical Briefing for DFID. December 2007.
- Targeted interventions for P. vivax. Medicines specifically targeting P. vivax must be considered, especially for the elimination stage. Primaquine and tafenoquine, as well as chloroquine, are available to treat P. vivax. However new protocols are needed: primaquine is currently once per day for 14 days, and chloroquine resistance is common. P vivax has the dormant liver stage hypnozoite form, and medicines which kill hypnozoites will be essential to prevent relapses after the primary infection.
- Drugs and approaches which target asymptomatic carriers. Asymptomatic reservoirs, parasite-positive individuals who contribute to the transmission pool but have no malaria symptoms themselves and are therefore not treated, is another issue that should be addressed. Mass screening and / or mass drug administration (MDA) may be considered in later stages to minimize or eliminate infectiousness of asymptomatic reservoirs.
MDA has been attempted in the past with mixed outcomes. In some instances, it has had poor long-term results and undesired consequences, and could potentially exacerbate drug resistance. However, some experts believe that MDA can be used effectively to eliminate parasites in asymptomatic carriers. More research is needed to determine when and where MDA is most appropriate, and which drugs work best while minimizing resistance. A preliminary target product profile for MDA includes safe, effective drugs that have a long half life and simple dosing; they would be different from the first-line recommended treatment to minimize risk of resistance development.
Proposed Recommendations. R&D opportunities for improving drugs for elimination include:
- Interventions and approaches which target asymptomatic reservoirs;
- Drugs which interrupt and sustain interruption of transmission;
- Treatments which target liver-stage disease; and
- More treatments which target P. vivax.
Diagnostic opportunities. Many of the recommendations listed for control are also relevant for elimination. For example, lower-cost, higher accuracy diagnostics will play an important role as more active case detection is undertaken. One requirement more relevant for elimination is the identification and targeting of asymptomatic reservoirs of disease. Targeting, diagnosing, and treating these individuals will be essential to interrupting transmission.
Proposed Recommendations: R&D opportunities for elimination include
- RDTs which target asymptomatic reservoirs of disease.
Vaccine opportunities. Many scientists believe that the development and implementation of effective malaria vaccines, especially against the predominant species P. falciparum and P. vivax, will be critical to achieve malaria eradication. With malaria vaccines potentially within reach, it is important that the international community continue to support and increase investments in malaria vaccine research.
- P. vivax: A vaccine for P. vivax is increasing in development priority. Vaccines which target P. vivax may in fact prove to be necessary to achieve elimination and eradication.[103]Lines J, Whitty CJM, Hanson, K. Prospects for Eradication and Elimination of Malaria: A Technical Briefing for DFID. December 2007. P. vivax is genetically distant from P. falciparum, and scientific evidence strongly suggests that vaccines targeting each species will be required. All four human malaria species in fact have their unique biological characteristics, which could prove to be relevant for targeting their ultimate eradication with malaria vaccines or drugs, along with other intervention tools. P. vivax and P. ovale, for example, both have dormant ‘hypnozoite’ forms in the liver. Very little is understood about these dormant forms, which can reinitiate blood-stage infections at a later point in time, in the absence of reinfection by the bite of an infected mosquito. The presence of these dormant forms is an added challenge, which adds epidemiological complexities and will require scientific investigation to devise special hypnozoite-specific interventions that will target these forms of the parasite.
- Transmission-blocking: As with treatment, a vaccine that can interrupt and sustain interruption of transmission would be a valuable tool in the arsenal for achieving elimination.
Proposed Recommendations. R&D opportunities for vaccine development for elimination include:
- Greater emphasis on developing and testing vaccine candidates that target P. vivax, whether alone or in combination with a P. falciparum vaccine component; and
- Vaccines that block transmission.
Delivery Research in All Stages
In ensuring successful control and elimination, the effective delivery of interventions is just as important as discovery and development to ensure the full potential impact of interventions is realized. In fact, inefficient rollouts have caused delays of up to 3 years for developing country populations awaiting interventions. Strategies to improve access and delivery should be developed, including for difficult-to-reach groups, and built into product characteristics when possible. These are described in more detail in other sections and include:
- Approaches to ensure policy and regulatory approval at global and country levels (See
- Part IV - Chapter 4: Policy and Regulatory
and Part II – Chapter 4B: Research to Inform Policy); - Plans to facilitate rapid introduction, roll-out, and scale-up of interventions (See Part II - Chapter 2: Control and Part II – Chapter 4C: Operational and Implementation Research);
- Advocacy and communication plans to ensure appropriate use and demand generation (See Part IV - Chapter 8, Communication and Behavior Change Methodologies);
- Advocacy and financial instruments to increase resources for R&D (See Part IV - Chapter 3: Resource Mobilization and Part IV - Chapter 6: Financing); and
- Approaches to enable effective, sustainable, distribution through all appropriate channels (See Part IV - Chapter 7: Procurement and Supply Management).
Additional Research in All Stages
Significant early-stage research is needed to enable later-stage drug development and understand mechanism of disease, disease targets, genome sequencing, mixed infections, biomarkers, transmission dynamics, vector biology and basic epidemiology. A better understanding and new discoveries of the basic biology of the malaria parasite and host will contribute to the development of the most appropriate, effective new tools and approaches (e.g. genetically-modified mosquitoes).
For example, the sequencing of the Plasmodium genomes allows a jump start on identifying new targets for anti-malarial drugs. It is possible to specifically identify new target classes, or members of well known target classes which are significantly different. In addition, the development of miniaturized assay formats and image processing enables the study of the effects of large collections of compounds on specific stages of the parasite life cycle. Over 5 million compounds have recently been tested this way, including using high content screening approaches. Taken together these approaches will be useful in identifying the novel starting points which are the basis of the new therapies required for malaria elimination.
Other research and modeling. Combinations of tools will be needed in the battle to control and eventually eliminate malaria; however there is a knowledge gap regarding the impact of combinations of interventions, in particular, whether intervention benefits are synergistic or additive. Therefore, more research should be conducted on the impact of using a portfolio of tools, not just on single interventions. See Section II – Chapter 4C: Operational and Implementation Research.
Modeling can also be used to predict the potential impact of combinations of tools, such as the impact of vaccines of different efficacy levels on the amount and type of treatment needed. In addition, models can help predict optimal product profiles to inform the R&D agenda.
Additionally, as transmission declines, more knowledge will be needed on the impact of drugs in the context of decreasing immunity and the consequential increase in adult disease.
Table II.2: Overview of R&D opportunities for control and elimination
