Novel Intervention Strategies
Challenges
Two major types of challenge for the development of new medicines against malaria remain: difficulties in the nature of the disease (including virulence factors, epidemiology, and environment) and difficulties centering around drug discovery and the pharmaceutical industry. Emergence and spread of resistance are always major concerns in infectious disease, and recent reports in the literature confirm decreased patient responses to artemisinin derivatives in South-East Asia combined with decreasing efficacy of the partner drugs used in artemisinin combination therapy (ACT). Replacements for artemisinin-based endoperoxides and combination partners are urgently required. Ideally at least one component needs to be as fast-acting as the artemisinin derivatives to provide rapid relief of symptoms, and as affordable as chloroquine was when it was used as first-line treatment. Modeling studies underline the key role that medicines can play in malaria eradication. Medicines can be used both to treat patients' symptoms and cure them of acute disease, as well as prophylaxis or chemoprotection, and these can play a complementary role alongside a partially effective vaccine. In addition, there are indications that the mosquito vector ( Anopheles ) is developing behavioral strategies to evade insecticide treated nets, and resistance to the pyrethroid class of insecticides used in the nets is increasing. The cost of failure in malaria control is high: the historical experience with chloroquine and DDT resistance shows that the loss of frontline interventions can have a devastating effect if a new generation of therapies and other interventions are not available.
The goal of long-term malaria eradication brought to light several issues relating to drug discovery for novel antimalarial therapies. First, the new medicines need to be able to reduce and, ideally, prevent transmission. Additionally, they need to safely prevent disease relapses with Plasmodium vivax and Plasmodium ovale, which can occur when dormant infections re-emerge, even after leaving malaria endemic sites. Significant post-treatment prophylaxis (treatment of a malaria case providing protection against future infection) may help to reduce the clinical burden of malaria especially in high-transmission areas, but currently available drugs are too toxic and/or expensive for this to be possible at this time. Lastly, new medicines will be needed for chemoprotection (causal or chemoprophylaxis) for vulnerable populations such as infants and expectant mothers. All of these medicines must be safe enough for use in sensitive patient groups, including pregnant women, the youngest of children and patients with other co-morbidities, such as HIV and TB infection, or malnutrition, and correct doses must be selected for each group. It is important to emphasize that due to the combination of these constraints there is unlikely to be a one-size-fits-all solution in the campaign to eliminate malaria; and many of these issues cannot be tested or addressed until Phase IV, after extensive and expensive trials have already occurred.
Malaria Vaccine
Malaria vaccines are considered amongst the most important modalities for potential prevention of malaria disease and reduction of malaria transmission. Research and development in this field has been an area of intense effort by many groups over the last few decades. Despite this, there is currently no licensed malaria vaccine. The complexity of the malaria parasite makes development of a malaria vaccine a very difficult task. Given this, there is currently no commercially available malaria vaccine, despite many decades of intense research and development effort. Over 20 subunit vaccine constructs are currently being evaluated in clinical trials or are in advanced preclinical development.
There are a number of ongoing attempts to develop an effective vaccine for malaria, but at this writing, RTS,S is the most promising and is currently being evaluated in phase 3 clinical trials in Africa. This vaccine was developed through a partnership between GlaxoSmithKline Biologicals, the PATH Malaria Vaccine Initiative (MVI) and the Bill & Melinda Gates Foundation. Phase 2 trials suggested about a 50% reduction of malaria in children. If the phase 3 trials confirm the safety and efficay of the vaccine, it could be widely available in 5-10 years. Unformtunately, RTS,S provides protection against only Plasmodium falciparum alone, with no protection against P. vivax malaria. Phase 2 trials also suggested that the effectiveness waned over time.
Genetically Engineered Mosquitoes
Current insecticide-based vector control strategies such as insecticide-impregnated bed nets, as well as other population-suppression strategies. [e.g., sterile-insect technique (SIT) and or RIDL (release of insects with dominant lethality) have the drawback of creating an empty ecological niche. Since the environment in which mosquitoes thrive remains unchanged, the mosquito population will return to its original density when the intervention ends or when mosquitoes become resistant to the insecticide. As a result, any population-suppression strategy would need to be implemented indefinitely. An alternative approach would be to hinder the ability of the mosquito to support parasite development in order to reduce or eliminate transmission. For example, it might be possible to genetically modify the mosquito in a way that enable secretion into its midgut of gene products that inhibit parasite development.
Transgenesis and Paratransgenesis
Transgenesis and paratransgenesis are two novel promising means for interfering with Plasmodium development or infection of the vector mosquito through delivery of anti-Plasmodium effector molecules within the mosquito. Both are population-replacement strategies that, once implemented, should require much less follow-up effort than population-suppression strategies. Rather than reducing mosquito populations and creating an empty niche, these strategies work to render the current population of mosquitoes unable to harbor and transmit the malaria parasite.
Mosquito transgenesis has the advantage of having no off-target effects because transgene expression is restricted to the engineered mosquito. The anti-Plasmodium effector genes can be engineered to express in specific tissues (midgut, fat body, and salivary glands), only in females, and in a blood-induced manner.
Paratransgenesis refers to an alternative approach for delivery of effector molecules via the genetic modification of mosquito symbionts. Advantages of paratransgenesis are the simplicity of genetic modification of bacteria, the ease of growing the genetically modified bacteria in large scale, the fact that it bypasses genetic barriers of reproductively isolated mosquito populations, and effectiveness does not appear to be influenced by mosquito species.
Concerns with Genetic Modification
A major challenge is the development of effective means to introduce engineered bacteria into field mosquito populations. This may be accomplished by placing around villages, bating stations (cotton balls soaked with sugar and bacteria placed in clay jar refuges) using engineered symbiotic bacteria that are vertically and horizontally transmitted among mosquito populations. However, no experimental evidence for the effectiveness of such an approach is presently available. Moreover, for future use in the field, the effector genes need to be integrated into the bacterial genome to avoid gene loss and also to minimize the risk of horizontal gene transfer.
Although many technical aspects have been successfully addressed, several major issues need to be resolved before transgenesis and paratransgenesis can be implemented in the field. Resolution of regulatory, ethical, and public acceptance issues relating to the release of GM organisms in nature must be addressed before these interventions can move forward. Although the subject of genetically modified organisms is controversial, its resolution will ultimately rely on weighing risks against benefits. As these issues are considered, the benefit of saving lives should provide a strong argument in its favor.
Transgenesis or paratransgenesis is not a cure-all solution for malaria control. Rather, both are envisioned as a complement to existing and future control measures. In this regard, transgenesis and paratransgenesis are compatible with each other (possibly additive) and with insecticides and population suppression approaches. Moreover, the diversity of effector proteins make both approaches not unique to malaria but might also be extended to the control of other major mosquito-borne diseases, such as dengue and yellow fever.
Outlook for Eradication
Global eradication of malaria is technically possible, but currently not feasible. Since malaria has a limited natural primate reservoir and the parasite-vector lifecycle is complex and vulnerable, multi-pronged intervention strategies could, in theory, eradicate the disease. Eradication is a long way off, and would require stronger tools for detection, prevention, and treatment than are currently available. An eradication strategy must begin with an inclusive dialogue that elucidates a clear global strategy and connects researchers, information, and funding to promote a unified approach. Eradication also requires better vector and parasite control methods, since current practices either promote resistance or leave populations vulnerable to re-emergence. Novel treatments are needed to combat resistance to antimalarials, and these should ideally be non-toxic and inexpensive enough for mass administration and prophylaxis, where appropriate. Perhaps most importantly, detection and surveillance systems need to be implemented and supported across national borders, to pinpoint and control outbreaks early on, and to maintain vigilance for disease re-emergence and vector encroachment in places where the disease has been eliminated.
Current strategies and those in development, when used in combination, have the potential to reduce the global burden of malaria to lower levels than have ever been possible. For the first time in over 40 years, eradication is no longer being discussed as a fantastical Holy Grail, but as something that is actually possible, if far off.
Below are two provocative talks from TED.com.
- TED Video: Sonia Shah: 3 reasons we still haven't gotten rid of malaria
- TED Video: Bill Gates: Mosquitos, malaria and education
