Big thanks to Alanna Shaikh and Bill Brieger for feedback and comments.
Debates about malaria eradication in the aid blogosphere, along with recent scientific evidence, highlight the urgent need to improve our understanding of the complex dynamics of this terrible affliction and to use it to adapt ongoing eradication programmes.
A nearly hopeless case?
According to the WHO, one in every five childhood deaths in Africa is due to the effects of the disease and an African child has on average between 1.6 and 5.4 episodes of malaria fever each year. A child dies every 30 seconds of malaria. The latest estimate from the 2010 World Malaria Report is that in 2009 the disease killed almost 800,000 people and afflicted 225 million others. And while a 2009 global malaria risk map suggests that while risks are worst in Africa, there are clear indications of dangers in many other countries too.
Last week Chris Blattman posted a justifiably scathing response to an article in Guernica, which had suggested that attempts to eradicate malaria are ‘nearly hopeless‘, and that current global attempts to do so are doing more harm than good.
Chris put forward an eloquent and moving counter-argument which included the following points (a) disease eradication is one of the few successes of big aid (b) we can’t simply let malaria take its toll and do nothing (c) presenting malaria as a symbol of African honour – as the Guernica article does – is at best inaccurate and misleading and (d) development is the key to successful eradication.
Many (myself included) would agree wholeheartedly. Evidence suggests that the cessation of malaria control programmes can lead to severe epidemics, as in Swaziland in 1984-85, or Madagascar in 1987-88. Shortfalls in ongoing responses have also led to resurgences in Zambia and Rwanda. Much of what is presented in the Guernica article can be dismissed as bizarre, confused or just plain wrong. However, one point made is worth looking at in more detail.
Premature pronouncements and cheap mainstays
The author suggests that current approaches to malaria tend to be narrowly focused on a limited number of technical solutions, or the search for such solutions. Think bednets, drugs or the investment in the development of vaccines.
In fact, this narrowness in the focus of malaria programmes appears to have been a relatively constant feature over the last 40-50 years. In 1969, the Pearson Commission (the source of the ubiquitous 0.7% of GDP aid target for donor countries) pronounced the disease ‘virtually eliminated’. Today it is hard not to see this declaration alongside Chamberlain’s ‘peace for our time’ as one of the most premature statements ever (as well as a little disingenuous from the standpoint of developing countries).
[the 1960s eradication campaign] was far too monodimensional, relied too much on DDT [insecticide] spraying, and neglected the palpable problem that the delivery infrastructure was not in place in too many parts of the malarious world.”
It goes on:
The emergence of widespread mosquito resistance to DDT, and parasite resistance to the cheap mainstay of therapy compounded the difficulties.” (emphasis added)
In short, narrowness of responses allowed evolutionary dynamics to play out at various levels, changing the efficacy of those responses. This problem has not gone away. As clinical microbiologists Richard Carter and Kamini Mendis see it, for the most part, the types of tools that are available and are used for malaria control today are the same as those which were available during the ‘virtual elimination’ era.
This point does need some nuancing. There was one approved insecticide during the first eradication effort, whereas there are now a dozen. The use of treated nets – which weren’t around in the 1960s – has been responsible for large drops in some countries. But even in those countries there is growing acknowledgement of the need for a better combination of responses to make further progress. ‘Cheap mainstays’ will not do the trick. As noted on Malaria Matters:
The malaria lifecycle is complex, and health systems designed to deliver malaria interventions [are] equally complex (and challenging), which means we cannot and should not expect a magic bullet in the near future.
If we want to better understand the complexity of malaria, a good place to start would be to understand the evolutionary dynamics at play.
Exploring evolutionary dynamics
Resistance to responses – whether among mosquitoes or the parasite itself – has been identified as an evolutionary phenomenon. Biology 101 tells us that all populations of organisms display genetic variation across members which enable some to handle particular environmental stresses and opportunities better than others. Natural selection has been shown to favour the evolution of pathogen populations that can resist the drugs and insecticides in their environments.
As the Lancet article cited above notes, resistance has evolved at two distinct levels. The malaria parasite evolves, developing drug resistance. One team of researchers has found that “Drug development programs exhibit a high attrition rate and parasite resistance to… drugs exacerbate the problem. Strategies that limit the development of resistance and minimize host side-effects are therefore of major importance.”
Specific parasites also adapt at the molecular level, according to the antibodies encountered in the host’s immune system. There is also the prospect of inter-species infections, whereby – for example – parasites mainly responsible for malaria among chimpanzees find ways to adapt to new human hosts, facilitated by greater human penetration of forest environments.
Mosquitoes also evolve to adapt to changing physical environments, human behaviour and pesticides. As described by Bill Brieger on his excellent Malaria Matters blog:
…Resistance to insecticides in [a mosquito sub-species] is receiving increasing attention because it threatens the sustainability of malaria vector control programs in sub-Saharan Africa. An understanding of the molecular mechanisms conferring… resistance gives insight into the processes of evolution of adaptive traits and facilitates the development of simple monitoring tools and novel strategies to restore the efficacy of insecticides…”
There have been numerous calls for more studies into how insects exposed to pesticides undergo strong natural selection and develop various adaptive mechanisms to survive.
Of course, human populations have also have co-evolved with malaria, and developed different kinds of resistance. The protective effects of the sickle cell trait is certainly the best known example, but there are others that have been identified, including genetic variations in the populations of Thailand and New Guinea which prevent against malaria-induced miscarriages. However, humans adapt genetically less quickly than the malaria parasite or the mosquito – waiting for or relying human evolution of resistance (as the Guernica piece seems to imply) is clearly not an adequate fall-back option.
Professor Karen Day, who has studied the historical evolution of malaria, is clear about the importance of this line of inquiry:
…From Ronald Ross’s discovery that malaria is transmitted by mosquitoes came the idea that we could control malaria by impacting the life span of the mosquito. If we can better understand the evolution and diversity of malaria, we may find an Achilles heel in the parasite or new ways to thinking about control….”
Slow take-up, slow scale-up?
However, while there is some basic research attempting to bring an understanding of evolutionary dynamics to the design of better drugs, pesticides, and even vaccines, there are still questions as to whether this knowledge is ready to be applied in programmes and at the necessary scale. The overall global malaria response may still be relatively limited in terms of its repertoire of responses.
For example, a 2009 study notes that the Global Malaria Action Plan (GMAP) of the Roll Back Malaria initiative sought to spray 172 million houses annually, and distribute 730 million insecticide-impregnated bed nets. The study concluded that if this was implemented with existing insecticides, with no acknowledgement of the scope for evolutionary response, the program would create unprecedented opportunities for the development of resistance among mosquitoes, and may also create new variants of mosquitoes.
The World Malaria Report 2010 shows that global efforts to prevent malaria through bednets and sprays reduced cases from 233m in 2000 to 225m in 2009 and 985k deaths in 2000 compared to 781k deaths in 2009. However, tellingly, the statistics also show that several African countries saw a resurgence of the disease – in part because of resistance and changing contextual factors.
Researchers at Maastricht University have argued that a fundamental issue is that much malaria modelling does not take into account evolutionary dynamics. By modelling global malaria as a complex adaptive system, the researchers have been able to review the efficacy of malaria strategies, and were also able to assess the potential implications of climate change.
Overall, their conclusion was that continued changes in human behaviour (such as in agricultural methods or urbanisation, which presents its own set of challenges), as well as human impact on the environment, will mean malaria will continue to evolve and confound current interventions in areas of high prevalence. They also make a complementary point to Professor Karen Day’s – eradication and control strategies that do not take account of these complex evolutionary dynamics may well make things worse, and could ‘substantially exacerbate the significance of malaria in coming decades’.
Some of these fears may be becoming reality. An article published in Science magazine in October 2010 suggested that the mosquito strain that is responsible for most disease transmission is in the process of rapidly evolving into two genetically distinct species. The hypothesis is that the two species are evolving in different directions in reaction to differences in environment and the challenges they face. The Imperial College researchers confirmed fears that this development is likely undermine efforts to control and treat malaria – conventional strategies are unlikely to be effective against both strains.
Forty years ago, malaria eradication failed at least in part because of a lack of diversity in the mechanisms employed, and the related evolution of resistance. Although global responses are broader than before, there are still questions about whether they are diverse enough, and whether the full breadth of approaches and knowledge are being applied at scale. Narrowness in responses may, in the worst case scenarios, be making human populations more vulnerable to malaria.
This means supporters of eradication and control programmes must continue to fund research that advances an evolutionary understanding and use it to keep ahead of the disease. This makes the levelling off of aid commitments reported in World Malaria Report 2010 all the more worrying, because much hope now lies in more funding for innovative basic and applied research. At least some of this research should start with the premise that the dynamics of malaria requires a rethinking of global efforts, with a special focus on capacity of existing health systems to deliver a broader range of treatments.
In this area, like in so many other aspects of international aid, silver bullets may well be red herrings. But history and recent research suggests that this is not a battle that should be conceded easily. Rather, as Chris Blattman notes, we can take some heart and some lessons from previous eradication programmes.
Smallpox was famously wiped out in the 1970s, with the last case being in Merca, Somalia in 1977. When the eradication was announced in 1980, the campaign was described “a triumph of management, not medicine”. This was an especially unusual pronouncement given it was made by the-then Director-General of the WHO.
But what exactly did this mean? According to one major account, the DG was referring to the emergent process of adaptation and learning – the evolutionary process within the programme itself – which
…more than any other element in the campaign, [was] the key explanatory factor of the ultimate success of the program… ”
What eventually eliminated smallpox was the combined approach of top-down problem-solving—mass vaccination to reduce disease incidence to certain levels —and bottom-up emergent experimental innovations in early detection, isolation and control - to push towards complete eradication.
Of course, smallpox is a very different disease, and may have been a better candidate for eradication than malaria – exactly because of the evolutionary nature of malaria.
But there is an interesting message here: if we want to deal with the evolving problem of malaria, we also need the global response to adapt and evolve, for organisations involved to think and act ‘outside the box’.
It is not clear what this would look like yet, of course – but it is worth noting that the eventual strategy for dealing with smallpox eradication was not originally employed or even envisaged by the implementing organisations.
Whether current efforts are able and willing to take on such an adaptive management mentality remains to be seen.