Developing methods to assess the impact of malaria interventions upon transmission and the progress towards elimination

Malaria, an infectious disease transmitted by mosquitoes, is estimated to cause around 1 million deaths per year, with the majority of these deaths occurring in sub-Saharan Africa, primarily amongst young children. Over the last decade there has been an increase in funding from high-income countries and global agencies with the aim of reducing transmission and hence decreasing the burden of disease. This has resulted in the large-scale distribution of interventions of cheap and effective interventions such as the provision of protective bed nets and antimalarial medication in many parts of the world.

Malaria is, however, a complicated disease. It is spread between humans by mosquitoes and people become more immune to the disease the more they are infected (and less immune when they are not). This makes it difficult to work out the progress that has been made in reducing transmission. For example, a 50% reduction in the number of mosquito bites would not necessarily produce a 50% reduction in the proportion of people with malaria. Moreover, as transmission is imperfect and requires an infected mosquito to survive until it becomes infectious to humans, it is not necessary to kill all mosquitoes or prevent all members of the population from being bitten to achieve elimination.

In Western Kenya, particularly around the shores of Lake Victoria, malaria transmission remains intense, even in areas where bed nets have been used by the majority of the population for over a decade and despite the availability of effective anti-malarial medication for those with the disease. As a result, further intervention measures are currently being considered, including a forthcoming trial looking at the effects of testing all residents within a village for infection and giving highly effective anti-malarial medication to all those who test positive to infection in an attempt to break transmission. In order to better understand the progress towards this goal, and the implication the trial outcome has for malaria elimination more generally, it is important to understand where the trial started and where the trial ended in terms of transmission (i.e. the chances of an infected person passing infection to others via a mosquito), as this is the only reliable measure of the extent to which elimination is likely to be sustainable.

In this project, Dr Patrick Walker, a researcher at the Department of Infectious Disease Epidemiology, Imperial College, will use mathematical models of the spread of malaria to estimate the changes in transmission that occur during this trial to assess the progress being made towards local elimination of the disease. This will first involve developing a statistical technique which is able to estimate changes in transmission intensity during a previous trial of protective nets in the same area This work will also allow him to investigate the extent to which the disease spreads from one village to another and how this is affected by the presence of nets within different areas. This technique will then be adapted and applied to the different arms of the drug trial, taking into account changes in transmission up to the beginning of the trial.

In the event that the mass administration of anti-malarials proves effective as a tool for helping Western Kenya to eliminate malaria, this research will help to further define the criteria by which to judge where else in the world the intervention could be effective. Alternatively, if the intervention does not prove effective the work will provide an indication of the additional level of control required to achieve elimination. Moreover, monitoring whether transmission changes throughout the trial could provide an indication as to whether the effectiveness of anti-malarial drugs remains the same throughout the trial, which is an important consideration in light of concerns about drug resistance.

Malaria is estimated to cause around 1 million deaths per year, with the majority of these deaths occurring in sub-Saharan Africa, primarily amongst young children. Over the last decade there has been an increase in funding from high-income countries and global agencies and renewed interest in achieving local elimination in various regions and the prospects of global eradication of the disease.
Measuring progress towards elimination requires an estimate of the reduction in transmission that has occurred over time and the proximity to the threshold reproduction number value of one. However, these changes are not linearly related to measures of disease prevalence and burden (the quantities often used to track progress). The first aim of this project is to develop and adapt methods used for reproduction number estimation in epidemic models to estimate the changes in transmission which have occurred in an area of Western Kenya which has served as a key focus for malaria research over the past few decades. This will provide estimates of the additional control necessary to achieve elimination in an area of intense transmission with high LLIN coverage. It will also provide insights into the direct and indirect effects of insecticide treated nets and how this varies during a long-term intervention.
The second objective of this fellowship is to estimate the impact of different control strategies involving the mass administration of artemisinin combination therapy on transmission during a forthcoming trial in the same area. The detailed data likely to be collected during this trial will be used to estimate transmission at a high spatial and temporal resolution. Using the results from the first part of the project of the level of transmission and trajectory of changing transmission prior to the trial, I will then assess the extent to which reductions in prevalence are likely to be sustainable and the prospects for elimination, both within the study area and more generally.

The proposed research involves developing methods to assess the impact of interventions in terms of changes in transmission and progress towards elimination. This will also involve looking at the specific examples of the implementation and long-term use of ITNs and the impact of MSAT in areas of Western Kenya, a region which itself is the focus of much research interest. As a result, there are a wide range of likely beneficiaries of this work on a number of different levels.

At the local level, modelling the spatial and temporal dynamics of transmission in the area will provide public health officials and authorities with more information about how best to target available interventions, the possible impact of catch-up campaigns upon the likely spread of infection and the identification of key hotspots in transmission. Understanding the main foci of transmission in the area, before and after the IMSAT trial, is likely to be of particular importance when attempting to prevent any resurgence of malaria, if elimination has not been achieved by the end of the trial, or in ensuring elimination is sustained, in the event the trial is successful in completely interrupting transmission.

At a regional level, the work will provide insight into how the baseline epidemiological state of malaria endemicity and trends in intervention scale-up in different areas of Western Kenya, with the resulting impact this has had upon transmission, interact with the incremental prospects of MSAT for reducing the reproduction number below one. This will help inform malaria researchers from CDC/KEMRI, as well as Ministry of Health officials, as to whether these interventions can be applied more widely in the region to help move the level of transmission in Western Kenya and, in turn, the country itself towards achieving WHO-defined pre-elimination status.

The model outputs, in terms of the changes in transmission and the reproduction number achieved during the trial are also likely to be useful for comparing and explaining the effectiveness of MSAT in western Kenya, in terms of progress towards elimination, with those observed during similar trials in other countries. As member of the Imperial College Malaria Group, which is already heavily involved in determining optimal combinations of control packages in different settings, this will then help to inform the feasibility of using strategies involving mass drug administration across Africa as part of a globally integrated malaria control program. The development of tools capable of translating observed changes in readily available malariometric indices, either within the context of a trial or following the implementation of an intervention strategy, into reductions in transmission and the reproduction number are also likely to be of increasing importance as research effort continues to focus upon looking at strategies which aim to reduce transmission and which could feasibly lead to achieving malaria elimination. The beneficiaries of these outputs are likely to include major international agencies concerned with public health such as the World Health Organisation, the Bill and Melinda Gates Foundation and the US Centers for Disease Control.

Finally, in the long-term, an aim of the proposed research is to provide benefits to the wider public. The eradication of malaria would remove one of the greatest burdens upon global development, health and life-expectancy. It is hoped, by better understanding the capacity of the currently available tools, and some of those proposed in the near-future, to reduce transmission towards elimination in one of the historically most intense areas of transmission in the world, that this research will help to improve our knowledge about the feasibility of this aim.