I have read the journal's policy and the authors of this manuscript have the following competing interests: JC receives funding from UNITAID. AMN is a member of the Editorial Board of
¶ Full listing of the members of the malERA Refresh Consultative Panel on Characterising the Reservoir and Measuring Transmission can be found in the Acknowledgements.
This paper summarises key advances in defining the infectious reservoir for malaria and the measurement of transmission for research and programmatic use since the Malaria Eradication Research Agenda (malERA) publication in 2011. Rapid and effective progress towards elimination requires an improved understanding of the sources of transmission as well as those at risk of infection. Characterising the transmission reservoir in different settings will enable the most appropriate choice, delivery, and evaluation of interventions. Since 2011, progress has been made in a number of areas. The extent of submicroscopic and asymptomatic infections is better understood, as are the biological parameters governing transmission of sexual stage parasites. Limitations of existing transmission measures have been documented, and proof-of-concept has been established for new innovative serological and molecular methods to better characterise transmission. Finally, there now exists a concerted effort towards the use of ensemble datasets across the spectrum of metrics, from passive and active sources, to develop more accurate risk maps of transmission. These can be used to better target interventions and effectively monitor progress toward elimination. The success of interventions depends not only on the level of endemicity but also on how rapidly or recently an area has undergone changes in transmission. Improved understanding of the biology of mosquito–human and human–mosquito transmission is needed particularly in low-endemic settings, where heterogeneity of infection is pronounced and local vector ecology is variable. New and improved measures of transmission need to be operationally feasible for the malaria programmes. Outputs from these research priorities should allow the development of a set of approaches (applicable to both research and control programmes) that address the unique challenges of measuring and monitoring transmission in near-elimination settings and defining the absence of transmission.
Christopher Drakeley and colleagues propose an updated research agenda for characterizing the reservoir and measuring transmission in malaria elimination and eradication.
Understanding the sources of transmission (the infectious reservoir) and those at risk of infection at the population level in order to inform programmatic decision-making can progress malaria elimination.
There is considerable evidence for malaria infections at densities beneath the limit of conventional diagnostics. However, the contribution of these low-density infections to malaria transmission in different settings is not known.
Characterising the spatial and temporal heterogeneity of the infectious reservoir becomes increasingly important as transmission declines if interventions are to be efficiently implemented to accelerate malaria elimination.
The proportional contributions of low-density, asymptomatic, and symptomatic infections will differ by malaria typology and will determine the programmatic approach required to reduce transmission.
There is a need to standardise both existing transmission metrics and new metrics with greater sensitivity, particularly for their use in low-transmission settings.
Transmission of malaria requires sexual-stage parasites, gametocytes, in humans to be taken up by female
In 2011, one of the main conclusions of the Malaria Eradication Research Agenda (malERA) process was the need to develop tools to measure transmission at low levels in elimination contexts. This article summarizes progress made since 2011 and for the first time develops a research agenda addressing the reservoir of transmissible parasites and measuring transmission [
Since the 2011 malERA process, research has ranged from illuminating the basic biology of the development of sexual-stage parasites in humans and mosquitoes to evaluating operational approaches targeting infectious individuals in endemic communities. Additionally, a harmonised set of definitions relevant to malaria transmission and elimination has been developed (
Malaria typology is the characterisation of malaria epidemiology according to ecology (climate and environment) and other determinants of transmission for the purpose of guiding malaria interventions. Relevant ecologies include (but are not limited to) savannah, lowland plains and valleys, highlands, desert and oasis, forest and jungle, coastal and marshland, and urban or peri-urban. The unique features of malaria transmission in each ecological area are also strongly driven by region-specific vectors and parasites (species, biology, behaviour, insecticide and antimalarial drug susceptibility), human biology and behaviour, and economic and health-system factors. These are discussed more comprehensively in [
This paper discusses progress in the measurement and understanding of malaria transmission, highlighting the different malaria typologies in which transmission occurs (
Malaria infection and transmission can be detected and measured with a variety of metrics (Tables
Metric | Definition [ |
Measure of transmission | Sampling method and resolution | Discriminatory power |
---|---|---|---|---|
Entomological inoculation rate (EIR) | Number of infective bites received per person in a given unit of time, in a human population | Transmission intensity | Human landing collection; light traps Resolution: Household or community level |
Insensitive at low transmission Lack of standardised sampling design Collected by malaria control programmes |
Sporozoite rate (SR) | Percentage of female |
Risk of infection | Human landing catch; baited traps; gravid traps Resolution: Community level |
Insensitive at low transmission |
Human biting rate (HBR) | Average number of mosquito bites received by a host in a unit of time, specified according to host and mosquito species | Risk of exposure | Human landing collection Resolution: Person or community level |
Allows determination of the primary vector |
Vectorial capacity | Rate at which given vector population generates new infections caused by a currently infectious human case | Efficiency of transmission | Derived from human biting rate, parasite inoculation period, mosquito to human density and mosquito survival Resolution: Community level |
Measures potential, not actual, rate of transmission—includes no parasitological information Sensitive to changes in mosquito survival and biting behaviour but may not translate to significant change in human incidence Can be useful when infection rates are low and mosquito sampling difficult |
Metric | Definition [ |
Measure of transmission | Method | Discriminatory power |
---|---|---|---|---|
Annual blood examination rate (ABER) | The number of people receiving a parasitological test for malaria per unit population per year | Level of diagnostic monitoring activity | Microscopy or RDT | Dependent on health-system provision |
Case, confirmed | Malaria case (or infection) in which the parasite has been detected in a diagnostic test | Current transmission or incidence if data collection is repeated or routine | Microscopy or RDT positive | Insensitive at low transmission; saturates at high transmission Underestimates due to system inadequacies and poor health-seeking behaviour |
Case, fever | The occurrence of fever (current or recent) in a person | Current transmission or incidence if data collection is repeated or routine | Reported or observed fever | Overestimates malaria infection |
Proportion of fevers parasitaemic (PFPf) |
Proportion of fever cases found to be positive for |
Current transmission or incidence if data collection is repeated or routine | Microscopy; RDT; NAAT | Depends on diagnostic sensitivity Insensitive at low transmission |
Slide positivity rate (SPR) | Proportion of blood smears found to be positive for |
Current transmission or incidence if data collection is repeated or routine | Microscopy | Depends on ABER Insensitive at low transmission |
RDT positivity rate (RDT-PR) | Proportion of positive results among all RDTs performed | Current transmission or incidence if data collection is repeated or routine | RDT | Depends on RDT sensitivity Insensitive at low transmission |
Parasite rate (PR) | Proportion of the population found to carry asexual blood-stage parasites | Current transmission or incidence if data collection is repeated or routine | Microscopy; RDT; NAAT | Depends on diagnostic sensitivity Insensitive at low transmission |
Gametocyte rate (GR) | Percentage of individuals in a defined population in whom sexual forms of malaria parasites have been detected | Potentially infectious human population | Microscopy; NAAT | Depends on diagnostic sensitivity Insensitive at low transmission |
*No WHO definition is available for this term.
Abbreviations: ABER, annual blood examination rate; GR, gametocyte rate; NAAT, nucleic acid amplification test; PF
In children in Papua New Guinea, 4 of every 5
Both primary and relapse
Estimating transmission using the typical entomological measures is of limited relevance when clinical disease can emerge from an individual not recently infected by a mosquito bite.
Access to existing anti-hypnozoite therapy needs to be expanded where possible in order to reduce the burden of disease and minimise the risk of human-to-mosquito transmission via relapse.
However, several barriers to mass drug administration (MDA) for
Without being able to identify hypnozoites, MSAT is of no practical value in reducing
Compared to
Parasites can be transported undetected into areas where malaria has been eliminated, leading to outbreaks and the reestablishment of transmission where conditions are receptive. More effort needs to be directed at understanding specific parasite vector interactions to develop targeted vector control strategies for
Diagnosis and treatment of clinical malaria is vital for disease control, particularly if this can be rapidly implemented to reduce the likelihood of gametocyte production. There is also a good public health rationale for identifying and treating ‘asymptomatic’ malaria detectable with microscopy or RDTs, as it is increasingly recognised that this is associated with ongoing morbidity (e.g., anaemia, increased susceptibility to bacterial infections, and cognitive function; reviewed in [
While the countries that have achieved malaria elimination to date have done so largely without specific attempts to detect and treat low-density parasitaemia, these may not be representative of malaria typologies in higher-transmission settings. In many areas, the persistence of malaria can occur despite high coverage of vector control measures and the availability of effective treatment, suggesting that novel approaches are needed for both surveillance and interventions that will accelerate the elimination process [
It follows that the cost-effectiveness of existing or novel surveillance methods and interventions in reducing malaria transmission cannot be predicted or evaluated unless the relative contribution to transmission of (1) clinical/symptomatic malaria, (2) asymptomatic parasitaemia (detectable by microscopy or RDT), and (3) low-density parasitaemia (not detectable by microscopy or RDT) are estimated for a particular setting. With an increasingly diverse array of potential approaches for malaria elimination [
There are currently no field diagnostics with sufficient sensitivity to identify low-density submicroscopic parasitaemia, though various approaches are under evaluation for performance and scalability (discussed in the malERA Refresh ‘Tools’ paper) [
Understanding the contribution of low-density parasitaemia to the infectious reservoir for a given malaria typology is critical to determine the diagnostic sensitivity required. It will also affect how much effort a programme should commit to detecting and treating these infections and when and where this effort is best deployed. As noted above, the proportion of low-density parasitaemia increases as transmission declines [
Currently, the only way to measure human infectiousness is by feeding colony-reared mosquitoes either on humans directly (direct feeding assay [DFA] [
All malaria infections have the capacity to produce gametocytes. Therefore, in the context of community chemotherapy programmes, treating any individuals who test positive for asexual parasites is a realistic programme aim. However, research tools that measure gametocytaemia are essential to further our understanding of transmission biology and to define the populations and individuals that drive transmission. Some studies have suggested that transmission efficiency may increase as malaria prevalence falls due to higher gametocyte densities. As the development of new transmission-blocking drugs and vaccines advances, understanding the factors that drive this transmission efficiency will be needed to determine in which settings interventions can be successfully trialled and/or implemented [
While there is an overall positive association between mosquito infection rates and gametocyte density, there is also evidence of infectiousness for individuals with very low gametocyte densities [
Where data are available, they suggest differences between high- and low-transmission settings in the gametocyte density needed for human infectivity to mosquitoes. In African populations, submicroscopic
While data demonstrate an advance in our understanding of malaria transmission, they are limited and suggest the infectious reservoir differs across malaria typologies [
As transmission declines and heterogeneity increases, programmes need to adjust in order to respond to increasingly rare clinical cases. The persistence of residual transmission requires more aggressive and/or novel strategies, and targeting these areas will be key to local elimination. Significant progress has been made in approaches to identify transmission foci using a number of field-based, geo-spatial, and modelling approaches [
Surveillance systems at low-transmission settings will also need to be equipped to monitor emerging insecticide and drug resistance [
Improved and validated metrics of transmission would enable the optimal design of control programmes and surveillance systems needed for malaria elimination [
Measures of malaria transmission can be defined at different points in the transmission cycle (
NAAT, nucleic acid amplification test; RDT, rapid diagnostic test.
Between 30–40 species of
New approaches are particularly needed in settings where vector densities are low or heterogeneous. For example, reexamination of vectorial capacity using mathematical modelling to simulate settings with different baseline epidemiological and entomological characteristics has led to new insights into the effective deployment of vector control measures [
Current epidemiological metrics of malaria transmission in humans, diagnosed via passive and active systems, microscopy and RDTs, remain key for national malaria control programmes in tracking progress in the reduction of malaria cases and identifying outbreaks and epidemics (
To generate practical estimates of infection without excessive sampling, more sensitive diagnostics and/or combinations of diagnostic approaches are needed. While the utility of RDTs will need to be monitored in regions where deletions in the gene encoding HRP2 have been detected in the parasite population [
Recent technical advances have produced a number of transmission metrics that are suitable for low-transmission settings (
Metric | Definition | Measure of transmission | Method | Discriminatory power |
---|---|---|---|---|
Force of infection | Rate at which susceptible individuals contract malaria | Probability of transmission |
Time from birth to first malaria episode; microscopic detection of parasites following successful antimalarial treatment | Difficult to measure Difficult to standardise Depends on diagnostic sensitivity Cannot differentiate superinfections |
mFOI | The number of new parasite clones acquired by a host over time | Population-level transmission intensity Transmission heterogeneity |
Cohort study >6 months with parasite genotyping | Highly sensitive for monitoring changes in malaria exposure Superinfections can be differentiated |
MOI | The number of different parasite strains coinfecting a single host | Population-level transmission intensity Transmission heterogeneity |
Parasite genotyping of positive samples | Saturates at high transmission Restricted by age dependency Insensitive at low transmission Highly sensitive to spatial heterogeneity Highly sensitive to increases in imported infection Less sensitive to changes in seasonality |
Genotyping: |
Genetic diversity, i.e., number of alleles in a population Parasite signatures to map geographical relatedness of infection (i.e., spatial–temporal transmission) |
Population-level transmission intensity Transmission heterogeneity Geographical tracking of transmission patterns |
Haplotypes composed of >12 informative SNPs from single clone infections Haplotypic signatures from highly variable loci |
Sensitive to changes in malaria exposure and spatial–temporal flow of infection Standardisation of measures needed Methods for analysis and interpretation of data needed |
Antibody seroprevalence | The percentage of seropositive individuals in a population | Population-level transmission intensity |
Seronegative or seropositive defined using appropriate cutoff points | Dependent on antibody target tested Saturates at high transmission Sensitive at low transmission |
SCR | The rate (typically annual) by which seronegative individuals become seropositive upon malaria exposure | Population-level transmission intensity Temporal changes in transmission can be detected from a single sampling time point |
Detection of antibodies in sera using serological assay (IFAT, ELISA, bead-based assays microarray) | Dependent on antibody target tested Restricted by age dependency Saturates at high transmission Sensitive at low transmission Sensitive to risk of malaria in absence of transmission |
Abbreviations: ELISA, enzyme-linked immunosorbant assay; IFAT, Immunofluorescence Antibody Test; mFOI, molecular force of infection; MOI, multiplicity of infection; SCR, seroconversion rate.
Antibody seroprevalence and the seroconversion rate (SCR) exploit human antibody responses to characterise previous parasite exposure and are specific to a particular antigen or combination of antigens [
For all these metrics, however, standardisation of methods is necessary, as well as a quantitative comparison to understand the relationship with existing and other new metrics. The development of operationally suitable platforms will ultimately be required to inform real-time or rapid response in programmatic settings. In relation to this, there needs to be a clearer understanding of what measures are needed to better define and monitor transmission, and what measures are useful for control programmes. New approaches to analyse metrics from different sources to improve estimates of transmission, or confirm its interruption, are needed. Looking to the veterinary world could be informative, where probability-based survey methods such as “freedom from infection” are used for animal disease surveillance in the food and agriculture industry [
The increasing availability of spatial databases on parasite rate [
Considerable progress has been made not only in understanding the biology and epidemiology of malaria transmission but also in the development of new tools to more accurately quantify transmission; however, challenges remain and
Objective: Determine the relative contribution to transmission of symptomatic malaria, asymptomatic malaria detectable with microscopy or RDTs, and low-density infections detectable by molecular methods across different malaria typologies; data from low-transmission settings are particularly required.
Determine the kinetics of infectiousness of low-density parasitaemia.
Determine the infectiousness of low-density gametocytaemia.
Refine mosquito feeding assays (DMFA or DFA) of human infectivity to mosquitoes and validate these against natural infectivity to local vector species.
Determine the required sensitivity of field-based diagnostics to identify malaria infections contributing to transmission.
Continue to develop field-based molecular and serological diagnostics with sensitivities relevant for evaluation of infectious low-density parasitaemia and gametocytaemia. Investigate non-invasive diagnostics of malaria infection and infectivity. Develop hypnozoite diagnostics predictive of Develop cost-effective programmatic triggers and protocols for the optimal deployment of transmission-based diagnostic tests and their incorporation within surveillance systems. Evaluate the cost-effectiveness of programmatic actions and interventions directed by transmission-based diagnostics.
Characterise changes in the transmission reservoir as transmission declines.
Conduct longitudinal studies in areas of declining transmission to investigate changes in the nature and distribution of the transmission reservoir. Evaluate which surveillance activities and metrics are most informative and cost-effective for programmatic goals. Develop operational methods to rapidly identify antimalarial drug-resistant parasites and insecticide-resistant vectors.
Determine the relevance of spatial–temporal heterogeneity in the transmission reservoir to the acceleration of elimination.
Identify foci of residual transmission. Identify areas at risk for outbreaks and the reestablishment of malaria transmission following local elimination.
Objective: To develop a standardised and validated ‘toolkit’ of metrics and surveillance activities for characterising the infectious reservoir and measuring malaria transmission, which can be applied programmatically to direct interventions, evaluate interventions, and quantify progress towards malaria elimination.
Development of entomological as well as human measures and surveillance of transmission.
Continue to develop alternatives to HLC sampling for entomological measures of transmission risk.
Continued quantification of the relationships between different metrics of transmission.
Develop validated metrics for use in low-transmission settings and in the absence of transmission.
Continue to develop methods for evaluating transmission risk in low-transmission settings or in the absence of transmission. Evaluate multimetric combinations for the efficient integration and analysis of low-intensity and/or heterogeneous transmission. Evaluate the most cost-effective and informative metrics aligned to programmatic goals as transmission declines.
Develop validated metrics for the evaluation of new tools directed at transmission interruption.
The absolute and relative incidence of clinical and asymptomatic infections can vary widely between different low-transmission settings. Transmission can occur as focal outbreaks caused by human and vector migration. It can also persist for long periods despite aggressive control strategies or quickly rebound after reaching zero. These scenarios are caused by varying patterns of malaria risk across demographic groups, vectors, and parasite species in different ecological settings, which may not be easily captured by simple incidence and prevalence measures.
The application of new and/or refined metrics for routine surveillance activities or research-specific contexts requires investigation. This needs to be done in the context of existing standard measures and the newer data collection platforms to understand the true utility. Metrics will also need to be optimised for the quality of the healthcare system in which they will be implemented. The same applies to the infectious reservoir. Whilst its characterisation across different transmission settings is important, translating this information into actionable programmatic decisions will be key to achieving zero malaria transmission.
We dedicate this paper to the memory of Alan Magill. Before Alan passed away in 2015, he generously accepted to play an active role in this work. We remember his extraordinary commitment to defeat malaria.
The Malaria Eradication Research Agenda (malERA) Refresh Consultative Panel on Characterising the Reservoir and Measuring Transmission was chaired by Chris Drakeley, London School of Hygiene & Tropical Medicine (LSHTM, UK) and co-chaired by Abdisalan M. Noor (KEMRI Wellcome Trust Research Programme, Nairobi, Kenya). The paper was written based on consultations during a malERA meeting held in London, UK on 14–15th December 2015. A systematic literature search was performed by Vittoria Lutje. Panel members reviewed several iterations of the manuscript to finalise it. Laurence Slutsker (PATH Malaria and the Neglected Tropical Diseases (NTD) Program, Seattle, WA, USA) reviewed and commented on a draft of the manuscript. Figures were designed by Rachel Papernick. Additional writing and editorial support was provided by Naomi Richardson of Magenta Communications Ltd and was funded by MESA Alliance.
Chris Drakeley (Chair), LSHTM, London, UK; Abdisalan M. Noor (Co-chair), WHO, Geneva, Switzerland; Nicole L. Achee, University of Notre Dame, USA; Teun Bousema, LSHTM, London, UK and Radboud University Nijmegen Medical Centre, the Netherlands; Ewan Cameron, Oxford Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, UK; Gonzalo Domingo, PATH, Diagnostics Program, Seattle, USA; Thomas P. Eisele, Center for Applied Malaria Research and Evaluation, Tulane School of Public Health and Tropical Medicine, New Orleans, USA; Ingrid Felger, Swiss Tropical and Public Health Institute, Basel, Switzerland and University of Basel, Switzerland; Peter Gething, Oxford Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, UK; Bryan Greenhouse, University of California, San Francisco (UCSF), USA; Ivo Mueller, ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic—Universitat de Barcelona, Barcelona, Spain, Institut Pasteur, Paris, France, and The Walter and Eliza Hall Institute of Medical Research (WEHI), Melbourne, Australia; Jetsumon Sattabongkot, Mahidol Vivax Research Unit, Faculty of Tropical Medicine, Mahidol University, Thailand; Regina Rabinovich, Harvard University T.H. Chan School of Public Health, Boston, USA and ISGlobal, Barcelona Ctr. Int. Health Res. (CRESIB), Hospital Clínic—Universitat de Barcelona, Barcelona, Spain; Sarah Volkman, Harvard University T.H. Chan School of Public Health, Boston, USA; Lotus van den Hoogen, LSHTM, London, UK; Lindsey Wu, LSHTM, London, UK.
annual blood examination rate
direct feeding assay
Demographic and Health Surveys
direct membrane feeding assay
enzyme-linked immunosorbant assay
human landing collection
Malaria Eradication Research Agenda
mass drug administration
molecular force of infection
Multiple Indicator Cluster Surveys
Malaria Indicator Surveys
multiplicity of infection
mass screen and treat
nucleic acid amplification test
rapid diagnostic test
reverse transcription qPCR
seroconversion rate