Program for Resistance, Immunology, Surveillance, and Modeling of Malaria in Uganda
Lead Institution: University of California, San Francisco
The Program for Resistance, Immunology, Surveillance, and Modeling of Malaria in Uganda (PRISM) represents the East African region for the ICEMR network. Uganda is emblematic of the challenges faced by high burden countries, where routine surveillance systems are inadequate to assess trends in the burden of malaria or to monitor the impact of control interventions. Through PRISM, researchers have implemented a comprehensive malaria surveillance program including enhanced health facility-based surveillance and detailed longitudinal studies with differing transmission intensities. Complementary laboratory-based studies include surveillance for markers of antimalarial drug and insecticide resistance and serologic measures of malaria exposure. These studies have greatly improved the understanding of the epidemiology of malaria in Uganda and of the impact of control interventions. In recent years, the program has expanded its malaria surveillance work and the scope of longitudinal studies to address more fundamental questions about interactions between the parasite, mosquito vector, and human host. Cutting-edge molecular studies have been implemented to better measure exposure to infective bites including membrane feeding assays; identify asexual and sexual bloodstream infections; and characterize parasite, vector, and human genetic factors that impact malaria and assess impacts of these factors on infectivity and transmission.
The program consists of five research projects:
- Surveillance project: individual patient level data is collected at 68 health facilities located across Uganda. These data are used to monitor temporal and geographic trends in malaria burden and evaluate the impact of population level control interventions.
- Resistance project: uses samples collected over time at multiple sites to characterize the evolution of phenotypic and genotypic markers of drug and insecticide resistance and assess the impacts of these markers on malaria transmission.
- Epidemiology project: uses longitudinal samples from cohorts to characterize factors that determine whether sporozoite inoculation (bite of an infected mosquito) results in the establishment of blood stage infection and characterize factors affecting the duration, density, and clinical consequences of blood stage infections.
- Transmission project: uses longitudinal samples from cohorts to determine factors associated with gametocyte production (the sexual stage of the parasite life cycle in the human host, which infects mosquitos), evaluate infectivity of the human host to mosquito vectors, and characterize the human infectious reservoir.
- Implementation project: using health facility-based malaria surveillance data, the incidence of malaria in catchment areas around the health facilities is being estimated. These data will be utilized to conduct a cluster randomized trial of two different newer generation long-lasting insecticide treated bednets (LLINs) in the context of a national LLIN distribution program.
These highly interrelated projects will be conducted in settings with varied malaria epidemiology and differing population level control intervention to provide critical information needed to optimize strategies for the control and ultimate elimination of malaria in Uganda.
The use of detailed cohort studies to improve our understanding of the epidemiology of malaria in different settings
PRISM has been at the forefront of efforts to conduct detailed longitudinal studies in representative cohorts in a variety of epidemiological settings. These studies involve enrolling residents of households representative of populations living in areas with differing transmission intensity and community level control interventions. The first series of cohort studies (PRISM 1 cohort studies) were conducted in three areas with different transmission intensity from October 2011 through June 2016.
The PRISM 1 studies found a dramatic decrease in the burden of malaria at the highest transmission intensity site (Nagongera sub-county, Tororo District) following the implementation of indoor residual spraying (IRS) in the setting of universal LLIN distribution. To further investigate this phenomenon and better understand the epidemiology of malaria in the setting of successful malaria control intervention, a PRISM 2 cohort study was conducted in Nagongera from October 2017 through October 2019. Methods similar to the previous cohort studies were used, with more frequent routine visits (every four weeks).
Over the two years of follow-up, only 38 episodes of malaria were diagnosed (incidence 0.04 episodes/person/year) and there were no cases of severe malaria or malaria deaths. After five years of intensive vector control measures in Tororo, the burden of malaria was reduced to very low transmission levels. However, a significant proportion of the population remained parasitemic, primarily school-aged children with sub-microscopic parasitemia, providing a potential reservoir for malaria transmission. Preliminary data analyses have shown that asymptomatic infections in school aged children are responsible for the majority of onward transmission events and infectious gametocytes are produced for several months in chronic infections, rendering a minority of individuals highly infectious to mosquitoes.
Plans are underway to conduct a third cohort study in an area bordering one district (Busia) where IRS has not been implemented and the burden of malaria is extremely high and in another district (Tororo) where IRS has been implemented for over 5 years and the burden of malaria is very low. Similar methods will be used as in the PRISM 2 cohort study to allow for comparison of key malaria metrics such as malaria incidence, repeated measures of parasite prevalence, and a variety of entomological measures across a continuum of transmission intensity.
The use of enhanced health-facility based surveillance to monitor temporal and geographic trends in malaria burden and assess the impact of population level control interventions
Malaria surveillance, which encompasses monitoring and evaluation of malaria control efforts, is essential to guide program planning and management. Most malaria control programs rely on routinely collected health facility-based data for surveillance needs. However, these data are often inadequate to monitor trends due to incomplete reporting, poor accuracy, limited diagnostic testing, and the reliance on aggregate measure of disease burden. In 2006, the Uganda Malaria Surveillance Program (UMSP) was established to collect high quality malaria surveillance data at six government run Malaria Reference Centers (MRCs) in collaboration with the Ugandan National Malaria Control Program. With support from PRISM, the surveillance network was expanded from 2014 to 2020 to include 68 MRCs located in 37 districts across the country.
In 2018, UMSP began collecting data on the village of residence of all patients and identifying catchment areas around the MRCs to help estimate malaria incidence. It is anticipated that these estimates will provide the most useful metric for monitoring temporal and geographic trends in malaria morbidity and help guide resource allocation.
Temporal and geographic trends in measures of antimalarial drug and insecticide resistance
ICEMR researchers have been monitoring trends in drug and insecticide resistance using samples from a range of sources, including the PRISM cohort studies. The studies identified changes over time in the prevalences of drug resistance-mediating single nucleotide polymorphisms (SNPs) in pfcrt, pfmdr1, pfdhfr, and pfdhps genes. Data from three PRISM surveillance sites from 2012-15 showed loss of transporter mutations and emergence of mutations that mediate high level resistance to sulfadoxine-pyrimethamine (SP). Data from surveys conducted in 2016-17 at ten sites showed an increasing prevalence of antifolate SNPs consistent with high level SP resistance, but low prevalence of markers of resistance to artemisinins or piperaquine that are now common in parts of southeast Asia. Data from surveys at 16 sites in 2018-19 showed the increasing prevalence of previously rare antifolate mutations.
High levels of pyrethroid resistance have been observed primarily in areas where a single intervention (LLINs) has been implemented. Resistance to carbamates (bendiocarb) has been observed in some areas where indoor residual spraying with bendiocarb was implemented previously and stopped. Characterization of underlying mechanisms of resistance is ongoing.
Genotypes in mosquitoes with and without sporozoite infections were compared and no differences were found in the prevalence of insecticide resistance mutations, suggesting that insecticide resistance does not have a major impact on the likelihood of mosquitoes being infectious vectors. Genotyping of samples from membrane feeding assays are currently underway to test the hypothesis that drug resistance-mediating mutations alter the ability of parasites to establish mosquito infections.
There has recently been a dramatic increase in the scale up of control interventions and reduction in the burden of malaria across Africa. However, progress has not been uniform, and in fact has been slowest in countries with the highest burden, such as Uganda. Malaria covers a wide range of epidemiological settings in the country. This ICEMR is conducting studies in health centers and cohorts around Uganda, ranging from areas of relatively low transmission intensity to areas with some of the highest transmission intensities recorded in the world. Researchers hope to use the varied settings to evaluate intervention strategies and assess optimal control methods.
View Associated sites for the East Africa ICEMR in a larger map
Map description: Associated sites with the Uganda ICEMR: Districts of Amuru, Arua, Gulu, Oyam, Kole, Apec, Mubende, Kanungu, Kabale, Pader, Lamwo, Kitgum, Agago, Otuke, Alebtong, Nagongera, Dokolo, Amolatar, Tororo, and Jinja.
Principal Investigator: Grant Dorsey, MD, PhD
- Epidemiology: Moses R. Kamya, Makerere University and Infectious Diseases Research Collaboration (IDRC), Uganda
- Resistance: Samuel Nsobya, Makerere University and IDRC, Uganda
- Transmission: Sarah Staedke, London School of Hygiene and Tropical Medicine, U.K.
- Infectious Diseases Research Collaboration (IDRC), Kampala, Uganda
- Makerere University College of Health Sciences, Kampala, Uganda
- Liverpool School of Tropical Medicine, Liverpool, UK
- London School of Hygiene and Tropical Medicine, London, UK
- Radboud Institute for Health Sciences, Netherlands
- Stanford University, Stanford, CA
- Durham University, Durham, UK
- Institute for Health Metrics and Evaluation, Seattle, WA