US President's Malaria Initiative

CDC supports malaria control efforts for Kenya's National Malaria Control Program as part of the US President's Malaria Initiative (PMI). For more information on PMI activities in Kenya, see www.pmi.gov*.

KEMRI/CDC Research Station in Kenya

The KEMRI/CDC Field Research Station in Kenya was established in 1979 by the Division of Parasitic Diseases (DPD), working in collaboration with the Kenya Medical Research Institute* (KEMRI). KEMRI is a parastatal organization of the Kenyan Ministry of Health and is responsible for conducting research into the major public health problems of the country. Over the past nearly three decades, CDC's investment in the Research Station has resulted in a well-trained staff of Kenyan scientists, clinicians, laboratory technicians, and field workers.

The Research Station is located in an area in western Kenya where P. falciparum malaria and HIV are major public health problems. It is estimated that globally, approximately 300-500 million persons suffer from malaria each year, resulting in approximately one million deaths. The burden of disease is located largely in sub-Saharan Africa. Western Kenya, where the Research Station is located, has intense malaria transmission; on average, each inhabitant in this area receives 150-300 infective mosquito bites per year. HIV has also had a devastating impact in Kenya. The overall HIV infection prevalence is estimated at approximately 7.4% (Kenya AIDS Indicator Survey 2007), and in some groups such as pregnant women attending antenatal clinics, rates as high as 25-30% have been observed. Diarrheal and respiratory pathogens are also major causes of infectious disease morbidity and mortality in western Kenya.

Major Areas of Research

Since 2000, in response to these national, regional, and global health challenges, the Research Station has expanded its mission and staff. Before this time, most activities focused on the major public health problem of malaria. Although malaria remains a priority, HIV research supported by CDC's Division of HIV/AIDS Prevention, National Center for HIV/AIDS, STD, and TB Prevention (NCHSTP), HIV prevention and care program activities supported by the Global AIDS Program, and tuberculosis research are now also a primary focus. The U.S. President's Emergency Plan for AIDS Relief (PEPFAR) supports many of the HIV and TB/HIV programmatic activities.

Another focal area is the International Emerging Infectious Diseases Program (IEIP). IEIP has one person directly hired by CDC at the Research Station in Kisumu and three people in Nairobi, along with close to 100 Kenyan staff members in both sites. Activities focus on surveillance for emerging infections, outbreak response, applied public health research, and training of Kenya Ministry of Health clinicians and laboratory technologists.

Currently, there are eight American employees directly hired by CDC at the Research Station (five scientists and three public health advisors), several other expatriate staff, and over 900 locally hired Kenyan staff. Among the locally hired staff are PhD and post-doctorate level scientists, PhD candidates and master's students, research assistants and field workers, as well as data entry and management personnel.

Laboratory and Communications Capabilities

The KEMRI/CDC Research Station has well-developed malaria, HIV, microbiology, and tuberculosis laboratories that perform a range of standard diagnostic procedures (serology, hematology, microscopy, sputum smears/cultures, blood cultures).

• The malaria laboratory has the capability to perform sophisticated research assays such as polymerase chain reaction (PCR), gene sequencing and microsatellite work, real-time PCR, lymphocyte subtyping, cytokine measurement, immunologic functional assays and malaria parasite cultures. It is actively engaged in research on parasite diversity and the immunology of malaria in children under five years and pregnant women. In addition, the laboratory supports all the malaria epidemiologic studies, providing expert microscopic diagnosis of malaria, other malaria-related clinical tests, molecular biology assays, and oversees laboratory quality control, sample collection, processing, management, and shipping.
• The HIV laboratory conducts a range of HIV diagnostic tests, including rapid tests, enzyme-linked immunosorbent assay (ELISA), Western blot, BED HIV incidence testing, viral load and infant DNA PCR, CD4 immunology; a variety of chemistry and hematology assays; and diagnostic tests for sexually transmitted infections (chlamydia, gonorrhea, syphilis, HSV-2, Trichomonas vaginalis) and, using both rapid diagnostic tests and ELISA, hepatitis B and C. The HIV research laboratory also has the capacity to perform HIV drug resistance testing and HIV subtyping.
• The microbiology laboratory performs primary isolation and identification of enteric organisms from stool and blood (e.g., Vibrio cholerae, Shigella) and respiratory organisms (Streptococcus pneumoniae) as well as antimicrobial susceptibility testing for these pathogens. In addition, the laboratory performs tests for viruses, rotavirus and norovirus in stool, and multiple viral pathogens including influenza from respiratory swabs. The microbiology laboratory is also supporting the RTS,S malaria vaccine trial being conducted by CDC's Malaria Branch in Siaya district, western Kenya, by identifying bacterial pathogens in young children admitted to Siaya District Hospital with symptoms of malaria. Research on the immunology of schistosomiasis is also conducted, and a biosafety level 3 laboratory is being built for investigations of avian influenza.
• The tuberculosis laboratory conducts sputum concentration and fluorescence microscopy; currently a biosafety level 3 laboratory is being built in order to perform sputum cultures and drug susceptibility testing

A computer network and geographic information system/geographic positioning system capabilities have been established at the Research Station, and a VSAT satellite link has improved Internet linkage and communication capability.

The KEMRI/CDC Research Station is well positioned to play an important role in global surveillance to monitor malaria and other emerging and re-emerging infectious diseases, assess problems of public health importance such as the spread of antimicrobial resistance, and provide a basis for evaluating interventions designed to reduce the burden of disease among vulnerable groups.

KEMRI/CDC's Recently Completed Malaria Studies

Intermittent preventive treatment for infants (IPTi)

Specific objectives of this study were to:

• Compare the efficacy of iron supplementation and intermittent preventive treatment for infants (IPTi) with sulfadoxine-pyrimethamine and three doses of artesunate (SP/AS) given at routine Expanded Programme on Immunization (EPI) visits with iron supplementation and IPTi using one of two alternative antimalarial drug regimens: Lapdap (chlorproguanil-dapsone), or amodiaquine + three doses of AS (AQ/AS); or iron supplementation alone, on the prevention of clinical malaria, moderate anemia, and severe anemia in the first two years of life;
• Assess the impact of IPTi on response to routine childhood immunizations; and
• Assess the impact of IPTi with the aforementioned regimens (particularly SP/AS) on the nasal carriage rates of Haemophilus influenzae type b and the immune response to Haemophilus influenzae type b (Hib) vaccine.

Enrollment was completed in March 2006, and the study was completed in March 2008. Preliminary findings show that IPTi with AQ/AS or SP/AS is an efficacious means to prevent malaria during the first year of life.

Additional research questions still being explored include acceptability of IPTi by community members and health facility staff, and a cost analysis of the intervention.

A report evaluating the safety and efficacy of IPTi with SP was recently released by the Institute of Medicine (IOM). The pooled analysis of completed trials of IPTi with SP has shown a 30% protective efficacy against clinical malaria in the first year of life. The IOM committee concluded that an intervention with results of this magnitude is worthy of further investment as part of a public health strategy to decrease morbidity and mortality from malaria infection in infants. The report is available at http://www.ipti-malaria.org/*.

Use of methods to prevent malaria in pregnancy

The survey objectives were to assess among recently pregnant women their perceptions of the burden of malaria in pregnancy, document use of malaria prevention measures during pregnancy, evaluate use of and access to antenatal clinics, measure how many women received the correct numbers of doses of intermittent preventive treatment (IPTp), and identify factors important for decisions to deliver at home or at a health unit. The survey was conducted in 2005, in three divisions in western Kenya (Rarieda, Wagai, and Yala), where insecticide-treated nets were distributed among women who had delivered in the previous 6 months.

The results of the IPTp portion of the survey showed an overall increase in the percentage of women who received the recommended two doses of IPTp—from 7% in 2002 to 21% in 2005. IPTp usage was significantly higher in areas where health-care workers were trained in focused antenatal care compared to areas where health-care workers had not received training. The study identified confusion among the health-care workers on when to give IPTp (trimester and month of antenatal care visit) as one of the barriers to receiving IPTp. Therefore, study researchers recommended that health-care workers be given a simplified message to give IPTp at every antenatal care visit provided there is a space of one month or unless it is contraindicated. The Kenyan Ministry of Health has adopted this new strategy, and KEMRI/CDC will evaluate implementation of this new guideline.

Rapid diagnostic test (RDT) evaluation

In July 2006, KEMRI/CDC, CDC, and the Kenya Ministry of Health initiated a study to determine whether the introduction of RDTs with artemisinin-based combination therapy (ACT) and malaria case management guidelines would lead to more accurate treatment of febrile patients than ACT and malaria case guidelines alone.

The study's objectives were to evaluate how best to incorporate RDTs for malaria into the current health care system, accompanying the introduction of artemether-lumefantrine (Coartem) as first-line treatment for malaria in Kenya. The study was conducted July–September 2006, using a cluster-randomized trial in two districts with different patterns of malaria transmission, one with intense transmission, and one with seasonal transmission.

The study found that RDTs in the hands of health workers were accurate in diagnosing malaria. In addition, health workers respected the RDT result, and only treated with the nationally recommended first-line treatment of malaria (artemether-lumefantrine or AL) if the RDT was positive. However, health workers did not use RDTs on all patients with fever, as recommended in national guidelines. Consequently, RDTs as used by health workers resulted in a reduction in the provision of AL for patients who had malaria. The authors concluded that RDTs could result in improved rational treatment for malaria with acceptable costs, but health workers would need to follow guidelines on when to use RDTs, and training should include the message that if RDTs are not used, AL can be used to treat a symptomatic diagnosis of malaria.

KEMRI/CDC's Current Studies

Vaccines

Malaria vaccine trial preparation study (Mal-055 [Pre])

The overall objective of this study is to prepare Siaya District Hospital (SDH) for a Phase III multicenter efficacy trial of GSK Biologicals' candidate malaria vaccine, RTS,S/AS01E, to begin in 2009.

This study is

• piloting a hospital-based surveillance system for the detection of severe malaria disease and other serious illnesses in children aged 2 months to 4 years
• developing support for the clinical trial's use of the hospital's laboratory and digital X-ray systems
• improving staffing at the SDH Pediatric Ward, increasing the numbers of Clinical Officers, Nurses, Medical Officers, and other support staff
• instituting electronic case report forms rather than conventional paper case report forms.

RTS,S malaria vaccine study (Mal-055)

This study is a phase III, double-blind (observer-blind), randomized, controlled multi-center study to evaluate, in infants and children, the efficacy of the RTS,S/AS01E candidate vaccine against malaria disease caused by P. falciparum infection, across diverse malaria transmission settings in Africa. RTS,S/AS01E is the most advanced antimalarial vaccine candidate yet developed and shows the most promising results to date: 60% protection against severe malaria.

Patients will be recruited and followed at five health facilities in Karemo Division, including Siaya District Hospital and surrounding clinics and dispensaries. The patients will be male and female infants and children aged 6-12 weeks and 5-17 months at age of first vaccination if eligible according to inclusion and exclusion criteria. This Phase III study of GSK Biologicals candidate malaria vaccine has been designed to address the key safety and efficacy information required for vaccine licensure. In addition, other disease endpoints that allow the evaluation of the full public health impact and cost effectiveness of vaccine implementation are included.

Co-primary objectives are to investigate the efficacy against clinical disease in children from 5-17 months of age at first dose and the efficacy in infants 6-12 weeks of age who receive the vaccine in co-administration with EPI antigens (i.e., DTPw Hep B/Hib).

All participating centers will use standardized case definitions for efficacy endpoints and a structured approach to case-assessment. Cases of clinical disease will be pooled across participating centers to determine the primary endpoint of efficacy against clinical disease in each age category. Secondary objectives will assess the efficacy of the vaccine on severe malaria disease, severe anemia, and malaria hospitalization.

Analysis by site will allow the evaluation of efficacy under different conditions of malaria transmission; randomization to a booster dose will allow the evaluation of the duration of efficacy of a primary course and the requirement for boosting. Exploratory objectives include determination of efficacy of the vaccine against all medical hospitalization, non-malaria serious illness, fatal malaria, and all-cause mortality. In addition immunological correlates of protection will be investigated. Where technically possible, this study will use electronic case report forms (eCRF) by remote data entry (RDE) in preference to conventional paper case report forms (CRF). Participants will be randomized using an Internet-based system. The primary study will continue for 32 months per child, plus a screening period of 2 months.

Malaria in Pregnancy

Use of cotrimoxazole in preventing malaria among HIV-infected pregnant women

The objective of this study is to determine the effectiveness of daily cotrimoxazole (CTX) prophylaxis in preventing placental malaria parasitemia in pregnant HIV-infected women who received CTX for prevention of opportunistic infections during pregnancy. The results of this study will either validate the current Kenya national guidelines and WHO recommendations or will lead to recommendations to evaluate alternative strategies which might include 1) malaria testing and treatment before the initiation of daily CTX, 2) presumptive malaria treatment before the initiation of daily CTX prophylaxis, or 3) the use of non-sulfa-based drugs for intermittent preventive treatment for malaria in pregnancy (IPTp) to be given concurrently with CTX. Data collection for this study is ongoing (commenced August 18, 2008, and expected to take 12 months).

Effect of mefloquine plus daily septrin in HIV-infected women

The objective of this project is to determine whether mefloquine, added to daily septrin for the prevention of opportunistic infections, provides added benefit in preventing malaria in pregnancy among HIV-infected women. This is a multi-site study conducted within the Malaria in Pregnancy Consortium.

A randomized double-blind placebo-controlled trial will be conducted among pregnant women attending antenatal clinics at two district hospitals in Nyanza province. Consenting women will receive HIV counseling and testing. Eligible HIV-infected women will receive daily CTX and be given a long-lasting insecticide-treated net; they will be randomized to receive either IPTp-MQ or IPTp-placebo and be followed through delivery and infants up to 2 months after birth.

Use of simplified policy messages to scale up IPTp

This survey will assess whether the percentage of women using sulfadoxine-pyrimethamine intermittent preventive treatment for malaria in pregnancy (SP-IPTp) increases after a simplified policy message is introduced in the study area in Western Kenya stating that SP-IPTp should be given directly observed at every ANC visit unless contraindicated.

The policy messages will be implemented by the Kenyan Ministry of Health's Division of Malaria Control (DOMC) and the District Management Teams (DHMTs) in conjunction with CDC in early 2009. A cross-sectional survey will be conducted in December 2009 to evaluate the effect of this policy.

The main outcome measure for this study will be the percentage of women receiving the recommended dosage of IPTp: two or more doses.

Transmission Reduction

Measurement of malaria transmission and evaluation of interventions

KEMRI/CDC Research Station is a member of The Malaria Transmission Consortium, a Bill and Melinda Gates Foundation–funded transnational collaborative research project between Notre Dame University and 4 malaria-endemic countries including Kenya, Tanzania, Zambia, and Indonesia.

The project, to be implemented over 5 years, aims to establish an evidence base to help malaria control program managers monitor malaria transmission and implement and adjust malaria control interventions across a range of malaria transmission intensities.

The project has two main components

• Comparing mosquito trapping methods to determine the best method for collecting mosquitoes in surveillance or during evaluation of mosquito control interventions. The method should also be suitable for implementation by national malaria control programs. The methods being compared are light traps, exit window traps, tent traps, outdoor clay pots and resting boxes, pyrethrum spray catch, and human landing catches (as a gold standard comparison only).
• Measuring malaria transmission to evaluate and compare the impact of control interventions. Measurement of malaria transmission is an essential, but often overlooked component in evaluating malaria control program effectiveness. There is need to develop inexpensive, easy, rapid standardized tools for the measurement of transmission so that transmission data can be compared across sites.

The two most effective malaria prevention strategies, IRS and ITNs, have similar efficacy in preventing malaria, but it is unclear how best to integrate these interventions in a coherent malaria prevention strategy. A major question is whether ITNs and IRS have an additive effect on malaria transmission and illness and death. The effect of these two strategies when used simultaneously likely depends on transmission levels, with a greater impact at higher transmission levels.

We will measure and compare the change in malaria transmission in two districts of high malaria transmission, one that has implemented ITNs, and a second that has implemented both ITNs and IRS. The results are expected to provide critical information for malaria control programs on how to measure malaria transmission as well as how to best integrate IRS and ITNs.

Three types of surveys will be used:

• Cross-sectional surveys: To determine parasitemia and other malaria-related parameters.
• Cohort study: To determine reinfection rates among a cohort of uninfected participants. This study is under way.
• Entomologic surveys: Monthly mosquito surveys by pyrethrum spray collections. These surveys are already in progress.

In third quarter 2009, we will begin similar assessments in a nearby area of high malaria endemicity, evaluating the added benefit of using long-lasting insecticide treated-materials such as eave nets in addition to ITNs. The same epidemiologic and entomologic evaluations will be conducted, as well as health facility surveillance using RDTs and school cross-sectional surveys.

Entomology

Eave material study

Insecticide-treated eave curtains have been evaluated in the past along with insecticide-treated nets. While curtains reduced mosquito densities and malaria transmission, they were difficult to hang and retreat at regular intervals. As a result they were recommended as an alternative in areas where nets were impractical and have not been widely implemented.

The development of long-lasting insecticide treated materials may make eave curtains a more feasible option for malaria prevention. A small-scale study on the operational feasibility and the entomologic impact of insecticide-treated eave curtains in an area with high ITN coverage is now being conducted. After 1 year of use, results demonstrate that eave curtains reduce mosquito populations; in addition, the eave curtains remained largely intact and retained high levels of insecticidal activity. The study will continue for an additional 2 years to measure the duration of efficacy of insecticide-treated eave curtains and assess physical wear and tear over time.

Entomologic evaluation of long-lasting insecticide-treated nets (LLINs)

This project compared six different LLIN products (DAWAplus, InTection, DuraNet, Interceptor, Olyset, and Permanet) and a conventional ITN, which were distributed to 267 homes in Kisian village in May, 2007. WHO cone bioassays commenced in October 2007 on each net at 3-4 month intervals in each of the selected households. Households with nets whose remaining insecticide killed less than 70% of mosquitoes are revisited within 1 month. If mortality is <50% for two consecutive months, the nets are considered failures and replaced with a new LLIN. The study is planned to continue for up to 5 years.

Larval ecology

The objectives of larval ecology studies were to evaluate, map, and record the characteristics of productive larval habitats. Initial studies focused on surveys of water bodies to determine how various physical and chemical parameters related to the presence or absence of An. gambiae. Subsequent studies followed these habitats longitudinally and showed that most habitats with larvae are largely unproductive with few adult mosquitoes emerging. The addition of remotely sensed data has further refined our understanding of where and when mosquito larvae are found: larval habitats were largely found in maize fields that were close to streambeds. A statistical model to predict where larval habitats will be found and which will be productive for adult mosquitoes is currently under development.

Related studies on the oviposition behavior of Anopheles gambiae have identified soil moisture as the main determinant of where female mosquitoes lay their eggs. Additional studies are being conducted to identify other attractants for gravid females. The ultimate aim of these studies is to develop oviposition traps for surveillance and control of mosquito populations.

Source reduction trial

In early 2008, KEMRI/CDC, collaborating with Michigan State University, began a study to determine whether an integrated vector management strategy that uses both ITNs and larval control is superior to a strategy of ITNs alone. Twenty zones (2 km x 2km) were delineated using a geographic information system and randomized into intervention and control zones. In the intervention zones, local residents were hired to canvas the area and treat all bodies of standing water with the biological agent, Bacillus thuringensis var. israelensis (Bti). Mosquitoes were collected weekly in both intervention and control zones; larval surveys were conducted every other week. Over 4 months, larval populations declined significantly. However, no impact was observed on adult populations.

To assess why no impact was observed, the study has been scaled back and is focusing on a single zone. The number of field personnel allocated to cover this zone has been doubled and additional supervisory visits have been included to improve monitoring of field staff performance. The study began in May 2008 and will continue for at least one year.

Insecticide resistance

A major concern for any insecticide-based control strategy—including insecticide-treated nets (ITN)—is the development and spread of insecticide resistance in the mosquito population. Insecticide resistance is currently being monitored using both bioassays to detect phenotypic resistance as well as molecular and biochemical assays to detect markers associated with resistance. In the demographic and health surveillance (DSS) study area, where ITN use is > 80%, the frequency of the knock down resistance gene has increased, although our standard bioassays have yet to demonstrate a clear increase in phenotypic resistance. Behavioral changes in Anopheles gambiae are also being monitored, such as earlier biting or outdoor biting, which would limit mosquito exposure to ITNs. In 2008, this program has been expanded to include some districts where the Kenya Division of Malaria Control is implementing an indoor residual spray program. Lastly, strategies to slow the development and spread of insecticide resistance and to prolong the effectiveness of insecticide-based interventions are being developed.

Surveillance

Demographic and health surveillance (DSS)

The populations of Asembo and Gem (135,000 total) in Bondo and Siaya Districts in western Kenya, respectively, have been visited 3 times per year since 2001 to record changes in the status of all residents and to register new in-migrants. Linked to this demographic data are all pediatric out-patient visits to peripheral clinics in the study area and in-patient admissions at two district hospitals. Verbal autopsies are performed on all deaths. Entomologic surveillance to measure correlates of malaria transmission is conducted. Similar data are available going back to 1996. In April 2007, Karemo Division, Siaya District, was incorporated into the DSS. Thus, the DSS now covers 384 villages with a population of approximately 204,000, and encompasses the Siaya District Hospital. Further, the DSS also initiated data collection on individual immunization status (children < 2 years) and self-reported HIV and marital status and history in 2007. Since its inception, the DSS has successfully collected morbidity, demographic, socioeconomic, and entomologic data. Studies and evaluations in the DSS take advantage of the sampling frame inherent in a DSS, whether at individual, household/compound, or neighborhood level, thereby removing many of the biases found in study designs that are not based on a whole population sample. The DSS also provides the ideal platform and infrastructure to evaluate the safety and effectiveness (Phase IV) of new vaccines, providing the critical data to move these vaccines into policy and routine implementation. The DSS is an integral part of the Research Station's activities and is a resource to researchers within and outside CDC.

Parasitemia/anemia survey

KEMRI/CDC conducts annual malaria parasitemia and anemia surveys in the demographic surveillance area. Data show a steady and steep decline in malaria prevalence among children < 5 years of age beginning in 2004, coincident with improved national malaria control measures. We will continue to monitor this decline and provide feedback to the Kenya Division of Malaria Control and the PMI as a measure of malaria control program effectiveness.

Coartem's effects on clinical and entomologic measures

The objectives of the study are to measure the change in malaria morbidity, all-cause and malaria-specific mortality, and community parasitemia and anemia prevalence before and after the introduction of guidelines promoting artemether-lumefantrine (Coartem) as first-line treatment for uncomplicated malaria. This antimalarial drug has gametocytocidal properties, and potentially could result in decreased malaria transmission once the drug is in widespread use. If this is shown to be the case, the findings could be used to provide clinical and cost-effectiveness evidence supporting the Kenyan Ministry of Health's decision to choose this highly effective but relatively expensive drug for first-line treatment of malaria.

Other Laboratory Research

Malarial anemia study

The objective of this study is to assess whether the gene polymorphisms in patients' Interleukin 12 [IL-12] and Migration Inhibitory Factor [MIF] influence the production and balance of IL-12 and MIF in severe malarial anemia in Kenyan children. If polymorphism in these two genes is a risk factor in severe malarial anemia, it may be possible to predict severe malarial anemia using IL-12 and/or MIF related genetic markers.

Effect of ITNs on parasite diversity

The genetic complexity of the parasite causing malaria infection is thought to be one determinant of drug resistance. Use of insecticide-treated bed nets (ITNs) may actually reduce antimalarial drug resistance development by reducing the genetic complexity of infection among those who sleep under ITNs.

The objective of this study is to assess the change in complexity of infection and drug-resistant molecular markers from blood specimens collected from patients before and after widespread ITN introduction, using molecular methods. Findings will help us to understand whether ITNs not only prevent malaria among those who sleep under them, but also reduce the development of drug resistance. If we demonstrate that ITNs help restore drug susceptibility genes associated with sulfadoxine-pyrimathamine (SP), we may be able to use the older inexpensive antimalarial drug SP, and the public health impact will be substantial.

As of July 2008, genes encoding leading vaccine candidate antigens, MSP-1 and CSP, had been sequenced, and molecular markers associated with SP are now being genotyped. Preliminary analysis of MSP-1 and CSP results shows that ITNs change the multiplicity of infection and suggests that CSP could be under strong selective pressure compared to MSP-1 even after transmission reduction.

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