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Malawi ICEMR Program Director/Principal Investigator (Last, First, Middle):

Taylor, Terrie, Ellen

PROJECT SUMMARY (See instructions):

Successful malaria prevention, control and elimination activities depend on the sustained application of effective and well-targeted interventions. Developing innovative approaches and establishing novel applications of established approaches requires multi-disciplinary research. The research should be carried out in sites which span the ecological spectrum in which malaria thrives. Close coordination with policy makers enhances the transition from “data” to policy. Malawi, a landlocked country in southern Africa, is the ideal setting for transformative malaria research. Malawi contains within its boundaries nearly all of the eco-geographic settings relevant to malaria control. Malaria research in Malawi has been ongoing for over 20 years, and is concentrated in its one medical school, the University of Malawi College of Medicine. The National Malaria Control Programme, the relevant policy-making body in Malawi, has made a series of data-driven decisions, and its link with investigators in the College of Medicine is strong. The Malawi ICEMR will harness all of these advantages to establish a self-sustaining research entity capable of developing the scientific basis for designing, implementing, and evaluating malaria control and prevention strategies. Core activities (Administrative, Data Management and Biostatistics, and Molecular and Genomic) will be based in the College of Medicine, and research activities will take place in 3 epidemiologically diverse sites, all located within 50 kilometers of each other. The primary objectives of the research are to identify, understand and evaluate interventions that target the determinants of malaria disease. We will accomplish these objectives by systematically surveying populations of vectors, hosts and parasites using newly developed molecular and genomic tools in conjunction with well-established epidemiologic approaches. Two synergistic epidemiology projects (both with entomological components) are described. Through existing and new communication channels we will ensure that research findings are brought to bear on policy development. The surveillance mechanisms established during this work will provide a mechanism for determining the impact of those policies on malaria infection and disease.

RELEVANCE (See instructions):

By identifying the contributions made by the parasite, the human host and the mosquito vector to the incidence and prevalence of malaria disease in diverse eco-geographic settings in Malawi, we will be able to tailor prevention and control strategies to specific seasons (dry, rainy) and locales (highland and lowland, urban and rural), and we will determine the critical parameters required for monitoring impact.

PROJECT/PERFORMANCE SITE(S) (if additional space is needed, use Project/Performance Site Format Page)

Project/Performance Site Primary Location

Organizational Name:

Michigan State University

DUNS:

193247145

Street 1:

B309 West Fee Hall

Street 2:

City:

East Lansing

County:

Ingham

State:

MI

Province:

Country:

United States of America

Zip/Postal Code:

48824

Project/Performance Site Congressional Districts:

Additional Project/Performance Site Location

Organizational Name:

 University of Malawi College of Medicine

DUNS:

565543253

Street 1:

1 Mahatma Gandhi Road

Street 2:

City:

Blantyre

County:

State:

Province:

Country:

Malawi

Zip/Postal Code:

3

Project/Performance Site Congressional Districts:

PHS 398 (Rev. 11/07) Page 2Form Page 2

Malawi ICEMR Program Director/Principal Investigator (Last, First, Middle):

Taylor, Terrie, Ellen

SENIOR/KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information in the format shown below.

Start with Program Director(s)/Principal Investigator(s). List all other senior/key personnel in alphabetical order, last name first.

Name

eRA Commons User Name

Organization

Role on Project

Taylor, Terrie

MSUTAYLOR

Michigan State University

PI and Core Leader

Chagomerana, Maganizo

University of Malawi College of Medicine 

 Core Leader

 

Laufer, Miriam

mlaufer

University of Maryland

Project Leader

Mathanga, Don

dmathanga

University of Malawi College of Medicine 

Project Leader

Seydel, Karl

MSUSEYDEL

Michigan State University

Core Leader

OTHER SIGNIFICANT CONTRIBUTORS

Name

Organization

Role on Project

Babbage, Jonathan

Michigan State University

Collaborator

Gondwe, Esther

University of Malawi College of Medicine

Co-Investigator

Mande, Lynn

Michigan State University

Co-Investigator

Molyneux, Malcolm

Liverpool School of Tropical Medicine

Co-Investigator

Mukadam, Rabia 

University of Malawi College of Medicine

Laboratory Manager

Mwapasa, Victor

University of Malawi College of Medicine

 Co-Investigator

Mzilahowa, Themba

 ";Text4";University of Malawi College of Medicine 

Co-Investigator  

Phiri, Kamija

";Text4";University of Malawi College of Medicine 

Co-Investigator 

Plowe, Christopher

University of Maryland

Valim, Clarissa

Harvard School of Public Health

Co-Investigator 

Walker, Edward

Michigan State University

Co-Investigator 

Wilson, Mark

University of Michigan

Co-Investigator 

 

Human Embryonic Stem Cells

x No

 Yes

If the proposed project involves human embryonic stem cells, list below the registration number of the specific cell line(s) from the following list: http://stemcells.nih.gov/research/registry/. Use continuation pages as needed.

If a specific line cannot be referenced at this time, include a statement that one from the Registry will be used.

Cell Line

PHS 398 (Rev. 11/07) Page 3Form Page 2-continued

Number the following pages consecutively throughout
the application. Do not use suffixes such as 4a, 4b.

Insert Project/Perfomance Site Format Pages (with the correct congressional district ;-)

Should we re-do the overall Table of Contents??

Insert the Composite Budget here . . .

Response to the Summary Statement

The Malawi ICEMR team appreciates the thorough, thoughtful review provided by members of the Special Emphasis Panel. We will address the primary weaknesses identified by the Panel but first, we would like to highlight the key strengths of the proposal, as noted by the Panel:

  • The high quality and cohesiveness of the multidisciplinary team (Project Director, Project Leaders, Core Leaders)

  • The significance of the proposed studies

  • The synergy between projects and cores

  • The strong links to the Malawi National Malaria Control Programme, and the great potential of the findings for impacting on public health and the NMCP’s policies in Malawi

  • The excellent choice of the three study sites

  • The appropriate timelines

  • The well-written and comprehensive application

One reviewer noted that “Malawi is the ideal African country for transformative malaria research because it has nearly all of the ecological settings relevant to malaria control.”

(Overall score 30)

Summary of changes:

  1. The most significant change in this revised proposal is that Projects 2 and 4 are not present, per se. We made this decision on the basis of the specific reviewers’ comments about these two projects:

Project 2: Vector Biology and Transmission(Overall score: 39)

One reviewer recognized that this project would likely impact the public health policy of Malawi because it would answer an important vector control question related to the effectiveness of insecticide-based tools. By studying how vector populations respond, evolutionarily, to the insecticide-based interventions, Project 2 will determine which of two outcomes is occurring: development of strong insecticide resistance in mosquito vectors that will reduce effectiveness of available insecticide-based tools or the replacement of human vectors with zoophilic vectors resulting in ‘anophelism without malaria’.

Several substantive weaknesses were identified:

  • “This is a small project without important or new objectives. Seven years of funding is very long for this small project. This is a major objection.”

  • “The requested funds are very high.”

  • “The success appears to be linked to Dr. Janet Hemingway, but her clear involvement is not described.”

We have decided to withdraw this project as it submitted, and retain only the entomological activities required to support Project 1 (“Epidemiology of Malaria in Malawi”) and Project 3 (“Malaria Epidemiology in an Urban Setting”).

Project 4: Molecular Epidemiology of Malaria Transmission(Overall score: 39)

The importance of this study was recognized, as was the fact that the infrastructure for Project 1 could be harnessed for the collection of samples that would be ideal to identify the gametocyte reservoirs in Malawi.

There were major criticisms:

  • “No real new ideas are presented and the proposed new biomarker of transmission appears not to be really applied to field conditions on a large scale.’

  • “It is a very weak project to go on for seven years. It may we be just a study.”

  • “Minimum consideration of other new epidemiological tools (except sex ratio of gametocytes) is proposed.”

  • “The application lacked clarity concerning the biomarker test. The test measures the amount of RNA in gametocytes, not the amount of protein as is suggested by the wording in the text.”

  • “No individual with a strong background and expertise in mosquitoes was identified as a team member.”

We have decided to withdraw this project entirely. If the Malawi ICEMR is funded, we will revise this project and submit it, in conjunction with an entomologist, as a separate, small study.

  1. The budget has been reduced significantly, largely in response to criticisms of the budgets proposed for the three Cores. We have re-allocated some project-related costs (travel, accommodation, vehicle purchase, fuel insurance and maintenance, the PD’s involvement in Projects 1 and 3) to the specific project. The scope of the Malawi ICEMR no longer includes constituting and convening the Scientific Advisory Group, hosting an annual meeting, or supporting training fellowships, so the time commitment of those involved in the Administrative Core has diminished.

  1. The reviewers’ concerns that we address issues of HIV co-infection and include key meteorological data were noted, and those data will be collected and included in Projects 1 and 3.

Project- and Core-specific weaknesses will be presented by Project and Core, with our comments and responses in italics.

For this revised proposal, we have followed the structure of the original submission for the Projects and Cores:

Cover Page: present

Project Summary: present

List of Key Personnel, Other Significant Contributors present

Table of Contents: not included here

Detailed Budget for Initial Budget Period present

Budget for Entire Proposed Period of Support present

Budgets Pertaining to Consortium/Contractual Arrangements present

Resources: not included here

(no changes from the original submission)

Response to Summary Statement present

Research Plan: present

  • Specific Aims – included

  • Background and Significance – not included here,no significant changes

  • Preliminary Studies – anot included here, no significant changes

  • Research Design and Methods – included in abbreviated form, emphasizing additions

and changes

  • References Cited – included in “Overview” only. These have not changed from the original proposal

  • Protection of Human Subjects - not included as these have not changed from the original

proposal

  • Inclusion of Women and Minorities - not included as these have not changed from the

original proposal

  • Targeted/Planned Enrollment Tables - not included as these have not changed from the

original proposal

  • Inclusion of Children - not included as these have not changed from the original proposal

  • Consortium/Contractual Arrangements – a revised letter from the University of Michigan

is included with Project 3. Otherwise, these have not changed from the original proposal

PROGRAM OVERVIEW

1. Introduction

Malaria research in Malawi began in 1984, when the Ministry of Health created the national Malaria Control Program and began studies of therapy aimed at guiding treatment policy. The national program designated “severe malaria in children” as a research priority, and research activities on this topic started in 1986. These efforts, based at the Queen Elizabeth Central Hospital, became one of the first ‘research affiliates’ in the University of Malawi College of Medicine when it was established in 1989. Research on malaria has remained an important component of the College’s research agenda, expanding into health centers and communities, but continuing to be responsive to the Ministry of Health.

Clinical and epidemiological research on malaria in Malawi has informed national treatment policies and has made major contributions to our understanding of malaria pathogenesis, antimalarial drug resistance, chemoprophylaxis of malaria in pregnancy, severe malarial anemia, ednet distribution strategies, interactions between HIV and malaria”

  • Hypoglycemia complicates up to 20% of cases of cerebral malaria and is an indicator of a poor prognosis (Taylor, et al., 1988).

  • The Blantyre Coma Score is a reproducible measure of coma in children with cerebral malaria and identifies a subset (those with scores /U> 2) with a worse outcome (Molyneux et al, 1989).

  • Two doses of sulfadoxine/pyrimethamine were effective as chemoprophylaxis in pregnancy (Mangochi Malaria Project, 1994); later, artesunate accelerated parasite clearance times, and adding azithromycin reduced recrudescence (Kalilani, et al, 2007).

  • The increasing prevalence of chloroquine resistant parasites persuaded the Malawi Ministry of Health to switch its first line antimalarial to sulfadoxine/pyrimethamine (Bloland, et al, 1993). Thirteen years later, in the absence of chloroquine drug pressure, chloroquine-sensitive parasites ‘returned’ to Malawi (Laufer, et al, 2006).

  • HIV-infected individuals with malaria infection have higher viral loads than aparasitemic HIV-infected individuals (Hoffman, 1999); over the course of a malaria transmission season, infections are associated with an increase in HIV viral load (Kublin, et al, 2005).

  • Placental malaria infection is associated with increased HIV viral loads in peripheral blood and placenta (Mwapasa, et al, 2004).

  • Social marketing approaches to the distribution of insecticide-treated bednets in Ndirande (a township within Blantyre) were highly effective - - - individual risk was diminished by 50% among those using bednets (Mathanga, et al,, 2009).

  • The use of insecticide-treated nets, distributed in conjunction with routine immunization services, increased from 10-14% prior to distribution to 40-44% afterwards (Mathanga, et al, 2009).

  • Among children with clinically-defined cerebral malaria who die, approximately 25% will be found to have died for reasons unrelated to their malaria infection (Taylor, et al, 2003).

  • The most detailed population-based study to date of the sexual tages of P. falciparum showed that the parasite is a sexual organism whose genomes are in linkage disequilibrium - - this acts to slow the emergence of parasite resistance to drugs and vaccines (Mzilahowa, et al, 2007).

  • There is a surprisingly high “hidden” morbidity and mortality post-hospital discharge in children admitted for treatment of severe malarial anemia (Phiri, et al,, 2008).

  • Severe anemia in Malawian children is multifactorial - - malaria was associated with anemia in an urban study site (Blantyre) but not in a rural site (Chikwawa) (Calis, et al, 2008).

Research activities have been ongoing since 1984 and have served as an important source of capacity-building in the University of Malawi College of Medicine. All of the Project and Core Leaders in this proposal obtained much of their training in the context of projects funded through competitive, peer-reviewed mechanisms.

Successful malaria prevention, control and elimination programs depend on the deployment of effective interventions. Developing and targeting those approaches requires multi-disciplinary research conducted in settings that span the ecological spectrum in which malaria thrives. Malawi has sustained robust research for over two decades, and contains nearly all of the relevant ecosystems within its borders (highlands, lowlands, savannah, forests, irrigated and non-irrigated agricultural areas, rivers, a large lake, cities, towns and villages). The government of Malawi has been unusually responsive to indigenous biomedical research findings. Malawi, with its demonstrations of political will, its track record in malaria research, and its ecological diversity, has the potential to be a site for transformative research on malaria control, prevention and elimination.

2. Research Goals and Objectives

2.1 Special features of Malawi that facilitate the research goals and objectives

2.1.a Country characteristics

Malawi, a small, landlocked country surrounded by Mozambique, Tanzania and Zambia (Figs 1-3, below), has made a peaceful transition to democracy. The UN Human Development index ranks Malawi 166 out of 177 countries and the tenth poorest country in the world. It is the most densely populated country in Africa with few natural resources: HIV/AIDS, low educational attainment and deforestation are some of its more serious challenges. Health services provided by the Government of Malawi, through a system of hospitals, health centres and health posts, are free. There is a parallel system of private practice, and many itinerant shops and pharmacies sell medications over-the-counter.

Figure 1: Malawi in Africa Figure 2. Regional map of Malawi

2.1.b Burden of malaria – current estimates

Malaria transmission occurs throughout the year in most parts of Malawi, except for the mountainous areas in the North and the South (Fig 2). There is a seasonal peak in transmission during the rainy season (November – April). Between July 2006 and June 2007, nearly 4.4 million cases of malaria were reported in this country of 13.1 million people (CMERD 2008). Malaria accounts for 18 percent of all hospital deaths, and 40% of outpatient visits to health centers. The highest burden is born by young children; in 2007, 83% of caretakers cited “fever and malaria” as the impetus for seeking health care for a child under the age of five years (CMERD 2008). Cross-sectional surveys show that, on average, 60% of pre-school children and 47% of school-age children are infected with malaria parasites, and the estimated incidence of malaria disease episodes for pre-school children is 1,038 per 1,000 children per year (Dzinjalamala, 2006). Malaria imposes a significant economic burden with the direct and indirect costs of malaria borne by individuals and households representing about 28% of their annual income (Ettling, et al, 1994).

2.1.c. Data-driven malaria policies

Malawi was one of the first countries to abandon chloroquine in favor of sulfadoxine/pyr-imethamine (SP) as first-line treatment for malaria in 1993 (Bloland,PB et al., 1993) - - and it was one of the last countries in sub-Saharan Africa to move from SP to artemisinin-based combination therapies. This transition occurred in December, 2007, when lumefantrine-artemether became the recommended treatment for uncomplicated malaria (Malenga et al., 2009). Both of these decisions were made on the basis of research carried out at the request of the National Malaria Control Programme, in Malawi.

In 2006, Malawi was included among the first fifteen countries in sub-Saharan Africa to benefit from the President’s Malaria Initiative (PMI). PMI is an initiative emanating from the government of the United States, and its overarching aim is to reduce mortality by 50% in the target counties. In Malawi, this will be accomplished principally by scaling up proven, established malaria prevention and treatment interventions to reach at least 85% coverage of the groups at highest risk (children under the age of five, and pregnant women). These interventions include

  • Prompt treatment of malarial illnesses with artemisinin-based combination therapies

  • Intermittent preventive treatment of pregnant women (IPTp) with sulfadoxine-pyrimethamine

  • Distribution of insecticide-treated nets (ITNs), especially long-lasting ITNs (LLINs)

  • Indoor residual spraying.

Most of the pilot studies in Malawi have been completed, now, and scale-up activities are expected to begin in 2010-2011.

Recent data indicate that the incidence of malaria disease has remained constant in Malawi as a whole (Figure 3).

Figure 3: Summary statistics in malaria cases and deaths attributable

to malaria in Malawi between 1999-2006.




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