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Request for Proposal
Development and Management of Dengue Cohort Studies
The Pediatric Dengue Vaccine Initiative (PDVI) seeks to accelerate the introduction of safe and effective dengue vaccines. The Initiative is funded by the Bill and Melinda Gates Foundation and the Rockefeller Foundation; it is hosted by the International Vaccine Institute in Seoul, South Korea. The program will support two or more sites, at least one each in the American and Asian tropics, for up to 1 million US dollars per site per year for 3 years. Lower study costs may allow support for more sites. Renewal of grants beyond 3 years is possible. Proposals will be submitted in two steps, starting with letters of intent (LOI) followed by a full proposal from those invited to submit. Limited funding is available to support preparation of full proposals. 1. Objectives of the Prospective Cohort Study: Establish or maintain a study cohort to measure flavivirus infection and dengue disease rates in a population at risk for primary and secondary (to include tertiary or quaternary) dengue virus infections. Cohorts will be sufficiently large to anticipate five or more hospitalized dengue hemorrhagic fever cases per year. If a DHF-endemic area is not available in the Americas, then the study should anticipate fifteen or more cases of dengue fever per year. It is planned that these sites will be made available as sites for Phase 3 trials of candidate dengue vaccines. As a secondary objective, the cohort study will produce pedigreed clinical samples to support laboratory-based research on dengue organized and funded by the PDVI under a separate funding initiative. 2. Cohort Study Methods: Blood samples will be obtained from all members of the cohort prior to seasonal flavivirus transmission and at least one and two years later. Demographic features of the cohort will be recorded, including age, gender, race, childhood vaccination status (in particular, yellow fever and Japanese encephalitis), prior history of dengue-like illness, residence. Using the plaque reduction neutralization test or another test of superior specificity, primary and heterotypic flavivirus infections will be identified from a sample of cohort members, thus permitting estimates of primary and heterotypic infection rates for the entire cohort for each year of the study. A comprehensive surveillance system must be developed to permit early identification of cohort volunteers with the presumptive diagnosis of dengue fever and/or dengue hemorrhagic fever. From all enrolled participants who develop presumptive dengue, acute and convalescent blood samples will be obtained, processed, stored and assayed for viremia and serological response. Sera containing virus (detected by RT-PCR and or infectivity assay) will be carefully preserved at ultra-low temperature to permit future genotypic analysis. Experienced and suitably trained health care professionals will record details of each clinical illness. This will provide an accurate characterization of the clinical syndrome for all dengue-infected cohort members to include data on the severity of illness and on the clinical and laboratory features that will distinguish dengue from DHF. Pre-season blood samples from all cohort members will be stored at ultra-low
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temperatures. These samples will be matched with cohort members who develop laboratory-documented dengue virus infections during the period of observation. The grantee recipient at the direction of the PDVI will furnish partial serum samples and viral strains to participating research laboratories. An off-site, back-up, research quality, flavivirus laboratory may be required to support the study site. 3. Period of Performance: The initial grant will be for 3 years with an option for renewal. 4. Application Process a. Letters of Intent (LOI). Deadline: 15 November 2003. LOI will describe in not more than 3 letter-size pages (1 inch margins, single spaced, 12 point font), the name and qualifications of the Principal Investigator and key co-investigators, the names and locations of collaborating institutions, plans to establish or maintain a prospective cohort study of dengue infection and disease, and evidence from published or non-published sources that substantiate the designated population as being at risk for dengue disease and free or relatively free of exposure to flaviviruses other than dengue either as wild-type viral infections or vaccination (see evaluation criteria below). The LOI should outline the administrative framework to provide the serum samples requested in step b of the application process, including scientific and ethical review of the human volunteer protocol (provide names and locations of review committees). b. Test Serum Samples. Candidate grantees whose LOI is selected for further evaluation will propose a budget and timeline to collect not less than 1.0 ml of serum from each of 100 randomly selected children resident in the designated study site and born in calendar year 1997. Sera will be shipped to a laboratory to be designated by the PDVI and screened for neutralizing antibodies to dengue 1 – 4 viruses and Japanese encephalitis, West Nile or yellow fever, as appropriate. This requirement will be waived for prospective grantees who can document dengue virus infection rates in multiple recent years among their proposed study cohort. c. Full proposal. Candidate grantees whose LOI is selected for further evaluation will be invited to submit full proposals. The text of the full proposal should not exceed 15 pages (1 inch margins, single-spaced, 12 point font) plus annexes and include the results of the serosurvey described above. The full proposal should be written so as to provide information relevant to the following evaluation criteria. 5. Evaluation Criteria: The grant will be awarded based on a best value analysis of the submitter’s proposal. Best value will be determined by evaluating the following factors. a. Study site is located in an area with periods of high dengue virus transmission based on dengue hospitalization rates in the age group of the designated cohort population for the previous ten years.
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b. Documented circulation within the past six years of two or more different dengue virus serotypes. c. Clear plan, including timelines, to measure prospectively the incidence of dengue disease (particularly DHF) in a designated open study cohort of specified size. d. A plan to measure on an annual basis for at least three consecutive years primary and secondary (second, third or fourth) dengue virus infections during seasonal transmission period in a cohort at risk to severe dengue disease. e. Stable cohort population to allow long-term follow up for collection of blood samples with necessary quality control and quality assurance. e. Adequate infrastructure to support study site laboratories, transportation of specimens and personnel to vaccinate and follow-up a large volunteer population. g. Host country anticipates use of a dengue vaccine should it become available. h. Population willing to support longitudinal studies of dengue incidence (concurrence of community leaders). i. Quality of people making clinical assessments. j. Study site located in an area with no or low incidence of natural infection or vaccination with other flaviviruses (e.g., Japanese encephalitis, West Nile, yellow fever). Low incidence is defined as prevalence of non-dengue flavivirus neutralizing antibodies in less than 5% of children born in 1997. k. Political stability of host nation. l. Integration into study of all medical treatment centers serving the cohort population or a plan to direct cohort population with febrile illnesses to designated health centers. m. Ability of collaborating medical treatment facilities to provide research-level diagnosis and national standard ability to treat DHF patients. n. A dengue diagnostic laboratory able to perform standard dengue EIA, HI, neutralization titers, virus isolation and molecular detection techniques with adequate staff to evaluate estimated number of samples. Laboratory methods should be compliant with Good Laboratory Practices (GLP). o. Demonstrated ability or clear plan to develop the capacity to conduct the study to include training of host-country physicians, scientists and laboratory staff in Good Clinical Practice (GCP) and data and safety monitoring.
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p. Community education and cooperation to include investment in local public health personnel and clinics to support 1) a vaccine trial, 2) an education program to train the parents of pediatric volunteers to recognize dengue and severe disease and 3) how to prevent dengue through vector control. q. Project cost. Up to $1,000,000 US per year per site for two sites is available. However, if a site has the ability to meet the evaluation criteria at lower cost, this will be weighed in the final selection and may allow for the selection of more than two sites. r. (Optional) Research plan to investigate unique pathogenesis or immunogenicity issues associated with dengue. Definitions: Dengue hemorrhagic fever, a dengue syndrome characterized by plasma leakage due to increased vascular permeability (hematocrit > 20% of recovery value, pleural effusion, or ascites) and abnormal hemostasis (at least thrombocytopenia with a platelet count <100,000 mm3 ); dengue shock syndrome, a subset of dengue hemorrhagic fever with hypotension or narrow pulse pressure (< 20 mm Hg); undifferentiated fever, a febrile illness without localizing or pathognomonic signs; virulence, capacity to cause disease measured as a ratio between clinically defined syndrome and total infections. heterotypic, referring to different serotypes within a virus group; homotypic, referring to different virus strains within a single serotype; monotypic, referring to a single serotype; multitypic, referring to two or more serotypes in a virus group; primary infection, initial infection with a virus serotype; secondary infection, heterotypic infection of a monotypic immune individual; tertiary infection, heterotypic infection of a multitypic (two infections) immune individual; For more information on preparation of proposals, contact Ms. Eunyoung Kim, International Vaccine Institute, SNU Research Park, San 4-8, Bongcheon-7dong, Kwanak-gu, Seoul, Korea, 151-818 (eykim@ivi.int; fax: 82-2-872-2803). Letters of Intent should be sent to Ms. Kim no later than November 15, 2003.
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