Department of Immunology and Medicine:Research Projects

1. Malaria Vaccine Preclinical Development with WRAIR (Department of Immunology), GlaxoSmithKline, USAID and WHO:
    a). Completing reports for Pf erythrocytic stage vaccine, MSP142, in rhesus models with various adjuvant systems.
    b). Completing reports for Pf pre-erythrocytic vaccine RTS,S/TRAP in neonates.
    c). Continuing efforts to incorporate ways to enhance immune response using novel adjuvants and delivery systems and prime-boost approach (such as recombinant adenovirus/protein).
    d). Studying interplay of a combination of sporozoite (RTS,S) and blood-stage (AMA-1 and MSP-1) vaccines in rhesus and mouse models.

2. Basic Immunology Researches:
    a). Studying the role of dendritic cells (myeloid and plasmacytoid), regulatory T cells (CD4+CD25+) and gd T cells in immunoregulation and immunopathogenesis of human falciparum malaria.
    b). Investigating interplay of MSP-1 with the innate immune system and how this causes aspects of severe malaria.

3. New Antimalarial Drug Discovery and Development:
    a). Azithromycin/quinine combinations (partnered with Experimental Therapeutics and Pfizer Inc.): Completed Phase II dose ranging trial of azithromycin/quinine combinations for the treatment of uncomplicated falciparum malaria. This is the first clinical trial completed in the new AFRIMS clinical trial center co-established with Kwai River Christian Hospital in Sangkhlaburi along the Thai-Myanmar border.
    b). Preclinical Development of Intravenous Artemisinins (partnered with Experimental Thaerapeutics and the Medicines for Malaria Venture (MMV):

• adapted and validated in vitro bioassay and HPLC-ECD to rhesus plasma to allow measurement of total antimalarial activity of intravenous artemisinins (structure) as well as measurement of major metabolites, in support of rhesus efficacy and toxicity trials.
• Developed a severe malaria model using P. coatneyi in splenectomized rhesus and evaluated artelinate and artesunate in this model. The studies support down-selection efforts to a lead intreavenous candidate.
• Tested intravenous artemisinin candidates in standard toxicology protocol (including throrough neurotoxicity studies) in rhesus.

• Completing reports of Phase II testing of P. vivax radical cure with Mahidol University
• Developed a program to test tafenoquine (WR238605) in adults and children for further evaluation of radical curative ability and pharmacokinetics in P. vivax malaria.

• Search for lead antimalarial compounds from natural products and existing chemical database at WRAIR.
• Development of new methods to screen antimalarials: Supported continuing efforts to develop a hepatocyte cell line to screen activity in the liver of antimalarial drugs. Developed a model for assessing toxicity in neuronal cell lines.

4. Diagnostics/Rapid Diagnosis of Malaria (partnered with USAMMDA):
    a). Completed clinical trial (N=300) of a second generation prototype of new rapid diagnostic kits (MRDD) at Mae Sod field site, that establishes this prototype as the lead agent for further development by USAMMDA.
    b). Completed the in-life and microscopic assessment portions of the definitive multi-center trial of a second generation rapid diagnostic kit (NOW ICT Pf/Pv, Binax Inc.) in Mae Sod (n=2400).
    c). Field test other prototype and marketed malaria rapid diagnostic tests against expert microscopy
    d.) Evaluated two methods of real-time PCR to diagnose malaria, especially mixed infections, which are difficult to detect by microscopy. Supported a blinded comparison of these methods to expert microscopy.
    e.) Completed an analysis of scrub typhus assays for comparison to scrub typhus rapid diagnostics under development

5. Epidemiology of Malaria Drug Resistance (partner with GEIS):

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a) Maintain archive of P. falciparum parasites collected around SE Asia, well characterized by in vitro IC50s and clinical data
b) Collect parasites from new locations across SE Asia to map aspread of drug resistant strains
c) In vivo testing of mefloquine in high-risk regions of Thailand
d) Molecular testing for DHFR mutations in Nepal in areas where Fansidar is failing
e) Characterizing mutations associated with mefloquine resistance both in vivo and in vitro

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    a) Ongoing surveillance of febrile illness at a crucial junction along the central Thai-Myanmar border in coordination with Kwai River Christian Hospital
    b) Characterization of flea and tick-borne illness seen in this areas and rickettsia and ehrlichia found in arthropods from the region
    c) Identification of leptospirosis (presentation) as a major cause of febrile illness along the border
    d) Identification of novel flaviruses isolates from human and sentinel animals
    e) Field assessment of rapid diagnostics for unknown febrile illnesses

Results of the Study of Febrile Disease in Sangkhlaburi (WRAIR protocol #896) were presented to the Sangkhlaburi community on March 30, 2004. There were 70 participants, including medical personnel from Sangkhlaburi Hospital and Kanchanaburi River Christian Hospital (where the study is based), medical staff from nearby refugee camps (Medicines Sans Frontieres and American Refugee Committee), and local government and public health officials. AFRIMS investigators from the Immunology and Enterics Departments presented results based on enrollment of over 800 study patients over the past 5 years. Local prevalence and clinical presentation of leptospirosis (previously not known to be common in the area), scrub typhus, dengue, and infectious diarrhea were discussed, as well as other causes of fever. Results of malaria drug resistance testing from local samples were also presented.

Discussion among participants after the event focused on how to incorporate findings into local practice. Several attendees also expressed interest in participation in future studies. Results are being disseminated further through distribution of a CD-ROM, and meetings with local providers are ongoing.

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