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.
c). Tafenoquine
radical curative ability in P. vivax (partnered with Experimental
Therapeutics/Glaxo Smith Kline and the NIH):
- 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.
d). Drug
optimization: Rhesus-P. cynomolgi screening models and pharmacodynamic/pharmacokinetic
interplay of candidate antimalarials
e) Drug Discovery:
- 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
6.
Febrile Illness Surveillance (partner with GEIS):
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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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