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Protection of military personnel against vector-borne diseases: a review of collaborative work of the Australian and US military over the last 30 years.

The role of the Royal Australian Army Medical Corps and the US Army Medical Department is to provide the best medical care for members of the Australian and US armed forces. The task to provide protection against vector-borne diseases such as malaria, dengue, arboviruses, and others is undertaken by various groups in both countries. In Australia, this work has been undertaken by a small group of medical officers and scientists at the Army Malaria Research Unit (AMRU), which became the Army Malaria Institute (AMI), (1-6) and in the United States, the Walter Reed Army Institute of Research (WRAIR) in Forest Glen, MD, and its overseas laboratories. (7)

Collaboration between the United States and Australia was important during World War II in the Pacific. The work conducted between 1941 and 1945 by the Australian Land Headquarters Medical Research Unit is described in detail by LTC A. W. Sweeney in his book, Malaria Frontline. (8)

During the Vietnam War, many cases of vector-borne disease were observed in Australian, United States, and other Allied defense personnel. The medical resources and personnel of both countries collaborated to optimize and evaluate measures against diseases. The high number of malaria cases in Australian soldiers in Vietnam in 1965 resulted in the establishment in 1966 of the 1 Malaria Research Unit, under the direction of Professor Robert H. Black at the University of Sydney. This unit was moved to Ingleburn, 35 km southwest of Sydney, New South Wales, in 1974. (1)

In 1985, LTC Sweeney visited medical research units in the United States and fostered a formal collaboration between AMRU and US military scientists. One of the first collaborations involved field testing of new mosquito repellents and permethrin treated military uniforms at Cowley Beach, northern Queensland, Australia. This field trial was conducted by 4 scientists from the Letterman Army Institute of Research, Presidio of San Francisco, and AMRU. The study showed that a combination of wearing permethrin treated battle dress uniforms and repellents containing deet provided the best protection against mosquitoes. (9) A subsequent field trial at the same site in 1990 conducted by AMRU and the US Department of Agriculture compared methods of protection against trombiculid larvae (chiggers). This study showed that permethrin treated uniforms provided protection against mites that cause scrub itch. (10)


Medical Officers in Malaysia

Australian medical officers first worked in Malaysia at the US section of the Institute of Medical Research (IMR) in Kuala Lumpur in the early 1980s. They collaborated with US Army and Malaysian medical officers on protection against scrub typhus and snake envenomation. The joint studies conducted showed that doxycycline was an effective prophylaxis for scrub typhus, (11) and field surveillance showed that disease in Malaysia was underreported. (12,13)

Exchange Scientists in Thailand and Australia

In 1988, the US section of IMR Malaysia closed and an exchange was established with the Armed Forces Research Institute for Medical Sciences (AFRIMS) in Bangkok, Thailand, and the Australian AMRU. Between 1989 and 1992, mAj M. D. Edstein from AMRU worked at AFRIMS primarily on preclinical drug development and clinical evaluation of standard and new antimalarial drugs. During this 3-year period, MAJ Edstein and US Army and Thai Army collaborators researched new antimalarial compounds using nonhuman primates for causal prophylactic and radical curative activity. Of these studies, WR182393, a non-8-aminoquinoline guanylhydrazone, exhibited both causal prophylactic and radical curative properties in the rhesus monkey (Macaca mulatto)/ Plasmodium cynomolgi test model, a vivax malaria-like model. (14) However, using the same model, the prophylactic combination of proguanil plus sulfamethoxazole was found not to be causally prophylactic. (15) Additionally, the proguanil analog WR250417 (also known as PS-15) was shown to extend the prepatent period of P cynomolgi from 8.5 days to 18.3 days in drug-treated monkeys, but did not prevent a primary infection. (16)

For clinical studies, new high performance liquid chromatographic (HPLC) methods were developed for the analysis of antimalarial drugs such as quinine, (17) halofantrine, (18) mefloquine-sulfadoxine-pyrimethamine, (19) and ciprofloxacin. (20) These HPLC methods were used to characterize the pharmacokinetic-pharmacodynamic interaction of mefloquine in resistant P falciparum malaria on the Thai-Burma/Myanmar ** border, (21) assess the efficacy of halofantrine in treating Thai patients who failed mefloquine chemoprophylaxis, (22) evaluate the potential of ciprofloxacin in treating drug-resistant falciparum malaria, (23) assess the effect of food on the disposition of halofantrine in treating falciparum malaria (24) and determine the effectiveness of high-dose mefloquine in treating multidrugresistant falciparum malaria. (25)

At the time of those studies, mefloquine was the treatment of choice for uncomplicated multiresistant falciparum malaria. A standard dose of 15 mg/kg of mefloquine became ineffective in treating acute falciparum malaria in an area with deteriorating multidrug resistance on the Thai-Myanmar border. By increasing the mefloquine dose to 25 mg/kg, the clinical and parasitologic responses were significantly more rapid with high dose mefloquine compared with the standard dose. (26) The failure rate by day 28 of follow-up was 40% and 9% with 15 mg/kg and 25 mg/kg of mefloquine respectively. Adverse events were dose-related and included dizziness, anorexia, nausea, vomiting, and fatigue.

Mefloquine in combination with sulfadoxine and pyrimethamine (MSP) at a single dose of 15/30/1.5 mg/kg, respectively, also became ineffective. In 1985-1986, MSP cured over 98% of 5,192 patients with falciparum malaria on the Thai-Myanmar border. Four years later, the efficacy of MSP in 395 patients at the same location had declined to 71%. In these patients, the mean serum mefloquine concentration at the time of first recrudescence was 638 (546-730) ng/mL, a value previously associated with successful treatment. These findings suggested that P falciparum had rapidly developed resistance to mefloquine, despite the addition of sulfadoxine and pyrimethamine. The recommendation was to abandon the MSP combination. (21) The development of resistance to mefloquine highlighted the urgent need to evaluate new antimalarial drugs such as halofantrine. The recommended regimen of halofantrine was 3 doses of 500 mg (1,500 mg total or 24 mg/kg) at 6-hour intervals given with food to enhance drug absorption. However, this halofantrine regimen was found to be ineffective in treating 30% (7/23) of Thai soldiers who showed slide-positive results for malaria while receiving mefloquine chemoprophylaxis. (22) The serum halofantrine concentrations were higher in patients cured by halofantrine compared with those who failed treatment. These observations suggested that the 24 mg/ kg regimen of halofantrine was not optimal for the treatment of multiple drug-resistant falciparum malaria in Thailand. A higher dose of halofantrine (72 mg/kg) was more effective in treating uncomplicated falciparum malaria with a failure rate of 15%, but evidence of possible cardiotoxicity was observed and required investigation. (26) Studies by other investigators led to the demise of halofantrine due to cardiotoxicity.

In 1992, MAJ Edstein was replaced at AFRIMS by MAJ S. P. Frances, an entomologist, who worked on personal protection measures against malaria vectors, and biology of the vectors of scrub typhus. While at AFRIMS, Frances conducted laboratory and field evaluations of repellents and toxicants against mosquito vectors of malaria and mite vectors of Orientia tsutsugamushi. (27-33) He also worked on vectors of scrub typhus, resulting in the establishment of colonies of Leptotrombidiun deliense (mites) naturally infected with O tsutsugamushi, and improved understanding of the ecology of mites, rodent hosts, and the pathogen that causes scrub typhus in Thailand. (34-44)

During the same time (1992-1995), LTC G. D. Shanks worked at AMRU in Australia. He worked closely with MAJ Edstein, who had returned to Australia, on development of anti-malarial drugs. A number of valuable findings during this time included several clinical trials in Papua New Guinea. (45-48)


Collaboration between AMI and US military scientists has continued. In the 1990s, evaluation of repellent active ingredients deet, AI3-37220, and CIC4, ** along with personal protection measures against mosquitoes was undertaken. In 2001, an evaluation of Australian and US repellents was conducted in Australia at Cowley Beach by the AMI with US Army MAJ M. Debboun from WRAIR. The study compared the protection provided by commercial and military repellent on human volunteers. (49) This collaboration continued with evaluation of additional active ingredients in the laboratory and field, (50) as well as field evaluation of a low profile US bednet in Papua New Guinea. (51) The prototype bednet that was tested has been in use by US military personnel for more than a decade. (52) More recently, 3 books on repellents and personal protection measures used by civilian and military personnel were edited by US Army and Australian Defence Forces entomologists. (53-55)

Financial support from the Defence Warfighters Program of the Armed Forces Pest Management Board to AMI in 2008, allowed evaluation of Australian military shirt fabrics treated with permethrin to be tested to determine protection against mosquito bites of malaria and dengue vectors. (56,57)

Drug Development

The development of mefloquine as an anti-malarial drug was reviewed by Shanks. (58) The constraints of shrinking military and civilian budgets for development of antimalarial drugs highlighted the need to continue to conduct collaborative development of drugs. Despite this, collaborative research to develop new anti-malarial drugs between the two nations has continued.

From 1998-2011, exchange scientists from WRAIR undertook collaborative evaluation of the new anti-malarial drug tafenoquine (formerly known as WR238605 or etaquine) for malaria prevention and in vitro studies into artemisinin induced dormant ring-stages of P falciparum as a plausible explanation for recrudescence. In 1998, a field study of tafenoquine was conducted in Ubon Ratchatani province, Thailand, with Thai soldiers and collaborators from Australia, United States, and Thai military. (59) The major focus of the study was to determine the safety, tolerability, efficacy, and pharmacokinetics of tafenoquine following an oral loading dose of 400 mg daily for 3 days and monthly administration of 400 mg for 5 consecutive months. (59) In participants completing the follow-up period (96 tafenoquine and 91 placebo recipients), there were 22 P vivax, 8 P falciparum, and one mixed infection. With the exception of one P vivax infection in the tafenoquine group, all infections occurred in placebo recipients, giving tafenoquine a protective efficacy of 97% for all malaria, 96% for P vivax malaria, and 100% for P falciparum malaria. The soldier in the tafenoquine group who developed malaria during the study had a lower plasma tafenoquine concentration of 40 ng/mL at the time of diagnosis, which was approximately 3-fold lower than the trough concentrations of the other soldiers who were protected from infection by tafenoquine. (60) The phase II study revealed that monthly tafenoquine was safe, well tolerated, and highly effective in preventing P vivax and multidrug-resistant P falciparum malaria in Thai soldiers during 6 months of prophylaxis. This study was the first investigation of tafenoquine in Southeast Asia and in protecting volunteers from both P vivax and P falciparum malaria.

To assist in the development and evaluation of tafenoquine, a rapid and sensitive HPLC method for tafenoquine was developed by CPT D. A. Koscisko, US Army, during his assignment to AMI from 1999-2001. With this method, the population pharmacokinetics of tafenoquine was characterized in Thai soldiers who participated in the phase II study. (61,62) A one-compartment model was found best to describe the pharmacokinetics of tafenoquine after oral administration. The drug is widely distributed to body tissues with a high apparent volume of distribution and a lengthy elimination half-life of 16.4 days, suitable for weekly prophylaxis.

LTC D. E. Kyle, US Army, established the WRAIR laboratory at AMI in 2001. He collaborated in studies of the drug Artimisone, which showed it was more effective than artemisinin drugs in curing P falciparum in Aotus monkeys. (6,63,64) He has continued collaboration with AMI in his role as a professor at South Florida University with studies of the role of gene amplification and expression that induces resistance in P falciparum. (65-68)

In February 2004, LTC Kyle returned to the United States and was replaced at AMI by MAJ Mike O'Neil. From 2004 to 2006, he participated in the assessment of the pharmacodynamics and pharmacokinetics of the novel dihydrofolate reductase inhibitor, JPC2056, and its principal active metabolite JPC2067 in cynomolgus monkeys using an in vivo-in vitro (ex vivo) model. (69) In a 2-phase crossover design, cynomolgus monkeys were administered multiple doses (20 mg/kg daily for 3 days) of JPC2056. Plasma samples collected from treated monkeys were assessed for ex vivo antimalarial activity against P falciparum lines having wild-type (D6), double-mutant (K1) and quadruple-mutant (TM90-C2A) DHFR-thymidylate synthase (TS) and a P falciparum line transformed with a P vivax dhfr-ts quadruple-mutant allele (D6-PvDHFR). Plasma JPC2056 and JPC2067 concentrations were measured by LC-mass spectrometry. The mean inhibitory dilution (ID90) of monkey plasma at 3 hours after the last dose against D6, K1, and TM90-C2A was 1613, 1120, and 1396, respectively. Less activity was observed with the same monkey plasma samples against the D6-PvDHFR line, with a mean [ID.sub.90] of 53. Geometric mean plasma concentrations of JPC2056 and JPC2067 at 3 hours after the last dose were 150 and 17 ng/mL, respectively. The elimination half-life of JPC2056 was shorter than its metabolite after both regimens (6.6 versus 11.1 hours). The high ex vivo potency of JPC2056 against P falciparum DHFRTS quadruple-mutant lines provides optimism for the future development of JPC2056 as a therapeutic agent.

In 2006, LTC N. Waters (US Army) was assigned to the WRAIR laboratory at AMI. He participated in a major AMI activity and Australian Government Pacific Malaria Initiative assisting in malaria eradication efforts in the Solomon Islands and Vanuatu. (70) The Drug Resistance and Diagnostics department of AMI collaborated with LTC Waters on studies of the molecular assessment of parasite drug resistance. (71) They found that Pfalciparum from both Solomon Islands and Vanuatu had high levels of resistance to Chloroquine (72) and Fansidar. (73) LTC Waters was next assigned to the US Military Academy, West Point, NY, in 2011, and has brought cadets to Australia each year from 2011-2015 to work in the AMI laboratories.


After more than 20 years of having US Army officers working in Australia at AMI, the exchange program has lapsed due to nonavailability of those officers. However, the collaboration between the 2 countries continues, especially in the fields of entomological research, drug development, and pharmacology. With the continued meager funding of some fields of medical research and different priorities within the US and Australian Defence Forces, continued collaboration is important to continue to conduct valuable research on a variety of vector-borne diseases. The effect of malaria, dengue, and scrub typhus have remained focal for both countries, and collaborative research will continue to minimize the impact of these diseases on military personnel and civilians alike.


We thank Mrs Oranuch, AFRIMS, Bangkok, Thailand, for allowing us to use archival photos from AFRIMS collection. Studies reviewed in this paper were supported by a number of funding agencies, and we thank them for their support of both the Australian Defence Force and the US Department of Defense. The opinions expressed herein are those of the authors and do not reflect those of the Joint Health Command (Australia) or any Defence policy.


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(73.) Gresty K, Gray KA, Bobogare A, et al. Genetic mutations in pfcrt and pfmdrl at a time of the artemisinin combination therapy introduction in South Pacific islands of Vanuatu and Solomon Islands. Malaria J. 2014:13:406.

Stephen P. Frances, PhD

Michael D. Edstein, PhD

Mustapha Debboun, PhD, BCE

G. Dennis Shanks, MD

Mention of a commercial product does not constitute an endorsement of the product by the Australian Defence Force or US Department of Defense.

* The country of Burma was renamed Myanmar in 1989.

** deet (diethylmethyl benzamide); AI3-37220 (1-(3-cyclohexen1-cabonyl)-2-m ethyl piperidine); CIC-4 (2-hydroxomethylcyclohexl) acetic acid)


Dr Frances is with the Australian Army Malaria Institute, Enoggera, Queensland.

Dr Edstein is with the Australian Army Malaria Institute, Enoggera, Queensland.

Dr Debboun is the Director of the Mosquito Control Division, Harris County Public Health, Houston, Texas.

Dr Shanks is with the Australian Army Malaria Institute, Enoggera, Queensland. He is also a Professor at the University of Queensland School of Public Health, Brisbane, Australia.
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Author:Frances, Stephen P.; Edstein, Michael D.; Debboun, Mustapha; Shanks, G. Dennis
Publication:U.S. Army Medical Department Journal
Date:Oct 1, 2016
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