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History of u.s. military contributions to the study of malaria

History of U.S. Military Contributions to the Guarantor: COL Christian F. Ockenhouse, MC USAContributors: COL Christian F. Ockenhouse, MC USA*; COL Alan Magill, MC USA*; Dale Smith, PhD†;COL Wil Milhous, MS USA (Ret.)* More so than any other infectious disease, malaria has all too prevention of diseases, particularly intermittent fevers.
often affected the conduct of military operations in war and in Throughout the 19th century, Army meteorological data were some cases has disproportionately influenced the outcome.
collected and reported but unfortunately did not provide any From Napoleon’s defensive action at Walcheren, to the Union better guidance for the prevention of disease.
Army’s attempts to take control of the Mississippi River atCorinth and Vicksburg, to the dreadful numbers of malaria The knowledge of the intermittent fevers accumulated in the casualties suffered by U.S. Marines on the islands of Efate and 17th and 18th centuries was largely observational, and all types Guadalcanal during World War II and more recently in Liberia of remedies were proposed. However, in the 1600s, teas and in 2003, malaria has extracted a heavy toll. In this article, we brews concocted from the bark of the cinchona tree provided summarize a few of the significant contributions to malaria relief and cure for numerous maladies and fevers, with the most control by U.S. military personnel throughout its history. We prominent effects on the agues or intermittent fevers. In 1820, review examples of scientific achievements, medical break- Joseph Pelletier and his associate Joseph Caventau isolated throughs, and lessons learned from preceding wars that con-tinue to drive the quest for effective antimalarial therapies and quinine sulfate from the bark of the cinchona tree and proved preventive vaccines. This review is by no means comprehen- that the vegetable alkaloid was the specific component or active sive or complete but serves as a testament to the skill, cour- principal of the bark. By the late 1820s, the medical profession age, self-sacrifice, and devotion to duty of the many who have in the United States, as in Europe, was increasingly uncertain faithfully served their country in the past and to those today regarding the appropriate dosage of quinine required to combat who continue the struggle against this disease.
intermittent fevers and, in retrospect, the dosage given was anorder of magnitude too low to be effective.
Malaria Control in the Pre-Germ Era (1600 –1900) In the 1830s, the Army was ordered into the Florida territory to protect white settlers from the attacks of the Seminole Indi- Malaria,knownthroughmostofhistoryasintermittentfever ans,whohadpreviouslyoccupiedtheland.From1838through or ague, was endemic in the American colonies and was 1842, the Army was engaged in a campaign known as the Sec- reported as early as 1610 in letters and diaries from settlers of ond Seminole War. The chief medical officer for the deployed Jamestown, Virginia. The germ theory of disease had not yet force was surgeon Benjamin Franklin Harney, a career medical been appreciated when the Hospital Department of the Army of officer with considerable experience in the American Southwest.
the United States was organized in 1775. The best preventive Dr. Harney had heard of the experiences of some Southern medical advice available at that time was to avoid marshes and physicians who were making a habit of using higher doses of beware of “miasmata,” especially during spring and late sum- quinine and even giving it in the paroxysm of fever, with report- mer, and it was hoped the troops would stay healthy. Unfortu- edly good results. As the Army moved into the Florida swamps in nately, like much preventive medical advice in the 18th century, pursuit of the Seminole raiders, the troops suffered from partic- this sometimes worked and frequently did not, which under- ularly pernicious intermittent and remittent fevers. Dr. Harney mined the confidence of line officers in their doctors’ recommen- began to insist that physicians prescribe a high-dose regimen, dations. It was and continues to be necessary for those respon- particularly for remittent fever, and the records of success con- sible for the health of the command to support efforts to improve vinced even the most skeptical. Soon thereafter, the use of larger the knowledge base and apply proven preventive modalities. In doses of quinine rather than smaller doses became standard the 18th century, the United States inherited two research tra- practice for medical officers. The AMEDD reports convinced the ditions, an ancient one of clinical observation and a more recent physicians of the nation and helped improve treatment recom- one in which conditions were modified to yield insights. Condi- mendations for the use of quinine by military physicians around tions changed in 1818 with the establishment of the Army Med- the globe.1 However, the use of quinine had detractors as well as ical Department (AMEDD) under the leadership of Joseph champions. Surgeon General Thomas Lawson doubted quinine Lovell, the first Surgeon General of the Army, who believed that as a cure and erected obstacles to its use. Thomas Lawson, physicians should increase medical knowledge. He required reg- “more soldier than doctor,” was neither as talented a physician ular weather and disease incidence reports by all Army physi- nor as level-headed an administrator.
cians in an effort to correlate disease with climate, an ancient Through the middle of the 19th century, the AMEDD contin- epidemiological observation, with the idea that knowledge of the ued to be interested in the periodic fevers but little new infor- weather and climate would allow more precise guidance for the mation was added. During the Civil War, malaria affected bothsides but especially Union soldiers from the North, many of *Walter Reed Army Institute of Research, Silver Spring, MD 20910-7500.
whom had never been exposed to malaria-infected mosquitoes.
†Uniformed Services University of the Health Sciences, Bethesda, MD 20814.
Reprint & Copyright by Association of Military Surgeons of U.S., 2005.
The farther south they advanced, the more soldiers fell ill or died Military Medicine, Vol. 170, April Supplement 2005 from malaria. In 1862, malaria thwarted and delayed for more Commission, where as chief health officer he quickly removed than 1 year the Union’s seizure of Vicksburg in Mississippi, the threat of yellow fever from the workers’ lives. However, ma- leaving General Henry Halleck to say, “if we follow the enemy laria remained a much more intractable problem. Gorgas estab- into the swamps of the Mississippi there can be no doubt that lished four avenues of attack, i.e., (1) elimination of Anopheles our army will be disabled by disease.”2 Within 1 month, he was breeding grounds by draining swamps and spraying oil, (2) em- relieved of his command. By the time the Civil War started, ployment of mosquito “swatters,” (3) installation of screens in quinine had been widely accepted as treatment and was used by living quarters, and (4) institution of quinine for antimalarial many as a prophylactic therapy. The Army was celebrated for prophylaxis (at a dose of 150 mg twice daily, diluted as needed keeping accurate records and the records reported that more in lemonade). The result was staggering, perhaps the greatest than 19 tons of quinine were in its inventory, but delivery to the single achievement in public health prevention in the 20th cen- troops was delayed or never occurred at all. It was reported that tury.2,5 Within 3 years, Gorgas had reduced the incidence of the Union Army suffered more than 1.3 million cases of malaria, malaria from 800 cases per 1,000 workers to 16. The eminent physician Sir William Osler later commented, “there is nothing While the United States was engaged in the Civil War, Euro- pean scientists were busy developing the germ theory of dis- to match the work of Gorgas in the history of human achieve- eases, so that by the late 1870s the etiological agents of many diseases were being identified. In 1879, the German and Italian During the first third of the 20th century, environmental team of Edwin Klebs and Ettore Marchiafava announced the control of disease-carrying mosquitoes was standard practice discovery of Bacillus malariae as the presumptive cause of ma- but the dream of chemical prophylaxis, and particularly immu- laria. An AMEDD officer, George M. Sternberg, undertook to nization, drove further research efforts. When World War II confirm their work. While reviewing the literature, he came broke out in the Pacific, the United States and its allies had little across the alternative claim of a French Army doctor, Alphonse to offer to protect troops in forward areas. Although German Laveran, who reported a protozoan parasite in the blood of pharmaceutical researchers developed a variety of drugs with malaria patients. Unable to fully confirm either set of observa- antimalarial properties, little systematic drug research was un- tions, Sternberg arranged a study visit to Europe, where he dertaken in the AMEDD. The events of World War II illustrate observed the laboratories of the principal investigators and re- the enormous burden of malaria in military campaigns. It was turned home convinced of the accuracy of Laveran’s claim of the not unusual for cases of malaria to be as numerous as battle- Plasmodium as the etiological agent causing malaria. In 1886, at field casualties. From the South Pacific to the China-Burma- the founding meeting of the American Association of Physicians, India theater to Sicily, malaria extracted a heavy toll. Three days Sternberg was able to endorse the true causative organism of after the attack on Pearl Harbor in December 1941, the Japa- malaria and convinced many American practitioners to study nese seized control of the Philippines, forcing Gen Douglas MacArthur and 100,000 soldiers to retreat to the Bataan pen-insula. In a matter of weeks, encamped in the hot, humid, Malaria Control by the U.S. Military, 1900 to mosquito-filled jungle, 500 to 700 men per day suffered the ravages of fever and delirium, resulting in 24,000 malaria casu-alties. From 1943 to 1945, the number of cases of malaria During the 1898 war with Spain, the AMEDD again experi- increased each year, eventually totaling more than 572,000.
enced outbreaks of camp diseases that BG Sternberg, then the The military strategy was control, prevent, and treat, identical Surgeon General, thought were fecal-oral typhoid fever. Be- to the successful strategy implemented by William Gorgas 40 cause of the clinical and diagnostic imprecision and uncertainty years previously. However, the tactics were left to the ingenuity of diagnosis, an inspection and research board led by Maj Walter of officers entrusted with developing a workable plan. Malaria Reed was appointed to investigate. The board proved that typho- survey and control units set up by both the U.S. Navy and U.S.
malarial fever did not exist as a unique disease but, more im- Army7 were greatly aided by the first large-scale application of portantly, it helped establish for the large numbers of American residual insecticides, particularly dichlorodiphenyltrichloroeth- physicians serving in the volunteer mobilization that micro- ane (DDT). DDT was added to U.S. Army supply lists in the scopic diagnosis of malaria was the only safe standard. By the spring of 1943, field-tested in August 1943, and applied suc- beginning of the 20th century, malaria was receding throughout the northern sates but remained endemic in the old Confeder- In addition to the use of residual insecticides, the develop- acy. With the majority of physicians being trained in the north- ment of synthetic antimalarial drugs was accelerated. Quinine ern cities, malaria became increasingly exotic in the United was in short supply because the quinine plantations of Java and States but remained important to the AMEDD, with the respon- Mindinao in the Philippines had been overrun by the Japanese sibility of protecting the health of troops deployed worldwide.4 and the Germans controlled much of the manufacturing capa- In part because of his success with the fevers in the camps in bility for what drug remained. It soon became clear that alter- 1898, Walter Reed was tasked by BG Sternberg to investigate natives were desperately needed and, as the war broke, the U.S.
outbreaks of yellow fever in Cuba. In 1900, COL William Craw- government began an intensive search for new synthetic anti- ford Gorgas, working with Carlos Finlay and Walter Reed in malarial agents. Sitting on the shelf was a compound that had Havana, recognized the importance of mosquito transmission of been synthesized earlier by the Germans, 9-aminoacridine, li- infectious agents in human disease; soon he instituted the censed under the name atabrine. In 1938, the U.S. Army re- greatest vector control program the world had ever seen. Dr.
ceived samples of atabrine from Winthrop Stearns, a sister com- Gorgas was secunded from the AMEDD to the Panama Canal pany of the German conglomerate IG Farben. Soon thereafter, Military Medicine, Vol. 170, April Supplement 2005 atabrine was tested among soldiers in Panama; in the autumn of threat. The mission of this program was to develop new prophy- 1942, the drug was issued to troops in the southwest Pacific. A lactic and therapeutic drugs for military use. Using a multidis- byproduct of the dye industry, atabrine was both physically and ciplinary approach with combined in-house and contract re- psychologically intolerable to the troops. Well known for turning search, this program was coordinated through the Division of the skin a yellow color, atabrine had been the subject of intense Experimental Therapeutics at the Walter Reed Army Institute of Japanese propaganda, leading to major compliance problems Research (WRAIR) in Washington, DC. The Army recognized associated with rampant but unfounded rumors that its use that there was little economic incentive for private pharmaceu- could “make the strong man impotent.” tical firms to undertake antimalarial drug discovery activities.
Although atabrine was a welcome relief, the U.S. military From a commercial perspective, it makes little sense to produce desperately needed additional antimalarial drugs. A Malaria costly pharmaceuticals for people who cannot afford shoes.
Drug Development Program was set in high gear, which led to Therefore, the WRAIR program assumed responsibility as the powerful new antimalarial drugs such as chloroquine, amodia- lead federal agency for antimalarial drug development, and the quine, primaquine, proquanil, and pyrimethamine.
program was fully expected to maintain the expertise and labo-ratory capability to manage an experimental compound from the Malaria Contributions during the Korean Conflict chemist’s bench through clinical trails and on to the FDA for Malaria attributable to Plasmodium vivax presented its own licensure. During this tumultuous period, significant advances set of predicaments, primarily in the frequent relapses of illness in antimalarial research and clinical product development were that occurred when quiescent, latent, hypnozoite parasites achieved. With increases in drug-resistant malaria, soldiers re- emerged at unpredictable times from their dormant habitat quired more efficacious treatment and prophylaxis regimens, within the confines of the liver. P. vivax malaria was a time bomb because the standard weekly chloroquine-primaquine tablet that exploded during and immediately after the Korean War, as was no longer effective. The additions of dapsone to prophylaxis soldiers returned to the United States after completion of their regimens and pyrimethamine-sulfadoxine (Fansidar) to treat- tours of duty. Chloroquine, which was quite effective in killing ment regimens were welcome albeit temporizing solutions. Dap- the asexual parasites circulating in the peripheral blood, had no sone, in particular, led to severe (although infrequent) cases of effect on the hypnozoite parasites in the liver stage of infection.
agranulocytosis and methemoglobinemia,11 and Stevens-John- In 1944, a new class of antimalarial drugs, the 8-aminoquino- son syndrome was observed occasionally with Fansidar. The lines, demonstrated potent activity against the hepatic tissue accelerated pace of research and development during the 1960s forms of the parasite. Several compounds were selected for fur- and 1970s resulted in two FDA-approved antimalarial drugs, ther development on the basis of nonhuman primate testing.
mefloquine (Lariam) and halofantrine (Halfan), that were in- The U.S. Army had set up human clinical research sites at several locations within the continental United States to testvarious dosages and durations of therapy of newly synthesized Malaria Drug Development, 1980s to Present compounds among human volunteers challenged with mosquitoinoculation of malaria parasites. Such studies, performed with The rapid development of mefloquine resistance, coupled with the highest levels of ethical conduct, recruited volunteer in- concerns about potential, significant, adverse side effects of the mates from the Illinois State Penitentiary at Stateville in Joliet, drug, stimulated the search for new drugs or novel indications Illinois. These volunteers were the unsung heroes of the anti- for existing, FDA-approved drugs in prophylaxis regimens. In malarial effort, which led to the Food and Drug Administration pivotal field trials conducted in Thailand, the WRAIR conducted (FDA)-approved indications for primaquine for radical cure. Un- Phase II challenge studies and clinical trials of doxycycline and der contract to the U.S. Army, Dr. Alf Alving at the University of obtained FDA approval for doxycycline prophylaxis for both Chicago led a research team whose primary objective was to Plasmodium falciparum and P. vivax malaria.12,13 In recent optimize and evaluate, with respect to safety, toxicity, and effi- years, a multidisciplinary working group from WRAIR and the cacy, antimalarial compounds synthesized by the drug develop- Navy Medical Research Institute reviewed the existing data on ment teams.10 The results from these clinical studies were im- primaquine with the goal of supporting a new indication for mediately transferred to U.S. troops when they returned primaquine as a prophylactic drug.14,15 In addition, clinical tri- stateside after completing their tours of duty in Korea. The FDA als in Kenya demonstrated that the macrolide antibiotic azithro- approval of primaquine as radical cure for P. vivax malaria was mycin was 85% effective in preventing P. falciparum malaria in based as much on the logistics of ensuring compliance (directly an area of intense malaria transmission.16 Although the drug observed therapy every day for 14 days on the trans-Pacific was less effective in nonimmune populations, combinations of journey) as on the need to ensure safety among patients with azithromycin and quinine or chloroquine are being actively mild glucose-6-phosphate dehydrogenase deficiency.
A new 8-aminoquinoline drug, tafenoquine (WR238605), is in Drug-Resistant Malaria during the Vietnam War advanced clinical testing as a replacement drug for primaquine.
Preclinical evaluations in animal models suggest that this drug During the Vietnam conflict, malaria became the leading might have improved efficacy, excellent oral bioavailability, and cause of medical disability. When chloroquine-resistant malaria a better half-life than primaquine, a drug with a narrow thera- was first encountered by U.S. troops during the Vietnam con- peutic index. Animal and in vitro studies designed to evaluate flict, the U.S. Army responded by establishing a sustainable gametocytocidal and sporontocidal activities suggested a poten- malaria drug research program to address this new military tial role in transmission blocking. In Phase II human trials, Military Medicine, Vol. 170, April Supplement 2005 tafenoquine proved highly efficacious in preventing malaria itary is working to design and synthesize new drugs and vac- among subjects naturally exposed to P. falciparum malaria in cines that can circumvent the malaria parasite’s elusive mech- The United States has a critical need for a drug to specifically treat severe complicated malaria infections. Intravenous formu- lations of quinine sulfate are not available in the United States,and the supply of the antiarrhythmia cardiac drug quinidine The WRAIR and the Naval Medical Research Center, both cannot be ensured. The WRAIR is developing an intravenous located in Silver Spring, Maryland, currently serve as our na- formulation of artesunate, a unique artemisinin derivative, as a tion’s lead agencies for the development of new antimalarial drug for severe complicated malaria. Artemisinin drugs were drugs and vaccines. It is not by accident but rather by design first developed by Chinese military research investigators, on and initiative that scores of U.S. military physicians and scien- the basis of centuries-old traditional medical uses of artemisi- tists have played pivotal roles throughout its history to control nins for malarial fevers, and have now been used for thousands malaria and its vector, to develop new antimalarial therapeutic of adults and children with severe malaria.
agents to treat all forms of the Plasmodium parasite, to under-stand the parasite’s complicated biology and life cycle and itspathological effects in humans, and to develop preventive ther- Contributions to Vaccine Development and Malaria apies such as vaccines. The officers of the U.S. Army and Navy have stepped into the breach left by private industry, with thescientific and financial burdens of drug and vaccine discovery Integrated approaches for malaria control and prevention are falling almost entirely on the Department of Defense.
essential for the success of the military’s infectious disease Although this program has been touted as one of the most research program. Although the challenge of malaria vaccine successful in the world, the current products are dividends from development is perhaps more daunting than that of drug dis- research that occurred decades ago. The process of antimalarial covery, remarkable progress has been made in the past 20 years drug discovery and vaccine design and testing is extraordinarily toward an effective human vaccine. In the 1980s, U.S. Army and long and complex, and our immediate concern is for the next Navy investigators were among the first groups to use recombi- generation of products for our future deployments. To protect nant DNA methods to synthesize a recombinant protein com- our military forces from this serious and fatal disease, we must posed of the surface coat of the infectious-stage malaria sporo- maintain the required critical mass of multidisciplinary investi- zoite as a human malaria vaccine, which led to clinical testing gators and resources focused on the objectives of discovering and demonstration of protection.18,19 Although the level of pro- and developing new antimalarial drugs and vaccines. Not only tection was low and duration was short, these outstanding are the U.S. military contributions to malaria research and achievements paved the way for a multitude of clinical trials control in the past 100 years important because they providesolutions to a continuing threat, but these same achievements using combinations of malaria antigens delivered by novel vac- have forever benefited mankind, whether friend or foe, in our cine-delivery platforms, such as attenuated vaccinia pox virus- es,20 synthetic peptide vaccines,21 DNA vaccines,22 and hepatitisB recombinant particles containing malaria proteins combinedwith new immune response-stimulating adjuvants.23 In the past 25 years, military scientists have led the way in making important discoveries related to the culture of the 1. Smith DC: Quinine and fever: the development of the effective dosage. J Hist Med pathogen,24 understanding the basic biology of the parasite and 2. Rocco F: The Miraculous Fever-Tree. New York, HarperCollins, 2003.
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in total,25,26 and the functional characterization of these ge- nomes using the tools of proteomics and gene expression mi- 6. Russell PF: Man’s Mastery of Malaria, p 138. London, Oxford University Press, croarrays has been accomplished in large measure by contribu- 7. Cline D: Skeeter Beaters. Elk River, MN, DeForest Press, 2002.
8. Gahan JB, Travis BV, Morton PA, Lindquist AW: DDT as a residual-type treat- Malaria still represents a significant health threat to the com- ment to control Anopheles quadrimaculatus: practical tests. J Econ Entomol bat effectiveness of U.S. Armed Forces, and recent experiences worldwide indicate that the solution for the current military 9. Soper FL, Knipe FW, Casini G: Reduction of Anopheles density effected by the malaria problem is to maintain a necessary critical mass of pre-season spraying of building interiors with DDT in kerosene, at Castel Vol-turno, Italy, in 1944 – 45 and in the Tiber Delta in 1945. Am J Trop Med 1947; 27: investigators, collaborators, and clinical centers that are fo- cused on and committed to discovering and developing new 10. Garrison PL, Hankey DD, Walter GC: Cure of Korean vivax malaria with pama- drugs for soldiers. Development of new drugs and vaccines for quine and primaquine. JAMA 1952; 149: 1562–3.
drug-resistant malaria is regarded as one of the most critical 11. Ognibene AJ: Agranulocytosis due to dapsone. Ann Intern Med 1970; 72: 521– 4.
military medical requirements. Using structure-based drug dis- 12. Pang L, Limsomwong N, Singharaj P: Prophylactic treatment of vivax and falci- parum malaria with low-dose doxycycline. J Infect Dis 1988; 158: 1124 –7.
covery, insights from the malaria genome, molecular modeling, 13. Pang LW, Limsomwong N, Boudreau EF: Doxycycline prophylaxis for falciparum and recombinant DNA-produced protein vaccines, the U.S. mil- Military Medicine, Vol. 170, April Supplement 2005 14. Baird JK, Fryauff DJ, Basri H: Primaquine for prophylaxis against malaria among candidate for Plasmodium falciparum malaria. J Infect Dis 1998; 177: 1664 –73.
nonimmune transmigrants in Irian Jaya, Indonesia. Am J Trop Med Hyg 1995; 21. Nosten F, Luxemburger C, Kyle DE: Randomised double-blind placebo-controlled trial of SPf66 malaria vaccine in children in northwestern Thailand: Shoklo SPf66 15. Fryauff DJ, Baird JK, Basri H: Randomised placebo-controlled trial of prima- Malaria Vaccine Trial Group. Lancet 1996; 348: 701–7.
quine for prophylaxis of falciparum and vivax malaria. Lancet 1995; 346: 22. Wang R, Doolan DL, Le TP: Induction of antigen-specific cytotoxic T lymphocytes in humans by a malaria DNA vaccine. Science 1998; 282: 476 – 80.
16. Andersen SL, Oloo AJ, Gordon DM: Successful double-blinded, randomized, 23. Stoute JA, Slaoui M, Heppner DG: A preliminary evaluation of a recombinant placebo-controlled field trial of azithromycin and doxycycline as prophylaxis for circumsporozoite protein vaccine against Plasmodium falciparum malaria: RTS,S malaria in western Kenya. Clin Infect Dis 1998; 26: 146 –50.
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Military Medicine, Vol. 170, April Supplement 2005



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