Mankind’s Struggle with Its Perennial Scourge, Malaria
D. Gray Heppner
Division of Malaria Vaccine Development
Walter Reed Army Institute of Research
About the Lecture
Malaria, especially deadly falciparum malaria, kills 3,000 children every day, causes chronic illness in survivors, wreaks economic havoc, and steals hope from countries already afflicted by poverty. The global burden of malaria is amplified by the emergence of multiple drug-resistant malaria parasites that are no longer curable with once effective drugs such as chloroquine or Fansidar. In much of Africa, an effective malaria treatment course (such as Coartemether) costs a week’s wages, sadly putting curative treatment beyond the reach of all but the richest. Ultimately, eradication of malaria will likely require a vaccine.
About the Speaker
D. GRAY HEPPNER is Director of the Division of Malaria Vaccine Development at the Walter Reed Army Institute of Research. He leads DoD malaria vaccine development in the USA and Europe, and clinical and field trials in the USA, Thailand, Mali, and Kenya. He was Chief of Medicine & Immunology at the Armed Forces Research Institute of Medical Sciences in Bangkok, Thailand (1993-1997), then Chief of Immunology and later Director of Communicable Diseases and Immunology at WRAIR. COL Heppner deployed to the Middle East as a part of a Biologic Warfare Countermeasures team in 2003. He has published on malaria in leading journals, including the New England Journal of Medicine, the Lancet, PLoS Clinical Trials, Infection and Immunity, and the Journal of Infectious Diseases. COL Heppner holds a B.A. in Biochemistry and German (1978) and a M.D. (1983) from the University of Virginia, and completed residency and fellowship training at the Universities of Minnesota and Maryland. He is board certified in internal medicine and in infectious diseases, and is a member of the Order of Military Medical Merit. COL Heppner is a Fellow of the American College of Physicians and of the Royal Geographical Society (London). Walter Read Army Institute of Research http://wrair-www.army.mil/: The Walter Reed Army Institute of Research (WRAIR) in Silver Spring, Maryland is the Department of Defense’s Center of Excellence for Infectious Diseases Research. 1250 military and civilian scientists conduct research to develop United States Food and Drug Administration (FDA)-approved diagnostic devices, drugs and vaccines to protect Soldiers against tropical diseases and other biomedical threats. The WRAIR has played a crucial role in military medicine and public health in the development of FDA-approved antimalarial drugs (doxycycline, mefloquine, Malarone) and vaccines against hepatitis A, Japanese encephalitis, meningococcal meningitis, and anthrax. Current malaria efforts include development of a better treatment for severe malaria, and co-development of a pediatric malaria vaccine.
President Ruth McDiarmid called the 2,216th meeting to order at 8:18 pm December 15, 2006 in the Powell Auditorium of the Cosmos Club. The Recording Secretary read the minutes of the 2,214th Meeting and they were approved.
Ms. McDiarmid departed from the tradition of recent decades and made announcements before the featured talk of the evening.
She then introduced Colonel D. Gray Heppner, MD, FACP, FRGS, Director of Malaria Vaccine Development at the Walter Reed Army Institute of Research. Col. Heppner spoke on Mankind's Struggle with Its Perennial Scourge, Malaria.
Scope of Malaria
Col. Heppner pointed out that malaria, an ancient and deadly disease, was eliminated in the USA and Europe in the 20th century, but in the tropics still claims the lives of 3,000 children everyday. Malaria also threatens pregnant women, accounting for many mother and infant deaths.
Life Cycle and Disease
Anopheles gambiae is the most common mosquito transmitting the malaria in Africa, and thus the chief agent of global malarial death. The female mosquito seeks a blood meal, and while probing for a small blood vessel to feed from, simultaneously injects both a blood thinner and infectious malaria sporozoites. Within minutes, each sporozoite is safely ensconced in the liver, where it exponentially multiples before releasing 30,000 parasites, each able to invade and ultimately destroy a red blood cell. Malaria, especially deadly falciparum malaria, is a terrible disease. Victims experience fever, headache, back pain, chills, fatigue, and rigors. If not treated, kidney failure, severe anemia, convulsions and coma may lead to death. Untreated survivors often become chronic carriers of this disease, thus serving as reservoirs of infection, capable of infecting mosquitoes that in turn, transmit the infection to subsequent victims.
Two disease mechanisms were emphasized. One, the recurrent cycle of red blood cell invasion, growth and destruction, leading to severe & sometimes fatal anemia. Clinical signs of malarial anemia include eerily white inner eyelids, ghastly pale hands, and shortness of breath with minimal exertion. The second mechanism is the sticky nature of the malaria infected red cell. Malaria infected red cells can stick together, blocking circulation to the brain or kidneys or lungs thus explaining the syndromes of cerebral malaria, complete kidney failure, or respiratory failure. Survivors of cerebral malaria suffer long term brain damage and learning delays. Chronic carriers may suffer severe enlargement of the spleen, extending deep into the pelvis. Pictures were shown of children in New Guinea and Africa with terribly distended abdomens from parasites-induced enlargement of the spleen.
History of Malaria
The Jamestown settlers were wracked by fevers due to milder Plasmodium vivax malaria. The lethal Plasmodium falciparum that later infested the Americas came from Africa. Malaria was eliminated in the USA and other wealthy countries through effective diagnosis and treatment of cases, coupled with public health measures such as use of DDT, introduction of screened houses, and elimination of mosquito breeding sites. Incidentally, the Anopheline mosquito, fully capable of transmitting malaria from a malaria victim to a healthy person, remains widespread in much of the USA, including nearby Rock Creek Park.
Malaria is an ancient disease, emerging from Africa into Asia & Europe with Neolithic man some 200,000 years ago, and reaching the New World only after Columbus. Worldwide efforts have failed to control this scourge. In 1900, 53% of land area was malarious and 0.9 billion people were at risk, in 2002, only 27% of the Earth was malarious but 3.4 billion people live in malaria endemic tropics and subtropics.
Is Control Possible?
Cheap, cost-effective countermeasures exist but are not widely used in malaria-stricken countries. Insecticide-treated bed nets, indoor residual spraying with DDT at ecologically safe low levels, and intermittent presumptive treatment with antimalarial drugs of young children and pregnant women save lives, but are woefully under-employed measures. Diagnostic accuracy is poor due to shortages of reliable microscopy, resulting in the inability of health care providers to rule-out malaria and consequent wasteful overuse of expensive antimalarial drugs to treat all cases of fever. Lastly, the continued development of resistance to formerly effective antimalarial drugs (such as chloroquine, Fansidar and mefloquine) means that effective, affordable drugs are not available to the poor. There is no malaria vaccine yet licensed.
There have been four Nobel Prizes in malaria. British Army Surgeon Ronald Ross was awarded the Prize in 1902 for discovering in Secunderabad, India that the mosquito transmitted the disease, which led to methods of vector control. French Army Surgeon Alphonse Laveran, serving in Algeria, was awarded the Prize in 1907 for his discovery of malaria parasites in the blood of a patient. Julius Wagner-Jauregg, an Austrian physician, received the 1927 Prize for discovering that experimental malaria inoculation could be used to treat dementia paralytica, caused by syphilis of the brain. Paul Hermann Müller, a Swiss chemist, received the 1948 Nobel Prize for discovering DDT, which sped the elimination of malaria in Europe, and has since saved tens of millions of lives.
Military & Malaria
Why is the Walter Reed Army Institute of Research (WRAIR) combating malaria? It is the WRAIR’s mission to develop drugs, diagnostic devices and vaccines to safeguard Soldiers against infectious diseases. Malaria remains the leading infectious disease threat to military operations in the tropics. During WWII, General Macarthur famously observed, “Doctor, this will be a long war if for every division I have facing the enemy I must count on a second division in hospital with malaria and a third division convalescing from this debilitating disease!” In Liberia in 2003, a 225 Marine Task Force was struck by malaria in a 2 week period. Incredibly, 80 Marines contracted malaria, 43 were evacuated to Europe or the USA for treatment, and 5 required intensive care to survive. As is true for all travelers, malaria prevention requires the constant, uninterrupted use of mosquito repellants, bed nets, treated uniforms and antimalarial drugs. This is an especially difficult logistical and practical burden for deployed, mobile forces. A malaria vaccine, administered before exposure, would dramatically reduce risk.
Eradication in the Face of Poverty
What about eradication? Malaria, which until 1900 afflicted half of the planet, has been beaten back to ¼ of its land area through use of insecticide treated nets, indoor residual spraying with DDT of households, and effective treatment. The poverty in the remaining areas of the world prevents widespread employment of these effective methods. The per capita income in many of those countries is less than $1 per day.
As an example of effective interventions, Col. Heppner cited the case of KwaZulu-Natal Province, were there were 600 malaria cases in 1991. After a DDT ban, cases rose to 30,000 per year in 2000. Then DDT was re-introduced along effective antimalarial drugs, dropping malaria cases to pre-1991 levels, but not eliminating malaria. Col. Heppner asserted again that a vaccine would be a highly cost effective public health measure for endemic populations.
Drug obsolescence is a problem requiring constant research and development of new antimalalarial drugs. The most effective current drugs are based on a 2000-year old Chinese discovery, the animalarial properties of the Artemisinin plant. Presently, the Walter Reed Army Institute of Research is working to develop an US Food and Drug approved version of this drug (artesunate) to be given intravenously for the treatment of severe malaria.
The challenges in developing a malaria vaccine are great. There is as yet no vaccine against any human parasite. Malaria is a master of disguise, taking different forms as it progresses from the mosquito to the liver before emerging into the blood stream to cause disease. Although immunity against infection does not occur in nature, the late Dr. David Clyde at the University of Maryland had demonstrated complete protection of volunteers who had been experimentally immunized with radiation-attenuated malaria parasites.
Major milestones toward a malaria vaccine were noted. In 1983, Drs. Ruth & Victor Nussenzweig led identification of the target gene for a vaccine. In 1986, trials at the University of Maryland and at the Walter Reed Army Institute of Research (WRAIR) independently proved that volunteers could be protected by a vaccine. From 1996 through 2000, collaboration between GlaxoSmithKline (GSK) and WRAIR identified and proved the first consistent 40% protection of volunteers against experimental challenge with the prototype vaccine known as “RTS,S.” In 2004 & 2005, Dr. Pedro Alonso in Mozambique, with support from the Malaria Vaccine Initiative, CISM and GSK, demonstrated that 3 doses of “RTS,S” gave an unprecedented 48% reduction in severe malaria in young children for an 18 month period. Efforts are underway to improve this magnitude and duration of protection.
Malaria Delenda Est
(Malaria Must Be Destroyed)
Col. Heppner called for greater action. Malaria remains an economic, political, and personal tragedy. Malaria retards development, destabilizes nations and kills 3,000 children every day. Malaria hastens the spread of HIV/AIDS, and HIV/AIDS increases malaria disease and deaths.
He ended with two quotations. The first came from Proverbs (29:18): “Where there is no vision, the people perish.” The second came from Sir Francis Drake: “There must be a beginning of any great matter, but the continuing unto the end until it be thoroughly finished yields the true glory.”
Col. Heppner offered to answer questions. In response to questions, he made the following observations:
Attempts have been made to genetically modify mosquitoes so they will not transmit malaria and to develop mosquitoes to displace the carrier mosquitoes. Neither has produced much success yet.
Monkeys have carried malaria that was transmitted to humans, but that doesn’t happen often enough to have much effect. Humans are the reservoir.
Drug resistance is inevitable, and is hastened when people don’t take the full antimalarial treatment. They take some of the medicine, they feel better, and then they save the rest for later or for their children. This provides opportunities for the development of genetically-resistant strains now known as “multiple drug resistant malaria”.
Mosquitoes inject a blood thinner before they suck blood. It is a lubricant, like diluting a milk shake before drinking it. The malaria parasite is thereby introduced into the human host.
The tide of public opinion and world usage is changing for DDT. The World Health Organization has recently reconsidered and now endorsed the use of DDT for household spraying in effective, but ecologically harmless doses. DDT is effective even at extremely low doses as both an insecticide and a repellant.
After discussion of questions, President McDiarmid thanked our speaker and presented a plaque commemorating the occasion. Finally, at 9:38 pm, she adjourned the 2,216th meeting to the social hour. Since the speaker donated a case of good Chilean wine, the social hour was a happy hour.
Temperature: 2° C
Weather: Light overcast, damp
Ronald O. Hietala