SABIN REPORT the newsletter of the Albert B. Sabin Vaccine Institute at Georgetown University Volume II, Number 1, March 1999 IN THIS ISSUE Gates donates $100 million for children’s vaccine developed The newly developed vaccine for BY JOHN CLYMER AND DIANE MYERS Decreasing the “lag time” intestinal disease could improve the health of over 500 million children Microsoft billionaires Bill and Melinda Gates have Why is the Gates Foundation program of such importance? made a $100 million gift to establish a program to acceler- New, life-saving vaccines generally are in broad use in in- worldwide. ate access to new vaccines for children in developing na- dustrialized countries several years before they become widely 1 tions. The goal of the Bill and Melinda Gates Children’s used in developing countries where the need is greatest. This Vaccine Program’s is to significantly reduce the time it cur- time lag in vaccine “uptake” is due to economic, logistical rently takes for vaccines to reach children living in poor coun- and other challenges. tries. “We have a social imperative to work together to The initiative is a program of the William H. Gates SPECIAL REPORT: MALARIA address this basic inequity,” said Bill Gates, trustee of the A report on the impact of malaria on Foundation and will Fiset photo by PATH/J. William H. Gates Foundation. global health, the search for a vaccine, be administered by Sabin Vaccine Institute chairman and the risks travelers face when the Program for H. R. “Shep” Shepherd ap- visiting malaria-endemic areas. Appropriate plauded Gates’ vision and the es- 2-5 Technology in tablishment of the Children’s Vac- Health (PATH). cine Program. “Vaccines are the Headquartered in most powerful tool available to Seattle, PATH will equalize the health of human be- work with the World ings in every corner of the Profile: Herbert Herscowitz Health world,” he said. “Enlightened Institute scientist combines career in Organization, leaders understand the power of research and teaching. UNICEF, the vaccines to help bring peace and 6 World Bank, the Phillip Russell (l), Suryanarayan Ramachandran, and James Maynard. opportunity to the most troubled Children’s Vaccine places in our world. Vaccines are Initiative, vaccine the microchip that will revolution- manufacturers, ize healthcare,” Shepherd de- governments and clared. Aerosol measles workshop nongovernmental organizations. The Children’s Vaccine Program will specifically support Researchers meet to dicuss PATH plans to focus on four recently developed ways to make the vaccines widely available to children in alternerative vaccine delivery systems. or about-to-be-marketed vaccines against respiratory, in- developing countries. It will not be used to buy the vac- 6 testinal and liver diseases. Global use of the vaccines could cines. reduce childhood deaths by 33%, representing 2.5 million The program will be managed by a Secretariat lives, and reduce liver cancer deaths by 75%. Two of the based at PATH, under the guidance of a Strategic Advisory vaccines prevent respiratory ailments caused by the bacte- Council that is composed of seven international experts in ria Haemophilus influenzae type b, or Hib, and strepto- vaccinology and vaccine introduction. Philip K. Russell, coccus pneumoniae; a third prevents rotavirus , founding president of the Albert B. Sabin Vaccine Institute, which causes severe diarrhea;, and the fourth vaccine be- is a member of the Strategic Advisory Council. He lauds the ing considered prevents , a viral liver disease. Gates’ program as a “very exciting development in the field In the United States, vaccines for Hib and hepati- of international health.” tis B are part of the recommended childhood immuniza- tion schedule, and vaccines for rotavirus and streptococ- An “entreprenurial” approach cus pneumonia are expected to become part of the recom- mended immunization schedule soon. According to Russell, who has years of experience continued on page 7 Rotavirus vaccine could benefit 500 million children

BY RACHEL LIBERATORE veloped by Albert Z. Kapikian of the Laboratory of Infectious Diseases (LID) at the National Institute of Allergy and Infectious Although rotavirus affect 300-500 million Diseases (NIAID) along with other colleagues at the National children every year, this disease has only recently provoked the Institutes of Health. The vaccine is manufactured by Wyeth- kind of intense research investment one might expect for such Ayerst Laboratories at a cost of approximately $38 per dose. a ubiquitous affliction. Unfortunately, the reason for this is Ideally, a vaccine is supposed to save society money the same for many diseases whose primary because the price of the vaccine is less than the cost of treating the targets are nations in which the average per disease. From the perspective of the health care capita health expenditure hovers just around system, however, the cost of the vaccine should $10. In the case of , this trend of be high enough that the system does not lose apathy toward diseases in developing nations money due to the decreased need for treatment. was turned around following studies demon- A study headed by Roger I. Glass, chief of the strating that this disease actually leads to a sig- Viral Section at the Centers for nificant amount of health care expenditure in Disease Control and Prevention (CDC), deter- developed countries, where the ability to pay mined that a rotavirus vaccine would be cost- for preventive and prophylactic treatments is effective to both society and the health care sys- much greater. Once a lucrative market was es- tem in the United States if the cost fell within a tablished, a vaccine for rotavirus was soon de- range of $9-$51 per dose. Glass’s pivotal study veloped and has been recently licensed. is widely credited with providing the impetus

Rotaviruses are the infectious agents photo by Erica Seiguer for the pharmaceutical industry to devote re- sources to rotavirus vaccine development, which responsible for most cases of childhood diar- Roger Glass rhea. Ninety-five percent of children worldwide ultimately led to the approval of Rotashield™. are exposed to rotaviruses between the ages of three and five, According to Glass, although “there is a clear need for though in developing nations initial exposure is usually within rotavirus vaccine for all children, without the demand and money the first year of life. Such intestinal infections are particularly of the developed countries, it is unlikely that any country would dangerous in children because they are more likely than adults to be interested.” As evidence, he points to the failures of new chol- suffer from dehydration, especially if they have previously com- era and typhoid vaccines, needed in developing countries but promised health. now priced and sold for travelers—a tiny and nonviable market. In August 1998, the Food and Drug Administration (FDA) approved the first rotavirus vaccine since the discovery of continued on page 7 Sabin Vaccine Report Vaccine Sabin Institute Vaccine Sabin Albert B. at Georgetown University NW Road, Suite 154, 4000 Reservoir Building D, Washington, DC 20007-2145 rotaviruses in 1973. The vaccine, called RotaShield™, was de- Malaria Report Malaria Report Malaria Report Malaria Report Malaria Report Mala SABIN VACCINE REPORT March 1999 ALBERT B. SABIN VACCINE INSTITUTE Controlling Malaria Will Require an International Effort AT GEORGETOWN UNIVERSITY

BY HOWARD ENGERS, PHD CHAIRMAN Malaria alone accounts for over 2% of the total global disease burden and five times this figure in Africa, H.R. Shepherd ranking third among major infectious disease threats. There are an estimated 300-500 million cases of malaria each year, resulting in over 1 million deaths, mainly of children under five years old in Africa. Augmented by the more recent EXECUTIVE VICE PRESIDENT impact of globalization, the disease is often linked to poverty, the movement of refugees or populations seeking work Edward Neiss MD PhD and to environmental change, including forestry, mining and water development projects. We can conquer malaria. But to do so, will require a concerted global effort, involving Private and Public SENIOR VICE PRESIDENT sector participation and that of civil society. All manner of resources will need to be brought to bear. Better ways must Joseph A. Bellanti MD be found to apply existing control methods. Improved tools must be developed and solutions need to be identified to circumvent and combat emerging problems including social/political unrest, the widespread resistance of the malaria BOARD OF DIRECTORS parasite to existing drugs and the potential change in the distribution and incidence of malaria due to anthropogenic Jason S. Berman climate change. Zev Braun Reflecting its prominent status as a global killer, malaria has been a priority for World Health Organization Kenneth L. Dretchen PhD (WHO) since its founding in 1948. A revised WHO Global Malaria Control Strategy was adopted at the Amsterdam Robert E. Fuisz MD Summit of 1992, based on a renewed global commitment to malaria control. Recognizing the widespread political E. Andrews Grinstead III desire that has been building over this decade, the new Director General of WHO, Dr G.H. Brundtland, declared upon Jerome Jacobson taking office in July 1998 that there should be a deeper commitment to win the fight against malaria. Greater financial David J. Meiselman Esq resources and a higher visibility for malaria control activities would be necessary. This declaration led four UN-System Lewis A. Miller agencies (UNDP, UNICEF, WHO and the World Bank) to launch Roll Back Malaria (RBM) on 30 October 1998. Louis Padovano SJ MD The RBM project, co-ordinated by WHO, aims to: 1) support governments and partners; 2) improve technical effi- Maj. Gen. Philip K. Russell MD ciency and capacity, including the development of new methods, new tools and capacity strengthening in the malaria Heloisa Sabin endemic countries; 3) to improve resource allocation, utilization and mobilization. Carol Ruth Shepherd The development of an effective malaria vaccine represents one of the most important strategies for providing H.R. Shepherd a new, cost-effective tool to be added to the currently available armamentarium of malaria control interventions. Its effectiveness will depend on having a sound and adaptable delivery structure. An affordable malaria vaccine which could be implemented through the existing Expanded Programme on Immunization (EPI) and which would reduce overall BOARD OF TRUSTEES childhood mortality by 20-30% or more, with a duration of immunity of three years or more, would represent a very Ruth Arnon PhD powerful intervention strategy. However, as no single intervention tool is likely to represent a panacea for malaria, an Nancy Gardner Hargrave effective vaccine would be applied together with other appropriate cost-effective methods. Joseph L. Melnick PhD Over the past decade, there has been significant progress in the identification of vaccine candidate antigens Gustav J.V. Nossal MD PhD and their genes. However, due to the complexity and cost of vaccine development and the relative lack of commercial George C. St. Laurent Jr interest, only recently have the leading candidates started to enter clinical and field trials. At least three are now under Andrea Scott clinical trial and several additional candidates are in the development pipeline. Despite the fact that no acceptable Kathryn G. Thompson vaccine has emerged to date from the many field trials conducted, scientists have made major progress in conceptual Donna Twist thinking and in the design of the trials required for the evaluation of candidate malaria vaccines. Recent advances in Stephen G. Valensi Esq research technology, including the availability of synthetic antigens, DNA vaccines, malaria parasite genome sequences, James D. Watson PhD functional genomics and novel adjuvants have led to an acceleration in the rate of progress. The hope, and increasingly Barbara Wilson the expectation, is that this will herald a new era of malaria vaccine development. In order to capitalize on this technological progress, sustained political commitment and investment in malaria INTERNATIONAL COUNCIL vaccine development will be essential. Such investment has a high probability of success and is likely to pay dividends in OF SCIENTIFIC ADVISORS the form of new, highly effective tools for use in improving the control of malaria at the global level. In addition to the Peter J. Hotez MD PhD Chair new RBM project, several public-private sector initiatives which were established recently, including the Multilateral Kenneth I. Berns MD PhD Initiative for Malaria in Africa (MIM) and the New Medicines for Malaria Venture (MMV), provide renewed hope that Fred Brown PhD FRS these institutions and agencies can work together to agree upon, establish and implement a common global strategy for Robert M. Chanock MD the development and clinical testing of leading malaria vaccine candidates over the next five to ten years. The UNDP/ Stephen N. Chatfield PhD World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) is fully committed to the Jonathon M. Fine MD promotion and implementation of such a global strategy, in collaboration with its Public and Private sector collabora- Warren Grundfest MD tors. Partnerships will have to be forged or strengthened at the national and international levels to ensure that funda- Ian Furminger PhD mental infrastructures, and production and delivery systems are in place. Neal A. Halsey MD Provided that scientists, malaria control programs and donor agencies succeed in working better together Maurice R. Hilleman PhD worldwide, the next decade will certainly bring many significant advances in the quest to develop and implement an Brian R. Murphy MD effective, affordable malaria vaccine—allowing people to be free from a life of disease and misery, hopefully sooner Erling Norrby MD PhD MTC rather than later. v Wade P. Parks MD PhD Michael Sela PhD James D. Watson PhD Howard D. Engers has been with the World Health Organization since 1987. Engers has a record of achievement SCIE internationally as a scientist, educator and manager in the academic community, national research institutes and IN MEMORIAM international agencies. From 1991-1999, he has held the position of manager, Steering Committee on Vaccines Mary Lou Clements-Mann MD MPH for Malaria, and Malaria Research Coordinator, Special Programme for Research and Training in Tropical Diseases (TDR). SCIENTIFIC ADVISORY COMMITTEE AT GEORGETOWN UNIVERSITY SABIN VACCINE REPORT The Sabin Vaccine Report is published by the Herbert B. Herscowitz PhD Chair Albert B. Sabin Vaccine Institute Erica Seiguer Joseph A. Bellanti MD at Georgetown University. EDITOR John L. Gerin PhD Subscriptions are free. Please direct inquiries to: Charlene Flash A. Bennett Jenson MD SABIN VACCINE REPORT ASSOCIATE EDITOR C. Richard Schlegel MD PhD Joseph G. Timpone Jr MD Building D, Room 154 WRITERS/STAFF 4000 Reservoir Road, NW Joseph A. Bellanti, MD Washington, DC 20007-2145 John Clymer BOARD OF ADVISORS phone: 202.687.9145 Elizabeth de la Paz Mary Alderman facsimile: 202.687.9242 Gboku Lumbila Francis E. Andre MD email: [email protected] Timothy Mahoney John V. Bennett MD Diane Myers Barry Bloom PhD A scientist who is also a human being cannot rest while Jessica Quinn Betty F. Bumpers knowledge which might be used to reduce suffering sits on Francis Cano PhD CONTRIBUTORS the shelf. Ciro A. de Quadros MD MPH Howard Engers, MD Albert B. Sabin Phyllis Freeman Esq Rachel Liberatore Bruce G. Gellin MD MPH The Albert B. Sabin Vaccine Institute is a non-profit Lance K. Gordon PhD institute dedicated to continuing the work and achieving Editor’s Note: Scott B. Halstead MD the vision of Albert B. Sabin: to fully realize the potential As I will be leaving the Sabin Vaccine Insti- Samuel L. Katz MD of vaccination to prevent disease. tute in June to begin medical school, I leave the Sabin Vaccine Report in the capable hands of the new Editor, Stanley M. Lemon MD Sister Collette Mahoney Founded in 1994, the Institute strives to prevent Charlene A. Flash. The Sabin Vaccine Report will Frederick C. Robbins MD disease by promoting the conitnue to bring you interesting, thorough coverage Harvery S. Sadow PhD development of new vaccines and delivery systems. of the latest in vaccine research, development and pub- lic policy. I wish Charlene and the staff the best of Ronald J. Saldarini PhD Dedicated to Disease Prevention luck. Donald S. Shepard PhD Arnold Stang www.sabin.georgetown.edu Patricia Thomas 2 aria Report Malaria Report Malaria Report Malaria Report Malaria Report Malaria SABIN VACCINE REPORT March 1999 Quantifying the global burden of malaria remains difficult but essential can include persistent cortical blindness, deafness, se- jor histocompatibility complexes, suggest that genetic BY SEAN C. MURPHY AND JOEL G BREMAN, MD, DTPH vere cerebral palsy, hemiplegia, and other less extreme factors play an important role in the clinical and epide- The worldwide burden of malaria is difficult symptoms. A small percentage of all malaria cases and miologic manifestations of malaria. The role of host to precisely quantify because current morbidity and up to 12% of cerebral patients experience these disor- factors on morbidity and mortality remain to be de- mortality estimates are variable and imprecise. Despite ders. Most of these problems appear to resolve within fined. these inadequacies, the World Health Organization six months in properly treated patients, however, up to (WHO) and other groups suggest that up to 500 mil- 25% of these disorders result in permanent disability What next? lion clinical cases of acute malaria occur globally each (6). A large percentage of these patients is severely ill year, primarily in Africa (1). The lack of precise esti- and does not receive comprehensive medical care and Research efforts in drug discovery, vector con- mates is due to the protean clinical manifestations of rehabilitation services. The long-term impact of severe trol, and vaccine development will yield interventions the disease and poor surveillance worldwide. Among and milder forms of malaria on these complications, in the 21st century that will ultimately reduce substan- those who contract malaria, it is estimated that about including learning and behavioral disabilities, is not tial malaria morbidity, mortality and economic loss. 1.5-2.7 million die annually. In Africa, most deaths are known or fully appreciated. Precise estimates and increased knowledge of the toll of not reported by health authorities because of inadequate malaria are needed urgently to assess the current status health care delivery systems and because malaria com- Malarial anemia of the disease, to monitor the progress of prevention monly occurs in rural settings; 1.0-1.9 million African and control programs, and to measure the success of deaths have been estimated yearly since Bruce-Chwatt’s Malaria-induced anemia results in substantial new and improved anti-malarial drugs, vector control first study in 1952 (2,3). In addition, malaria morbid- morbidity and mortality and is accelerating with para- agents, and vaccines. v ity weighs very heavily on Africa’s fragmented health site resistance to drugs. Hospital records in Africa show programs — a large percentage of hospital admissions that anemia in children is increasing. Malaria is a ma- References 1. World malaria situation in 1994. Part I. Population at risk. and patient visits to dispensaries are malaria-related. In jor cause of anemia-associated hospital admission, and Wkly Epidemiol Rec 1997 Sep 5;72(36):269-274. all endemic areas, malaria also has important economic very low hemoglobin (£5gm%) is associated with death 2. Bruce-Chwatt, LJ. Malaria in African infants and children in implications resulting from decreased productivity of within a short time of admission (7). The precise in- southern Nigeria. Ann Trop Med Parasitol 1952; 46:173-200. infected individuals and their care-givers. terrelationship and impact of malaria on anemia and 3. Sturchler D. How much malaria is there worldwide? Parasitol Despite the inadequacies in surveillance, there its clinical manifestations have not been addressed fully. Today 1989:39-40. is a consensus that 90% of malaria cases and deaths 4. McCormick, MC. The contribution of low birth weight to infant mortality and childhood morbidity. New Eng J Med occur in Africa, where Plasmodium falciparum and Host factors 1985;312:82-90. Anopheles gambiae predominate and the greatest toll is 5. Steketee, RW et al. The effect of malaria prevention in preg- in children less than five years of age. The widely vari- Studies in the 1960s showed that sickle cell nancy on offspring birthweight, prematurity, and intrauterine able data do not sufficiently account for the impact of trait confers some protection against death from growth retardation in rural Malawi. Am J Trop Med Hyg malaria during pregnancy, on childhood anemia, and falciparum malaria and that Duffy blood group anti- 1996;55(supp):33-41. as a cause of neurologic and developmental disorders. gen must be present on red blood cells to allow vivax 6. Brewster DR et al. Neurological sequelae of cerebral malaria in children. Lancet 1990;336:1039-1043. Malaria epidemiology markedly varies in different ar- malaria to enter. These observations, coupled with re- 7. Lackritz EM et al. Effect of blood transfusions on survival eas and is rarely considered in regional or global calcu- cently reported associations between malaria and ma- among children in a Kenyan hospital. Lancet 1992;40:524-8. lations. Increasing resistance of Plasmodium falciparum to drugs and Anopheles mosquitoes to insecticides will undoubtedly worsen the malaria situation worldwide. Recently, national governments, WHO, and Malaria on the Web other international health agencies have shown greatly The following websites provide information on malaria. The Sabin Vaccine Institute does not assume renewed interest in malaria. These partners are inter- responsibility for the information contained in these sites. ested in research, control, and prevention, and are aware of the importance of carefully measuring the impact of The Malaria Foundation International www.malaria.org new and improved interventions (including vaccines) Malaria Research at the National Institutes of Health www.niaid.nih.gov/dmid/panel.htm on malaria-endemic populations. To aid these efforts, WHO Research and Training in Tropical Diseases www.who.int/tdr an attempt to define more accurately the range of ma- Multilateral Initiative on Malaria at the Wellcome Trust www.wellcome.ac.uk/mim laria-related morbidity and mortality is being under- Rotarians Against Malaria www.bednet.org/ taken. A review of clinical and epidemiologic reports Malaria information at the Sabin Vaccine Institute www.sabin.georgetown.edu indicates that acute febrile illness, with or without para- sitologic confirmation, has been the basis of reporting to national officials and WHO. Thus there are several important malaria-associated conditions and several host When preparing for travel, consider malaria factors that are generally not considered in national and The most common imported disease can humble the unprepared traveler. international studies. against the bites of flying insects. It is effective on BY CHARLENE A. FLASH clothing for up to 3 weeks after initial application. Malaria in pregnancy Before the Hot Zone brought the vi- DEET (N,N-diethylmetatoluamide) is considered rus into the public eye, and before HIV became a to be the most effective insect repellant for use on Malaria plays an important role in newborn household term, malaria was the exotic disease of exposed skin. survival, through pregnancy-related complications such th as abortion, stillbirth, and low birth weight (LBW the 20 century. Although malaria is considered by Antimalarial medications should be taken £2500 g). In 1985, it was reported that LBW was the some to be a disease of the tropics, relegated to the two weeks prior to travel. Aralen, a medication con- most important predictor of neonatal and infant mor- developing world, mosquitoes carrying malaria have tality, and a major cause of newborn neurologic disor- been found in various regions of the United States Although malaria is considered ders (4). The relative frequencies of these pregnancy as well as many non-rural areas in third world coun- to be a disease of the tropics, relegated outcomes have not been fully quantified, although LBW tries. to the developing world, mosquitoes and its consequences are the most frequent pregnancy- Malaria kills 1.5-2.7 million each year and carrying malaria have been found in associated complications of malaria, particularly in Af- is the most common imported disease. Malaria is various regions of the U.S. rica, where up to 17% of all live births and 34% of caused by the Plasmodium parasite and is spread by first-born infants have LBW. LBW has been highly cor- the bite of the Anopheles mosquito, which serves as taining choloroquine phosphate should be taken a related to placental malarial infection, which is linked the parasite’s vector. Vector-borne diseases travel very week or two prior to departure and for four weeks to maternal parasitemia (5). quickly with an exponential infection rate. Accord- following return. Other related medications include ing to the CDC, malaria may lie dormant in an Lariam, a medication containing mefloquine doxy- Malaria and neurological disorders infected individual for as much as year and then cycline and Mefloquine. Many travelers neglect to will show symptoms such as fever, chills, muscle take their malaria pills, leading to preventable fa- Neurologic sequelae following cerebral malaria aches, headache, nausea, vomiting and diarrhea, talities. have been recognized for over 50 years. Complications which may not necessarily be immediately recog- Be sure to consult the appropriate travel nized as malaria by physicians. health professional or inform your physician that Protection must begin with your immedi- you have been travelling in a region where Malaria Sean C. Murphy ([email protected]) is a junior at Iowa ate surroundings. Bug sprays, netting and clothing is prevalent. Different geographical locations have State University. He was an intern at the Fogarty Interna- which covers most of the body can protect people different strains of malaria characterized by varying tional Center (FIC), National Institutes of Health (NIH) levels of resistance to anti-malarial drugs. A travel during the summer of 1998, where he studied the impact of from getting bitten by the mosquito. Bed netting is malaria on populations, particularly those in Africa. Joel G indispensable because mosquitoes are very active health professional can advise you as to the appro- Breman, MD, DTPH is Deputy Director of the Division of during the evening hours. Pyrethum is an insect priate anti-malarial drugs to take and the schedule International Training and Research, FIC, NIH. repellant which when sprayed in the air is effective of administration.v 3 Malaria Report Malaria Report Malaria Report Malaria Report Malaria Report Mala

SABIN VACCINE REPORT March 1999 History of malaria control and vaccine development highlights s effective health intervention known to man. Much like HIV it has remained an indomitable foe. In May 1969, the Walter Reed BY ERICA SEIGUER vaccine research, which has been plagued by meager in- Army Institute of Research (WRAIR) convened a panel workshop Out of sight, out of mind, the old adage goes. vestment and a decline in the number of companies that on malaria. At that meeting, Major General Joe Blumberg, the Com- Nothing could be closer to the truth for malaria, a disease maintain HIV vaccine research programs, malaria vaccine manding General of United States Army Medical Research and De- which, it can be convincingly argued, is to blame for crip- research has been passed over by industry and generally velopment, reflected on the challenges posed by malaria and the pling health and economies all over the world—especially left to the public sector. efforts of the military to control the disease. “I have come to realize those of developing countries. Despite the demonstrable Malaria, in concert with HIV and tuberculosis, that the U.S. Army carries the brunt of this program for the free impact of malaria, research and development of treatments form a kind of oppressive junta that is devastating the world,” he said. “No other concerted effort is being made since in and prophylactic strategies have been neglected, most prob- world’s poor. The combined efforts of malaria, HIV and the United States malaria is not a public health problem. However, ably due to the fact that malaria is primarily a disease of tuberculosis, if not reigned in, could profoundly stunt eco- when our military are called upon to serve out of the United States, the developing world and is of little perceived threat to the nomic and health development and jeopardize global fi- in areas where malaria exists, it becomes an important problem.” developed world where most biomedical research is con- nancial prosperity. Worldwide, malaria is responsible for The impact of malaria on the ability of the military to pro- ducted. Roughly 40% of the entire world’s population is the deaths of 3000 children every day— a higher mortal- tect U.S. interests in endemic regions has been quite dramatic. In at risk for becoming infected. ity rate than the more visible and more studied HIV. In the year 1968 alone, for example, U.S. military forces in Vietnam Malaria is a crafty parasite, and has developed Western industrialized nations, however, malaria, like many documented 12,000 cases of malaria, resulting in 250,000 man- resistance to virtually every agent man has devised in at- tropical diseases, is a curiosity and not a major concern to days lost. Clearly, malaria poses a major threat to the success of mili- tempts to humble it. the general public. Private Sector Public Sector tary interventions. Perhaps it is no surprise It also takes on many Most Americans then that it is the military that has consis- forms within its hu- are probably not tently maintained its malaria research pro- man hosts, tricking aware that malaria gram, despite the fact that malaria is a rare the immune system was a major cause occurrence in the United States. with every morpho- Dept. of Defense of morbidity in the Today, the USAID remains com- logical switch. Its bio- (WRAIR, NMRI) DHHS USAID Civil War, when mitted to the development of a vaccine for logical savoir-faire 80% of the Black malaria and other approaches to lessen the independent Collaborative Research has made chemo- corporate research and Development soldiers in the burden of the disease in developing nations. therapeutic and pro- programs Agreements (CRADAs) Union army got As an integral component of the ad hoc phylactic agents elu- NIH malaria annually. Federal Malaria Vaccine Coordinating extramural CDC sive. Drugs that once Moreover, data Committee (FMVCC), which includes seemed to spell the intramural from the early part representatives from the National Institutes end of malaria have academic research Div. of Parasitic of this century of Health, the Centers for Disease Con- Diseases failed because of the DOMESTIC RESEARCH shows that there trol, the Walter Reed Army Institute of emergence of resis- Lab. Parasitic Div. Microbiology & were more than half INFRASTRUCTURE Diseases Infectious Diseases Research (WRAIR) and the Naval Medi- tant parasites. A suc- a million cases of cal Research Center (NMRC), USAID has cessful vaccine could malaria in the worked to improve coordination and co- save millions of lives and have a major positive impact on United States in 1914. The United States was able to eradi- operation among researchers. According to the global economy; a 1991 study by DS Shepard et al., of cate malaria for all practical purposes in the early 1950s Carter Diggs, a Senior Technical Advisor the economic impact of malaria in Africa found that ma- with the advent of powerful insecticides, after years of drain- for the Malaria Vaccine Development Pro- laria costs more than $1.7 billion per year in medical care ing swamps in an effort to destroy the favorite breeding gram (MVDP) at USAID, this is a tall or- and lost productivity. For economies struggling to survive locales of the Anopheles mosquito. der. “Scientific culture rewards individual in the global market, the impact of malaria and other ma- creativity, thus fostering competition and jor diseases create seemingly indomitable obstacles to pros- An old plague the perceived need for secrecy regarding perity. scientific discoveries, at least until first pub- According to a 1996 report by the Unit for Policy Malaria is by no means new to humankind. Since lication. Program managers’ objectives and Research in Science and Medicine (PRISM) at the the beginning of the written word, about 6000-5500 BC, responsibilities are institutional, not global, Wellcome Trust, support for malaria research has fallen there have been references to a disease marked by deadly preventing pooling of resources to advance the recently. In their audit of international activity in malaria fevers which experts believe were malarial in root. common good.” research, PRISM concluded that Hippocrates wrote about malaria 2500 years ago— he There is no easy solution to the po- Malaria is a linked malaria transmission with pools of still water. It was litical nature of the scientific enterprise, pos- parasitic protozoa of t Despite the extent and severity of the not until 1882, however, that the transmission of malaria its Diggs. “FMVCC has not transcended these and is transmitted th condition, as well as the proven value of research by mosquito was hypothesized; this theory was proven by forces that impede coordination and coopera- Anopheles mosquito for practical health gain, global expenditure for English scientist Ronald Ross at the turn of the century. tion,” he says. “But in practical terms, it has cies of Plasmodium t malaria research is very low. Total identifiable He was awarded the Nobel Prize for Physiology or Medi- begun to circumvent them, at least to some ease in humans, P worldwide spend was approximately US$84 mil- cine in 1902 in recognition of his seminal work. extent.” Diggs is hopeful that FMVCC will malariae and P. falc lion in 1993, representing a research investment Treatment and control of malaria has a long, if succeed in opening the lines of communica- which is the most co for each malaria-related death of approximately ultimately unsuccessful, history. Quinine, derived from the tion among those in the malaria vaccine de- tion and death. The p US$42. This figure compares very poorly with bark of the Cinchona tree, has been used since the 1600s velopment community. One of FMVCC’s female mosquito who available data indicating that research expendi- to treat malaria. Chloroquinine was developed in 1943, goals is to develop mechanisms to increase in order for her eggs ture per death may be orders of magnitude higher but by the 1960s and 1970s, resistance had been estab- private sector investment in malaria vaccine she bites a human, sh for conditions such as cancer, HIV/AIDS or lished in Asia and South America. By the 1980s, resistance development. her salivary glands w asthma. (p.73) had spread to most of Africa. laria parasites (1), at At the turn of the century, vector control, or the Is the science there? as sporozoites. Perhaps the lack of investment of malaria is a reflection of targeting of the mosquito as the carrier of malaria, was a The sporozo the United States’ tendency towards isolationism; malaria popular intervention with the United States Military. From It could be argued (as it has been the liver (4) where th has been classified de facto as a disease of the developing 1904-1906, the U.S. military worked to drain swamps in very vociferously by some) that a vaccine for within twelve days to world, and not of great concern to the West. It is clear the Panama Canal Zone and in the 1930s and 1940s, the malaria is an impossible pipe dream. The com- zoites per liver cell. upon inspection, however, that malaria is of great impor- U.S. government through the Works Progress Administra- plex life cycle (please see diagram accompany- enter red blood cells tance to developed countries. And, as Breman and Murphy tion engineered the draining of swamps throughout the ing article) of the malaria parasite is perceived rupture (5), where the describe in an accompanying article, the worldwide bur- southern regions of the U.S.. The Public Health Service as one of the greatest challenges to designing and asexual forms. den of malaria extends far beyond the actual 500 million funded more malaria control programs in the late 1940s. a vaccine, as is the fact that correlates of im- male and female g annual cases of malaria and the 1.5 to 3 million deaths the The arrival of insecticides like DDT was instrumental in munity are not well known. That is, it is not duced and are in turn World Health Organization (WHO) blames on the dis- turning the tide against malaria. The result of the various clear which immune responses would be pro- mosquito when takin ease. malaria control efforts was the declaration in 1953 that tective against the parasite and at which stage In the mosquito’s stom the U.S. was malaria-free. That is not the case today. In in its life cycle a certain immune response (3) develop into spor A neglected disease the United States there are at least 1000 documented cases would be effective. Those working on malaria to the salivary glands of malaria each year. vaccine development have espoused several into another human Malaria is, in many respects, a neglected disease. The 1950s saw a world increasingly optimistic of approaches; each tactic has consequences for takes another blood Why? Because it is a disease of the developing world. Beyond the possibility of global eradication, most of this hopeful- the population who could most benefit from stage, the developi the formidable scientific challenges posed by the wily para- ness a result of the use of the insecticide DDT to kill the the vaccine. Transmission-blocking vaccines, leased from rupture site, malaria’s victims are for the most part the poorest of Anopheles mosquito, the carrier of malaria. Ten years after targeting the sexual and sporogonic stages are the merozoites then the poor in the world. The fact that they could never pay the beginning of the global eradication campaign, the goal under development, and would be of great The clinical manifest western prices for a vaccine gives the private sector little was scrapped and malaria control became the new aim of benefit to individuals in geographically iso- include fever, convu incentive to invest millions of research and development international efforts. The United States, through the U.S. lated areas and would prevent the reintroduc- and death. Breman an dollars. Furthermore, vaccines have traditionally been ne- Agency for International Development (USAID), contrib- tion of the parasite in malaria-free zones. A disease burden in de glected in terms of research dollar investment. This is de- uted $790 million for the initial eradication campaign from pre-erythrocytic vaccine— that is, a vaccine ing article. Graphic c spite the fact that vaccines are the most humane and cost- 1959-1969, and a total of $1 billion from 1955-1970 to that seeks to create immune responses to the ment of Clinical Bioc the WHO and other agencies for eradication efforts. Hospital, Perth, Austra Erica Seiguer, a research fellow at the Institute, graduated in parasite before it enters the blood cells, would Reading the literature of malaria research, the Microscopical Diagn 1998 from Princeton University with a degree in molecular be of greatest benefit, it is thought, to indi- impact of malaria is striking. Malaria is a humbling scourge; eases” by Farbenfab biology and a certificate from the Woodrow Wilson School of viduals traveling to malaria-endemic locales. despite its co-habitation with humans for thousands of years Public and International Affairs. For populations that live in regions where 4 aria Report Malaria Report Malaria Report Malaria Report Malaria Report Malaria

SABIN VACCINE REPORT March 1999 successes and failures, points to great public health potential malaria is endemic, and who are thus constantly exposed to and in- by pulling a generation of scientists and physicians out of that there needed to be more north-south, east-west collabo- fected by the parasite, a blood-stage vaccine is viewed as essential for academia and into the army. The NIH and USAID have also ration to address some of these health issues. reducing disease burden. Both approaches are being explored in great picked up the slack left by meager industry investment in the At the end of the day, when it was time to settle detail by researchers in the Department of Defense (DOD), with con- disease. Russell asserts that the current global effort is “totally on a disease focus for the Dakar meeting, the winning en- siderable support for the blood-stage effort contributed by USAID. insufficient. We need more money, and more effective inter- try came from none other than Harold Varmus, director The malaria vaccine program at WRAIR is developing pre- action between biotechnology firms and the public sector.” of the NIH, who had had research experience early in his erythrocytic (RTS,S) and sexual stage (MSP-1) vaccines. In collabora- career in India and was familiar with the problem of ma- The military threat, an angle espoused by Ralph tion with researchers at the pharmaceutical company SmithKline laria. Thus began what can only be referred to as a rein- Nader’s Malaria Project, housed in the Center for the Study Beecham, Rip Ballou and colleagues have produced the first malaria vigorated effort to address malaria in a spirit of global co- of Responsive Law (CSRL), is perhaps the most compel- vaccine to reach Phase III clinical trials. Their sporozoite vaccine, ac- operation with the NIH, through the National Institute of ling and it is supported by the experience of the military in cording to Philip Russell, the founding president of the Sabin Vaccine Allergy and Infectious Diseases (NIAID) taking an active recent armed conflicts. According to Amir Attaran, the Institute and a retired general in the U.S. Army who chaired an Insti- role. At the Dakar meeting, the acronym, MIM, for the project’s director, “A sick soldier not only fails to carry out tute of Medicine Committee on malaria vaccine development, proves Multilateral Initiative on Malaria, was coined. The MIM a mission, but in a war situation, can delay troop move- that a vaccine is possible. “The WRAIR/SKB vaccine proves you can is an alliance of organizations and individuals attempting ments and waste resources that are needed to fight an en- do it,” he said. “You can get a protective effect and this gives us hope to maximize the impact of scientific research against ma- emy.” Furthermore, says Attaran, “History is full of wars that we can move on to a blood stage vaccine that will be of great laria in Africa. MIM’s strategy is to work towards greater lost because an Army was sick. In fact, in every war this values to developing country populations.” scientific capacity in Africa. According to John La century, soldiers have spent more time in the hospital sick At the NMRC Captain Montagne, deputy director of NIAID, “At least two major with infectious diseases than with combat wounds.” The Stephen L. Hoffman has been working on themes were clear from the very beginning of the MIM CSRL’s case is supported by the facts: in World War I, when a DNA vaccine in collaboration with and the NIAID effort to develop malaria vaccines and other laid low or killed hundreds of thousands of troops; Vical, a California biotechnology firm, interventions. The first of these is that there is a critical in Vietnam soldiers got over 600,000 cases of malaria; and with support from the DOD Military In- research need in the area and that this need had to be filled in the 1990s in Somalia, malaria was the number one cause fectious Diseases Research Program, the with collaborative efforts that actively engage African sci- of hospitalization. Office of Naval Research’s Advanced Tech- entists as partners in this research and the African scien- nology Development Program, the Fed- tific establishment. The second essential element that was A second rationale for investment in malaria re- eral Defense Laboratories Diversification readily apparent was the need to work with control efforts search is the increase in international travel that has been Program and the pharmaceutical company in the region.” credited with the introduction of malaria in previously Pasteur Meriuex Connaught. In Phase I The NIH, says La Montagne, is involved in col- malaria-free regions. In recent years, the Centers for Dis- trials testing primarily for safety, tolerance ease Control (CDC) in Atlanta has reported 1000-1200 cases laborative efforts with global agencies concerned with eco- and immunogenicity in humans, the vac- of malaria acquired abroad but diagnosed in the United States nomic development and disease control, such as the World cine was able to elicit cytotoxic T lympho- annually, though officials believe that an equal number of Bank. La Montagne asserts that the World Bank, “will in- cyte responses and was safe. This vaccine malaria cases go unreported. Thus, a traveler’s market for a deed enhance its investment in Africa, not only in support is directed towards the pre-erythrocyte malaria vaccine would not be insignificant. According to of the health infrastructure that is needed for malaria con- stage parasites. NIAID director Tony Fauci, each year, approximately 30 trol, but also in the general economic development of the The most recent study to hit million Americans are put at risk for contracting malaria when region.” the scientific community, and even make they travel to endemic countries. In addition to working with the World Bank, the it onto the network news, was conducted NIH is coordinating its efforts with those of the WHO’s by researchers in the United States and in In the 1996 IOM report issued by a committee regional office’s in Africa and the African Development India. The experiments involved testing a chaired by Russell, Vaccines Against Malaria: Hope in a Gath- Bank, USAID, the Department for International Devel- multi-stage malaria vaccine that would, it ering Storm, the blue-ribbon panel concluded that there opment (DFID) of the United Kingdom, and the Euro- was hoped, induce immunity to the vari- needed to be more research on the market influences on in- pean Union, among others. La Montagne believes that ous stages of the parasite. The rationale was vestment in vaccine development. According to the report, “these efforts will result in an increased level of economic that any vaccine based on only one stage of “a clearly identified market is essential…traditionally most activity in the region and ultimately and elevation of the the parasitic life cycle would be necessarily attractive markets have been thought to be the military and standard of living for Africans. This will take time cer- less efficacious than one that induced immu- ‘traveler’ markets of North America and Europe— the vast tainly and progress may be slow at first.” nity in the host to the parasite and every stage emerging middle classes of South and Central America, Af- The very vocal and active role taken by the NIH a disease caused by of infection, from sporozoite, to liver-stage, to may have been one of the factors leading to the Roll Back the genus Plasmodium rica, India, and Southeast Asia, where the risk of malaria is erythrocytic sexual to sexual stages. Research- widely recognized, have been largely ignored.” Malaria (RBM) campaign announced by Gro Harlem hrough the bite of the ers in the study immunized rabbits with a Brundtland last May, after becoming the new director-gen- o. There are four spe- vaccine that contained synthetic genes encod- Russell contends that, until recently, there was little eral of the WHO. Brundtland’s vision for RBM is a global that cause malaria dis- ing for antigens corresponding to the various interest in understanding the principles of vaccine econom- partnership, drawn from malaria affected countries, UN P. vivax, P. ovale, P. stages. They found the vaccine to be highly organizations, bilateral development agencies, development ics. Without this kind of information it is very difficult, if not lciparum, the latter of immunogenic in the rabbit model. Future banks, non-governmental organizations and the private impossible, to address the issues peculiar to vaccine research ommon cause of infec- studies are needed to determine whether the sector reduce burden of malaria. Though exactly how the and development. parasite resides in the vaccine is safe, immunogenic and efficacious WHO project will function is not totally clear, its empha- Lastly, should all humanitarian impetus fail, the o requires a blood meal in non-human primates and then in humans. sis on drugs for malaria might alarm those in the vaccine socio-economic argument for controlling malaria is pow- s to mature (2). When But the malaria research community research community. The RBM program aims to cut ma- erful. In its most simple form, it goes something like this: he injects material from has been burned before. In the early 1990s, laria deaths by 75% by 2015. The feasibility of this goal, while malaria continues to stunt economic growth in de- which contains the ma- Colombian scientist Manuel Patarroyo an- considering the emergence of resistant strains of malaria veloping nations, the United States and other developed t this stage referred to nounced the results of studies that showed and limitations of vector control measures, is up for de- countries are losing potential markets. Moreover, the po- high efficacy of his SPf66 malaria vaccine. His bate. As if overnight, malaria has become the hot disease, litical instability associated with countries ravaged by dis- oites move quickly to results have yet to be duplicated elsewhere. with a host of foundations and organizations springing up ease and little economic growth is a constant drain on ey multiply, giving rise But the optimism brought about by the ini- to advocate on its behalf. Western foreign policy. This argument contends that it is o thousands of mero- tial announcement of the potential vaccine the West’s best economic interest to address the malaria The young parasites has taught malariologists to be cautious about problem. According to James D. Wolfensohn, president of Where to next? s when the liver cells contributing to false expectations. Ballou, the World Bank, malaria control is essential for economic ey develop into sexual Diggs and Hoffman have been humbled by If malaria is the “it” disease, does this mean that development in Africa. In the sexual cycle, the parasite as well. In 1987, they put their a vaccine is imminent? Maybe. The scientific challenges to gametocytes are pro- confidence in a vaccine directed to the developing a vaccine that is safe, efficacious, and accessible n ingested by a female circumsporozoite protein (CS) to the test: they A reinvigorated effort to combat malaria to the people who could most benefit from the vaccine, are ng another blood meal. were injected the vaccine in themselves and formidable. In the past two years, beginning most publicly mach, the gametocytes then were challenged by having malarious Conquering malaria will be one of the greatest with the International Conference on Malaria held in rozoites which migrate mosquitoes feed on them. Despite their confi- feats of mankind. Not only would it be a scientific coup, Dakar, Senegal in 1997, malaria has come into the spot- s and are then injected dence that the vaccine had worked, they both but it would be an amazing humanitarian victory, provid- light. Much of this is due to the fact that the National host when the female developed malaria infection. ing a blue-print for how we can, as a global society, address Institutes of Health, the nation’s premier source of funds meal. In the asexual health and development issues in a more productive fash- for basic biomedical research, has put malaria and interna- ing parasites are re- ion. With 40% of the world at risk for infection from a Why the west should care tional health issues, on the research agenda. The origin of d red blood cells and disease with enormous economic and social costs, control- this emphasis is a good lesson in how the government, in invade new red cells. Despite the fact that malaria is per- ling malaria is a humanitarian and economic imperative. particular the NIH, develops research priorities. At a meet- tations of the disease ceived as a disease of the developing world, The challenges, however, can be overcome. The ing at the NIH convened in mid-summer 1995 between ulsions, coma, anemia there are convincing arguments for the pub- proof is in the science: scientists have demonstrated a level the Wellcome Trust, the Pasteur Institute and the NIH, nd Murphy describe the lic and private sectors in developed coun- of success in developing a sporozoite vaccine, and thus we the topic on the agenda was to identify areas in which the etail in the accompany- tries to invest in research and development know that a vaccine is possible. There is great reason for participatns might develop productive collaborations and courtesy of the Depart- aimed at controlling or preventing the dis- optimism in the field of malaria vaccine development. to plan the Dakar meeting. Scientists spent the entire day chemistry, Royal Perth ease. Russell believes that the reason that the Given a willingness to cooperate among researchers and discussing many of the problems facing countries affected ralia; adapted from “The U.S. military is investing in malaria research is policy makers, and the kind of financial support essential by diseases such as HIV and tuberculosis. The European nosis of tropical Dis- the threat it poses to America’s troops. Accord- to such an endeavor, a malaria vaccine is possible. delegation was concerned about the lack of scientific capacity briken Bayer, 1955. ing to Russell, America’s involvement in World and infrastructure within developing countries and suggested War II “put the U.S. in an international mode,” v 5 SABIN VACCINE REPORT March 1999 Scientist and Teacher: Herbert Herscowitz Countdown to als who have the necessary skills that can be applied for the BY ELIZABETH DE LA PAZ benefit of society.” eradication continues His current research activities focus on immuno- “I wake up every morning happy to come to work,” BY JESSICA QUINN says Herbert Herscowitz, chair of the Scientific Advisory logical approaches to the treatment and prevention of can- Committee of the Sabin Vaccine Institute and one of the cer. He collaborates with several Lombardi Center labora- A world free of the ravages of Poliomyeli- Institute’s greatest assets. His happiness stems from a 30-year tories that are involved in developing immunologic ap- tis may be a reality with the arrival of the new mil- professional career that includes positions in teaching, re- proaches to controlling cancer, specifically tumors of the lennium. The World Health Organization (WHO) search, and various administrative appointments. Herscowitz breast, brain, and prostate gland. According to Herscowitz, reports that elimination of the disease would save is a professor of microbiology and immunology at the the best part of his current research effort is the feeling the world an estimated $1.5 billion on immuniza- that he has “the potential to save someone’s life directly.” Georgetown University photo by Erica Seiguer tion expenses alone, not counting the cost of treat- One of the School of Medicine, two ing Polio victims. However, $800 million is needed fields in which he became most recent contribu- to ensure the complete riddance of Polio. fascinated with early in his tions Herscowitz has educational career; he be- made to the Sabin Vac- In May of 1988, the World Health As- lieves that microbiology and cine Institute is the de- sembly predicted the eradication of Polio by the immunology explain the es- velopment of the Sabin- year 2000. This marked the beginning of an ex- sence of life. It was this at- Hilleman Fellows Pro- tensive four-step plan to eliminate the virus that traction to the two fields that gram, which gives local attacks the central nervous system. Poliomyelitis has led him to the profes- high school students op- usually enters through the mouth and spreads along sional success he enjoys to- portunities to take part the nerve cells often resulting in permanent pa- in research activities day. ralysis as well as fatigue, fever, vomiting and con- One testament to aimed at preventing dis- his personal achievements is ease through the devel- stipation. Herbert Herscowitz presents a book award for creativity and initia- his receipt of the 1998 Kai- opment and administra- Control of the disease began in 1954 when tive in scientific research to Eileen Tschetter at the annual Junior ser-Permanente Award for tion of vaccines. He sees a vaccine designed by Jonas Salk was declared safe Science and Humanities Symposium in January 1999. Sustained Teaching Excel- the program’s goal as an and mass inocula- lence. According to Kenneth L. Dretchen, Dean of Research opportunity to get young people excited about academic tion began. In In India, 130 million and Graduate Education, this prestigious award has only scientific research at an early age, so that they may “become 1963, Albert been given to a handful of select individuals who are chosen not only a scientist, but also a transmitter of information to Sabin developed children were immunized by a committee of students and colleagues. As Herscowitz others.” It is a chance to inspire and direct the young stu- an oral vaccine in a single day. began his professional career, he fell into teaching as an ap- dents into rewarding careers in vaccinology and immunol- called Trivalent purtenance to a research position at the medical center. He ogy, in which they can develop new ideas as well as follow in Oral Polio Vac- was unsure of himself as a teacher at first, confessing that, “I other’s footsteps. cine (OPV) was trained as an expert in a specific area of cellular immunol- Despite the numerous daily responsibilities, which replaced Salk’s injectable vaccine (IPV). The ogy, and I found myself spending a great deal of time teach- Herscowitz believes that the challenge of trying to balance ing medical and dental students. Yet when I began my career everything in his life gives him the stimulus to continue. existence of this effective and inexpensive vaccine at Georgetown, I had never taken a course in education and “If I had nothing to do, I’d be very unhappy,” he says. He has been the key to eradication. therefore, I didn’t know the right way to teach from the is satisfied with his current status in life, both personally The first step in the process is routine im- wrong way to teach.” and professionally and is most proud of the great successes munization. Second, mass immunization cam- Herscowitz has definitely overcome such feelings of his wife, their children, and the families they have started paigns are highlighted by National Immunization and has been recognized for his gift of teaching several in turn. A century from now, Herscowitz hopes to be re- Days (NID). During NIDs, every child under five times by his colleagues and students. He delights in work- membered for the impact he has made on young people by years of age is inoculated with 2 doses of OPV. A ing on a one-to-one basis with the medical students, watch- helping them reach their full potential. v recent NID in India immunized 130 million chil- ing them “acquire information and develop into individu- dren in a single day. The third step, surveillance, Aerosal Measles vaccine workshop draws on calls for the rapid reporting of suspected cases. Lastly, Mop-Ups, or house to house immuniza- reearchers from Mexico, CDC, FDA tions are conducted in high risk areas. tinued Weniger, “Needles and syringes have additional draw- BY CHARLENE A. FLASH Since the implementation of these steps backs such as unsterile reuse in developing countries, im- in 1988 the number of Polio cases has declined For many people, old and young, the thought of a proper disposal and needles-stick injuries.” nearly 85%. Polio has already been eradicated from needle injection is an unpleasant one. Needle injections are At the measles workshop, the CDC’s Peter Strebel also more cumbersome and require more rigourous storage reported on the state of measles in the world and described North and South America and most of Europe. and transportation conditions than orally delivered medica- the need for trained health workers, a “cold chain” for vac- Meanwhile, it is still endemic in South Asia and tions. These issues and others inspired , who cine transport, needles, syringes, and auto-destruct carry- Sub-Saharan Africa. developed the oral and for whom the Sabin ing cases. He also discussed the danger measles posed in areas The world will be certified as free of po- Vaccine Institute was named, to devise methods of vaccine where there are very few cases, comparing the disease to “a lio three years after the last confirmed case. Until delivery which were non-threatening and cost-effective. Sabin sleeping giant.” He elaborated: “Sometimes when the public then, immunizations will continue until eradica- performed research on an sees zero cases they get lax in tion is achieved, now predicted to occur around aerosol delivery system getting vaccinated.” 2010. for the measles vaccine, in Jorge Fernandez v the laboratory of Joseph de Castro, a past associate of A. Bellanti, now senior Sabin, shared the testimoni- vice-president of the In- als of Mexican parents who stitute. greatly preferred aerosol vac- Continuing cines over injected vaccines, the legacy of Sabin, the and described the incredible Matters of giving Institute hosted the effectiveness of the aerosol BY DIANE MYERS, DIRECTOR OF DEVELOPMENT Aerosol Measles Immu- technique in eradicating nization and Alternative measles in Mexico. There are Many of the initiatives that you have read Routes of Immunization currently on-going clinical

photo by Charlene A. Flash about in this issue of the Sabin Vaccine Report Workshop on January 13, trials in Mexico. Yvonne 1999. Public health offi- Hopkins’ Diane Griffin and Stanford’s Yvonne Maldonado Maldonado, of the Stanford were made possible through the generosity of cials and scientists from in- attended the workshop. University School of Medi- many donors. Philanthropic support is critical dustry and academia in Mexico and the United States gath- cine Department of Pediatrics, gave an epidemiological over- to the success of our efforts in supporting vac- ered to discuss the global impact of measles. According to view of vaccine efficacy. Maldonado stressed the need for cine research, advocating for sound public policy, Bellanti, the workshop was “meant to bring together those geographically specific programs. and educating the public about the enormous active in the field to review where we have been, where we The workshop ended with a brainstorming ses- are, and where we are going.” sion, facilitated by Mark Papania, the acting Chief of the benefits of immunization. The complications associated with needle injection Measles Elimination Activity National Immunization Pro- One of the Sabin Vaccine Institute’s new- of vaccines are not new. In a 1998 talk given at a National gram at the CDC, and James J. Barry, Principal Engineer est initiatives is its Sabin-Hilleman Fellows Pro- Foundation for Infectious Diseases press conference, the Cen- at CREARE, Inc, who succinctly described the logistical gram whose goal is to increase the number of ter for Disease Control’s (CDC) Bruce Weniger, assistant chief specifications of an aerosol device suitable for the measles bright young scientists who choose careers in of vaccine development National Immunization Program at vaccine. CDC, remarked about the impact of having so many vacci- Members of Bellanti’s research group continue vaccinology. This summer we will bring ten high nation requirements delivered by needle injection. “Many to work in tandem with Mexican scientists and officials to school students to the Georgetown campus and providers and parents,” he said, “are reluctant to administer perfect the aerosol measles and rubella vaccine. give them hands-on research experience in the so many injections during a single visit because of the child’s biological sciences. We will also provide learn- fear of needles and pain. This results in deferred vaccination, ing opportunities in public and health care policy additional time and cost for follow-up visits and potential v disease if follow-up is delayed or missed.” Furthermore, con- issues surrounding vaccines. v 6 SABIN VACCINE REPORT March 1999 Gates donates $100 million to children’s vaccines continued from page 1 in the science of vaccine development as well as the The Children’s Vaccine Program will support vari- will have an very important impact on the health of public policy aspects, the CVP is poised to have ma- ous activities in an effort to improve access to vaccines and children.” jor impact on world health. “It directly addresses the immunization rates. Research related to the “field effective- The Gates program will focus on increased difficult and complex problem of delivering the new vac- ness” of the four vaccines, the economic and social costs of communication as well by supporting the creation of cines to children in the developing world,” he said. He diseases, and analyses of the cost-effectiveness of preventing an international information program to generate sup- continued, “The program brings resources, innovation, those diseases will be a major aim of the CVP. This infor- port for rapid introduction of the new vaccines and to and an entreprenurial approach to the field which will mation will be invaluable to health program managers as help build global markets so that prices can be lowered. complement the efforts of the U.N. agencies.” they make plans for future use of the vaccines. In addition, Additional goals include designing activities to ensure the CVP will support model immunization programs in se- an adequate and competitive supply of vaccines and to Hepatitis B vaccine leads lected countries to establish the most cost-effective means of develop funding mechanisms to supply vaccines to to major decline in disease introducing the new vaccines and will fund international countries in need and spurring efforts to create new meetings and conferences aimed at developing consensus and diversified financing mechanisms to support child- BY JESSICA QUINN on use of the vaccines. hood global immunization. As much as 20% of the population in the areas of Russell is pleased with the approach taken by the PATH was founded in 1977 to improve health, China, Southeast Asia and much of Africa is infected with Gates’ and PATH. “The economic barriers to vaccinating chil- especially for women and children. The organization , despite the existence of an effective vac- dren in the developing world are formidable and new approaches emphasizes improving the quality of reproductive health cine. In the United States less than five percent of the and innovative solutions are needed. The CVP, working and preventing and reducing the impact of widespread population is infected. The majority of cases in the U.S. with governments in the poorest areas of the world, communicable diseases.v involve adults while in Asia and Africa mostly children are afflicted, contracting the disease from their mothers dur- Americans for Medical Process honor ing birth. A vaccine against Hepatitis B has been available

Albert B. Sabin “Heroes of Science” photo in the United States since 1982. The original was plasma On January 14th, the derived while the Hepatitis B Vaccine presently used is Americans for Medical Progress obtained from recombinant yeast cells. In the new, safer vaccine, yeast cells are genetically altered to produce the honored Barbara Barry, Thomas B. Hepatitis B surface antigen. The body recognizes an anti- Clarkson, Laurie Flynn, United gen as a foreign molecule and begins to produce antibod- States Senator Connie Mack and ies to eliminate it. Vaccines work by fooling the body into his wife Priscilla, Patricia S. FPO making the antibodies against a particular antigen, thus Schroeder, Beverly Sills and Den- heloisa.tif creating a state of protection against the disease. The re- nis J. Slamon. combinant vaccine is administered in three doses. After Heloisa Sabin, widow of the third dose, the vaccine is reported to be 85-95% effec- the late Albert Sabin, and a founder tive. Since 1985, Hepatitis B infection in the United States of the Sabin Vaccine Institute, at- has fallen by 55%. tended the event. “I was privileged This decline in Hepatitis B infection is attrib- uted to both the existence of the vaccine and awareness to help present the AMP’s Sabin award,” she said. “The award is a among high risk groups. Children under 20, health care courtesy of TISARA workers, injection drug users, sexually active heterosexuals wonderful tribute to Albert’s dedi- Beverly Sills, Barbara Barrie, Heloisa Sabin and Patricia Mack (l to r) partici- and homosexual men are all strongly advised to get vacci- cation to scientific excellence and pate in the 1999 Albert B. Sabin Heroes of Science Awards ceremony. nated. For more information on Hepatitis B, please visit progress.”v the Sabin Vaccine Institute Website or call the CDC at 1- 888-4-HEPDOC.v Rotavirus, from page 1. Now that the vaccine has been developed and more diffuse epidemiology. The virus is typically spread by supplement infant formula or even for administration to has won FDA approval the question remains as to whether the fecal-oral route, although there is some debate as to whether susceptible adult populations, such as those with weak- or not the children who need it most, those living in de- the virus can be transmitted through respiratory secretions. ened immune systems. veloping countries, will ever receive it. The success of RotaShield™ is encouraging, Clinical manifestations of rotaviral disease but there is still a long way to go before all children can The biology of rotavirus and Rotashield™ benefit from its success. RotaShield™ is administered In most cases, children first infected with orally and does not require special storage conditions such Rotaviruses are part of the family Reoviridae, rotaviruses initially experience a temporary bout of diar- as refrigeration, both of which make distribution of the which are characterized by their double-stranded, seg- rhea and possibly fever and vomiting then recover with a vaccine in developing countries more feasible. However, mented, RNA genomes. Each segment codes for a spe- partial immune resistance to further infection. In some at approximately $38 per dose, RotaShield™ is cific viral protein, however, these codes can vary within a cases though, the infection is more severe and children can unaffordable in these countries. It has been proposed population of viruses, resulting in different viral strains. become fatally dehydrated. Oral rehydration therapy, or if that if the pharmaceutical companies manufacturing a Because of their genomes, rotaviruses can undergo necessary, hospitalization and intravenous fluids, are the vaccine (which right now only includes Wyeth-Ayerst) reassortment, which is the exchange of gene segments most common treatment methods in developed countries. are able to charge a higher price in developed nations, during the coinfection of more than one strain. These therapies are not readily available in most develop- they will be able to offer it to developing nations at a Reassortment enables rotaviruses to generate diversity, an ing nations, however, where poorer health in general in- greatly reduced price. However, before the vaccine can evolutionary tactic which enhances their ability to evade creases the chances of developing severe and possibly fatal be distributed in these countries, more research is needed. the host’s immune system. The distribution of serotypes disease. This situation is glaringly apparent when com- For example, there is little data describing the varies geographically, with particular strains found pri- paring the effects of rotaviral infections in developed na- effect of administering the vaccine to children who are marily in developed nations and others in developing tions, particularly the United States, with those in devel- infected with HIV who might be susceptible to infec- nations. oping nations. In the United States, approximately one in tions caused by the vaccine itself. The report on RotaShield™ is a live vaccine developed against 30,000 rotavirus infections is fatal, however, that ratio rises RotaShield™ by the Advisory Committee on Immuni- most common serotypes. The vaccine is orally adminis- to one in 150 in developing nations. zation Practices of the U.S. Centers for Disease Control tered in three doses, recommended at ages two, four, and and Prevention states that RRV-TV should not be given six months. In efficacy trials in the United States, this More vaccines on the way? to infants with known or suspected immunodeficiency vaccine was found to protect against approximately 50% though they recommend it for healthy children. The of all rotaviral related disease, and 64-100% of severe Although RotaShield™ is the only rotavirus vac- situation is complicated by the fact that in developing disease. In developing nations, however, the results of cine currently licensed by the Food and Drug Administra- nations, many adults, and therefore children, are not even efficacy trials were not as decisive and were less consis- tion, others are being developed. Some of these use a non- aware of their HIV status. Regarding these issues Glass tent. Trials in Venezuela, Peru, and Brazil demonstrated Jennerian (live virus) approach in an effort to increase the admits that it is “hard to make a recommendation one a range of 24-48% protection from all rotaviral disease protection conferred by the vaccine against both mild dis- way or the other so the first recommendation is one of and 0-88% protection against severe disease. These num- ease as well as moderate to severe forms of infection. Both caution until we know more.” These questions will hope- bers could reflect complications due to the interference Merck and SmithKline Beecham are currently field testing fully be addressed by ongoing studies to facilitate the dis- of other enteric diseases or problems following up on rotavirus vaccines and investigating the relationship of strain tribution of an effective rotavirus vaccine to those in most patients’ progress. The trial in Venezuela was the most variety in the vaccine to the resulting protection, but these desperate need. successful and gives hope for the possible benefits of a are probably two to three years away from approval. In large-scale vaccine initiative in developing nations. addition, scientists at the Cancer Research Institute (CRI) In the United States rotaviral infections follow of Contra Costa in California found that lactadherin, a a temporal and geographical pattern, with the prime glycoprotein found in breast milk, inhibits rotavirus activ- v rotavirus season beginning in the Southwest in autumn ity in vitro. CRI is working on the development of a ge- Rachel Liberatore is a research assistant in the Laboratory of and moving in to the Northeast by spring. Globally, other netically engineered lactadherin that would protect against Molecular Genetics and Immunology of Jeffrey V. Ravetch at areas with temperate climates also have a peak rotavirus the development of the symptoms of rotavirus infections by The Rockefeller University in New York City. She graduated season in the fall and winter, however, in tropical environ- selectively binding the putative receptor associated with the in 1998 from Princeton University with a degree in molecu- ments and typically in developing nations, there is a much development of diarrhea. Such a product could be used to lar biology. 7 SABIN VACCINE REPORT March 1999 News from the Sabin Vaccine Institute Patricia Thomas awarded Leonard bringing a product from idea to design to testing to Sabin Gold Medal to be awarded to Silk Journalism Fellowship market. The colloquium was chaired by , founding president of Institute Patricia Thomas, a frequent contributor to chair of the International Council of Scientific Advi- Philip K. Russell, the founding president of Sabin Vaccine Report and a Research Fellow of the Sabin sors at the Institute, who is a professor of pediatric the Institute, will be awarded the Albert B. Sabin Gold Vaccine Institute, has been awarded the Leonard Silk infectious diseases at Yale School of Medicine. Medal Award at the Second Journalism Fellowship. This $30,000 prize will enable Hotez, who is actively involved in developing Annual Conference on Vac- Thomas to move ahead with her book on AIDS vac- a vaccine for worm infection, sees the colloquium as cine Research in Bethesda, cine research, an endeavor that has also been backed by the starting point for more collaboartion among vac- Maryland on March 28th, the Albert B. Sabin Vaccine Institute. Thomas' book cine researchers and hopes that, this and future collquia 1999. The Gold Medal was will be published by PublicAffairs. “lead to the creation of a translational vaccine network created in 1994 to recognize “Immediately after I learned about the award, that will help facilitate the development of the v next individuals who have made I was invited to an important AIDS vaccine meeting in generation of vaccines, both here and abroad.” major contributions to Africa and offered an inside look at two pioneering vac- Sabin Honors Student at Junior vaccinology and, in so do- cine trials in Thailand,” Thomas said. “Thanks to the ing, have improved the hu- fellowship, I'm going to be able to do both. It came Science & Humanities Symposium man condition. Previous re- just in time.” On January 8th, the Institute presented Eileen cipients include D.A. The Silk Fellowship was endowed by the fam- Tschetter, a 10th grader at Washington-Lee High School Henderson, Robert M. Chanock, Joseph L. Melnick, ily and friends of the late New York Times economics in Arlington, Virginia, with an award for Creativity Maurice R. Hilleman, Myron M. Levine and Allen C. columnist Leonard Silk, and is meant to help an estab- and Initiative in Scientific Research for her research on Steere. lished journalist complete a book on an important con- the flammability of sleepwear. Her paper, entitled Russell received his A.B. degree in biology from temporary issue. It is administered by The Century “Sleepwear: A Burning Issue,” was entered in the an- Johns Hopkins University in 1954 and his M.D. from Foundation/Century Fund in New York, and is awarded nual Junior Science and Humanities Symposium(JSHS) the University of Rochester in 1958. After an intern- to only one author each year. v at Georgetown University School ship in medicine at North Carolina Memorial Hospi- of Medicine. Ms. Tschetter’s goal tal, he entered the United States Army Medical Corps was to test if there was a differ- Immunization conference held in 1959. He completed residency training in internal ence in the ignition time of fire medicine at University Hospital in Baltimore and was Immunization program leaders gathered at the retardant and untreated 100 % “Every Child By Two (ECBT) Immunization Partners board certified in 1965. polyester fabric. During his military career, Russell conducted Conference in Washington, DC on December 7-8, JSHS was founded in 1998 to share successful strategies for raising vaccina- research on a variety of infectious diseases of impor- 1958 and is currently funded by tance to the military and managed several vaccine de- tion rates. the US Army Research Office, the photo by Erica Seiguer ECBT was founded by former first lady velopment programs. Air Force Office of Scientific Research and Office of Military assignments included several positions Rosalynn Carter and Betty Bumpers, former first lady Naval Research. of Arkansas, to ensure that all of America’s children are v at Walter Reed Army Institute of Research, including fully immunized on schedule, from birth to two years Chief of the Department of Virus Diseases, Director of of age. Conference presentations covered the latest strat- the Division of Communicable Diseases, Deputy Di- Institute debunks anti-vaccine rector and Institute Director and Commandant. Russell propaganda served as Commander of the U.S. Army Medical Re- The Sabin Vaccine Institute refuted a story search and Development Command (1986-90), and spread by anti-vaccination activists that alleged that retired as a Major General in 1990. FPO Russell's military awards include the Legion carter.tif certain forms of cancer may have been caused by in- jected polio vaccine manufactured before 1961. In- of Merit and the Distinguished Service Medal. He re- terviews with Institute senior vice president Joseph A. ceived the Gorgas medal for contributions to preven- Bellanti were included in news broadcasts by CBS Ra- tive medicine and the Joseph Smadel medal and lec- dio News and NBC4 television in Washington. The tureship. Following military service he was appointed stories accurately reported the absence of scientific Professor in the Department of International Health at evidence of the alleged vaccine-cancer link. Bellanti the Johns Hopkins University School of Hygiene and and other experts said other risk factors, such as smok- Public Health. ing and exposure to asbestos, are associated with the Russell has served on many national and in- ternational advisory groups including the Institute of Institute senior vice president Joseph Bellanti meets with cancers. They stressed the stringent safety testing that Medicine Committee on Microbial Threats to Health, former first lady Roslyn Carter. vaccines undergo and urged the public to continue and the President's Advisory Committee on Human getting vaccinated against polio. egies to raise immunization rates above 90%, and to v Radiation Experiments. He was a member of the Board maximize the effectiveness of state children’s health of Scientific Counselors of the National Center for In- insurance programs, vaccine partner outreach activi- IDSA announces availability of fectious Diseases. Dr. Russell served as Special Advisor ties and school-based immunization activities. Immunization News Briefs to the Internationalv Children's Vaccine Initiative and The Sabin Vaccine Institute was represented With grant support from the Robert Wood is on the Board of Directors of the International AIDS by its Senior Vice President, Joseph A. Bellanti. v Johnson Foundation, the Vaccine Initiative, a special Vaccine Initiative. project of the Infectious Diseases Society of America and the Pediatric Infectious Diseases Society, announces sabin calendar Institute sponsors translational the availability of a free news service, Immunization The Institute is not responsible for research colloquium News Briefs. This news resource brings immunization non-Institute events listed below. news to your computer three days a week. This service March 17-20, 1999 Scientists gathered at the Banbury Conference will focus on immunization efforts, vaccine develop- Walker’s Cay, The Bahamas Center at Cold Spring Harbor in mid-December to dis- ment, and disease outbreaks throughout the world as COLLOQUIUM ON CANCER VACCINES AND cuss issues in translational research. The colloquium, reported in the 1,400 news sources that are regularly CANCER IMMUNOTHERAPY Translational Research: From the Bench to the Bedside, reviewed, including major newspapers and magazines; Co-chaired by Drew Pardoll, the Johns Hopkins was part of an on-going effort at the Institute to en- regional, national, international, and business wire ser- University School of Medicine and James P. courage interaction between individuals involved in all vices; weekly and monthly trade journals; business pe- Allison, the Cancer Research Laboratory at the aspects of riodicals; legislative sources and non-industry sources. University of California-Berkeley. pharmaceuti- Delivered via e-mail on Monday, Wednes- cal develop- day and Friday, the condensed abstracts of the news ment. Basic about immunization and vaccine issues, Immuniza- March 28-30, 1999 scientists and FPO CSH.tif tion News Briefs provides a comprehensive, yet con- industry rep- cise, report on the latest news, issues and develop- Bethesda, MD resentatives ments about and affecting the immunization program. SECOND ANNUAL CONFERENCE ON VACCINE RESEARCH discussed the Immunization News Briefs will also keep you up to Sponsored by the National Foundation for Infectious challenges date on pending federal and state regulation, new prod- Diseases, the Centers for Disease Control, the International Society for Vaccines, the Center for faced by re- uct developments, and trends in vaccine development Biologics and Evaluation at the Food and Drug searchers in as reported in the press and scientific literature. In Administration, the Children’s Vaccine Initiative, the addition, this news will remain in a searchable archive Vaccine research Mike Levine, Cold Spring World Health Organization and the Albert B. Sabin Harbor president Jim Watson, colloquium chair on the Vaccine Initiative’s home page (within the Vaccine Institute at Georgetown University. Peter Hotez and Institute Chairman H.R. Shep- IDSA’s web site). www.nfid.org herd. Subscribe to Immunizationv News Briefs at http://www.idsociety.org/regform ON THE WEB AT WWW.SABIN.GEORGETOWN.EDU