Am. J. Trop. Med. Hyg.. 33(3), 1984, PP. 319—324 Copyright ©1984 by The American Society of Tropical Medicine and Hygiene

EXCELLENCE IN RESEARCH IS NOT ENOUGH*

PHILIP K. RUSSELLt Walter Reed Army Institute of Research, Washington, D.C. 20307

Members of the Society, Distinguished Guests, rious threats posed by the traditional enemies of Ladies and Gentlemen health in the tropics—yellow fever, plague, den gue, the arboviral encephalitides, other vector First, I would like to thank the Society for the borne virus diseases, malaria, cholera, and a long privilege of being President for the past year and list of other infectious diseases so well known to give special thanks to our Secretary-Treasurer, this audience. Dr. John Scanlon, for doing so much of the work Doctor Reeves went on to discuss the deteri necessary to the successful functioning of the So oration of our collective abilities to deal with the ciety. increasing infectious disease threat using the tra I found that one of the most difficult tasks as ditional weapons available to public health au President is choosing a topic for today's speech. thorities —sanitation, vector control, insecti I had an initial impulse to discuss field research cides, antibiotics and anti-parasite drugs, and the and use my experiences in Pakistan, Southeast available vaccines. Burgeoning populations in the Asia, the Caribbean, and the eastern shore as a developing world, social changes, increased mo basis for the talk. That approach would have bility due to modern transportation, rapidly in allowed me to give proper credit and recognition creasing drug resistance by parasites, and insec to several colleagues who have been very im ticide resistance by arthropod vectors all portant in my research career. However, that ap contributed to a world-wide situation which led proach would have been, of necessity, anecdotal Doctor Reeves to pose the question in the title and on some reflection I discarded the idea. of his address. And that question is as important I also considered an in-depth analysis of a sci today as it was in 1972. entific issue, but I decided that no matter which In the decade that has passed since that schol subject I chose I would run an almost certain risk arly and farsighted analysis the overall situation of boring a large segment of the audience who has become even worse in many respects. There do not share my personal scientific interests. have been some major accomplishments, most Having rejected those options I did what I notably the global eradication of smallpox suspect some of my predecessors may have done. through the efforts of WHO and several member I read many of the earlier presidential addresses nations, some national successes such as excel seeking either inspiration or a challenge to which lent control of Japanese encephalitis in Japan, I might respond. A presidential address that cap and some major advances in therapy such as oral tured my attention was presented just over a de rehydration for cholera and diarrheal diseases, cade ago and met both criteria of being inspiring but for every victory in the war on infectious and challenging. The message in that address is diseases, we have had major defeats. as important today as it was when it was deliv Malaria is clearly one of the most important ered to the Society by Doctor William C. Reeves problems. During the 1970s the world-wide in at the 1972 meeting. The title of Doctor Reeves' cidence of malaria increased significantly, peak address was “Canthe War on Infectious Disease ing I believe in 1978. In 1980 over 8 million Be Lost?―Doctor Reeves' paper dealt with some cases were recorded by WHO outside of Africa of the major public health issues facing the world, in addition to an estimated 6 million cases in and expressed a realistic concern about the se sub-Saharan Africa. It is certainly probable that these figures underestimate true incidence. In Af rica, by one estimate, over a million deaths per * Presidential Address given before the 32nd Annual year in children are associated with malaria. Meeting of the American Society of Tropical Medicine and Hygiene, San Antonio, Texas, 6 December 1983. Forty-six percent of the world's population re t Presentaddress:FitzsimmonsArmyMedicalCen main at risk of malaria. Some progress has been ter, Aurora, Colorado 80045. made in control of malaria in the past 5 years 319 320 PHILIP K. RUSSELL by intensified national control efforts, but these and, in addition, we saw the invasion of Cuba, have been costly and difficult and the overall Honduras, Guatemala, El Salvador, Mexico, and picture remains bleak. a few cases in south Texas. Huge areas where Drug resistance of Plasmodium fakiparum is Aedes aegypti had previously been eradicated or a continually increasing and expanding problem. well controlled became endemic. The dengue- 1 Chioroquine resistance is spread from Eastern epidemic in Cuba was followed by the introduc India throughout Southeast Asia. Resistant strains tion in 1981 of a dengue-2 strain which caused of P. falciparum are widespread in South Amer a disastrous dengue hemorrhagic fever (DHF) ica occurring in 10 countries. Africa has recently epidemic with hundreds of deaths and thousands become an area where drug resistance is a serious of cases which required an immense effort by the problem. Between 1978 and 1982, chloroquine Cuban health structure to care for cases and con resistance was confirmed in seven east African trol the vector. countries. Mutiple drug resistance is now wide I neglected to mention the introduction of den spread in Southeast Asia and South America, gue-4 virus into the Caribbean, probably from and we are reduced to relying on combinations the Western Pacific, which also became wide of expensive drugs for treatment in some areas. spread. We now have a situation in the Carib The combined effects of insecticide resistance, bean in which four serotypes of dengue have es vector biology, drug resistance, and economic tablished endemicity. factors produce a very unsatisfactory situation. To extend Doctor Reeves' analogy of a war on Dengue is another disease for which epide infectious diseases—the campaign against den miologic studies have very impressively record gue in the Americas has been about as successful ed a continuous series of losses to the dengue as Napoleon's invasion of Russia—a resounding viruses and their Stegomyia vectors—principally defeat. Aedes aegypti. This year, 1983, marks 2 decades During the same past 2 decades, parallel events of my personal interest in dengue. In 1963 the in Asia saw the extension of severe DHF epi first major Caribbean epidemic since World War demics into Burma, Indonesia and Vietnam with II began with a serious island-wide outbreak on continuous increases in morbidity due to DHF Puerto Rico. Our group at Walter Reed identified in the Southeast Asian and Western Pacific re the epidemic strain as a unique subtype of den gions as a whole. Other areas of the world, the gue-3. That serotype subsequently became widely Pacific Islands, India, and East Africa also have disseminated in the Caribbean Islands. seen large dengue epidemics. The dengue-3 epidemic was followed by an This has all occurred during an era in which outbreak of dengue-2 in Puerto Rico in 1969 laboratory and field research has produced a which subsequently involved all of the Carib wealth of new information on vectors, the vi bean Islands except Cuba, as well as Colombia ruses, the immunology on the pathogenesis of and Venezuela. This spread of dengue, and the disease, and on the quantitative epidemiology of fear that these events signaled a potential danger dengue. Excellence in research on dengue has so of even more dengue and the possibility of an far produced elegant explanations of why we are outbreak of dengue hemorrhagic fever or an Aedes losing the war. aegypti-borne epidemic, led to the establishment I have used two examples, malaria and dengue, by the Pan American Health Organization of a to illustrate the point that the many infectious Scientific Advisory Committee on Dengue. The diseases are very successful opponents. There are committee later became the Scientific Advisory many other examples where we are losing ground. Committee on Dengue, Yellow Fever and Aedes Other arthropod-borne virus diseases have also aegypti. This committee enabled PAHO and the been expanding their impact in recent years. Ross international community of scientists most in River virus, previously confined to Australia, terested in the problem to do a much better job joined the dengue viruses in producing epidemics of surveillance and epidemiologic studies. Thus, in the Pacific Islands. the next dengue epidemic in the Caribbean, which A few years ago, Rift Valley fever virus moved occurred following the introduction of an African out of its traditional endemic region and caused strain of dengue- 1 virus into Jamaica, was very an unprecedented epidemic in Egypt with a tre well studied and excellent epidemiologic and vi mendous impact on human life and also on the rologic data documented the spread of that virus livestock industry. to all the previously dengue-affected countries Japanese encephalitis is another disease which PRESIDENTIALADDRESS 321 is causing major problems in spite of impressive view, the moral obligation also resides within the research on the virus and on the epidemiology developed countries. At the present time, how and immunology of the disease. Development ever, I see in the United States a serious defi and use of killed virus vaccines have been as ciency of resources and lack of national com sociated with excellent control of the disease in mitment to the development of new products Japan and have probably had a significant effect and new methodology for control of diseases in in China. However, we are seeing major out the developing countries. The existing programs breaks of Japanese encephalitis in India and Ne of private foundations, the National Institutes of pal, and a very serious emerging pattern of an Health (NIH), the U.S. Agency for International nual outbreaks in northern Thailand. Current Development (USAID) and the Department of control technology is inadequate. A more effec Defense are commendable as far as they go, but tive and more inexpensive vaccine is very badly they are very limited in both dollars and, espe needed for Japanese encephalitis, and I am sure cially, in scientific manpower committed to de that one could be developed using either current velopment programs. technology or technical options which will soon A partial explanation lies in the fact that basic evolve from cloning of the Japanese encephalitis research is largely public funded and carried out virus genome. in academic and some government institutions. These events in which we appear to be con The development of drugs and vaccines and in sistent losers in the war on infectious diseases secticides has been heavily dependent on in have occurred in an era in which we have seen vestment by industry and to a large extent carried amazing advances in scientific research. This is out by industrial firms. The industrial sector has, an era in which molecular biology came of age, in the past, made the major investment of dollars and the terms genetic engineering, gene cloning, and human resources necessary to put new prod monoclonal antibiodies and synthetic peptides ucts into use. A notable exception has been the have become commonplace, and “biotechnolo drug and vaccine development done or under gy―has become a bureaucratic buzzword. One written by the U.S. Army where government might think from reading the scientific news re funds covered the early phases of development port and the popular press that solutions to many and subsidized the end-stage industrial devel of the world's major public health problems are opment. Here, the needs of the military were the near at hand. critical factor which caused government funding For myself and, I suspect, most members of of product development. this Society, the past decade has been an exciting The heavy reliance on industrial investment time to be involved in scientific research. Society for development of the products needed in the meetings have been important forum for presen tropical medicine field is, I believe, a thing of the tation and discussion of major advances in im past. I will not go into the reasons for the decline munology, molecular biology, pathogenesis and of vaccine development and manufacturing in epidemiology of tropical diseases. Every field has the United States but it is a well recognized prob been intellectually very exciting, and the mem lem, and leaves this country with a serious de bership of the Society can be justly proud of the ficiency in the ability to undertake development excellent research being done. of new products such as malaria vaccines, and Excellence in research, however, is not enough. new viral and bacterial vaccines, especially those Basic research, no matter how good, provides needed principally by the developing countries. only the information on which to base the es If we are to exploit the potential of our research, sential follow-on actions. The actions I refer to we cannot rely heavily on industry to make the are the steps needed to develop the useful prod investments. The profit motive is simply not suf ucts and practical methodology, and to get them ficient for many of the potential products needed into operational use in the field. In order to har in the tropical medicine field and disincentives, vest the immense potential benefits of the recent such as product liability, are great. A greater re and soon-to-come advances in basic research, a sponsibility for product development must be national and international effort in develop borne by the public sector through government mental research will be needed. The technology agencies and by foundations. required for the development of new vaccines, This poses an important problem because funds drugs, or other approaches to disease control lies for development efforts will, unfortunately, be in largely in the developed countries and, in my competition with funds for basic research. It is 322 PHILIP K. RUSSELL also true that undertaking major developmental and purification as well as on carriers, adjuvants, efforts increases rather than decreases the neces and vaccine formulation. This developmental sity for basic research, at least in the short term. work is of necessity largely empirical, and is very Those experienced in vaccine development re costly and time-consuming. alize that development efforts inevitably raise Just following through on the brilliant research new questions that need to be answered by basic on sporozoite immunity by Doctor Ruth Nus scientists. Thus, in any field a product devel sensweig and her collaborators at New York Uni opment effort must be in addition to, and not versity will be a formidable development task. replace, basic research in the same field. For re We should keep in mind that we need to do more search managers this is a restatement of the old than develop a reasonably effective vaccine which adage—there is no such thing as a free lunch. costs $25.00 a dose for use by travelers and the The recent advances we have all seen in basic U.S. military. The developing countries need very research have provided, or very soon will, the inexpensive and very effective long-lasting vac scientific basis on which to develop new disease cines. I am quite sure they can be developed, but control technologies. The creation of new sci it will require some major investments in both entific information which holds potential for de immunologic research and in development of velopment into practical disease control meth manufacturing technology. ods, I believe, carries with it an obligation to The sporozoite vaccine will be the first real follow through with developmental research and, challenge in the malaria field, but soon we will ultimately, the development of new control pro be faced with the problem of even more complex grams. blood-stage vaccines and transmission-blocking These advances in research are producing an vaccines. Vaccine developers will have to deal almost dismaying number of new options which with the several separate proteins associated with need to be pursued through the development protective immunity. These will have to be de process. Malaria is a prime example of this. Sev veloped into vaccines individually and in com eral antigenic proteins from various stages of the binations. I'm sure you can see the magnitude parasite which are related to protective immu of the problems if we are to do the work necessary nity are being ientified and characterized. Very to eventually produce the best vaccines possible sound theoretical concepts of vaccination of in for the developing countries. dividuals and populations have been developed Other fields face similar problems with mul which appear very promising and are currently tiple development options that need to be fully being tested. However, we are facing an immense explored. Research on the pathogenesis of bac developmental effort. Consider the fact that for terial diarrheas and on the genetics of the bac P. falciparum alone we foresee the possibility of terial pathogens has produced some very exciting three types of vaccines—anti-sporozoite, anti possibilities. Insertion of Shigella genes into the blood stage, and transmission-blocking vaccines. attenuated typhoid type 2lA vaccine strain to Each of these antimalarial vaccines may have an produce a typhoid-shigella vaccine is a very important future role in malaria control and all promising approach that can be extended to oth need developing. For each of these different vac er Shigella species. Similar approaches using ge cine concepts a developmental research effort will netically engineered Escherichia coli strains to have to evaluate and test several options. For carry Shigella antigens are also very promising. each malaria protein which has been shown to Add to that the potential of vaccination with play a role in protective immunity there will be pilus proteins, adherence factors, and toxin sub a need to deal experimentally with the issue of units of enteric bacteria one can readily see an using peptide synthesis to reproduce critical an overload of our existing capabilities to do the tigenic domains, or to use cloned genes and pro development work. duce fusion proteins as immunogens, or possibly I might mention here the very exciting recent use other approaches such as carrier organisms. studies by Moss and his colleagues at NIH in Development of a synthetic peptide vaccine will which they inserted hepatitis B genetic material require a large amount of work on configuration into vaccinia virus, producing an infectious virus of the peptides, on carrier proteins, on adjuvants, which immunizes against both. The whole con and on formulation of vaccines. Pursuing the cept of using carrier organisms, either viruses or development of malaria vaccines through gene bacteria, for immunizing adds another large new cloning will require extensive work on expression dimension to options for vaccine development. PRESIDENTIAL ADDRESS 323

Use of carrier organisms may ultimately prove to undertake development efforts in collabora to be an excellent method for producing inex tion with national and international agencies. pensive vaccines for the developing world. It is In the Army Medical Research and Devel certainly an area in which exploratory develop opment Command over the past several years ment efforts are well justified. we have come to a realization that options for The list of potential development options is a product development—whether drugs, vaccines, long one, and extends to most areas of our in or vector control measures—far exceed our cur terest. In the case of Rift Valley fever, genetic rent resources to exploit them. We are finding engineering appears to offer a very good oppor that we do not have the dollars or the scientific tunity for development of a second generation manpower to handle all the possibilities emerg vaccine that, if properly developed, can be man ing from basic research that need to be ex ufactured without the necessity of phase 4 bio plored—and do a thorough job. contaminant and may ultimately be inexpensive Current work on dengue vaccines, on menin enough to be of real value to the African nations. gococcal type B, gonorrhea, anti-parasitic drugs, The emerging new concepts on the basic reser and enteric bacterial vaccines, is extending our voir of Rift Valley fever in floodwater Aedes may developmental resources to the limit in both drug offer yet another important opportunity to con development and vaccine development. Some trol the virus at its source. Again, to exploit these very painful decisions and prioritizations have options will take resources and dedicated people to be made. In the civilian sector I see an even to do the development and carry out the work bigger problem. The investment in basic research in the field. is not balanced by an appropriate investment in The U.S. Army Medical Research and Devel development. Nor do the current programs of opment Command has long recognized the ne USAID and the funds in the World Health Or cessity to follow up basic research with product ganization's Tropical Disease Research Pro development efforts. The history of military gramme fill the need. As I said earlier, I do not medical research, with its long list of successfully believe private industrial investment will fill the developed vaccines from typhoid through Ven need and, unless there are some significant ezuelan equine encephalitis, adenovirus and changes in our national policies, new disease con meningoccal polysaccaride vaccines attests to the trol methods will not be forthcoming in the time fact that the Department of the Army expects a frame that is possible. return on its investments in research in terms of Let me digress for a few minutes to comment useful products and practical disease control on the current role of tropical medicine in regard methods. to international politics. I believe that this coun A good example of this view of research man try has a potential in tropical medicine that is agement is the antimalarial drug program, which not being effectively used. In the current Carib extends from very basic research to field trials. bean scene the U.S. has been using political, eco It is important to note here that the final indus nomic and military initiatives as instruments to trial development of drugs requires close collab achieve national policy objectives. I do not quar oration with private industry usually in the form rel with what has and is being done, but I per of collaborative development agreements which sonally feel that we have not utilized the poten recognize the needs of the government and the tial of medicine and public health as an effective needs of the industrial developer. tool to further our own national interest and to This type of collaboration with private indus improve the quality of life in the Caribbean try is also essential in vaccine development. countries which are in the news every day. This Industrial development must depend on the country has an immense potential to develop technical expertise which only experienced man better public health technology and capabilities, ufacturers can provide. Given the fact that, for and to get them into the field to do some real many of the drugs and vaccines that need to be good. Our most important adversary in the Ca developed, the private sector cannot or will not ribbean—Cuba—has a national policy to use take the initiative and the financial risks alone, medical research, training and public health to collaboration between government agencies and further Cuban political goals, and I believe they industrial developers becomes a necessity. are having an impact. The U.S. can and should I might add here that the many ethical man do much more in this field. Investing in an in ufacturing firms appear to be willing and anxious stitution with a defined mission of research, 324 PHILIP K. RUSSELL training, and developing public health technol tropical medicine research, development and ogy for the Americas south of Florida and Texas overseas initiatives. may well be an excellent long term investment, I'm sure that many Society members will par considering the political problems we are facing ticipate in the study, and if it is done well it can in the Americas. be very important in helping to achieve the ob Investing in public health initiatives for the jectives of the Society. We need to take that study underdeveloped countries based on exploitation very seriously, and see to it that it is compre and development of technologic options could hensive and takes on the difficult national issues. be a very wise long-range policy for the U.S. It will fail if it turns out to bejust another defense This Society has had and can have a significant of the status quo and current programs. It can role in effecting national policy. For many years, also fail if there is no follow-through. The sci unfortunately, a main role of the Society, both entific community will have to find ways to use through its Committee on Public Affairs and as its influence to obtain political support for our individuals, has been defensive and reactive. We collective views. The Society will have to work have been in the position of defending various hard if we want to see some real progress in this segments of the research community against area. budget and manpower cuts. At one time or In closing, I would like to summarize a few another we have collectively spoken out to de central points. fend the Army and Navy overseas laboratories, The research achievements of the recent past, the Gorgas laboratory, NIH overseas programs and the new information that is coming so rap and USAID programs, and we have been very idly, are producing exciting possibilities for new helpful in many instances. disease control measures which need to be de In the future, though, I think we have the op veloped and put into use in the field. This is a portunity to be proactive rather than reactive, major challenge to the U.S. scientific commu and do more than just defend the status quo. nity, the Society and to the several agencies and There are some favorable political signs of more institutions which must support the work. national interest, at least at the Congressional At the present time the manpower and dollar level, in the potential of tropical medicine. In the resources are inadequate to do the necessary de recent Office of Technology Assessment study of velopmental research to fully explore the options the Gorgas Memorial Laboratory (GML), a to produce the best and most inexpensive vac statement was made that it was ironic that the cines and drugs, and to put new disease control GML was in danger of extinction at a time when technologies into effective use. This issue must tropical medicine in Latin America has never be addressed jointly by the Society and the fund been more relevant to the U.S. Happily the fund ing agencies, and brought to the attention of na ing for GML funds has been restored. tional leadership. It will be all too easy to fail, Two years ago the Society appointed an ad hoc and to take 50 years to accomplish what may be Committee on the Future of Tropical Medicine, possible in a decade. headed by Doctor Robert Shope. This committee I believe that the members of this Society, col was charged to seek ways to focus the attention lectively and as individuals, will have an oppor of the political hierarchy on our national position tunity to develop the plans for a national effort on tropical medicine. This committee ap in tropical medicine that will exploit the oppor proached the Institute of Medicine of the Na tunities made available for research and to put tional Academy of Sciences and convinced the in the field some really effective new weapons in Institute to conduct a study on the U.S. Capacity the war on infectious diseases. of Addressing Tropical Disease Problems. This As a final answer to Dr. William Reeves' ques study will get underway soon, supported by sev tion, “Canthe war on infectious disease be lost?― eral government agencies and foundations. If the Not if we realize the potential of the results of study does as the Society intends, it can produce our research, and if we carry out our responsi a blueprint for an effective national policy in bilities to the developing world.