Current considerations in vaccination of humans against malaria: Malaria vaccine development

Bulletin of rne World Health Organization, 57 (Suppl 1): 273-^75 (1979) Malaria vaccine development ROBIN D. POWELL' Prospectsfor the development ofeffective malaria vaccines have greatly imnproved over the last 15 years. Forfurtherprogress to be achieved rapidly, the needfor clinical research centres, where exposure and re-exposure to infection can be carefully controlled, is paramount. At such centres, it ispossible to evaluate the safety and efficacy ofvaccine pre- parations, using different strains and species ofparasite, aild to undertake studies in bothl nonimmune andpartially immune volunteers. However, as efficacy under these conditions may not be a good indicator of efficacy under other conditions, the results ofsuch studies should be complemented by field trials in endemic areas. It seems probable that vaccines may show degrees ofpartial effectiveness in relation to different strains, species, intensities ofparasite inocula, and hosts. The development by Plasmodiumfaciparum of re- sistance to chloroquine and to other widely used syn- thetic antimalarial drugs contributed to a resurgence of interest in malaria in the early 1960s. That re- surgence included not only efforts to identify and develop new and better chemotherapeutic and chemo- prophylactic agents, but also a rekindling of basic research in malaria and of research aimned at otier means ofcombating the infection, including immuno- logical means. Earlier attempts to produce acquired imyrunity with suspensions of killed or inactivated parasites had yielded mainly negatve or inconclusive results (1). Most of that work concerned preparations that con- tained erythrocytic forms of the parasite. Some posi- tive results had been observed with avian malaria parasites and P. knowlesa, but studies in man with suspensions of formalinized red cell stromata con- taining vivax parasites had yielded no evidence of a decrease in susceptibility to subsequent mosquito- induced vivax infection. Early studies by Etienne and Edmond Sergent had suggested that partial protection against P. relicturn infection is achievsed in canaries after injection of homologous stored sporozoites, and research by Russell and colleagues had provided evi- dence of partial protection against mosquito-induced P. gailinaceum infection in fowl inoculated with in- activated P. gallnaceurm sporozoites. In the intervening decade and a half, research on basic immunological mechanisms in malaria has pro- ceeded apace, with intensive further e-;ploration of prospects fot the development of a useful malaria vaccine (2-5). Valuable and encouraging information has been forthcoming on a variety of frouts, including work on sporozoite and merozoite vaCcines, and some evideince has been obtained suggesting partial efficacy Professor of Medicine and Assoc:ace Dean for Academnic V- fairs, Department of Medicinc, Northwestern Un.r r:;it .Mled:cala School, Chicago, IL 60611, USA of a malaria vaccine in man. The purpose of this report is to provide not a broadly based review of what has becomne a large and complex area of research, but, rather, a highly selective itemization of points that may warrant consideration in further work aimed at malaria vaccine development. Sources of definitive initial data in man Studies with inmate volunteers at clinical malaria research centres in the USA have afforded ways of assessing the safety and potential efficacy of new anti- malaria agents under carefully controlled conditions with respect to administration of the agents, infec- tions with malaria parasites, follow-up observation, and provision of close medical care. The circum- stances wvere also such that complicating factors, such as possible partial inimunity of the host or uninten- tional reinfecuon, could be definitely excluded. The discontinuation in recent years of several clinical malaria research programmnes involving inmate volun- teers has added considerably to the difficulties that confront those who are trying to obtain early infor- mation about the efficacy and limitations of new anti- malaria agents. As is the case wirh research on anti- malaria drugs, studies on malaria vaccines that in- volve human subjects sho may be partially immune to malaria or who may live in areas where transmis- sion of malaria is occurring can provide very useful information, but the results may not be pertinent to nonimmune subjects and may not yield details of efficacy in relation to re-exposure and reinfection. Efforts to identify, develop, and sustain opportunities for clinical malaria research to obtain such knowledge merit strong emphasis. Such research is needed to es- tablish, for example, that vaccines thought tocontain only inactivated paratites do not, in fact, cause malar,a and to document the presence or absence of prote:five effects as gauged by carefully controlled 3900 - s1- R. D. POWELL conditions of exposure and re-exposure to infection with particular strains and species ofmalaria parasites. Avoidance of contaminants Painstaking production controls are required to avoid bacteiial, viral, or other microbial contami- nation of vaccine preparations and to minimize the risk of the presence of non-parasite-related substances that might evoke adverse reactions of an iminunologi- cal or toxic nature. Even DPT (diphtheria-pertussis- tetanus) vaccines are not free from potential prob- lems, as witness a recent report of a high frequency of local reactions and abscess formation with a parti- cular lot of DPT vaccine (6). E'ven when preclinical and early clinical data suggest good local and systemic tolerance of a particular vaccine preparation. some caution in interpretation may be in order until wider and longer-term studies can be completed. Note- worthy local or systemic adverse reactions may elude detection during early stages of evaluation of a drug or vaccine in man. Preparation consistency Standardized procedures are needed to provide vaccines that exhibit lot-to-lot consistency in com- position and in biologtcal activity and to monitor and document that consistency. Different conditions of pieparation, handling, storage, or administration of the material may lead to variation in vaccine conipo- sition or activity. The conditions that contribute to reproducible and stable composition and activity, possible decreases in activity during storagc or sub- sequent processing, and details of administration of a vaccine that may affect activity warrant careful assessment. Evaluation ofefficacy in man Species-related and strain-related specificities in the acquisition of immunity or premunity to malaria; factors pertinent to the stage in the life cycle of the parasite from which a vaccine is prepared; the route, tinmng, degree, and duration of exposure to antigenic material; thepossible use ofan adjuvant; and a variety ofhost-related factors that caninfluence susceptibility to malaria and to immunization form a complex group of variables that may render clinical evaluation of a malaria vaccine difficult, even when the situation relating to other possible complicating factors is favourable. Considerable effort may be required to gain just a small amount of useful data. Well con- trolled clinical studies that furnish insight into the efficacy of different vaccine preparations in relation to these variables are needed and present a formidablv challenge. Cliiical studies on malaria at centres where ex- posure and re-exposure to infection can be well con- trolled and field studies in endemic areas generally complement each other. Each setting has its own investigative and interpretational difficulties and limitations, and each may contribute knowledge the other cannot, Information from both settings is needed. In both settings, the primary questions relate to safety and efficacy. Detailed preclinical studies on tolerance and toxicity are essential as a basis for initial clinical evaluation of safety, and preclinical data pertinent to efficacy often furnish needed bases for the design and conduct of initial studies of efficacy in man. Without a firm foundation of prechnical infor- niation, initial clinical evaluation may be a shot in the dark and involve a risk of initial impressions or coIn- clusions that are not well based. One such risk is that on the basis of limited initial evaluative information, the potential value of a new drug or vaccine may be re- garded as slim and its development set back without sufficient exploration to justify a decision one way or the other. Studies with nonimmune volunteers at clinical malaria research centres offer prospects for obtaining detailed information about the protective effects of a particular vaccine preparation and the duration of protection in relation to exposure or re-exposure at specified times to inocula containing small or large concentrations of homologous or heterologous strains and species of malaria parasite. They offer opportunities for parallel detailed laboratory studies and for the correlation of clinical and laboratory ob- servations that may be difficult or imnpossible to obtain in other circumstances. The insight thus gained may be the key to initial understanding of the potential value and limitations of a particular pre- paration and may help guide further preclinical re- search and field studies. One limitation is that conditions at such centres differ from those in the field and efficacy in one set of conditions may not be a good indicator of efficacy in another. Factors relating to parasite inocula, dif- ferent strains, host partial imuniity, or other vari- ables may contribute to divergent results in different centres, just as the results of field studies in one area or set of circumstances may differ from those in another. In the same way that an antimalarial drug may prove useful for a certain purpose in a certain set- ting but not useful for other purposes in other settings, a malaria vaccine may prove of value in relation to certain purposes or circumstances but not to others. The main point in this regard is that evaluation of the clinical efficacy of different malaria vaccine prep- arations is not likely to be a simple and easily or quick.k. -esolved matter. If a particular preparation displays r;ome dcgree of effectiveness in initial clinical 27 MALARIA VACCINE DEVELOPMENT 275 studies, a lengthy period of further evaluation is apt to be required to examine adequately the value and limitations of the preparation in different settings or circumstances. If past experience relating to the development of antimalarial drugs and previous clinical observations relating to the acquisition of immunity or premunity to malaria (7, 8) are a guide, it seems probable that data on the efficacy of malaria vaccines in man may largely involve degrees of partial effectiveness. Sporo- zoite vaccines could prove to be an exception, but, in general, it appears likely that if effective, a vaccine may prove only partially effective in relation to different strains, different species, perhaps different intensities of parasite inocula, and different hosts. It is conceivable, for example, that a vaccine of narrow or limited value in nonimmune persons could be of considerably greater or broader value in partially immune persons, boosting protective mechanisms to a sufficient degree to lessen morbidity, blunt asexual parasitaemia, and/or, perhaps cut down gametocyte formation. In this way, such a vaccine, although only partially effective, could have considerable value in preventing morbidity and/or in lessening subsequent transmission by mosquitos. It may be wise to antici- pate the possibility that the results of evaluative studies in man will not involve all-or-nothing phenom- ena and that adequate assessment may require careful examination of partial efficacy considered from a variety of standpoints. Conclusions Encouraging advances in basic and preclinical re- search and recent setbacks in malaria control efforts in some parts of the world combine to justify solid further exploration of the prospects for development of effective malaria vaccines. The clinical elements of that exploration may be lengthy, complicated, and difficult. RPSUME M1SE AU POINT D'UN VACCIN ANTIPALUDIQUE Si les perspectives de mise au point de vaccins antipalu- diques efficaces se sont beaucoup am6lior6es depuis quinze ans, des progr&s nouveaux et rapides ne peuvent &tre attendus qu'avecle concours de centres de recherche cLrnique oil seront soigneusement contrOl6es 1'exposition et la rkemposition i l'infection. La collaboration de tels centres permettrait d'evaluer la s6curit6 et I'efficacite des pre- parations vaccinales i base d'especes et de souches diff&- ientes de parasites au moyen d'etudes sur des v-olontaires non immunises ou partiellement immunisEs. Cependant, 1'efficacit6 constatee dans de telles conditions peut netre pas. pleinement r6v6latrice de 1'efficacite dans d'autres condi- tions-en particulier celles pr6valant dans les zones d'endemie-et ces etudes devraient donc etre complWtees par des essais sur le terrain. Divers facteurs influent vraisembla- blement sur le degr6 d'efficacitk des vaccins, notamment I'espece, la souche et la virulence du parasite inocule et les caracteristiques de l'hOte. REFERENCES 1. POWELL, R. D. & BREWER, G. J American journal of tropicalnmedicine and hygiene, 13: 228-232 (1964). 2. NEVA, F. A. American journal of tropical nzedicine and hygiene, 26: 211-215 (1977). 3. ALLISoN, A. C. & CLARK, J. A. American journal of tropical medicine and hygiene, 26: 216-222 (l977). 4. COHEN, S. ET AL. Aminericanjournal oftropical medicine and hygiene, 26: 223-232 (1977). 5. HOUBA, V. American journal of rropical medicrne and hygiene, 26: 233-239 (1977). 6. CE1TER FOR DISEASE CONTROL. Mforbidity and mortality weekly report, 27: 331 (1978). 7. JEFFERY, G. M. Bulletin of the World Heafth Organiz- alion, 35: 873-882 (1966). 8. POWELL, R. D. ET AL Proceedings of the He/mmn- thological Society of Washington, 39 (Special issue): 51- 66 (1972).