- Email: [email protected]
THE CHALLENGE OF MALARIA VACCINE: TRIALS AND TRIBULATIONS
371
collaboration in a new area, such as the molecular biology of
Malaria THE CHALLENGE OF MALARIA VACCINE: TRIALS AND TRIBULATIONS
L.-J. BRUCE-CHWATT Wellcome
Tropical Institute, 200 Euston Road, London NW1 2BQ "Our doubts are traitors, And make us lose the good we oft may
win, By fearing to attempt." Shakespeare: Measure for Measure. I.iv.77. 1985 and 1986 saw remarkable progress in the development, testing, and clinical trials of malaria vaccines. 1 -10 The need for a new approach to malaria control had become evident by the 1970s, from the gradual depletion of means of controlling, let alone of eradicating, malaria in endemic tropical areas.11,12 The growing menace of resistance of Anopheles vectors to most of the effective (and increasingly expensive) insecticides, the resistance of malaria parasites to many therapeutic compounds,13-16 and the remarkable advances in modem immunology stimulated the World Health Organisation and the USA Administration for
International
Development (USAID) to encourage the development of new methods of malaria control, at least against Plasmodium falciparum.17-19 Vaccination against malaria had been conceived some 75 years ago by Celli in Italy and by the Sergent brothers in Algeria, but their efforts were unequal to the task. In 1941, Mulligan and his colleagues in India found that killed sporozoites of avian plasmodia were highly immunogenic .20 In the USA Heidelberger and his colleagues attempted to vaccinate man against vivax malaria in 1946.21 In the late 1960s the feasibility of developing a vaccine was promoted in the USA, in the face of general scepticism.8 The initial studies on rodents and monkeys showed how difficult the enterprise would be but the new knowledge acquired was very valuable.18.22 In 1973 Clyde’s23 reasonable success at immunising three human volunteers, by using many millions of P vivax and fakiparum sporozoites obtained from experimentally infected Anopheles previously exposed to intensive X-ray irradiation (to attenuate the virulence of parasites), indicated that some form of active immunisation might be possible. Three years later came a major advance-the establishment, by Trager and Jensen ’24 of a continuous in-vitro culture of human P falciparum. This provided an unlimited source of specific parasite material for isolation and characterisation of antigens suitable for future vaccines.2S Moreover, it coincided with Kohler and Milstein’s26 development of the hybridoma technique, which enabled the preparation of monoclonal antibodies that recognise, with great sensitivity, specific antigens in the
plasmodial genome.27 From then
the progress was spectacular.s In his of the early scope of the progress Cohen22 masterly drew attention to the paradoxical finding that the immune response obtained by attenuated malaria vaccines is greater than that produced by natural infection, because living parasites often activate processes that favour their own survival. Other accounts of the progress dealt with wider scientific issues and with practical aspects of international on
account
host-parasite relationship. The three stages of malaria infection in mammals are: (a) sporozoite inoculation and invasion of exo-erythrocytic sites in internal organs; (b) exo-erythrocytic asexual multiplication; (c) erythrocytic asexual parasitaemia and formation of sexually differentiated gametocytes. These gametocytes start the infective process in the mosquito vector, which transmits the plasmodium to the new host. The first step in the development of a malaria vaccine is the identification of antigens that elicit a protective immune response against the main stages of development of the malaria parasite in man and in the mosquito vector .211-30 Subsequent steps comprise cloning of genes that code for the protective antigens, analysis of the nucleotide composition of the antigen, deduction of the aminoacid sequence of the encoded molecule, and then production of the relevant peptides by solid-phase synthesis. With recombinant DNA technology bacteria or yeasts can produce specific proteins suitable as candidates for malaria vaccines when combined with a carrier molecule and an
adjuvant. SPOROZOITE VACCINES
the immune system in present on the surface of the malaria parasite or on the surface of the infected red blood cell. Since the infection starts with the injection of sporozoites from the salivary
The
specific antigens exposed to
man are
glands of an infective Anopheles mosquito into man, special attention was given to this part of the infective process. The early studies were conducted on plasmodia of rodents and monkeys, but most of the later work aimed at the development of vaccine against human P falciparum. A more recent milestone has been the isolation in the early 1980s of circumsporozoite (CS) proteins on the outer surface of sporozoites in the salivary glands of infected Anopheles mosquitoes.3o On contact with specific antibodies these sporozoites shed the strictly CS-specific protein, which contributes considerably to their antigenicity. All CS proteins of malaria sporozoites have similar immunological properties. Their structure was clarified in 1983 by cloning CS genes, first of P knowlesi of monkeys and a year later of the human P falciparum.31 The CS protein for P falciparum has a large central domain of 412 aminoacids, which comprise nearly half of the polypeptide chain. The aminoacids do not differ widely in molecular weights and are composed of 37 tetrapeptides with the sequence NANP (asparagine-aspartic acid-asparagine-proline) interspersed with 4 tetrapeptides having a sequence NVAP (Asn-Val-Asp-Pro). The NANP repeat is found in all falciparum strains investigated so far; and the monoclonal antibody which binds it neutralises its infectivity. Mice and rabbits produce high antibody titres when immunised with a synthetic peptide containing the P falciparum repeat (NANP)3 coupled with tetanus toxoid as a carrier and adsorbed on aluminium hydroxide.32 Work done in 1985 confirmed not only the molecular structure of the CS protein but also its remarkable similarity in many isolates of P falciparum from different parts of the world. In the meantime field studies in endemic malarious areas showed that populations with a naturally acquired immunity have high antibody levels to sporozoite antigens.33 Moreover, a recombinant product of an expression of the CS protein of P falciparum in the bacterium Escherichia coli injected into experimental animals induced the formation of
372
specific antibodies that reacted with live P falciparum sporozoites and prevented their invasion of cultured human hepatoma cells .34,35 These findings justified the hope that a relevant CS vaccine may elicit a specific protective immune response in non-immune subjects.34
infection, whether naturally acquired or artificially induced, are far from adequate. The organisation, implementation, and appraisal of these field trials may thus be more difficult than the development of the vaccine.39 RESULTS OF PHASE I TRIALS
MEROZOITE VACCINES
Although the work on the sporozoite vaccine has undoubtedly proceeded further than that of other malaria vaccines, attention has also been given to the development of a vaccine against the asexual blood stages of malaria parasites of primates. Studies with rodents and monkeys showed that schizont/merozoite vaccines, prepared from proteins isolated from P falciparum infected erythrocytes, confer various degrees of protection.36 Antigens from erythrocytic forms of P falciparum parasites show great diversity in their composition but the list of potentially valuable vaccine candidates has now been substantially reduced; the most promising ones are those derived from the merozoite surface or from one of the organelles (rhoptry) of merozoites situated at the point of invasion of erythrocytes. There is some new and impressive evidence that a falciparum vaccine consisting of a merozoite-schizont membrane-associated antigen, a high molecular weight rhoptry antigen, and a potent adjuvant may produce a high degree of immunity in Aotus monkeys challenged with P falciparum. 37 TRANSMISSION-BLOCKING VACCINES
The third type of vaccine aims at prevention of fertilisation of female gametes of the parasite by male gametes or at interference with the growth of the oocyst in the mosquito gut, if the specific antibodies are ingested by the Anopheles. PURPOSE OF DIFFERENT VACCINES
Current work on the three basic types of vaccines is aimed the achievement of practical objectives. A sporozoite vaccine should prevent development of these forms into liver schizonts and subsequent blood invasion so that infection is not followed by clinical illness. The asexual erythrocytic (or merozoite) vaccine should stop or limit the multiplication of malaria parasites in the blood or internal organs and thus prevent or reduce clinical symptoms and the consequent mortality; it may also lower the amount of transmission. The third type of vaccine should block the transmission of malaria in a community. Perhaps all three vaccines could be combined for greater effect.
at
PLANS FOR CLINICAL AND FIELD TRIALS
reached
at
two
-
proliferation assay.
major international
Agreement meetings on the planning of clinical and field trials of prospective malaria vaccines6,9 that these trials should proceed sequentially through five main phases. The first phase was to be limited to the evaluation of all necessary physical, biochemical, and immunological characteristics of the products and processes used in laboratory animals. The development of a highly immunogenic vaccine that does not produce adverse effects is a primary objective. The next four phases were to involve human subjects and would range from small trials with volunteers to large trials under field was
The first results of phase I trials of the sporozoite vaccine presented at the conference convened in Washington by USAID last December.42 Workers from the Walter Reed Army Institute of Research, US Naval Medical Research Institute, and National Institutes of Health reported on their work with a vaccine based on a recombinant P falciparum CS protein expressed in E coli (labelled R32 tet32); in mice and rabbits this protein elicited an antibody against P falciparum CS protein and conferred protection on sporozoite challenge.42 The vaccine itself (designated FSV-1) consists of the recombined R32 tet32 product and aluminium hydroxide gel as adjuvant. 100 g or more were injected once a week for 5 weeks into 15 young male volunteers; tests for immunogenicity of the vaccine, as reflected in humoral and cell-mediated responses, were done during and after the course of vaccination. The immunogenic response evoked in man was weak, unlike that elicited in laboratory animals. Although 80% of vaccine recipients showed an immune response against P falciparum CS repeat antigens, the antibody titres were low, even after five consecutive booster injections. No serious side-effects were reported."" Regrettably, the lay press took a gloomy view of the outcome; the Dec 2, 1986, issue of the Washington Post, for instance, carried the headline Potential Malaria Vaccine Fails Test With Humans. Although the results were less satisfactory than expected, they certainly offer great promise, even though the eventual use of this type of vaccine as a practical method of immunisation still remains to be demonstrated. Another group of scientists, from the University of Maryland Center for Vaccine Development, described the early stages of their phase I clinical trials with a sporozoite vaccine prepared at the New York University. The product consists of a synthetic peptide that represents the repeating aminoacid subunit of the immunodominant portion of the CS protein, conjugated to tetanus toxoid, with aluminium hydroxide as adjuvant. The forty-five medical and dental student volunteers received a dose of 50-150 ug every 1-2 months. No serious adverse-effects have been noted. Sera and lymphocyte samples are being collected to test antibody response, for the test of inhibition of sporozoite invasion into a culture of hepatoma cells, and for the lymphocyte were
conditions.38°’ Solutions are likely to be found for the ethical, technical, and logistic problems of these trials. However, present methods of evaluating immune response to malaria
CONCLUSION
The development of a malaria vaccine is both a challenge and a necessity.44 Some progress has been achieved and a framework for its further development has been drawn up. However, it would be wrong to believe that malaria vaccines alone represent the ultimate solution to the problem of malaria control. Other methods of control should not be ignored, nor should socioeconomic conditions in the vast tropical areas where malaria is still endemic. REFERENCES 1. Malaria Action
Programme, World Health Organisation. World Malaria Situation. Wld Hlth Stat Quart 1985; 38: 193-231. 2. World Health Organisation, Expert Committee on Malaria. Seventeenth report Geneva: World Health Organization, 1979, (Tech Rep Ser 640).
373 3. World Health Organisation. Recent progress in the development of malaria vaccines; Memorandum from a WHO meeting. Bull WHO 1984; 62: 715-27. 4. Bell R, Torrigiani G, eds. Proceedings of a WHO Meeting (Geneva, 1983). New approaches to vaccine development. Basel: Schwabe, 1984. 5. Naval Medical Research Institute/US Administration for International Development/ World Health Organization. Immunology of malaria. Bull WHO 1979; 57 (suppl): 5-290. 6 United Nations Development Program (World Bank/WHO (1985)). Principles of malaria vaccine trials. TDR/IMMAL/Fieldmal/VAC/85.3. Cyclostyled report,
Geneva, 1985. Report to the Administrator US Agency for International Development. Malaria control in developing countries. Washington: US General Accounting Office (ID-82-27), 1982. 8. US Agency for International Development. Malaria: meeting the global challenge. Boston: Oelgeschlager, Gunn and Hain, 1985. 9. Siddiqui WA, ed. Proceedings of the Asia and Pacific Conference on Malaria (Honolulu April, 1985). Honolulu: University of Hawaii, 1986. 10. Ristic M, Ambroise-Thomas P, Kreier J, eds. Malaria and babesiosis; research findings and control measures. Dordrecht: Martinus Nijhoff, 1984. 11. World Health Organization. Malaria control and national health goals. Report of the Seventh Asian Malaria Conference. Geneva: World Health Organisation, 1982 (Tech Rep Ser 680). 12. World Health Organization Expert Committee on Malaria, Eighteenth report. Geneva: World Health Organisation, 1986. (Tech Rep Ser 735). 13. Wemsdorfer WH, ed. Drug-resistant malaria. Geneva: UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases, 1982. 14. Bruce-Chwatt L-J. Recent trends of chemotherapy and vaccination against malaria: new lamps for old. Br Med J 1985; 291: 1072-76. 15. Peters W, Richards WHE, eds. Anrimalarial drugs, vols I and II. Heidelberg:
Rehabilitation RECOVERY FROM PHYSICAL DISABILITY AFTER STROKE: NORMAL PATTERNS AS A BASIS FOR EVALUATION
7.
Springer, 1984. 16. World Health Organisation. Advances in malaria chemotherapy: report of a WHO scientific group. Geneva: World Health Organisation, 1984 (Tech Rep Ser 711). 17. Tropical Disease Research. Seventh Programme Report. Geneva: UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases, 1985. 18. Kreier J, ed. Malaria, vol II. Immunology and immunization. New York: Academic Press, 1980. 19. McGregor IA. Basic considerations concerning field trials of malaria vaccines in a human population. Bull WHO 1979; 57 (suppl 1): 268-75. 20. Mulligan HW, Russell PF, Mohan BN. Active immunisation of fowls against P falciparum by injections of killed sporozoie. J Mal Inst India 1941; 4: 25-34. 21. Heidelberger M, Mayer MM, Alving A. Studies in human malaria I-IV. J Immunol 1946; 52: 325-31; and 53: 101-20. 22. Cohen S. Progress in malaria vaccine development. Br Med Bull 1982; 38: 161-65. 23. Clyde DF, Most H, McCarthy V, Vanderberg JP. Immunization of man against sporozoite induced falciparum malaria. Am J Med Sci 1973; 266: 169-77. 24. Trager W, Jensen JB. Human malaria parasites in continuous culture. Science 1976; 193: 673-75. 25. Trager W. Cultivation of malaria parasites. Br Med Bull 1982, 38: 129-32. 26. Kohler G, Milstein C. Monoclonal antibodies. Nature (Lond) 1975; 256: 495. 27. Newmark P. The many merits of monoclonals. Nature (Lond) 1985; 316: 387. 28. Godson GN. Molecular approaches to malaria vaccines. Sci Am 1985; 251: 32-39. 29. Russell PK, Diggs CL. Planning for malaria vaccine development. In: Ristic M, Ambroise-Thomas P, Kreier J, eds. Malaria and Babesiosis. Dordrecht: Martinus Nijhoff, 1984. 30. Nussenzweig RS, Nussenzweig V. Development of malaria vaccine based on the structure of the circumsporozoite protein. In: Siddiqui W, ed. Proceedings of the Asia and Pacific Conference on Malaria. Honolulu: University of Hawaii, 1986. 31. Dame JB, Williams JL, McCutchan TF, et al. Structure of the gene endoding the immunodominant surface antigen on the sporozoite of the human malaria parasite P falciparum. Science 1984; 225: 593-609. 32. Zavala F, Tam JP, Hollingdale MR. Rationale for development of a synthetic vaccine against P falciparum malaria. Science 1985; 228: 1436-40. 33. Nardin EH, Nussenzweig RS, McGregor IA, et al. Antibodies to sporozoites: their occurrence in individuals living in areas of hyperendemic malaria. Science 1979; 206: 597-99. Young JF, Hockmeyer WT, Gross M, et al. Expression of P falciparum CS protein in E coli for potential use in human malaria vaccine. Science 1985; 228: 958-62. 35. Hollingdale MR, Nardin EH, Tharavanij S, et al. Inhibition of entry of P falciparum and P vivax sporozoites into cultured cells J Immunol 1984; 132: 909-13. 36. Perrin L, Perez A. Immunization with asexual blood stages of Pfalciparum. In: Bell R, Torrigiani G, eds. New approaches to vaccine development. Basel: Schwabe, 1984. 37. Siddiqui WA, Tam LQ, Kan S-C, et al. Induction of protective immunity to monoclonal antibody defined P falciparum antigens in Aotus monkeys. Infect
34.
Immun 1986; 52: 314-18. 38.
McGregor IA. Clinical trials of new malaria vaccines.
Parasitol Today 1985; 1: 1-13. 39. Bruce-Chwatt LJ. Malana vaccine trials: a guided step into the unknown. Ann Soc Belge Méd Trop 1986; 66: 5-13. 40. Perlman P. Immunogenicity assays for clinical trials of malaria vaccines. Parasitol Today 1986; 2: 127-30. 41. UNDP/World Bank/WHO Special Programme. Guidelines for the epidemiological evaluation of P falciparum sporozoite vaccines. Geneva, 1986, TDR/MAP/SVE/ PF 86.5 (Cyclostyled). 42. Hoffman SL, Wistar R, Ripley-Ballou W, et al. Immunity to malaria and naturally acquired antibodies to the circumsporozoite protein of P falciparum. N Engl J Med
1986; 315: 601-06. 43. American Institute of Biological Sciences/US Agency for International Development. Conference on Malaria in Africa: Practical considerations of malaria vaccines and clinical trials. Washington: American Institute of Biological Sciences (m press). 44. Nussenzweig V, Nussenzweig RS. Development ofa sporozoite malana vaccine. Am J Trop Med Hyg 1986; 35: 678 - 88.
C.
J. PARTRIDGE
M. JOHNSTON
S. EDWARDS
Department of Physiology, King’s College, London WC2R 2LS; and Departments of Psychology and Physiotherapy, Royal Free Hospital, London NW3 2QG In 368 patients with residual hemiplegia after stroke, monitoring of recovery over eight weeks showed a distinct time-related pattern. Patterns of this sort could provide useful baselines in various conditions entailing physical disability, allowing comparison of individual scores with the average for that phase of the illness, the setting of precise goals, and the examination of factors that influence recovery.
Summary
INTRODUCTION
HEALTH workers devote much time
to
the 10% of the
population1 who are physically disabled by arthritic, neurological, traumatic, and other conditions, yet little is known about the extent outcome. to
to
which their efforts influence
Objective monitoring of recovery could enable us
provide
more
effective
help
and
to
avoid
waste
of
resources, and Hiorns and Newcombe2 have proposed a model based on patterns of recovery in a substantial number
of patients. We report here a study of patterns observed after stroke. The term disability is used here as in the International Classification of Impairment, Disability, and Handicap3 which deals with the consequences of disease. Impairment is concerned with disturbances at the level of organs and systems, rather than the disease process; disability reflects these disturbances at the level of the individual person in terms of performance; and handicap describes the disadvantages experienced by the individual as a result of impairment or disability. Performance may be described in terms of movements or at the more complex level of functions4 such as ability to stand, walk, or dress. Although functions are more important we chose here to look at movements because they are less influenced by external variables (eg, floor surface or what the patient is sitting on). Use of recovery patterns is analogous to developmental assessment in children: milestones in, for example, height, weight, motor control, and language are related to patterns observed in large numbers of children. The recovery patterns will, of necessity, incorporate any changes due to treatment: the true natural history of recovery from physical disability could be examined only by withholding treatment, which would raise ethical difficulties. METHODS
Clinical Indices Ten senior clinical physiotherapists met on five occasions to define milestones in the recovery of performance of movements central to disability after stroke. Each movement or activity had to be easily recognisable and capable of being clearly described, reliably assessed, and scored as "does perform" or "does not perform" (with graded scoring, inter-rater agreement tends to be lows). The twenty items eventually agreed included both gross body
collaboration in a new area, such as the molecular biology of
Malaria THE CHALLENGE OF MALARIA VACCINE: TRIALS AND TRIBULATIONS
L.-J. BRUCE-CHWATT Wellcome
Tropical Institute, 200 Euston Road, London NW1 2BQ "Our doubts are traitors, And make us lose the good we oft may
win, By fearing to attempt." Shakespeare: Measure for Measure. I.iv.77. 1985 and 1986 saw remarkable progress in the development, testing, and clinical trials of malaria vaccines. 1 -10 The need for a new approach to malaria control had become evident by the 1970s, from the gradual depletion of means of controlling, let alone of eradicating, malaria in endemic tropical areas.11,12 The growing menace of resistance of Anopheles vectors to most of the effective (and increasingly expensive) insecticides, the resistance of malaria parasites to many therapeutic compounds,13-16 and the remarkable advances in modem immunology stimulated the World Health Organisation and the USA Administration for
International
Development (USAID) to encourage the development of new methods of malaria control, at least against Plasmodium falciparum.17-19 Vaccination against malaria had been conceived some 75 years ago by Celli in Italy and by the Sergent brothers in Algeria, but their efforts were unequal to the task. In 1941, Mulligan and his colleagues in India found that killed sporozoites of avian plasmodia were highly immunogenic .20 In the USA Heidelberger and his colleagues attempted to vaccinate man against vivax malaria in 1946.21 In the late 1960s the feasibility of developing a vaccine was promoted in the USA, in the face of general scepticism.8 The initial studies on rodents and monkeys showed how difficult the enterprise would be but the new knowledge acquired was very valuable.18.22 In 1973 Clyde’s23 reasonable success at immunising three human volunteers, by using many millions of P vivax and fakiparum sporozoites obtained from experimentally infected Anopheles previously exposed to intensive X-ray irradiation (to attenuate the virulence of parasites), indicated that some form of active immunisation might be possible. Three years later came a major advance-the establishment, by Trager and Jensen ’24 of a continuous in-vitro culture of human P falciparum. This provided an unlimited source of specific parasite material for isolation and characterisation of antigens suitable for future vaccines.2S Moreover, it coincided with Kohler and Milstein’s26 development of the hybridoma technique, which enabled the preparation of monoclonal antibodies that recognise, with great sensitivity, specific antigens in the
plasmodial genome.27 From then
the progress was spectacular.s In his of the early scope of the progress Cohen22 masterly drew attention to the paradoxical finding that the immune response obtained by attenuated malaria vaccines is greater than that produced by natural infection, because living parasites often activate processes that favour their own survival. Other accounts of the progress dealt with wider scientific issues and with practical aspects of international on
account
host-parasite relationship. The three stages of malaria infection in mammals are: (a) sporozoite inoculation and invasion of exo-erythrocytic sites in internal organs; (b) exo-erythrocytic asexual multiplication; (c) erythrocytic asexual parasitaemia and formation of sexually differentiated gametocytes. These gametocytes start the infective process in the mosquito vector, which transmits the plasmodium to the new host. The first step in the development of a malaria vaccine is the identification of antigens that elicit a protective immune response against the main stages of development of the malaria parasite in man and in the mosquito vector .211-30 Subsequent steps comprise cloning of genes that code for the protective antigens, analysis of the nucleotide composition of the antigen, deduction of the aminoacid sequence of the encoded molecule, and then production of the relevant peptides by solid-phase synthesis. With recombinant DNA technology bacteria or yeasts can produce specific proteins suitable as candidates for malaria vaccines when combined with a carrier molecule and an
adjuvant. SPOROZOITE VACCINES
the immune system in present on the surface of the malaria parasite or on the surface of the infected red blood cell. Since the infection starts with the injection of sporozoites from the salivary
The
specific antigens exposed to
man are
glands of an infective Anopheles mosquito into man, special attention was given to this part of the infective process. The early studies were conducted on plasmodia of rodents and monkeys, but most of the later work aimed at the development of vaccine against human P falciparum. A more recent milestone has been the isolation in the early 1980s of circumsporozoite (CS) proteins on the outer surface of sporozoites in the salivary glands of infected Anopheles mosquitoes.3o On contact with specific antibodies these sporozoites shed the strictly CS-specific protein, which contributes considerably to their antigenicity. All CS proteins of malaria sporozoites have similar immunological properties. Their structure was clarified in 1983 by cloning CS genes, first of P knowlesi of monkeys and a year later of the human P falciparum.31 The CS protein for P falciparum has a large central domain of 412 aminoacids, which comprise nearly half of the polypeptide chain. The aminoacids do not differ widely in molecular weights and are composed of 37 tetrapeptides with the sequence NANP (asparagine-aspartic acid-asparagine-proline) interspersed with 4 tetrapeptides having a sequence NVAP (Asn-Val-Asp-Pro). The NANP repeat is found in all falciparum strains investigated so far; and the monoclonal antibody which binds it neutralises its infectivity. Mice and rabbits produce high antibody titres when immunised with a synthetic peptide containing the P falciparum repeat (NANP)3 coupled with tetanus toxoid as a carrier and adsorbed on aluminium hydroxide.32 Work done in 1985 confirmed not only the molecular structure of the CS protein but also its remarkable similarity in many isolates of P falciparum from different parts of the world. In the meantime field studies in endemic malarious areas showed that populations with a naturally acquired immunity have high antibody levels to sporozoite antigens.33 Moreover, a recombinant product of an expression of the CS protein of P falciparum in the bacterium Escherichia coli injected into experimental animals induced the formation of
372
specific antibodies that reacted with live P falciparum sporozoites and prevented their invasion of cultured human hepatoma cells .34,35 These findings justified the hope that a relevant CS vaccine may elicit a specific protective immune response in non-immune subjects.34
infection, whether naturally acquired or artificially induced, are far from adequate. The organisation, implementation, and appraisal of these field trials may thus be more difficult than the development of the vaccine.39 RESULTS OF PHASE I TRIALS
MEROZOITE VACCINES
Although the work on the sporozoite vaccine has undoubtedly proceeded further than that of other malaria vaccines, attention has also been given to the development of a vaccine against the asexual blood stages of malaria parasites of primates. Studies with rodents and monkeys showed that schizont/merozoite vaccines, prepared from proteins isolated from P falciparum infected erythrocytes, confer various degrees of protection.36 Antigens from erythrocytic forms of P falciparum parasites show great diversity in their composition but the list of potentially valuable vaccine candidates has now been substantially reduced; the most promising ones are those derived from the merozoite surface or from one of the organelles (rhoptry) of merozoites situated at the point of invasion of erythrocytes. There is some new and impressive evidence that a falciparum vaccine consisting of a merozoite-schizont membrane-associated antigen, a high molecular weight rhoptry antigen, and a potent adjuvant may produce a high degree of immunity in Aotus monkeys challenged with P falciparum. 37 TRANSMISSION-BLOCKING VACCINES
The third type of vaccine aims at prevention of fertilisation of female gametes of the parasite by male gametes or at interference with the growth of the oocyst in the mosquito gut, if the specific antibodies are ingested by the Anopheles. PURPOSE OF DIFFERENT VACCINES
Current work on the three basic types of vaccines is aimed the achievement of practical objectives. A sporozoite vaccine should prevent development of these forms into liver schizonts and subsequent blood invasion so that infection is not followed by clinical illness. The asexual erythrocytic (or merozoite) vaccine should stop or limit the multiplication of malaria parasites in the blood or internal organs and thus prevent or reduce clinical symptoms and the consequent mortality; it may also lower the amount of transmission. The third type of vaccine should block the transmission of malaria in a community. Perhaps all three vaccines could be combined for greater effect.
at
PLANS FOR CLINICAL AND FIELD TRIALS
reached
at
two
-
proliferation assay.
major international
Agreement meetings on the planning of clinical and field trials of prospective malaria vaccines6,9 that these trials should proceed sequentially through five main phases. The first phase was to be limited to the evaluation of all necessary physical, biochemical, and immunological characteristics of the products and processes used in laboratory animals. The development of a highly immunogenic vaccine that does not produce adverse effects is a primary objective. The next four phases were to involve human subjects and would range from small trials with volunteers to large trials under field was
The first results of phase I trials of the sporozoite vaccine presented at the conference convened in Washington by USAID last December.42 Workers from the Walter Reed Army Institute of Research, US Naval Medical Research Institute, and National Institutes of Health reported on their work with a vaccine based on a recombinant P falciparum CS protein expressed in E coli (labelled R32 tet32); in mice and rabbits this protein elicited an antibody against P falciparum CS protein and conferred protection on sporozoite challenge.42 The vaccine itself (designated FSV-1) consists of the recombined R32 tet32 product and aluminium hydroxide gel as adjuvant. 100 g or more were injected once a week for 5 weeks into 15 young male volunteers; tests for immunogenicity of the vaccine, as reflected in humoral and cell-mediated responses, were done during and after the course of vaccination. The immunogenic response evoked in man was weak, unlike that elicited in laboratory animals. Although 80% of vaccine recipients showed an immune response against P falciparum CS repeat antigens, the antibody titres were low, even after five consecutive booster injections. No serious side-effects were reported."" Regrettably, the lay press took a gloomy view of the outcome; the Dec 2, 1986, issue of the Washington Post, for instance, carried the headline Potential Malaria Vaccine Fails Test With Humans. Although the results were less satisfactory than expected, they certainly offer great promise, even though the eventual use of this type of vaccine as a practical method of immunisation still remains to be demonstrated. Another group of scientists, from the University of Maryland Center for Vaccine Development, described the early stages of their phase I clinical trials with a sporozoite vaccine prepared at the New York University. The product consists of a synthetic peptide that represents the repeating aminoacid subunit of the immunodominant portion of the CS protein, conjugated to tetanus toxoid, with aluminium hydroxide as adjuvant. The forty-five medical and dental student volunteers received a dose of 50-150 ug every 1-2 months. No serious adverse-effects have been noted. Sera and lymphocyte samples are being collected to test antibody response, for the test of inhibition of sporozoite invasion into a culture of hepatoma cells, and for the lymphocyte were
conditions.38°’ Solutions are likely to be found for the ethical, technical, and logistic problems of these trials. However, present methods of evaluating immune response to malaria
CONCLUSION
The development of a malaria vaccine is both a challenge and a necessity.44 Some progress has been achieved and a framework for its further development has been drawn up. However, it would be wrong to believe that malaria vaccines alone represent the ultimate solution to the problem of malaria control. Other methods of control should not be ignored, nor should socioeconomic conditions in the vast tropical areas where malaria is still endemic. REFERENCES 1. Malaria Action
Programme, World Health Organisation. World Malaria Situation. Wld Hlth Stat Quart 1985; 38: 193-231. 2. World Health Organisation, Expert Committee on Malaria. Seventeenth report Geneva: World Health Organization, 1979, (Tech Rep Ser 640).
373 3. World Health Organisation. Recent progress in the development of malaria vaccines; Memorandum from a WHO meeting. Bull WHO 1984; 62: 715-27. 4. Bell R, Torrigiani G, eds. Proceedings of a WHO Meeting (Geneva, 1983). New approaches to vaccine development. Basel: Schwabe, 1984. 5. Naval Medical Research Institute/US Administration for International Development/ World Health Organization. Immunology of malaria. Bull WHO 1979; 57 (suppl): 5-290. 6 United Nations Development Program (World Bank/WHO (1985)). Principles of malaria vaccine trials. TDR/IMMAL/Fieldmal/VAC/85.3. Cyclostyled report,
Geneva, 1985. Report to the Administrator US Agency for International Development. Malaria control in developing countries. Washington: US General Accounting Office (ID-82-27), 1982. 8. US Agency for International Development. Malaria: meeting the global challenge. Boston: Oelgeschlager, Gunn and Hain, 1985. 9. Siddiqui WA, ed. Proceedings of the Asia and Pacific Conference on Malaria (Honolulu April, 1985). Honolulu: University of Hawaii, 1986. 10. Ristic M, Ambroise-Thomas P, Kreier J, eds. Malaria and babesiosis; research findings and control measures. Dordrecht: Martinus Nijhoff, 1984. 11. World Health Organization. Malaria control and national health goals. Report of the Seventh Asian Malaria Conference. Geneva: World Health Organisation, 1982 (Tech Rep Ser 680). 12. World Health Organization Expert Committee on Malaria, Eighteenth report. Geneva: World Health Organisation, 1986. (Tech Rep Ser 735). 13. Wemsdorfer WH, ed. Drug-resistant malaria. Geneva: UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases, 1982. 14. Bruce-Chwatt L-J. Recent trends of chemotherapy and vaccination against malaria: new lamps for old. Br Med J 1985; 291: 1072-76. 15. Peters W, Richards WHE, eds. Anrimalarial drugs, vols I and II. Heidelberg:
Rehabilitation RECOVERY FROM PHYSICAL DISABILITY AFTER STROKE: NORMAL PATTERNS AS A BASIS FOR EVALUATION
7.
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C.
J. PARTRIDGE
M. JOHNSTON
S. EDWARDS
Department of Physiology, King’s College, London WC2R 2LS; and Departments of Psychology and Physiotherapy, Royal Free Hospital, London NW3 2QG In 368 patients with residual hemiplegia after stroke, monitoring of recovery over eight weeks showed a distinct time-related pattern. Patterns of this sort could provide useful baselines in various conditions entailing physical disability, allowing comparison of individual scores with the average for that phase of the illness, the setting of precise goals, and the examination of factors that influence recovery.
Summary
INTRODUCTION
HEALTH workers devote much time
to
the 10% of the
population1 who are physically disabled by arthritic, neurological, traumatic, and other conditions, yet little is known about the extent outcome. to
to
which their efforts influence
Objective monitoring of recovery could enable us
provide
more
effective
help
and
to
avoid
waste
of
resources, and Hiorns and Newcombe2 have proposed a model based on patterns of recovery in a substantial number
of patients. We report here a study of patterns observed after stroke. The term disability is used here as in the International Classification of Impairment, Disability, and Handicap3 which deals with the consequences of disease. Impairment is concerned with disturbances at the level of organs and systems, rather than the disease process; disability reflects these disturbances at the level of the individual person in terms of performance; and handicap describes the disadvantages experienced by the individual as a result of impairment or disability. Performance may be described in terms of movements or at the more complex level of functions4 such as ability to stand, walk, or dress. Although functions are more important we chose here to look at movements because they are less influenced by external variables (eg, floor surface or what the patient is sitting on). Use of recovery patterns is analogous to developmental assessment in children: milestones in, for example, height, weight, motor control, and language are related to patterns observed in large numbers of children. The recovery patterns will, of necessity, incorporate any changes due to treatment: the true natural history of recovery from physical disability could be examined only by withholding treatment, which would raise ethical difficulties. METHODS
Clinical Indices Ten senior clinical physiotherapists met on five occasions to define milestones in the recovery of performance of movements central to disability after stroke. Each movement or activity had to be easily recognisable and capable of being clearly described, reliably assessed, and scored as "does perform" or "does not perform" (with graded scoring, inter-rater agreement tends to be lows). The twenty items eventually agreed included both gross body