476

Journal of the Royal Society of Medicine Volume 71 July 1978

Kingdom (Diagnosis of Brain Death 1976) has been influenced by the fact that not all hospitals with intensive care units have an EEG machine, let alone the technical skill to establish beyond doubt the fact of electrocerebral silence. Thus, complacency within the Health Service has been condoned. Technical problems arise in excluding artefacts from the EEG, but in proposing the ice-water caloric test as a feasible alternative, no reference is made to the fatiguability and repeatability of the test. Few British physicians have received proper instruction in the performance of caloric testing. Allen (1977), commenting on the statement by the Conference of Royal Colleges and Faculties that electroencephalography is not necessary in the diagnosis of brain death but may be used as a confirmatory procedure, maintains that 'such a view is not compatible with prevailing practice in the United States'. Foremost among the reasons for this view is the fact that the EEG represents a safeguard in the early recognition of severe drug intoxication, in which cephalic reflexes may be temporarily abolished. E M R Critchley Consultant Neurologist Royal Infirmary, Preston

References Allen N (1977) Neurology 27, 805-806 Bickford R G (1976) Practitioner 217, 100-107 Diagnosis of Brain Death (1976) Lancet ii, 1069-1070 (1976) British Medical Journal ii, 1187-1188 Evens R G & Jost R G (1977) Seminars in Nuclear Medicine 7, 129-136 Fordham E W (1977) Seminars in Nuclear Medicine 7, 137-160 Green R L & Busse E W (1960) Southern Medical Journal 53, 1076-1080 Jeavons P M (1975) Update 10, 269-280 Jefferson S S & Keogh A J (1977) Quarterly Journal of Medicine 46, 389-400 Jewesbury E C 0 (1964) Lancet ii, 863 Klass D W & Bickford R G (1958) Neurology 8, 333-337 Matthews W B (1964) Lancet ii, 577-579 Pampiglione G (1964) Lancet ii, 815 Parsonage M J & Exley K A (1964) Lancet ii, 753 Prior P F, Maynard D E, Sheaff P C, Simpson B R, Strunin L, Weaver E J M & Scott D F (1971) British Medical Journal i, 736-738

Development of a malaria vaccine' Malaria remains the most lethal of the human parasitic diseases, widely distributed in tropical areas and having an estimated incidence of 150 million cases per annum. In tropical Africa alone the annual mortality is about one million, mainly among children, and approximately 15% of all clinical illness is attributed to malaria. Eradication measures based upon vector control and prophylactic therapy have proved inadequate in Africa, and have produced only transitory benefit in Asia where the current resurgence of malaria is a source of grave alarm. The mortality and morbidity directly attributable to malaria constitute major constraints on economic progress in many tropical and subtropical areas of the world (WHO 1974). Under these circumstances, the development of alternative methods of control, including vaccination, is of obvious interest and importance. The chronic course of infection in malaria has often been taken to indicate that development of an effective vaccine was unlikely. However, studies on specific acquired resistance have shown that the immune response is potentially lethal for the malaria parasite and that vaccination may induce greater protective immunity than drug-controlled infections (Cohen 1977). In addition, the recent achievement of continuous culture of the erythrocytic stage of a human malaria parasite (Trager & Jensen 1976) has made feasible the provision of antigen for vaccination. The elaboration of a human malaria vaccine has therefore become a realistic goal.

Malaria life cycle (Garnham 1966) Malaria infection is initiated through the bite of infected female anopheline mosquitoes, which inoculate motile sporozoites into the bloodstream. In mammalian hosts these quickly localize in hepatic parenchymal cells through mechanisms at present unknown. The exoerythrocytic (EE) forms become multinucleate and after a variable period (usually about ten days) infected liver cells rupture and each discharges approximately 20 000 EE merozoites, which attach to specific red cell receptors and invade erythrocytes. The repeated rupture of red cells and reinvasion by erythrocytic merozoites is associated with clinical manifestations of malaria. A proportion of the asexual blood parasites develop into male and female gametocytes which undergo sexual reproduction in the mosquito. ' Paper read to Section of Medicine, Experimental Medicine & Therapeutics, 22 November 1977

0 1 41-0768/78/0071-0478/$O 1.00/0 v 1978 The Royal Society of Medicine

Journal of the Royal Society of Medicine Volume 71 July 1978

Vaccination against malaria The exoerythrocytic and erythrocytic cycles of parasite development in the vertebrate host have distinct antigenic specificities. Different methods of experimental vaccination have therefore been developed against these separate stages of the Plasmodium. The exoerythrocytic stage has been controlled in rodent but not in simian malarias by inoculation of sporozoites attenuated by irradiation (Nussenzweig et al. 1978). Optimum protection lasting about three months is obtained in mice after intravenous administration of sporozoites without the use of adjuvants. Protective sporozoite antigens are unstable and readily inactivated by higher levels of irradiation, freezing and thawing, formol treatment or mechanical disruption. A proportion of human subjects, repeatedly inoculated with attenuated P. falciparum sporozoites through the bite of irradiated mosquitoes, were found to be resistant to challenge (Clyde 1975). Despite this demonstration, the practical implementation of human sporozoite vaccination confronts major difficulties. The clinical manifestations of mammalian malaria are associated with the erythrocytic cycle of development. Effective vaccination against exoerythrocytic stages must therefore result consistently in the elimination of all viable tissue parasites, since any which mature would induce blood infection in a host fully susceptible to this stage of the parasite. Other constraints in regard to sporozoite vaccination concern the requirement for intravenous inoculation, the present inability to store the vaccine and the problem of producing sporozoites on a scale suitable for mass vaccination. Since neither sporogonic nor exoerythrocytic development is cyclical in human malaria spp., there is at present little prospect for successful serial cultivation of these stages (Table 1).

The evaluation of different methods of vaccination against the erythrocytic stage of malaria is complicated by the fact that the experimental infections used, mainly in rodent and simian hosts, induce widely divergent patterns of clinical immunity (Cohen & Mitchell 1977). Blood parasites attenuated by irradiation have proved effective in rat malaria, but gave weaker protection against more virulent infections of mice, rhesus and douroucouli monkeys. A parasite strain, attenuated by alternate in vitro culture and passage, effectively protected against rodent malaria, but the stability of such strains will require critical evaluation. Parasitized erythrocytes, killed by formol treatment or freezing and thawing, have been effective in rat malaria and were partially successful in more virulent infections of mice and monkeys. The elaboration of techniques for isolating blood stage morozoites has enabled this extracellular form of the parasite to be used for experimental vaccination. As indicated in Table 1, this is currently the most promising form of vaccine for potential human use. In conjunction with Freund's complete adjuvant, (FCA) such vaccines have proved effective against lethal P. knowlesi malaria in the rhesus (Mitchell et al. 1975). In addition, merozoite vaccination has protected douroucouli monkeys against P. falciparum, the most virulent of the human malarias (Mitchell et al. 1977 Siddiqui 1977). The successful, continuous cultivation of erythrocytic forms of P. falciparum has provided a potential source of merozoite antigen for mass vaccination (Trager & Jensen 1976). An interesting feature of merozoite vaccines is that they require no inactivation, as merozoites become noninfective for red cells within an hour at room temperature (Table 1). Several problems remain with regard to the development of a blood-stage malaria vaccine

Table 1. Current status of malaria vaccines in mammalian hosts Vaccine preparation Characteristics of vaccine

Inactivation Route Adjuvant Production Yield Contaminating host antigen Storage Immunity - specificityo - duration

Sporozoite

Parasitized rbc

Merozoite

Irradiation

FormolO Intramuscular FCACulture Low*

None Intramuscular

Intravenous* None

Mosquitoes* Low* Low Unstable* EEO 3 months@

High* Stable E 1 year

* unfavourable features of vaccines * EE, exoerythrocytic forms; E, erythrocytic stages

477

FCA@ Culture High Low Stable E

1 year

478

Journal of the Royal Society of Medicine Volume 71 July 1978

suitable for human use. Apart from the conventional problem of excluding pathogens, there will be a particular risk of contamination with blood group substance ifthe present techniques are used for cultivation of malaria parasites. In this connection, vaccines prepared from extracellular merozoites are likely to prove more acceptable than those isolated from erythrocytes containing normal or attenuated parasites. A further problem concerns the requirement for the clinically unacceptable Freund's complete adjuvant in vaccines such as those which have proved effective against simian malaria (Table 1). The relevance of such experimental models to human populations is difficult to assess. Susceptibility to malaria is influenced by many factors including bloodgroup specificity, haemoglobin constitution and genetically-determined differences in patterns of immune responsiveness. There is convincing evidence in human populations that malaria selects for genes controlling not only haemoglobin synthesis and blood-group specificity, but also HLA specificity. The immune response of a given population to malaria vaccination is likely to be strongly influenced by such antecedent selection. The adjuvant requirements in exposed subjects may, therefore, be less stringent than in experimental malaria, which relates almost exclusively to infections in unnatural hosts. The ultimatq choice of adjuvant will be restricted to those acceptable for human use and will be guided by knowledge of the mechanisms of malarial immunity and the action of available adjuvants; understanding of both of these topics is at present incomplete. S Cohen Professor of Chemical Pathology Guy's Hospital Medical School London SEI 9RT References Clyde D F (1975) American Journal of Tropical Medicine and Hygiene 24, 397 Cohen S (1977) Transactions of the Royal Society of Tropical Medicine and Hygiene 71, 283 Cohen S & Mitchell G H (1977) Current Topics in Immunology and Microbiology. Springer, Heidelberg Garnham P C C (1966) Malaria parasites and other haemosporidia. Blackwell, Oxford Mitchell G H, Butcher G A & Cohen S (1975) Immunology 29, 397 Mitcbell G H, Richards W H G, Butcher G A & Cohen S (1977) Lancet i, 1335 Nussenzweig R S, Cochrane A & Lustig H (1978) In: Rodent Malarias. Ed. W Peters and R KillickKendrick. Academic Press, London (in press)

Siddiqui W A (1977) Science 197, 388 Trager W & Jensen J B (1976) Science 193, 673 World Health Organization (1974) Technical Report Series No. 537, Geneva

The pharmaceutical industry and medical education The Medico-Pharmaceutical Forum was founded in 1968 for the purpose of promoting discussion and also for the making of recommendations on the role of the pharmaceutical industry in continuing education. It brings together representatives of the British pharmaceutical industry, the Royal Colleges and other professional bodies including the Royal Society of Medicine. It is fitting that the first ten years of the Forum should be marked by a report on The Role of the Pharmaceutical Industry in Postgraduate Medical Education (available from the Medico-Pharmaceutical Forum, 1 Wimpole Street, London WIM 8AE, price £3.00). The report comes from a working party of the Forum under the chairmanship of Dr T J Thomson, of the Department of Materia Medica, University of Glasgow, and it will be of interest to those in the areas of undergraduate and continuing medical education as well as the postgraduate education phase. The results of a survey of 200 general practitioners are included. The report underlines the important educational contribution of the pharmaceutical industry and recommends whole-heartedly that the present limitations which restrict patronage of the Postgraduate Medical Centres by the pharmaceutical industry should be lifted. To this end it is proposed that the Forum should set up an Education Advisory Board, which should do something to allay any anxieties that postgraduate deans and clinical tutors might have in such a changed climate. It is also recommended that each pharmaceutical firm which is actively engaged in postgraduate medical education should nominate an individual whom clinical tutors and others can contact on educational matters. Whilst such recommendations may not be universally popular they will probably seem satisfactory to the majority of the profession. Victor Bloom Editor 0141-0768/78/0071-0478/$01 .00/0

© 1978 The Royal Society of Medicine

Development of a malaria vaccine.

476 Journal of the Royal Society of Medicine Volume 71 July 1978 Kingdom (Diagnosis of Brain Death 1976) has been influenced by the fact that not al...
468KB Sizes 0 Downloads 0 Views