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VACCINES FOR PARASITIC DISEASES

Gene I. Higashi
Department Epidemiology, of Universityof Michigan,Schoolof Public Health, Ann
Arbor, Michigan 48109

INTRODUCTION
Protozoal and helminthic parasitic diseases remain a significant cause of morbidity and mortality in less developedcountries (130). Althoughmany these agents are worldwide distribution, their greatest impact on the health in of people and domestic animals is found in developing countries. Mostof these infectious agents have been important human pathogens since antiquity, but few have beencontrolled as have many the bacterial and viral of agents. Advances the development efficacious chemotherapeuticagents, in of vector control through insecticides and sanitation, provision of clean water, and elimination of vector habitat have all contributed significantly to the progress that has beenmadewith control of parasitic diseases in many parts of the world. Nevertheless, technical problems such as drug resistance, drug toxicity, insecticide resistance, financial constraints, and operational difficulties have contributed to a reduction in the rate of progress towardeffective control of parasitic diseases. Vaccinedevelopment parasitic diseases has been slow to progress until for recently. The spectacular technical advancesin protein separation, hybridoma technology, monoclonal antibody production, and recombinant DNA technology are nowbeing applied to parasites for identification and production of molecularly defined vaccine candidates. Much the slow progress can be of attributed to the difficulties of both in vitro and in vivo cultivation of protozoa and helminths, difficulties that are nowbeing rapidly overcome. Availability of vaccines for the mostimportantparasitic diseases will in the future be of benefit not only by protecting people against those diseases but also by reducing the detrimental effects of continued, intensive chemical 483 0163-7525/88/0510-0483502.00

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applications in the environment control vectors. Theprevention of infection to and disease by vaccines and other public health measuresis generally more satisfying than the continued, repetitive, and intensive use of chemotherapeutic agents in the infected population. Although several candidate vaccines have been developed, none has yet met the stringent tests of evaluation in humans.The vaccine for malaria is nowundergoing humantrials. A few vaccines for protozoal and helminthic parasites of domestic animals have been in use for sometime (58, 78, 99). This review discusses the present status of vaccine development malarfor ia, schistosomiasis, filariasis, leishmaniasis, and trypanosomiasis.Thesefive diseases are the primary targets of the WorldHealth Organizations Special Programme Research and Training in Tropical Diseases. Also considered for are the potential and need for vaccines for other parasitic diseases. MALARIA Malaria today remains the most important parasitic disease in the world, causing approximately 1.5 million deaths per year. Although a number of chemotherapeutic agents and insecticides have been effective in the control of transmission, many regions of the world remain foci of high endemicity. The difficulties in control have been attributed to the rapidly emergingPlasmodium falciparum resistance to chloroquine and the widespread resistance to insecticides by the anopheline mosquito vectors. Combined with financial constraints and operational and administrative failings, malaria is increasing in Latin America, Africa, the Indian subcontinent, and Southeast Asia. Although four species of Plasmodium responsible for humanmalaria, P. are falciparum is the most important, as it is responsible for almost all of the mortality in malaria, is prevalent worldwide,and is the only species that has developed drug resistance. P. vivax is also widely prevalent and causes extensive morbidity. The remaining species, P. malariae and P. ovale, are of lesser importance, with muchless prevalence and variable morbidity. Vaccine Development

SPOROZOITE VACCINE existence of immunity to reinfection has long The been surmised from analysis of the epidemiological data of endemicregions. Moreover, the experimental demonstration of vaccination against a murine malaria species, P. berghei, by the use of either inoculated irradiated sporozoites or irradiated, infected (sporozoite-bearing) anopheline mosquitoesestablished that protective immunitycould be readily engendered (90-93). Continuedworkon this irradiated sporozoite as a vaccine led to initial human volunteer studies with P. falciparumand P. vivax (16, 17, 104, 105). At least 6-8 exposures to irradiated mosquitoes over a 3-10 monthspan were required

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for effective protection. The precise quantitation of the exposurein terms of the numberof irradiated sporozoites entering the host could not be determined. Theselimited studies clearly demonstratedthat vaccination against P. falciparumand P. vivax could be achieved with irradiated sporozoites. The studies also pointed out the difficulty that wouldoccur if this vaccine was to be utilized: obtaining a supply of viable sporozoites to prepare the live, radiation-attenuated vaccine. The advent of monoclonal antibody and recombinant DNA technology providedthe tools for specific identification of the sporozoite protein responsible for the engenderedimmunity for cloning in bacteria the Plasmodium and gene coding for the protein. Thesetools provide a virtually unlimited source of antibody reagents and the protein for complete analysis. These methodsand the advent of an easy, reproducible in vitro methodof cultivating P. falciparum (44, 124) permitted study of the P. falciparum immunogens. becameevident that the sporozoite protein responsible for It engendering immunitywas situated on the surface of the sporozoite and was the only protein at this site (32-34, 87). It has been designated as the protein for circumsporozoite,indicating its location whenidentified by antibodies. The gene coding for this P. falciparum polypeptide has been cloned and sequenced(21). The polypeptide is about Mr44,000 and, interestingly, contains a large block of 41 tandemrepeats of the tetrapeptide, asparaginealanine-asparagine-proline, or NANP. This knowledgeallowed the production of synthetic peptides containing various repeats of this tetrapeptide for subsequent vaccination and serological studies (88, 140). A polypeptide comprisedof three repeats of this tetrapeptide, (NANP)3, found to serve was as antigenic epitope measuring the CSantibody in malaria sera (140). The epitope (NANP)3 occurred in all isolates of P. falciparum from around the world (88, 89). Furthermore, DNA extracted from 23 P. falciparum isolates was found to hybridize specifically with a DNA probe corresponding to the NANP repeat region (133). These data indicated that this putative vaccine wouldbe effective in all regions with P. falciparurn transmission. Great effort is nowbeing made to develop this molecularly defined sporozoite-derived vaccine. When synthetic peptide (NANP)3 coupled to a carrier protein, the is immunizationproduces antibodies in experimental animals. These react with live sporozoites, producing a typical immune reaction, the circumsporozoite precipitation, and neutralizes .sporozoite infectivity in vitro (3, 139). This sporozoite-derived vaccine will probably be the first to be used for human trials. The vaccine is currently undergoingphase I and soon phase II clinical trials in human volunteers. However, further experimental workhas revealed another problem. The synthetic peptide and recombinant product when used as an immunogen with adjuvants will stimulate immune responses b only in strains of mice bearing the H-2 major histocompatibility complex

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haplotype (23, 138). All other strains of mice tested failed to produce significant titers of antibodies (23,138). Thebasis for this wasidentified to controlled by the immune response genes, specifically that the responsiveness is restricted to the I-Ab allele (23). But previously nonrespondermice, immunized with (NANP)3 coupled to a carrier protein and mixed with adjuvant, will readily produce antibodies (23). This indicates the need for helper T-lymphocyteepitopes to provide antibody-stimulating help to the B cells specific for the (NANP)3epitope (36). If this (NANP)3 munodominant epitope is to becomea vaccine for human use, suitable carrier proteins are needed such that the vaccinated individual will be able to boost the specific immune response to (NANP)3 during natural exposure to sporozo~ ites from P. falciparum-infected mosquitoes. Otherwise the specific antibody titers wouldbe too low to be protective. That repeated stimulation is necessary to effect a favorable anti-sporozite antibody titer is shownin seroepidemiologic studies. The anti-sporozoite (anti-NANP3) titers are very low or nonexistent in up to 60%of sera from 5-8-year-old children, whereas over 90% adult sera have significant anti-sporozoite antibodies (86, of 87). It has been suggested that the unresponsiveness in children in endemic regions maybe partly related to the immune response genes, similar to the murine antibody responses (24). Such data clearly indicate the need for research to identify a more immunogenic sporozoite-derived vaccine. This need was further demonstratedby a recent experimental study that found that the whole, radiation-attenuated sporozoite vaccine in mice was muchmore efficacious in engendering protection than the synthetic peptide-carrier or recombinant DNA-produced subunit vaccines (31). This study further demonstrated that the live vaccine and subunit vaccines producedequivalent antisporozoite antibody titers but that the former induced an effective cellular immuneresponse, which has been demonstrated to be of importance in protection in experimental murine malaria (117, 134). Theprospects for a sporozoite-derivedvaccine that will be available for use in endemicregions are good nevertheless. Such a vaccine will be able to prevent the establishment of a P. falciparummalarial infection by eliminating the initial exoerythrocyticphase of infection, and thus producesterile immunity. But this vaccine is clearly species- and stage-specific (85, 125). The vaccine will have no effect on individuals with patent infections or infections with other species of parasites. Several laboratories have endeavored to develop vaccines for the schizogonic (erythrocytic) phase and the gametocyte phase. MEROZOITE VACCINE addition to diversifying the vaccine strategies, a In merozoite vaccine might be of importance when sporozoite vaccine is not

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totally effective. Anysporozoites that escaped the defenses induced by the sporozoite vaccine wouldreadily lead to a patent infection. Additionally, someantigens from P. falciparum schizogonic stages share epitopes with the immunodominant sporozoite protein (20, 47). It is possible that a vaccine prepared from these cross-reactive proteins from the asexual stage could engender protection against both infective sporozoites and morozoites. Much recent research has been devoted to cloning P. falciparum genes that encode for the various surface membrane proteins and identifying those proteins that are immunodominant utilizing humansera from endemic by regions (14, 67, 114, 118). Several vaccine-candidate antigens have been identified (83, 102, 106, 109). Two polypeptides of approximatelyMr 75,000 and 100,000 have been separated from P. falciparum blood-stage proteins and used successfully to vaccinate squirrel monkeys against a homologous challenge (30). A secondcandidate is a Mr155,000 glycoprotein (98, 129) that thought to be released by the merozoitc whenthe erythrocyte is invaded (7). This protein is a ring-infected erythrocyte surface antigen (RESA).RESA has been used successfully to protect nonhuman primates against challenge P. falciparum infections (4, 19). Successfulvaccination in these experimentalstudies has required the use of complete or incomplete Freunds adjuvant or other adjuvants. These are too toxic for human and so great effort is being madeto utilize the various use water-soluble derivatives of muramyldipeptide (110, 111). Although the search for molecularly defined candidate vaccine antigens will no doubt be successful, such proteins will have to be used in combinationwith adjuvants to stimulate the immune response. Analternative strategy is to clone the gene that codesfor the vaccine protein in a carrier vaccine such as vaccinia virus (115) and perhaps in the newly developed live oral typhoid vaccine (29). GAMETOCYTE VACCINE Since each stage--sporozoite (exoerythrocytic), schizogonic (asexual, erythrocytic), and gametocytic--will stimulate immunity that is stage-specific, a potential gametocytic vaccine wouldhave importance in preventing transmission but wouldbe without effect on the other stages in humans.The initial demonstrationof this type of vaccine was made in avian, rodent, and simian malarias (12, 41, 76). Through the use monoclonal antibodies, passive immunity against P. falciparum could be conferred on experimental animals (43). Such antibodies wouldalso readily prevent mosquitoes from becominginfected if antibodies were mixed with infected blood in cultures used to membrane the vectors (63, 103). The feed antigens to which such monoclonalantibodies are directed appear to be Mr 45,000 and 48,000 (126). Current effort is directed at cloning the genes encodingfor these antigens for large-scale production and subsequentanalysis and vaccine testing (122).

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SCHISTOSOMIASIS Approximately200-250 millions of the worlds population are afflicted by schistosomiasis caused primarily by Schistosomamansoni, S. japonicum, and S. haematobium.In more restricted foci, S. intercalatum in Africa and S. mekongiin Southeast Asia are the remaining human species. This helminthic trematode parasite lives as an adult in the mesenteric venules and vesical plexus and discharges eggs containing larvae in the excreta. All species require a freshwater intermediate snail host in which the larvae (miracidia) from eggs will transform and multiply into thousands of infective larvae or cercariae, whichemergefrom the snail and penetrate human skin during water contact. Theparasites enter the skin and migrate via the circulation to develop in the liver; ultimately they migrate to the venousvasculature of the gut and bladder. The adult worms generally not the direct cause of morbidity. The are eggs laid by the femalesare trapped in the liver, intestines, and urinary tract; these are responsible for disease due to the cellular immune response (granuloma) directed at each egg. The cumulative effect of the granulomas is fibrosis, which leads to the clinical problems commonlyencountered. Morbidity is correlated with the tissue egg burden and thus with the adult worm burden (131, 132). If only a few worms present, the likelihood are the infected individuals suffering clinical disease is relatively slight. In control strategies, therefore, the reduction of transmission and of the adult worm burden will ultimately lead to a reduction in morbidity even without a significant impact on prevalence. The ideal vaccine would provide the vaccinee with solid (sterile) immunity,but in schistosomiasis we must consider the practical alternative of a vaccine that wouldprevent the establishment of large wormburdens. All current experimental approaches to vaccination result in significant protection but never sterile immunity (22). Radiation-Attenuated Vaccine

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In 1961, the first report appeared on the induction of immunityin mice by vaccination with 6Cobalt-irradiated S. mansonicercariae (1.28). Since that time, a plethora of studies have confirmedand extendedthese findings (6, 22, 52, 84, 101,123). There is general agreementthat high dose radiation, 20-50 Krad, keeps organisms from surviving to adulthood but allows the live, attenuated larvae to stimulate immunityin mice, rats, guinea pigs, rhesus monkeys, and baboons (51, 53, 97, 119, 120). While these studies have evaluated various efficacy parameters such as dose of irradiated cercariae (500 cercariae), numberof doses (3-5 doses), duration of immunity(over year in mice), and minimum effective time of immunization (1-2 weeks), little is known the vaccines safety. Many these studies indicate that of of none of the vaccine organisms grew to adulthood, but inoculating large

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numbersof animals with the vaccine disclosed that one mousein 50 harbored 1-3 stunted adult worms(G. I. Higashi, unpublished observations). The histopathologic response to the irradiated vaccine has been fully described (9). The organismsdo induce a strong immune inflammatoryresponse (9) resolves without significant residual lesions within six weeks(G. I. Higashi, .unpublished observations). Improvedsafety and efficacy through the combined use of 6Co-radiation and radiosensitizer chemicals is currently being evaluated (H. J. Gomberg and G. I. Higashi, unpublished observations). Since it appears that this radiation-attenuated vaccine could serve as an experimental modeland that any human vaccine for schistosomiasis should be molecularly defined (35), current research on improvingthe live vaccine has diminished. The vaccine clearly induces in murinehosts an array of antibodies directed at various antigens of the schistosomelarval surface (95, 113, 114). A recent study has demonstrated that such serum antibodies will passively transfer immunity naive murinehosts (74). Here also, the protection transferred to still partial. The additional role that cell-mediated immunityplays in this vaccine modelhas not been discounted, as macrophages activated by specifically sensitized T lymphocytes in response to schistosome antigens are helminthotoxic (61, 62). Veterinary application of the radiation-attenuated vaccine has beensuccessful. S. bovis and S. japonicum cattle producea disease similar to that in in humans.6Co-radiated S. bovis cercarial vaccine protects cattle in the Sudan from acquiring large worm burdens and improves the health of those vaccin ated (8, 56). Initial effort in protecting cattle in Chinawithan X-irradiated japonicum cercarial vaccine also appears effective (55). Large scale application has not been carried out. Molecularly Defined Vaccines Significant progress has been madein the identification of antigens derived primarily from the surface membrane (tegument)of the early larval stage, the schistosomulum (112). That this stage is important in induction of immunity is evident from all of the live radiation-attenuated vaccine studies and recent studies in whichkilled schistosomula, either in combinationwith an adjuvant like Bacille-Calmette-Guerin (BCG) (59) or alone (54), engendered protection. Indeed, most of the positive reports of protective monoclonal antibodies and/or active immunizationhave mostly comefrom analysis of the surface antigens of schistosomula (Table 1). Thus, an impressive number defined antigens that confer some degree of protection havebeen identified. It is not known whether any of these of similar molecular weights from different laboratories are identical. The Mr >200,000, 38,000, and 28,000 antigens maybe identical (27, 66). Indeed, monoclonal antibodies recognize the same

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epitopes on the glycoconjugates of Mr 200,000 and 38,000 (66) as well as other stages of the schistosome and on the intermediate snail host (28). those that have had their genes cloned, the Mr 28,000 has a sequence apparently devoid of carbohydrates and engenders 52%protection in hamsters and 67% protection in rats after vaccination with aluminum hydroxide adjuvant (2). This protein is found on the tegument of schistosomula and is also produced by adult wormRNAduring in vitro translation (1), although its precise function is not known. Another protein with Mr 97,000 whose gene has been cloned and sequenced has been identified as schistosome paramyosin; this indicates that it is an integral component of the worms musculature (70). The protein confers protection on murine hosts by intradermal immunization with BCG, which preferentially stimulates the cell-mediated immune system (60). Each of these defined antigens may engender partial protection varying from 30% to 85%. No study has yet appeared in which a combination of two or more defined antigens has been simultaneously used for vaccination. It is entirely possible that the effect maybe additive or even synergistic and lead to sterile immunity. Several candidate vaccines should be available for human phase I trials in the next few years to evaluate their safety and im-munostimulatory qualities.

FILARIASIS
Filariae, a group of helminthic parasites, are responsible for extensive and severe morbidity, such as blindness from Onchocerca volvulus (River Blind-

Table 1 Molecularly defined antigens of S. mansoni that are protective Molecular weight Mr >200,000 155,000 97,000 45,000 38,000 32,000 30,000 28,000 22,000-26,000 22,000 20,000 16,000 Sourceof antigen schistosomula adult worms schistosomula cercariae schistosomula schistosomula cercariae schistosomula schistosomula schistosomula schistosomula schistosomula Passivetransfer by monoclonal antibody + + + + + + + + + + + Immunizationengendered Gene protection cloned + + + + + ? + + + + ? ? + + + -

Refs. (40, 42, 67) (116) (70) (112) (27) (5) (45) (10) (10) (112) (112) (5)

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ness) and lymphatic obstruction (elephantiasis) from Wuchereriabancroft~, Brugia malayi, and B. timori. Over 200 million individuals are at risk of infection by these filarial worms.Although very little progress has been made toward vaccination against onchocerciasis due to the absence of a reliable animal modeland difficulty in laboratory maintenance O. volvulus, signifiof cant developments have been made for the lymphatic dwelling parasites, particularly B. malayi. Irradiated infective stage larvae of B. malayi and the related zoonotic B. pahangi have been shownto confer somedegree of resistance to challenge infections in monkeys (135), jirds (137), and cats (94). In jirds, protection 91%can be readily induced (137) by vaccination with 75 6Co-radiated (15 Krad) infective stage larvae. Reducingas muchas possible the establishment of adult wormsin the lymphatics is of crucial importance in this vaccine model, as these are the primary cause of pathology, since the microfilariae laid by the females circulate with minimalassociated morbidity. Of particular importance is that the vaccination does not incite lymphatic obstruction, although studies to date have not fully characterized this feature. A number of antigens derived from B. malayi recognized by antibodies from humans various stages of lymphatic filariasis have been identified and (64, 72, 73), although none has been evaluated with respect to its ability confer active immunizationin experimental hosts. Based on the success of passive transfer of immunity vaccinatedjird sera (46), it wouldappear that by antibodies are responsible for the engendered resistance, but the addedrole of cell mediated immunityhas not been thoroughly assessed. Cross-reactive antigens betweenlarval and microfilarial stages mayalso be protective, as B. malayi microfilariae were shownto induce immunityin jirds to a challenge infection (65). Clearly, muchmore needs to be done before any candidate molecularly defined vaccine can be proposed.

LEISHMANIASIS
A diverse array of species infects humans around the world, causing cutaneousleishmaniasis (Oriental Sore), visceral leishmaniasis (Kala- Azar), and muco-cutaneous leishmaniasis (Latin American leishmaniasis), with widely varying degrees of clinical morbidity and mortality. Traditional methodsof control have been hampered the lack of safe, efficacious drugs by and, most importantly, the extensive zoonosesthat almost all species display, particularly for Oriental Sore and Latin Americanleishmaniasis (13). The primary mammalian hosts are all species of rodents and other small mammals in which elimination of the parasite would be almost impossible. Fortunately, the most common form of cutaneous leishmaniasis due to Leishmania major and L. tropica is self-healing, and recovery results in

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long-lasting immunitymediated by the cellular immune system (48). Historically, it has been a common village practice to allow the purposefulinfection of a part of the body other than the head, neck, and arms to promote the establishment of the lesion, recovery, and then immunity,leaving a scar that wouldnot be cosmetically disfiguring. In recent years, the USSR Israel and haveutilized cultures of L. tropica or L. majorto provide a source of infective organisms (promastigotes) for controlled infections as prophylaxis (39). Althoughtens of thousands have been vaccinated effectively in the Asiatic USSR about 5000 in Israel with significantly reduced rates of subsequent and infections, untowardside effects of secondaryinfections, skin allergies, and even immunosuppression have been frequently noted (39). Further attempts employingattenuated strains of Leishmania for L. major in the USSR,L. braziliensis in South America, and L. donovani (visceral leishmaniasis) Kenya for vaccination have been uniformly unproductive. But recently, avirulent strains of L. major(75) and L. braziliensis (37) have been produced by exposure to the mutagen, N-methy-M-nitro-N-nitrosoguanidinein v~tro, with the latter species at reduced temperature. Theseattenuated strains induced protective immunityin naive mice, although the resistance was not absolute in all animals. Other L. major avirulent strains have been selected that readily induce protective immunity mice (82). Lethally irradiated (150 in Krad) L. major cultured promastigotes will confer strong immunityin mice after intravenous inoculation (49, 50, 71). The immunitycross-reacts with several other Leishmania species and appears to be due to the induction of the cellular immune system. A genus-specific vaccine could be possible if these studies are confirmedand extended. Nevertheless, these studies suggest that a molecularlydefined vaccine is within reach in the immediate future. Although a number of promising candidate antigens have been identified, none have been isolated and used actively to vaccinate susceptible mice. TRYPANOSOMIASIS Trypanosomiasisin Africa is caused by Trypanosoma brucei rhodesiense and T. b. gambiense,commonly called African sleeping sickness, and is transmitted to humans the bite of the tsetse fly. This disease has beenthe scourgeof by Africa and has decimated populations. Today it is muchmore limited in scope, although tens of thousands becomeinfected yearly with a very high mortality rate, as there are no safe and totally effective drugs. T. b. rhodesiense and related trypanosomeskill hundreds of thousands of domestic animals each year, providing a further burden to agricultural productivity. These protozoan parasites have adapted to their hosts by a strategy of varying their outer surface antigenic proteins in successive wavesof parasite populations (127). Each waveof parasitemia displays an antigen to the host

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different from antigens of previous parasite populations, such that the host immune system is continually evaded. This process is called antigenic variation and is genetically controlled. Over a hundreddifferent variant surface antigens have been identified for each strain (127). Vaccinationwouldbe very difficult unless the vaccinecontainedall of the variant antigens or at least the predominant ones. Although a number of early studies have attempted to immunizeagainst African trypanosomes, no vaccination strategy has been devised that wouldcircumventantigenic variation. In Latin America,trypanosomiasisis caused by T. cruzi, whichis transmitted to humansby the activities of hematophagous reduviid bugs. No fewer than 15 million people are afflicted in Latin America.Drugtherapy is almost nonexistent. Thedisease is responsible for chronic cardiac and gastrointestinal problemsthat are uniformly fatal. A numberof attempts at vaccination have been tried using whole organisms or various extracts of these protozoans; findings have been inconclusive (107). Even though vaccinated animals can be shown to have diminished parasitemias from challenge infections, very few studies have assessed whetherall parasites are eliminated from the host. The chronic phases of the disease are the central issue in American trypanosomiasisor ChagasDisease. A further complication is that there appear to be cross-reactive antigens betweenthe T. cruzi parasite and mammalian heart and neuronal antigens, the two primary sites of pathology (121, 136). Thus any attempt at vaccination mayresult in a form of autoimmunization,with resultant autodestruction of these tissues, a decidedly unfavorable outcome.Antigens must be sought that do not cross-react with humantissues and must be isolated free of any extraneous components.It is plausible that protective immune responses can be induced in humans the use of the correct antigens, as specific comby plement-dependent lytic antibodies have beenidentified in patients sera (69). The antigen(s) inducing these antibodies have not been identified. Greater attention is neededto characterize and isolate surface antigens. A vaccine is clearly needed,since other formsof control are of little practical value for this disease of the economically poor. OTHER PARASITIC DISEASES

The literature is replete with reports of studies attempting the active immunization of experimental animals against almost every parasite of human and veterinary importance (15, 57, 80, 81). Vaccinations have consisted whole organisms, disrupted, homogenized,and fractionated, or of drug- or radiation-attenuated larval stages. In most situations, the use of radiationattenuated organisms has led to significant protection, such as with Trichinella spiralis in rats (38), Dictyocaulusviviparus in cattle (96), and

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Ancylostoma caninumin dogs (77), to nameonly a few. The D. viviparus live vaccine is still in use, particularly in Englandand Europe. The A. caninum was withdrawnfrom the market for commercial reasons unrelated to its safety and high efficacy (77). Very little work has been done to identify the importantfunctional, protective antigens in these parasites for potential isolation and use in vaccination. The greatest advancehas comefrom study of T. spiralis larvae, whereinthe specific protective antigens have been identified and isolated (25, 26). Contemporary studies of other helminthic parasites are starting to elucidate the sites of immune attack as well as the immunogenic antigens (11, 79, 100). Among the other protozoan parasites of humans, most studies on immunization have been directed at Entamoeba histolytica amebiasis (108) and Toxoplasmagondii infections (68). Encouraging results are noted but much more research is needed to define a useful vaccine model and then to molecularly characterize the immunogens responsible for the resistance. CONCLUDING REMARKS

The introduction of monoclonal antibody and recombinant DNA methodologies has been primarily responsible for the burst of data on vaccine development in parasitic diseases. The extreme difficulty of in vitro and in vivo cultivation that retarded the identification and recovery of candidate vaccine antigens from the important humanand veterinary parasites has to a large extent been circumvented with these technological advances. The rapidity with which the malaria sporozoite vaccine has been developed suggests that human trials in endemicareas will be conductedin the next few years. If such a vaccine were to, if not eliminate falciparum malaria, but drastically reduce the morbidity and mortality currently seen, it wouldhave accomplished its goal. Despite the significant progress toward a malaria vaccine, concurrent research is needed to develop better adjuvants and novel strategies to improvethe immunogenic qualities of the molecularly defined (synthetic or recombinantprotein) vaccines. Analternative strategy that has not been fully investigated is to search for anti-idiotype antibodies that upon inoculation into a host wouldinduce the production of antibodies specific for the parasite epitope responsible for protection. Progress too has been madein the search for a defined antigen vaccine for schistosomiasis. Several antigens are clearly protective, but the lack of solid (sterile) immunity still provides a significant obstacle. Moststudies with all vaccine candidates find no more than 60-70%protection. Is this enough to prevent large wormburdens and thus prevent the development of chronic morbidity?Althoughit is generally accepted that morbidity is correlated with wormburdens, nothing is knownin humansabout the threshold level. Inno-

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vative epidemiological investigations are still needed to ascertain the worm burdens that trigger the onset of clinical morbidity. It is unfortunate that the live, attenuated vaccine is not developed enough for application. The technological advances described above will afford greater attention to the other important parasitic diseases of humans. The developing worlds inhabitants suffer extensively from a multitude of parasitic infections (polyparasitism), which in aggregate contribute to significant morbidity. A need exists for a more diversified armamentarium of parasitic vaccines. ACKNOWLEDGMENT The author thanks Anne Glas for expert tion of this manuscript. Literature Cited merozoites and ring-infected erythrocytes. J. Exp. Med. 162:774-79 8. Bushara, N. O., Hussein, M. F., Saad, A. M., Taylor, M. G., Dargie, J. D., et al. 1978. Immunization calves against of Schistosomabovis using irradiated cercariae or schistosomula of S. bovis. Parasitology 77:303-11 9. Byram, J. E., yon Lichtenberg, F., Lewis, F. A., Stirewalt, M. A. 1983. Pathology of a live attenuated antischistosome vaccine in mice. Am. J. Trop. Med. Hyg. 32:94-105 10. Capron, M., Capron, A. 1986. Rats, mice and men--Models for immune effector mechanismsagainst schistosomiasis. Parasitol. Today2:69-75 11. Carr, A., Pritchard, D. I. 1987. Antigen expression during development of the human hookworm, Necator americanus (Nematoda). Parasite Immunol. 9:21934 12. Carter, R., Chen, D. H. 1976. Malaria transmission blocked by immunization with gametes of the malaria parasite. Nature 263:57-58 13. Chang, K.-P., Bray, R. S., eds. 1985. Leishmaniasis. Amsterdam/NewYork/ Oxford: Elsevier. 490 pp. 14. Cheung, A., Shaw, A. R., Leban, J., Perrin, L. H. 1985. Cloningand expression in Escherichia coli of a surface antigen of Plasmodiumfalciparum merozoites. EMBO 4:1007-12 J. 15. Clegg, J. A., Smith, M. A. 1978. Prospects for the developmentof dead vaccines against helminths. Adv. Parasitol. 16:165-218 16. Clyde, D. F., McCarthy,V., Miller, R. M., Woodward, W. E. 1975. Immunization of man against falciparum secretarial assistance in the prepara-

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Annu. Rev. Public. Health. 1988.9:483-501. Downloaded from arjournals.annualreviews.org by Indian Council of Agricultural Research-Institutes on 03/14/07. For personal use only.