A consistent feature of all parasite infestations is their ability to block or delay host defenses so that the parasites may survive for sufficient time to reproduce. Some parasites may simply delay their destruction until they complete a single life cycle. Other well-adapted parasites may contrive to survive for the life of their host, protected from immunological attack by highly evolved evasive mechanisms. A successful parasite will influence its host’s immune responses, selectively suppressing these to permit parasite survival, while at the same time allowing other responses to proceed, and thus minimizing the problems that result from nonspecific immunosuppression. Vaccination against parasitic diseases has therefore faced two hurdles. One is the complexity of the immune responses to these agents compounded by the fact that they, by definition, have successfully evolved to evade the immune system. Thus any antiparasite vaccine has to induce a protective immune response that is superior to the natural response. The second problem is economic. Many diverse drug treatments are available for parasite infestations, and newly developed vaccines are often much less effective. This is especially true of parasitic helminths. In addition, many parasites are only detected after an animal carcass has been processed. As a result, the farmer may have little incentive to spend money on parasite vaccines if there is no obvious economic return. A vaccine has been available to protect dogs and cats against the intestinal parasite Giardia duodenalis. The vaccine contained disrupted cultured Giardia trophozoite extracts administered subcutaneously. It protected experimentally challenged dogs and cats against infection and clinical disease. It has now been withdrawn from the market. Toxoplasma gondii causes a placentitis leading to abortions, mummified fetuses, and weak lambs in sheep and goats. It is spread by cats. Because a primary infection with T. gondii will confer strong immunity on an animal, protective immunization is a real possibility. A vaccine containing tissue culture grown live, T. gondii tachyzoites attenuated by over 3000 passages in mice, the S48 incomplete strain, has been used successfully to control toxoplasmosis in sheep. This strain has lost the ability to develop bradyzoites or to initiate the sexual stages of the life cycle in cats. It induces protection against a severe challenge for at least 18 months. This toxoplasma vaccine is available in some European countries and in New Zealand. It is made to order and is supplied as a concentrated suspension of tachyzoites plus diluent. It has a shelf life of only 7 to 10 days and must be handled very carefully to avoid human infection, especially by pregnant women. As with all such vaccines, it should be stored carefully, never frozen, or exposed to ultraviolet light. The vaccine is administered intramuscularly, but because it does not produce the cyst form (bradyzoites), vaccinated animals are not persistently infected. A single dose will provide lifetime immunity. It should be given at least four weeks before breeding. Neospora caninum is an important cause of bovine abortion. It is especially significant in the dairy industry. A killed tachyzoite vaccine was licensed in New Zealand in 2001. Its use resulted in a significant drop in the occurrence of abortions in some infected herds. It also appeared to protect against vertical transmission from cows to their calves. However, because of doubts regarding its efficacy, it did not gain widespread acceptance. This is an important neurologic disease caused by Sarcocystis neurona in horses. This organism’s sporozoites are shed in opossum feces and contaminate horse feed. Because treatment is of limited effectiveness, prevention is very important. A killed vaccine for intramuscular use in horses is available. Studies on experimentally challenged horses have, however, failed to show protection against neurologic disease. A disease caused by the protozoan parasites of the genus Leishmania transmitted by sandflies. It is endemic to the Mediterranean area, the Middle East, Central Asia, and Latin America. The most important cause is Leishmania infantum (also called Leishmania chagasi). Leishmania causes granulomatous lesions in both the internal organs and the skin of infected dogs. The disease is controlled by a combination of vector control and vaccination. Two different vaccines against canine leishmaniasis have been licensed in Brazil. Both are designed to stimulate T cell-mediated responses because this is an intracellular parasite. One such vaccine consists of a Leishmania component called the fucose-mannose ligand (or GP63) adjuvanted with Quil A (Leishmune, Zoetis) given in 3 doses at 3-week intervals. It induces an antibody response that blocks transmission of the organism to the sandfly vector by preventing the binding of the Leishmania to the sandfly midgut. This vaccine has been reported to have an 80% efficacy against disease and death. It may also serve as an immunotherapeutic agent, producing clinical improvement in dogs with disseminated disease. It has recently been withdrawn from the market. An alternative vaccine containing a recombinant protein (A2) from several different Leishmania species and a saponin adjuvant appears to be 43% effective against experimental challenge, and over 70% effective in field studies (Leish-Tec Hertape Calier, Brazil). Leish-Tec may also be of benefit in treating dogs with Leishmaniasis. Another vaccine is available in Europe (CaniLeish, Virbac, France). It contains L. infantum excreted/secreted proteins with a saponin adjuvant (QA-21). Its efficacy is about 68%. It is used in dogs over six months of age with three primary doses given three weeks apart, and repeated annually. Another L. infantum vaccine (Letifend, Leti SFU, France) contains a recombinant chimeric protein (protein Q). Four highly antigenic proteins from L. infantum were identified: LiP2A, Lip2B, Lip0, and a histone H2A. The genes for five antigenic determinants from these four antigens were fused and expressed in Escherichia coli to form the recombinant protein Q. It is given subcutaneously to dogs over six months of age. Only one priming dose is required followed by annual revaccination. The vaccine does not contain an adjuvant. Tritrichomonas is a protozoan disease clinically similar to Campylobacteriosis. It is caused by Tritrichomonas fetus. Convalescent cows are usually resistant to reinfection for about two years. Whole-cell killed Tritrichomonas vaccines only confer a relatively short period of immunity and are not highly effective. As a result, they should be administered to heifers and cows immediately before the breeding season. They are not effective in bulls. This vaccine may be used in combination with Campylobacter and Leptospira bacterins. Theileriae are intracellular parasitic protozoa. Tick transmitted Theileria parva is a major problem in cattle because it causes East Coast fever in subSaharan Africa. Theileria annulata occurs in southern Europe, Asia, and North Africa. Theileria orientalis is widespread globally but is usually subclinical. Although mainly prevented by tick control, vaccines are available against both pathogenic Theileria species. Theileria infections, because they are intracellular parasites, must be controlled by cytotoxic T cells and these can only be induced by live parasites. For T. annulata a vaccine is prepared from schizonts attenuated by culture in vitro. This vaccine has a short shelf life and it must therefore be frozen until immediately before use. Vaccination against Theileria parva is based on infection followed by treatment. Cattle are infected by subcutaneous injection of a mixture of three different strains of tick-derived sporozoites, “the Muguga cocktail,” and simultaneously treated with a long-acting tetracycline. As a result, the cattle get a mild infection followed by an immune response and recovery. Recovered animals develop a strong persistent immunity to homologous challenge. This is a tick-borne disease of cattle caused by the intracellular parasites Babesia bovis, Babesia bigemina, and Babesia divergens. It occurs globally, especially in tropical or subtropical countries. Animals that recover from acute babesiosis are resistant to further clinical disease. Subunit and killed vaccines have been uniformly unsuccessful. Available vaccines consist of live, attenuated strains of Babesia produced from the blood of infected donors, especially from splenectomized calves infected with attenuated strains, or by culture in vitro. The spleen is important in removing infected erythrocytes so splenectomy permits very high parasitemias, and thus high parasite yields. Rapid serial passage in splenectomized calves also selects parasite populations enriched for faster growing avirulent phenotypes. This selection also narrows the diversity of the parasite subpopulations, which may affect their immunogenicity. Babesia vaccines may be stored frozen or chilled depending upon facilities available. The risk of contamination by other infectious agents from the donors of these blood-derived vaccines is significant. They also may cause reactions in older animals. Many of these live vaccines contain specially selected strains of Babesia bovis and B. bigemina and are produced in government-regulated production facilities. In addition, cattle show a significant resistance to babesiosis in the first six months of life. It is therefore possible to infect young calves when they are still relatively insusceptible to disease, so that they become resistant to reinfection. As might be anticipated, the side effects of this type of infection may be severe, and chemotherapy may be required to control them. Protective immunity develops in three to four weeks and lasts at least four years (B. bovis) or less (B. bigemina) against local field challenges. The transfer of blood from one calf to another may also trigger the production of antibodies against the foreign red cells. These antibodies complicate any attempts at blood transfusion in later life and may provoke hemolytic disease of the newborn (Chapter 10). Two vaccines against canine babesiosis have been marketed in Europe (Pirodog and Novibac Piro). They contain soluble parasite antigens obtained from the supernatants of in vitro cultures of Babesia canis and Babesia rossi. The antigens are treated with formaldehyde and then freeze-dried. The lyophilized vaccine is adjuvanted with saponin. These vaccines do not prevent infection but reduce disease length and severity. The vaccines are given around five months of age and annual revaccination is recommended. Unlike other apicomplexan parasites, coccidia of the genus Eimeria induce strong, species-specific immunity. As a result, several live and recombinant coccidial vaccines are given to poultry. These are described in Chapter 19. Infection with gastrointestinal nematodes adversely impacts livestock productivity by affecting growth and fertility, in addition to meat, milk, and wool production. The financial costs of this worm burden affect almost all grazing animals. It is not surprising, considering the nature of the host response to parasitic worms and the availability of cheap and (until recently) effective broad-spectrum anthelmintics, that vaccines against helminth parasites are not widely available. Despite much ongoing high quality research and the identification of candidate vaccine antigens, parallel advances have not occurred in product development and clinical application. As a result, parasite prevention and treatment relies primarily on anthelmintic use. Nevertheless, the emergence of anthelmintic resistance and environmental concerns raised by excessive chemical use has resulted in a growing interest in the development of antihelminth vaccines. Vaccine use is predicated on the assumption that a host’s immune response can be manipulated to control or prevent an infestation. This is not always obvious in helminth infestations, and traditional vaccines may be of little use. Another issue that has impeded the development of vaccines against helminths is the tendency to develop immunoglobulin (Ig)E antibodies to helminth antigens. It has long been recognized that the biological function of IgE is to protect against helminth infestations. In many cases naturally parasitized animals make high levels of IgE. In such cases administration of irradiated larvae or helminth antigens may trigger severe allergic reactions such as anaphylaxis or generalized urticaria in previously exposed individuals. This problem was encountered when an irradiated L3 vaccine was developed for dogs against Ancyclostoma caninum, and humans against the hookworm Necator americanus. A recombinant Taenia ovis vaccine has been produced in New Zealand that can induce protective immunity to this tapeworm in sheep. This vaccine contains a cloned oncosphere antigen (To45W) with a saponin-based adjuvant. It stimulates a response that prevents parasite penetration of the intestinal wall. Although highly effective in reducing parasite numbers by 98%, and carcass condemnation by 89%, it has not yet been marketed successfully. Echinococcus granulosus is the causative agent of hydatidosis, an important cause of disease in sheep and humans in endemic areas. Sheep may be protected against E. granulosus using either oncospheres or secretory products from cultured oncospheres. Multiple antigens from E. granulosus were cloned into E. coli and then screened by the use of antibodies from immune sheep. An outer membrane protein called EG95 from activated oncospheres appeared to be highly effective as an immunogen. It was therefore cloned into E. coli and linked to glutathione-S-transferase (GST). (The GST assists in purifying the EG95). A commercially available vaccine (Providean Hitadil EG95 Tecnovax, Uruguay) containing recombinant EG95 adjuvanted with Montanide ISA70 and saponin has been licensed in several countries. It is administered intraperitoneally to sheep and goats and some camelid species and it is highly effective (96%–98%). The same vaccine also appears to be effective against alveolar echinococcosis caused by Echinococcus multilocularis. Taenia solium is a major cause of neurocysticercosis in underdeveloped countries. It may account for as many as 29% of seizure disorders in endemic areas. These cases are caused by the presence of the larval stages of the pork tapeworm, T. solium, in the brain or spinal cord. Ideally vaccination may be employed in conjunction with drug treatment and education to help break the transmission cycle of this tapeworm by preventing its establishment in pigs. Immunity is antibody mediated because antibodies and complement can lyse the early development stages of the parasite. An oncosphere surface antigen, TSOL18 is highly immunogenic in pigs, where it provides more than 90% protection against experimental infection. The antigen has been cloned into Pichia pastoris and adjuvanted with mineral oil. This vaccine has been licensed in India (Cysvax, Indian Immunologicals Ltd). The lungworm, Dictyocaulus viviparous, causes parasitic bronchitis in cattle. Worm infestations result in a temporary immunity. As a result, a radiation-attenuated larval-based vaccine has been commercially available in some European countries for many years (Bovilis Huskvac, MSD Animal Health). Unfortunately, it has all the disadvantages of live vaccines. In this vaccine, third-stage larvae hatched from ova in culture are exposed to 40,000 R X-irradiation. These larvae are then given orally to calves over eight weeks of age. Two doses of the vaccine are given at an interval of four weeks. The residual effects of long-acting anthelmintics will interfere with the efficacy of this vaccine, so calves should not be treated with these until at least 14 days after the second vaccine dose. The vaccine can also be administered to cows at pasture as long as it is given before exposure to a strong larval challenge. The irradiated L3 larvae penetrate the calf’s intestine, but because they are unable to develop to the fourth stage, they never reach the lung and are thus nonpathogenic. During their exsheathing process, the larvae stimulate the production of antibodies that can block reinfection. The efficiency of this vaccine depends very much on timing and on the size of the challenge dose, because even vaccinated calves may show mild pneumonic signs if placed on grossly infected pastures. The vaccine does not completely prevent establishment of small numbers of lungworms so pastures may remain contaminated. Likewise vaccine use is not justified in low-prevalence regions. A similar live irradiated L3 vaccine is available against Dictyocaulus filaria in India (Difil, Nuclear Research Laboratory, IVRI). Haemonchus contortus, the “barber’s pole” worm, a blood-sucking parasite of the abomasum, is one of the most significant helminth parasites of sheep and goats. It is a major cause of sheep mortality in wet and tropical climates because it draws large quantities of blood from the parasitized intestine. In addition, anthelmintic resistance in H. contortus is a serious and increasing problem. The major antigens produced by parasitic helminths are of two types: soluble excretory and secretory products, and antigens found on the parasite surface (somatic antigens). Some somatic antigens, such as those found in the worm gut cells, are not normally exposed to the host’s immune response, and may therefore be potential candidates for vaccines. A vaccine against H. contortus that makes use of antigens derived from the worm’s digestive tract is now commercially available for use in sheep in Australia and South Africa (Barbervax, Wormvax Australia Pty Ltd). This vaccine is not available in the United States. As the worm feeds, it ingests the sheep’s blood. Antibodies in the blood of vaccinated sheep are directed against antigens expressed on the worm’s intestinal enterocytes. These antibodies interfere with the worm’s digestion and growth leading to a greatly decreased egg output and a reduction in worm numbers by about 70% (Fig. 22.1). The worm vaccine antigens include two proteases: H11, an aminopeptidase expressed on the intestinal microvilli of adult worms; and H-gal-GP, a mixture of aspartyl, cysteine, and metalloproteases. Both antigens are highly protective in their native form but not if they are recombinant. This is likely caused by incorrect folding and/or inappropriate glycosylation. The vaccine is adjuvanted with saponin. This vaccine works in all classes of sheep, and worms have not evolved to cope with this challenge. However, because the antigens do not enter the sheep naturally, the protective response is not boosted by the presence of worms so repeated revaccination is necessary. These antigens can at present only be isolated from the worms extracted from infected slaughtered lambs. Three priming injections, three to four weeks apart are required to confer immunity before the high worm-risk season. Egg production increases during lactation; this vaccine can prevent this periparturient rise. Subsequently the vaccine is administered at six-week intervals to maintain resistance.
Vaccines against parasites
Protozoan vaccines
Giardiasis
Toxoplasmosis
Neosporosis
Equine protozoal myeloencephalitis
Leishmaniasis (leishmaniosis)
Tritrichomonas
Theileriosis
Babesiosis
Coccidiosis
Helminth vaccines
Taenia ovis
Echinococcus granulosus
Taenia solium
Lungworm vaccines
Haemonchus contortus
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