Current Drug Targets - Immune, Endocrine & Metabolic Disorders - Volume 2, Issue 3, 2002

Many parasitic diseases are an important cause of mortality and morbidity in humans. The resurgence of malaria and trypanosomiasis in countries where these diseases have been effectively controlled and the global increase of several other parasitic diseases, such as cryptosporidiosis and trichinosis [1] are major health problems.The WHO Special Programme for Research and Training in Tropical Diseases (TDR) includes seven parasitic diseases (African trypanosomiasis, leishmaniasis, malaria, schistosomiasis, Chagas disease, lymphatic filariasis, onchocerciasis) and one vector-borne viral disease (dengue) among ten major infectious diseases in its current disease portfolio [2].In spite of the great importance of these pathogens and the considerable efforts made to develop vaccines against parasitic infections, at present there are no licensed vaccines or immunotherapies for these human diseases.This is in part due to the genetic and antigenic complexity of these organisms, and to their ability to evade the immune response, which is often not completely efficient in parasite elimination. However, in recent years much progress has been made in understanding the immune mechanisms controlling parasitic infections, thus establishing the scientific background required for the design of safe and efficient vaccines against human parasites. Moreover, sequencing of genomes of protozoan and metazoan parasites will facilitate the development of new drugs and vaccines [3]. This issue summarizes recent developments in immunoprophylaxis and immunotherapy of major human protozoan diseases (malaria, leishmaniasis, Chagas disease, toxoplasmosis and cryptosporidiosis) and helminthiasis (schistosomiasis, trichinellosis and hydatidosis).

Leishmaniasis, that affects millions of people worldwide, is an infectious disease caused by the protozoan parasite Leishmania. Incidence of the condition appears to be increasing in several parts of the world. Of the three main presentations of the disease, i.e. cutaneous, mucocutaneous and visceral, only the first one tends to heal spontaneously, while the other two are considered fatal if left to run their natural course. Recovery from leishmaniasis, whether spontaneous or drug-induced, is usually accompanied by solid immunity against reinfection, which provides a rationale for attempting to design vaccines against the disease. This review presents an outline of the main immunological features of Leishmania infections and of the mechanisms thought to operate in recovery from the disease. It describes various experimental approaches to vaccination in man and animal models, including the use of virulent and avirulent organisms, of dead parasites and extracts thereof, and of purified parasite proteins. Assays using novel technologies, such as the direct injection of DNAs encoding parasite proteins, or the inoculation of viral or bacterial vectors expressing such molecules, as well as recent experiments aimed at inducing an immune response against saliva of the insect vector, are also reviewed. Observations made during the course of these studies have reinforced the notion that vaccination against leishmaniasis is indeed feasible. However, in spite of intensive efforts by many groups and many reports of success in man and in animal models, a consensus is yet to emerge as to what constitutes the best approach to vaccination against leishmaniasis.

Human toxoplasmosis is usually benign, but may occasionally lead to severe or lethal damages when combined with immunosuppressive states or when transmitted to the fetus during pregnancy. Only a vaccine could prevent these harmful effects. The oral route is the natural portal of entry of T. gondii. A protective immune response at the mucosal level is required to kill the parasite as soon as it penetrates the intestinal barrier thus preventing toxoplasma from invading the host and settling into tissues. The probable major roles played by both CD8 T cells and antibodies, specially IgA, suggest that the best strategy would be to stimulate both the cellular and humoral arms of the mucosal immune system. Mucosal dendritic cells have been shown to induce good protection against oral toxoplasma challenge. Our hypothesis is that an acceptable and effective human vaccine would have to carry the optimized synthetic vaccine (subunit, DNA or replicon) plus an appropriate adjuvant and to target the mucosal dendritic cells by means of an inert delivery system such as polymer microparticles, which can be endocytosed by M cells of the gut or nasal associated lymphoid tissues.

The latest developments in the molecular and cellular mechanisms that underlie Echinococcus infection have renewed interest in the immunodiagnosis of this disease and have helped in understanding the host-parasite relationship. This review discusses current concepts on the immune response to Echinococcus granulosus in humans, and relates these findings to diagnosis and clinical management. The two most promising molecular tools developed for the immunodiagnosis of cystic echinococcosis involve isolating native or recombinant parasite antigens to detect specific serum antibodies in patients with suspected echinococcosis and producing monoclonal antibodies to detect parasite antigens in clinical samples. Novel drugs should be designed to strengthen host immune responses thus combating parasitic survival. Currently, attention has been focused on understanding T-helper lymphocyte activity, in particular the role of Th1 and Th2 subsets in orchestrating immune responses. The Th1 / Th2 model explaining how selective immune responses -- including cell-mediated or humoral immunity -- develop, seems promising as the rationale for molecular tools that could lead to new therapeutic strategies.

The protozoan parasite Trypanosoma cruzi, causative agent of Chagas' disease, is transmitted to man and other mammals by triatominae insects, or ‘kissing bugs’. Since its discovery in 1909, by Carlos Chagas, this parasite has been the object of several publications in the domains of immunology, cellular biology and of control gene organization, regulation and expression. Although much progress has been made concerning prophylaxis of Chagas' disease, particularly vector eradication, additional cases of infection and disease development still occur every day throughout the world. Whilst infection was largely limited in the past to vector transmission in endemic areas of Latin America, its impact has increased in terms of congenital and blood transmission, transplants and recrudescence following immunosuppressive states. Reports on new insect vectors adapted to the parasite and domestic animals infected in more developed countries, emphasize the continuing worldwide public health issue. Therapy against this parasite is limited and cure is subjected to several criteria, such as susceptibility of the parasite strain, age of the host and stage of the disease. The ability of Trypanosoma cruzi to induce important and various host immune system dysfunctions makes the development of effective vaccines a laborious and complex task. These considerations strengthen the latent significance of Chagas' disease and encourage the search for new preventive procedures and the research on rational vaccines.

The demonstration of the i) acquired protective immunity in adults living in endemic areas, ii) cure of malaria patients with passive transfer of specific immunoglobulins, and iii) protection conferred by vaccination with sporozoites attenuated by radiation, justifies the search for a malaria vaccine. Given the improbability that a vaccine directed against a single antigen will be completely protective, the preferred option is to combine several antigens of different stages of the parasite in a multi-component multi-stage vaccine which is likely to protect both the travellers and the populations living in endemic areas. Potential manufacturing technologies include recombinant proteins, synthetic peptides and DNA vaccines, the relevant genes encoding malaria antigens being inserted into a plasmid or a live vector such as vaccinia or poxvirus. A number of human trials using different antigens and technologies have been carried out in the last ten years. Three vaccines have undergone safety and efficacy testing in the field. SPf66, comprising a linear polymerised synthetic peptide with several distinct epitopes, has been extensively evaluated in different epidemiological settings. The efficacy overall was 23%, but was only 2% in African infants, the most susceptible group. The circumsporozoite recombinant protein fused with the antigen S of the hepatitis B virus and formulated in a potent adjuvant (RTS,S) led to a high, but short-term, level of protection against infection and disease in Gambian adults. The first pure asexual blood-stage vaccine comprising three antigens of the merozoite stage (MSP1 & 2 and RESA, Combination B) had an efficacy of 62% in reducing parasite density in Papua New Guinean children. A malaria vaccine that can reduce the burden of disease in the most affected populations is thus an achievable goal, and each trial provides additional knowledge about mechanisms of protection as well as about new vaccine technology.

The review describes different aspects of the host immune response to Trichinella, not only at the intestinal level on which most of the studies have focused until now, but also in the muscles which represent the final target of host invasion. The role of antibodies, T cells, mast cells, eosinophils and neutrophils, respectively, in immune reaction to this nematode is considered, in the light of the recent data derived from experimental models, both “in vivo” and more recently “in vitro” and when available, from clinical observations. A section is also devoted to the principal escape mechanisms from host immune responses, described in Trichinella, which are in part common to other parasites, in part peculiar. Two groups of mechanisms are described: antigen-dependent, such as anatomic seclusion, antigen stage-specificity, shedding and renewal and molecular mimicry, and those directly affecting the host immune response. Of the latter, some act at central level like immune suppression, polyclonal activation and eosinophilia induction, others interfere with effector functions as in the case of host leukocyte modification, immune complex accumulation, blocking antibody production or complement assembly blocking.The antigenic composition of the different stages is the subject of another section which has the aim to give an overview of the principal antigens described up to now, without giving too many biochemical details, but just illustrating the candidates for possible vaccines.Finally, the perspectives for vaccination are described.Most of the results described are derived from the experimental studies, but their implications in human infection are relevant.

After some 20 years experience it is generally agreed that chemotherapy against schistosomiasis, a parasitic disease which should be considered a consequence of a chronic infection, does have significant limitations. In particular, chemotherapy does not affect transmission of the infection or the high re-infection rates and so limits the success by demanding frequently re-scheduled mass treatments. For this reason, a complementary approach that can be integrated and could sustain chemotherapy-based control programs, i.e. vaccination, is very much needed. The rationale is that drug treatment would provide short-term reduction of worm burdens and vaccination, long-term protective immune response. Vaccination can either be targeted towards the prevention of infection or to the reduction of parasite fecundity. A reduction in worm numbers is the “gold standard” for anti-schistosome vaccine development but, as schistosome eggs are responsible for both pathology and transmission, a vaccine targeted on parasite fecundity and egg viability also appears to be entirely relevant. This review considers various aspects of anti-schistosome protective immunity that are important in the context of vaccine development. The current status in the development of vaccines against the African (Schistosoma mansoni and S. haematobium) and Asian (S. japonicum) schistosomes is then discussed as the new approaches that may improve on the efficacy of the available vaccines and aid in the identification of new targets for immune attack.

Protozoans of the genus Cryptosporidium are the etiological agents of opportunistic infections mainly of the gastrointestinal tract of animals and humans. Young and elderly persons, those with concomitant infections, with AIDS, under an immunosuppressive therapy, with congenital T-cell, B-cell or other effector cell deficiencies develop persistent progressive infections of different degree of severity related to the level of immunodepression. Both humoral and cellular immunity play a role in the control of this infection, but the latter plays the major role, mainly in the intestinal mucosa. However, a natural resistance to these coccidian parasites is also involved. IgG, IgM and IgA have been detected in serum and mucosa of humans and animals with the resolution of the infection, but also high levels of these immunoglobulins have been detected in persons with AIDS with chronic cryptosporidiosis. In HIV-positive persons, CD4+ T-cells are required to prevent the establishment of the infection and IFN-γ and CD4+ T-cells can also limit the duration and the clinical manifestations of the infection. In persons exposed to cryptosporidial infections, it has been possible to show the important role of IFN-γ in both the innate and acquired cell mediated immunity. The severity of cryptosporidiosis has been also associated with the inability to produce IFN-γ. An antibody therapy using bovine colostrum from cows hyperimmunised with Cryptosporidium oocysts or monoclonal antibodies against sporozoite antigens has been developed at the experimental level mainly for persons with AIDS or with other immunodeficiencies, however, these preparations of antibodies have shown only a limited degree of efficacy both in animals and humans.