Induction of protective immunity against Schistosoma mansoni by a nonliving vaccine. II. Response of mouse strains with selective immune defects

The efficacy of a new vaccination procedure against Schistosoma mansoni, involving intradermal injection of nonliving antigen combined with the bacterial adjuvant Mycobacterium bovis strain bacillus Calmette Guérin, was tested in several strains of mice. Development of protection against subsequent infection was compared with in vivo skin test reactivity and in vitro humoral reactivity to soluble and surface-associated schistosome antigens. Significant levels of resistance and immune response were displayed by many inbred mouse strains, including C57BL/6J, C3H/HeN, and CBA/J, as well as outbred Swiss-Webster mice. However, no definite correlation was observed between the level of any particular immune response and the level of resistance to challenge S. mansoni infection. Development of protective immunity was also examined in mice with various immune defects, to determine whether these responses are relevant to resistance in this model. Animals with defective specific immediate hypersensitivity response due to deficiencies in IgE (SJL/J) or mast cell (W/Wv) production displayed strong resistance as a result of immunization. Likewise, mice bearing the lpsd (C3H/HeJ) or xid (CBA/N) mutations, affecting cellular or humoral response to certain thymus-independent antigens, developed significant levels of resistance after immunization. A/J mice, with defects in cellular recognition of bacterial endotoxin as well as deficiencies in natural killer cell activity and complement function, also showed significant protective immunity. Thus, these reactivities do not appear to be essential to the resistance against S. mansoni induced by the nonliving vaccine. Two nonresponder strains were identified, P and BALB/c. P mice were defective in specific delayed hypersensitivity response as well as resistance to infection. However, BALB/c mice showed no obvious immune deficiencies at the time of challenge. These results agreed with previous findings in mice immunized by exposure to radiation-attenuated cercariae with one exception; BALB/c mice were protected by vaccination with irradiated cercariae but not by the nonliving vaccine. Thus, further examination of immune response in mice identified in this study as high and low responder strains should allow characterization of critical immune resistance mechanisms induced by the nonliving vaccine, as well as immune mechanisms operating in common between these two models of resistance to S. mansoni.     

Studies with double cytokine-deficient mice reveal that highly polarized Th1- and Th2-type cytokine and antibody responses contribute equally to vaccine-induced immunity to Schistosoma mansoni.

A fundamental obstacle to vaccine development in schistosomiasis mansoni is a lack of understanding of what type of an immune response should be invoked. We have addressed this central issue by using the radiation-attenuated cercariae vaccine in mice genetically engineered to exhibit highly polarized type 1 (IL-10/IL-4-deficient) or type 2 (IL-10/IL-12-deficient) cytokine and Ab phenotypes. Our data show that while significant differences in immunity exist after a single vaccination with irradiated cercariae in double cytokine-deficient vs wild-type mice, these differences disappear after two vaccinations. The most important finding of these studies, however, was revealed in vaccinated IL-10-deficient mice. These mice developed a mixed and elevated type 1- and type 2-associated immune response and developed anti-schistosome immunity at levels equal to or better than those in wild-type mice. This immunity in IL-10-deficient mice correlated with higher parasite-specific Ab titers, greater proliferative capacity of lymphocytes, increased frequency of IFN-gamma- and IL-4-secreting cells, elevated perivascular/peribronchial inflammatory responses in the lung, and greater in vitro schistosomulacidal capacity of parasite Ag-elicited cells. These results suggest that optimal vaccine-induced immunity against schistosomes is linked not to the development of a highly polarized response, but, rather, to the induction of both type 1- and type 2-associated immune responses.     

Immunotherapy of hepatocellular carcinoma with a vaccine based on xenogeneic homologous alpha fetoprotein in mice

α-Fetoprotein (AFP) is a diagnostic marker for the presence of hepatocellular carcinoma, and a potential target for immunotherapy. Unfortunately, the immunity to AFP is presumably difficult to elicit because of immune tolerance acquired during the development of immune system. In the present study, we used AFP as a model antigen to explore the feasibility of the immunotherapy of AFP-positive liver cancer by the breaking of immune tolerance against AFP in a cross-reaction between the xenogeneic homologues and self molecules. Recombinant rat AFP was prepared as a vaccine, and mouse AFP was prepared as a control. Immunized with rat AFP was effective at protective and therapeutic antitumor immunity in hepatocellular carcinoma model in mice. Both humoral and cellular immune responses may be responsible for the antitumor activity against AFP-positive tumor cells, and no marked side effects were observed in the immunized mice. Thus, our study may provide an effective vaccine strategy for the treatment of AFP-positive hepatocellular carcinoma, and may be of importance to further exploration of the breaking of immune tolerance to self molecules.     

Overview: from the horse experimentation by Prof. Akira Fujinami to paramyosin

Professor Akira Fujinami demonstrated for the first time in the world that acquired immunity might be induced against macroparasites such as schistosomes. Since then, vaccination models have been developed using various species of animals, among which the attenuated vaccine model in the mouse has been utilized mostly to clarify immune effector mechanisms and define candidate vaccine molecules. However, further studies are necessary on immune responses to defined parasite molecules in humans, because some discrepancies in immune responses still exist between animals and humans, and apparently genetic influence should be taken into consideration in such studies on defined molecules. Despite of some limitations, vaccine trials in livestock against Schistosoma japonicum may provide useful information for development of vaccines against the other human infections caused by S. mansoni or S. haematobium. In this overview, studies carried out mainly by Japanese investigators towards vaccine development will be described.     

Induction of protective immunity against Schistosoma mansoni by a non living vaccine. I. Partial characterization of antigens recognized by antibodies from mice immunized with soluble schistosome extracts

A single intradermal injection of frozen and thawed schistosomula in conjunction with the bacterial adjuvant Mycobacterium bovis strain Bacille Calmette Guerin, Phipps substrain (BCG) induced significant levels of resistance to challenge Schistosoma mansoni infection in C57BL/6 mice. Immunization with the aqueous fraction remaining after 100,000 X G centrifugation of the larval lysate was also protective under these conditions, suggesting that some immunogenic determinants may not be membrane associated. Frozen-thawed cercariae and soluble components of adult worms also protected against challenge infection in these experiments. These observations indicate that soluble immunogens are present in both early and late developmental stages of the parasite, and therefore may be good candidate antigens for an immunochemically defined vaccine against schistosomiasis. Induction of humoral reactivity against soluble or membrane antigens was examined in mice protected against cercarial challenge by prior exposure to frozen-thawed larvae, soluble larval, or soluble adult antigens plus BCG. Animals that were immunized with frozen-thawed larvae produced low but significant levels of antibodies against larval surface antigens when examined by indirect immunofluorescence or by immunoprecipitation of surface-labeled schistosomula. Mice immunized with soluble antigens, however, showed negligible antibody reactivity against surface membrane antigens. Because mice immunized with soluble antigens were resistant to challenge infection, these results strongly suggest that anti-surface membrane reactivity is not required in the mechanism of protective immunity in this model. Sera from mice immunized with either total freeze-thaw larval lysate or soluble schistosome extracts all showed strong reactivity against soluble antigens, as detected by ELISA. Western blot analysis showed these antisera to react with a restricted number of high m.w. antigens that were present both in schistosomula and in adult worms. These antigens are therefore likely to play a major role in the development of resistance in this model as immunogens and/or as targets of protective immune response.     

A meningococcal factor H binding protein mutant that eliminates factor H binding enhances protective antibody responses to vaccination

Certain pathogens recruit host complement inhibitors such as factor H (fH) to evade the immune system. Microbial complement inhibitor-binding molecules can be promising vaccine targets by eliciting Abs that neutralize this microbial defense mechanism. One such Ag, meningococcal factor H-binding protein (fHbp), was used in clinical trials before the protein was discovered to bind fH. The potential effect of fH binding on vaccine immunogenicity had not been assessed in experimental animals because fHbp binds human fH specifically. In this study, we developed a human fH transgenic mouse model. Transgenic mice immunized with fHbp vaccine had 4- to 8-fold lower serum bactericidal Ab responses than those of control mice whose native fH did not bind the vaccine. In contrast, Ab responses were unimpaired in transgenic mice immunized with a control meningococcal group C polysaccharide-protein conjugate vaccine. In transgenic mice, immunization with an fH nonbinding mutant of fHbp elicited Abs with higher bactericidal activity than that of fHbp vaccination itself. Abs elicited by the mutant fHbp more effectively blocked fH binding to wild-type fHbp than Abs elicited by fHbp that bound fH. Thus, a mutant fHbp vaccine that does not bind fH but that retains immunogenicity is predicted to be superior in humans to an fHbp vaccine that binds human fH. In the case of mutant fHbp vaccination, the resultant Ab responses may be directed more at epitopes in or near the fH binding site, which result in greater complement-mediated serum bactericidal activity; these epitopes may be obscured when human fH is bound to the wild-type fHbp vaccine.     

The development of oral vaccines based on live attenuated Salmonella strains

Abstract Safe, live attenuated Salmonella strains can be produced by introducing defined non-reverting mutations into the chromosome. Such rationally attenuated strains have proved to be excellent oral vaccines in several animal species and can therefore be considered as candidate vaccines against invasive salmonellosis in both animals and man. A panel of attenuating lesions is now available from which it is possible to tailor the level of attenuation and hence produce strains with different immunogenic properties. Because of the spectrum of immune responses produced by such Salmonella vaccine strains they have been utilised extensively as vectors for delivering heterologous antigens to the mammalian immune system. We have focussed on the development of a single dose oral tetanus vaccine based on attenuated Salmonella strains expressing a non-toxic, immunogenic protein derived from tetanus toxin (fragment C). Several different expression systems have been used for fragment C and candidate vaccine strains have been constructed that are capable of protecting orally immunised mice against a lethal challenge with tetanus toxin. An oral tetanus vaccine may help to reduce the mortality rate from tetanus in the developing world by overcoming the problems associated with the implementation of vaccine programmes using the current parenteral vaccine.     

Plasmid DNA vaccine-elicited cellular immune responses limit in vivo vaccine antigen expression through Fas-mediated apoptosis

Particularly potent cellular or humoral immune responses are needed to confer protection in animal models against such pathogens as HIV/SIV, Mycobacterium tuberculosis, and malarial parasites. Persistent, high-level vaccine Ag expression may be required for eliciting such potent and durable immune responses. Although plasmid DNA immunogens are being explored as potential vaccines for protection against these pathogens, little is known about host factors that restrict long-term plasmid DNA vaccine Ag expression in vivo. We observed rapid damping of transgene expression from a plasmid DNA immunogen in wild-type, but not in T cell-deficient mice. This damping of Ag expression was temporally associated with the emergence of Ag-specific cellular immune responses. A requirement for Fas and the appearance of apoptotic nuclei at the site of vaccine inoculation suggest that T cells induce Fas-mediated apoptosis of plasmid DNA vaccine Ag-expressing cells. These studies demonstrate that high levels of in vivo Ag expression are associated with high-frequency cellular immune responses that in turn rapidly down-regulate vaccine Ag expression in vivo. These findings argue that it may not be possible to maintain persistent, high-level production of vaccine Ag in vivo to drive persistent immune responses as long as vaccine Ag production can be limited by host immune responses.     

Schistosoma mansoni: sex-specific modulation of parasite growth by host immune signals

Development of female schistosomes from infectious cercariae to mature egg-producing adults requires both male schistosomes and an intact adaptive immune system. By examining single sex infections in immunodeficient mice, we provide evidence that female schistosome development is not directly influenced by the adaptive immune system, whereas male development is. Our data are consistent with a sequential model of schistosome development, where the adaptive immune system signals development of mature males, which subsequently stimulate development of mature females. The male schistosome therefore appears to play a central role both in transducing signals from the adaptive immune system and in facilitating female development.     

A novel murine model of allogeneic vaccination against prostate cancer

Prostate cancer continues to be a major cause of death in men. Surgical and medical treatments of the disease have improved, but metastasic disease remains a significant clinical problem. Novel therapies such as whole cell vaccination offer the potential of treating disease by stimulating the immune system. To study the efficacy of a whole cell vaccine in prostate cancer two strains of mice were used: C57BL/6 (H-2Kb) and C3H/HeJ (H-2K^k) in combination with four different cell lines. Thus, a model was constructed of allogeneic and syngeneic vaccine, as well as a challenge tumour for each strain. Two novel cell lines were developed during this study. Firstly, the non tumourigeneic PMC-1 was derived from a normal mouse prostate and immortalized with HPV16. Secondly, the tumourigeneic PMC-1 C6ras1p1 was transformed with human ras gene which formed tumours in both SCID and C3H/HeJ mice. Protection, and the nature of the immune response to syngeneic and allogeneic vaccine, in males and females was examined in both strains. Vaccination with both syngeneic and allogeneic irradiated whole cell vaccines induced protection from syngeneic challenge in females. However, no protection was observed when allogeneic vaccine was given to male mice. This correlated with the immune response. Two types of cellular immune responses were generated in females. A NK-mediated response was observed in C57BL/6 mice, whilst C3H/HeJ mice developed a CTL response. Little or no cellular immune response was observed in males. The cytokine profile in C3H/HeJ females was a mixture of Th1 and Th2 whilst a mainly Th1 profile was observed in C57BL/6 mice. Male mice showed a diminished cytokine secretion compared to females which was further depressed after challenge. The difference in immunity was largely as expected, since tolerance to prostate antigens should not normally develop in female mice. However, this makes this model particularly relevant clinically since it directly mimics the human situation and thus may accelerate the development of whole cell vaccines for clinical use.     

A Safe Vaccine (DV-STM-07) against Salmonella Infection Prevents Abortion and Confers Protective Immunity to the Pregnant and New Born Mice

Pregnancy is a transient immuno-compromised condition which has evolved to avoid the immune rejection of the fetus by the maternal immune system. The altered immune response of the pregnant female leads to increased susceptibility to invading pathogens, resulting in abortion and congenital defects of the fetus and a subnormal response to vaccination. Active vaccination during pregnancy may lead to abortion induced by heightened cell mediated immune response. In this study, we have administered the highly attenuated vaccine strain ΔpmrG-HM-D (DV-STM-07) in female mice before the onset of pregnancy and followed the immune reaction against challenge with virulent S. Typhimurium in pregnant mice. Here we demonstrate that DV-STM-07 vaccine gives protection against Salmonella in pregnant mice and also prevents Salmonella induced abortion. This protection is conferred by directing the immune response towards Th2 activation and Th1 suppression. The low Th1 response prevents abortion. The use of live attenuated vaccine just before pregnancy carries the risk of transmission to the fetus. We have shown that this vaccine is safe as the vaccine strain is quickly eliminated from the mother and is not transmitted to the fetus. This vaccine also confers immunity to the new born mice of vaccinated mothers. Since there is no evidence of the vaccine candidate reaching the new born mice, we hypothesize that it may be due to trans-colostral transfer of protective anti-Salmonella antibodies. These results suggest that our vaccine DV-STM-07 can be very useful in preventing abortion in the pregnant individuals and confer immunity to the new born. Since there are no such vaccine candidates which can be given to the new born and to the pregnant women, this vaccine holds a very bright future to combat Salmonella induced pregnancy loss.     

针对结核分枝杆菌潜伏感染的DNA疫苗V569免疫原性及保护性的初步研究

为研究针对结核分枝杆菌潜伏感染的DNA疫苗,基于质粒A39构建了p-VAX1-Ag85B-Rv3425-Rv2029c-PPE26 (V569)质粒DNA,并对其免疫原性及保护性进行初步研究。免疫性评价试验共分6组：PBS、p-VAX1-Ag85B(A)、p-VAX1-Ag85B-Rv3425(A3)、A39、V569和BCG,采用左后腿肌内注射C57BL/6小鼠,用流式细胞术和酶联免疫吸附试验(enzyme linked immunosorbent assay,ELISA)分别检测细胞免疫和体液免疫水平;构建斑马鱼-海分枝杆菌潜伏感染模型,将PBS、A、A3、A39、BCG、V569分别通过腹腔注射免疫斑马鱼后,每日注射地塞米松10ug诱导海分枝杆菌复发感染,对斑马鱼肝脏进行菌落计数并绘制生存曲线。结果显示,与BCG组相比,V569能引发实验小鼠强烈的细胞免疫反应(IFN-γ高水平分泌),外周血CD4^＋/CD8^＋ T细胞比例明显增加。在斑马鱼-海分枝杆菌潜伏感染复发模型中,与BCG 免疫组相比,V569免疫斑马鱼后可显著减少其肝脏中海分枝杆菌数量,斑马鱼存活情况得到显著改善,表明V569 DNA疫苗可能是一种抗结核潜伏感染的候选DNA疫苗。     

Induction of protective immune responses against the challenge of Actinobacillus pleuropneumoniae by the oral administration of transgenic tobacco plant expressing ApxIIA toxin from the bacteria

Actinobacillus pleuropneumoniae is the causative agent of porcine pleuropneumonia. Among the virulence factors, ApxIIA, a bacterial exotoxin, is reportedly expressed in many serotypes and is considered as a candidate for the development of a vaccine against the bacterial infection. Previously, we isolated a field strain of A. pleuropneumoniae serotype 2 in Korea and characterized its exotoxins to develop an oral vaccine. In this study, we initially confirmed the immunogenicity of ApxIIA expressed in Escherichia coli. We then developed transgenic tobacco expressing ApxIIA and tested its efficacy to induce a protective immune response against A. pleuropneumoniae infection after oral administration of the plant powder. We observed that protective immune responses were induced in mice after oral administration of the plant powder once a week for 4 weeks. Immunoassays revealed that the levels of antigen-specific immunoglobulin G against ApxIIA increased in mice that were fed a powder made from the transgenic plant, but not in mice fed a powder made from wild-type tobacco. Additionally, mice fed the transgenic plant powder were protected from an injection of a lethal dose of A. pleuropneumoniae. These results support that the transgenic plant may be a suitable candidate for an oral vaccine that could be used effectively against A. pleuropneumoniae infection.     

CpG oligonucleotides enhance the tumor antigen-specific immune response of an anti-idiotype antibody-based vaccine strategy in CEA transgenic mice

A murine monoclonal anti-idiotype (Id) antibody, 3H1 has been developed and characterized previously. Anti-Id 3H1 mimics a specific epitope of carcinoembryonic antigen (CEA) and can be used as a surrogate antigen for CEA. 3H1 induced anti-CEA immunity in different species of animals as well as humans and showed promise as a potential vaccine candidate in phase I/II clinical trials for colon cancer patients. One area of interest to us has been the development of new immune adjuvants that may augment the potency of 3H1 as a tumor vaccine. Oligodeoxynucleotides containing unmethylated CpG motifs (CpG ODN) are potent immunostimulatory agents capable of enhancing the Ag-specific Th1 response when used as immune adjuvants. In this study, we have evaluated the efficacy of 3H1 as a tumor vaccine when admixed with a select CpG ODN 1826 in transgenic mice that express human CEA. The vaccine potential of 3H1 was also assessed in the presence of another widely used adjuvant, QS-21. 3H1 coupled to keyhole limpet hemocyanin (KLH) and mixed with Freund’s adjuvant (FA) was used as a gold standard in this system. 3H1 vaccination with different adjuvants induced both humoral and cellular anti-3H1, as well as anti-CEA immunity in CEA transgenic mice. The immune sera could lyse CEA-transfected murine colon carcinoma cells, C15 effectively in an antibody-dependent cellular cytotoxicity assay. The anti-CEA antibody responses were somewhat comparable in each adjuvant-treated group of mice, whereas cellular immune responses were significantly greater when CpG was used as an adjuvant. Splenocytes obtained from 3H1–CpG-immunized mice showed an increased proliferative CD4⁺ Th1-type T-cell response when stimulated in vitro with 3H1 or CEA and secreted elevated levels of Th1 cytokines (IL-2, IFN-γ). This vaccine also induced MHC class I antigen-restricted CD8⁺ T-cell responses. In a solid tumor model, C15 tumor growth was significantly inhibited by 3H1 vaccinations. In 3H1–CpG-vaccinated mice, the duration of survival was, however, longer compared to the 3H1–QS21-vaccinated mice. These findings suggest that 3H1-CpG vaccinations can break peripheral tolerance to CEA and induce protective antitumor immunity in this murine model transgenic for human CEA.     

Schistosoma japonicum: protective immunity induced by schistosomulum-derived cells in a mouse model

We previously reported that immunization with intact live cells from schistosomula of Schistosoma japonicum (S.j) partially protected the Kunming strain of mice from challenge infection. In the present work, 2 immune protective experiments were designed to further validate the protective effect induced by this type of vaccine and to optimize the immunization protocol, including the number of inoculations and parasite stages from which immunogenic cells were derived. Three antigens derived from 18-day-old postinfection live (LLC) and dead (DLC) larval worm cells and from dead 42-day-old postinfection adult worm cells (DAC) were used as immunogens. Our results demonstrate that live cells from 18-day-old worms are capable of inducing significant protection in mice using a murine-Sj challenge model as shown by reduction rates of worm recoveries and egg burdens. The development of adult worms was stunted. A Th1-biased immune response was reflected in the protected groups as evidenced by the ratio of IgG2a/IgG1. A 38-kDa polypeptide was recognized by sera from LLC immunized animals. We demonstrate that live parasite cells are a source of novel protective antigens that can be exploited for vaccine development.     

Immunostimulatory CpG oligonucleotides enhance the immune response of anti-idiotype vaccine that mimics carcinoembryonic antigen

We have developed and characterized a monoclonal anti-idiotype (Id) antibody, designated 3H1, which mimics a specific epitope of carcinoembryonic antigen (CEA) and can be used as a surrogate for CEA. Anti-Id 3H1 induced anti-CEA immunity in different species of animals as well as humans and showed promise as a potential vaccine candidate in phase I/II clinical trials for colorectal cancer patients. One area of interest to us has been the development of new immune adjuvants that may augment the potency of 3H1 as a tumor vaccine. Immunostimulatory oliogonucleotides containing the unmethylated CpG motif (CpG ODN) are potent inducers of both innate and adaptive immunity and can serve as suitable vaccine adjuvants. In this study, using the CEA-transduced MC-38 murine colon carcinoma model in syngeneic C57BL/6 mice, we assessed whether a select CpG ODN (1826) can function as immune adjuvant in immunization of mice with anti-Id 3H1. Complete Freund's adjuvant (FA) was used as a gold standard in this system. A single immunization of 3H1 mixed with CpG ODN 1826 was sufficient to induce measurable anti-CEA immunity in na?ve mice. However, 3 immunizations every other week were necessary to obtain and sustain peak immune reactivity over a long period of time. With FA and 3H1, single immunization was ineffective and multiple immunizations (5 to 6) were needed to achieve and sustain peak immunity. Anti-CEA antibody reactivity was comparable in both groups, but cellular immune reactivity as measured by immune splenic lymphocyte T cell proliferation and cytoxicity assay was slightly higher in the CpG ODN group. Mice immunized with 3H1 and either CpG ODN or FA were protected from challenge by lethal doses of MC-38-CEA cells. However, the degree of protection was slightly higher and the duration of survival was somewhat longer in the group of mice treated with 3H1 plus CpG ODN. Thus, CpG ODN 1826 was faster than FA in increasing anti-tumor immunity induced by anti-Id 3H1 immunization in this prophylactic model.     

Schistosoma mansoni: vaccination of mice with 10-krad-irradiated, cryopreserved schistosomules

Protection against a Schistosoma mansoni cercarial challenge was evaluated in mice immunized with a vaccine composed of 10-krad-irradiated, cryopreserved schistosomules. The level of resistance induced in C57B1/6 or NMRI (CV) mice increased with the number of schistosomules injected. Up to 83% reduction in challenge worm burden was achieved when 5000 schistosomules were injected per mouse. Intramuscular injection of the vaccine was superior to subcutaneous. Multiple immunizations, up to 3 at 4-week intervals, did not increase the resistance induced by a single immunization. A high level of protection developed in as little as 2 weeks and was maintained through at least 12 weeks postimmunization. The vaccine irradiated with 10 krad from either a 60-cobalt or 137-cesium source induced equivalent levels of resistance, and no differences were found in the immunogenicity of vaccines comprised of organisms irradiated as cercariae or as 1- to 3-hr-old schistosomules. These findings are basic to the development of a cryopreserved, live vaccine against schistosomiasis of humans or domestic animals.     

Schistosoma mansoni: The attrition of a challenge infection in mice immunized with highly irradiated live cercariae

Mice immunized percutaneously with 400 Schistosoma mansoni cercariae given 20 kR of ⁶⁰Co irradiation were shown to develop an immunity in which nearly 80% of the parasites that would be expected to survive in control mice were killed. The major attrition of parasites was shown to occur within the first 4 days after challenge. Marked differences in the number of parasites which were recovered from the skin of immune mice and the failure of the majority of parasites to reach the lungs of immune mice indicated that the major site of attrition was in the skin. A further trickle of parasite deaths was evident beyond Day 5, but after Day 14 no further attrition of parasites appeared to occur. Mice immunized in the abdominal skin demonstrated similar levels of immunity whether challenged in the abdominal skin or in the ear. Immunization intramuscularly with irradiated schistosomula induced a much lower level of resistance and the marked parasite attrition in the skin at Day 2 was absent. Immunization with only 50 irradiated cercariae was shown to induce a level of skin immunity equivalent to that seen with 400 irradiated cercariae. The majority of cercariae given 20 kR of ⁶⁰Co irradiation remained in the skin; approximately 2% only reached the lungs. These studies demonstrate that percutaneous immunization of mice with highly irradiated cercariae induced a strong immunity which was largely effective in the skin. This immunity differed from that developed by chronically infected mice where the major attrition of parasites occurs after the lung phase of migration. The results also suggest that the penetration or persistence in the skin of live attenuated schistosomula may play a crucial role in the induction of a high level of skin immunity.     

Defining a schistosomiasis vaccination strategy - is it really Th1 versus Th2?

Successful vaccine development for schistosomiasis has been hindered by a lack of consensus on the type of immune response that would provide maximum levels of protective immunity and incomplete knowledge of the key antiparasite effector mechanisms. Many vaccine studies conducted in mice support type-1-cytokine-mediated effector mechanisms, while acquired resistance in humans correlates with type-2-cytokine-mediated responses. However, recent data from cytokine-knockout mice suggest that choosing between these opposing pathways may be less important than previously hypothesized, as discussed here by Thomas Wynn and Karl Hoffmann.