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• W1983201829 abstract "Since the advent of techniques for the expression of recombinant peptide antigens, the availability of human vaccines for parasitic diseases has been ‘imminent’. Yet vaccines based on recombinant proteins are still largely aspirations, not realities. It is now apparent that vaccine development needs additional knowledge about host protective immune response(s), antigen characteristics, and the delivery required to induce those responses. The most successful immune protection against parasites has been generated by infection and treatment, the induction of protective immunity by truncating the course of an infection with drug treatment. Here, we consider the characteristics of an effective, protective anti-parasite vaccine and propose a conceptual framework to aid parasite vaccine development using malaria and schistosomiasis as examples. Since the advent of techniques for the expression of recombinant peptide antigens, the availability of human vaccines for parasitic diseases has been ‘imminent’. Yet vaccines based on recombinant proteins are still largely aspirations, not realities. It is now apparent that vaccine development needs additional knowledge about host protective immune response(s), antigen characteristics, and the delivery required to induce those responses. The most successful immune protection against parasites has been generated by infection and treatment, the induction of protective immunity by truncating the course of an infection with drug treatment. Here, we consider the characteristics of an effective, protective anti-parasite vaccine and propose a conceptual framework to aid parasite vaccine development using malaria and schistosomiasis as examples. Development of protective immune responses resulting from infectionsExposure to pathogens allows vertebrate hosts to mount pathogen-specific acquired immune responses that sometimes protect against subsequent infection, forming the basis of vaccinology [1Pichichero M.E. Booster vaccinations: can immunologic memory outpace disease pathogenesis?.Pediatrics. 2009; 124: 1633-1641Crossref PubMed Scopus (74) Google Scholar]. The original observation that protection often succeeds infection and recovery led to the artificial induction of immunity by infection with attenuated parasites [2Meeusen E.N. Piedrafita D. Exploiting natural immunity to helminth parasites for the development of veterinary vaccines.Int. J. Parasitol. 2003; 33: 1285-1290Crossref PubMed Scopus (35) Google Scholar, 3Meeusen E.N. et al.Current status of veterinary vaccines.Clin. Microbiol. Rev. 2007; 20: 489-510Crossref PubMed Scopus (311) Google Scholar], which triggered tremendous interest in the nature and development of naturally acquired protective immunity and characterization of measureable markers of immune protection. The broad range of veterinary [3Meeusen E.N. et al.Current status of veterinary vaccines.Clin. Microbiol. Rev. 2007; 20: 489-510Crossref PubMed Scopus (311) Google Scholar] and human [4Plotkin S.A. Vaccines: correlates of vaccine-induced immunity.Clin. Infect. Dis. 2008; 47: 401-409Crossref PubMed Scopus (577) Google Scholar] vaccines against bacterial and viral pathogens are predominantly live attenuated or inactivated pathogen formulations (Table 1). Similarly, a significant proportion of protozoan vaccines against economically significant veterinary parasites (e.g., Theileria) of livestock and companion animals are based on inoculation with attenuated or drug treated parasites. In humans, the most widely used ‘vaccination’ for a parasitic infection is the practice of leishmanization [5Nadim A. et al.Effectiveness of leishmanization in the control of cutaneous leishmaniasis.Bull. Soc. Pathol. Exot. Filiales. 1983; 76: 377-383PubMed Google Scholar], where children are inoculated with parasite-containing exudate from a cutaneous Leishmania sore in a location typically covered by clothing. The resulting, self-limiting lesion provides protection against subsequent infections that might otherwise form a disfiguring ulceration on an exposed area. However, no vaccines against parasitic infections are licensed for human use. This is at least in part attributable to the antigenic complexity of parasites, arising from multiple life cycle stages, immune evasion strategies, and use of intermediate and reservoir hosts. Unfortunately, obtaining adequate numbers of parasites, attenuated or otherwise, of consistent and acceptable quality to use in vaccinations is highly challenging, as demonstrated by recent studies of the Plasmodium falciparum attenuated sporozoite vaccine (PfSPZ vaccine) in humans [6Hoffman S.L. et al.Development of a metabolically active, non-replicating sporozoite vaccine to prevent Plasmodium falciparum malaria.Hum. Vaccin. 2010; 6: 97-106Crossref PubMed Scopus (223) Google Scholar]. Nevertheless, the recent Phase 1 trial demonstrating that injection of cryopreserved P. falciparum sporozoites can be used in controlled human malaria infections will greatly facilitate this research in the future [7Roestenberg M. et al.Controlled human malaria infections by intradermal injection of cryopreserved Plasmodium falciparum sporozoites.Am. J. Trop. Med. Hyg. 2013; 88: 5-13Crossref PubMed Scopus (111) Google Scholar].Table 1Currently licensed human vaccinesaTable adapted from [5] and definitions adapted from http://www.niaid.nih.gov/topics/vaccines/understanding/pages/typesvaccines.aspx.VaccineCommon name/combination vaccinePathogenType of vaccineAnthraxBacteriaSubunitbSubunit vaccine: a vaccine made up of only the antigens that best stimulate the immune system. They are made in one of two ways: either by chemical extraction of the native antigen, the whole organism, or as recombinant proteins expressed in other organisms (e.g., bacteria), in which case they would be termed ‘recombinant subunit vaccines’.Chicken poxVaricellaVirusLive, attenuatedcLive attenuated vaccine: a vaccine made from the living microbe that has been weakened in the laboratory so it cannot cause disease but may still be able to replicate in the host.CholeraInactivateddInactivated vaccine: a vaccine made by killing the disease-causing microbe with chemicals, heat, or radiation.DiptheriaDPTBacteriaInactivated toxinHaemophilus influenza type BHibVirusConjugateeConjugate vaccine: a vaccine created by covalently attaching a poorly immunogenic antigen (e.g., a polysaccharide) to a carrier protein thereby conferring the immunological attributes of the carrier to the attached antigen. This type of vaccine is a special type of subunit vaccine.Hepatitis AVirusInactivatedHepatitis BVirusSubunitHuman papillomavirusHPVVirusSubunitInfluenza vaccineVirusLive, attenuatedJapanese encephalitis vaccineInactivatedMeaslesMMRVirusLive, attenuatedMumpsMMRVirusLive, attenuatedRubellaMMRVirusLive, attenuatedPertusisWhooping cough (DPT)SubunitPneumococcal infectionsMeningitis and pneumonia MeningococcusBacteriaSubunitPolioVirusInactivatedRabiesVirusInactivatedRotavirusVirusLive, attenuatedSmall poxVirusAttenuated (Sabin polio vaccine) Inactivated (Salk polio vaccine)ShinglesHerpes zoosterVirusLive, attenuatedTetanusDPTBacterial toxinInactivated toxinTuberculosisBacilli Calmette–Géurin (BCG)bacteriaLive, attenuatedTyphoidbacteriaInactivatedYellow fevervirusLive, attenuateda Table adapted from 5Nadim A. et al.Effectiveness of leishmanization in the control of cutaneous leishmaniasis.Bull. Soc. Pathol. Exot. Filiales. 1983; 76: 377-383PubMed Google Scholar and definitions adapted from http://www.niaid.nih.gov/topics/vaccines/understanding/pages/typesvaccines.aspx.b Subunit vaccine: a vaccine made up of only the antigens that best stimulate the immune system. They are made in one of two ways: either by chemical extraction of the native antigen, the whole organism, or as recombinant proteins expressed in other organisms (e.g., bacteria), in which case they would be termed ‘recombinant subunit vaccines’.c Live attenuated vaccine: a vaccine made from the living microbe that has been weakened in the laboratory so it cannot cause disease but may still be able to replicate in the host.d Inactivated vaccine: a vaccine made by killing the disease-causing microbe with chemicals, heat, or radiation.e Conjugate vaccine: a vaccine created by covalently attaching a poorly immunogenic antigen (e.g., a polysaccharide) to a carrier protein thereby conferring the immunological attributes of the carrier to the attached antigen. This type of vaccine is a special type of subunit vaccine. Open table in a new tab An alternative to infection with attenuated parasites is the infection and treatment (I&T) approach where immunity is induced by the release of antigens from parasitic infections that are treated or naturally die in the host (Figure 1). One of the most striking examples of the effect of previous infection on subsequent protection is the relative resistance to symptomatic malaria in older children and adults who have grown up in areas endemic for P. falciparum. Recently, an I&T trial for malaria was performed by exposing volunteers who were receiving chloroquine prophylaxis to P. falciparum sporozoites. The chemoprophylaxis with sporozoites (CPS) protocol succeeded in inducing sterile immunity in all immunized participants and was maintained in four of six participants for >2 years [8Roestenberg M. et al.Long-term protection against malaria after experimental sporozoite inoculation: an open-label follow-up study.Lancet. 2011; 377: 1770-1776Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar]. An I&T effect is also observed in schistosome infections as praziquantel treatment of persons infected with Schistosoma haematobium or Schistosoma mansoni can induce partially protective immunity against subsequent infections [9Bethony J.M. et al.Vaccines to combat the neglected tropical diseases.Immunol. Rev. 2011; 239: 237-270Crossref PubMed Scopus (128) Google Scholar, 10Woolhouse M.E.J. Hagan P. Seeking the ghost of worms past.Nat. Med. 1999; 5: 1225-1227Crossref PubMed Scopus (94) Google Scholar].Another outcome of I&T is that individuals from areas where they are likely to have been exposed to malaria or schistosome antigens early in life tend to have a lower risk of developing severe pathological consequences such as cerebral malaria or hepatosplenic schistosomiasis, respectively. Protective mechanisms against pathology are poorly understood but are hypothesized to involve induction of different regulatory or memory immune responses. In addition to modulation of pathology in subsequent infections, I&T effects on host immune responses are also instructive with respect to development of defined antigen vaccines. Most vaccine recipients in endemic areas are likely to have had some exposure to the parasite, leading to reactions during immunization that may differ from those of parasite naïve vaccine trial participants. For example, the Phase I clinical trial evaluating the vaccine against human hookworm using Ancylostoma secreted protein (ASP-2) was discontinued when vaccination induced urticarial reactions in people with pre-existing IgE responses to ASP-2 [9Bethony J.M. et al.Vaccines to combat the neglected tropical diseases.Immunol. Rev. 2011; 239: 237-270Crossref PubMed Scopus (128) Google Scholar]. No such adverse events have been reported in I&T.Similar to inoculation with attenuated parasites, I&T has limitations that may preclude it from being a feasible public health tool; for some parasite species, it may not be possible to generate sufficient quantities of infectious stage parasites to vaccinate the millions of people exposed to these infections. Nevertheless, I&T approaches provide key answers to some fundamental intellectual and practical questions for successful vaccine development. By concentrating on the principles of classical vaccination, we describe how I&T protocols have overcome some of the challenges of using recombinant protein immunizations.Desirable I&T characteristics for successful vaccinesParasites causing the greatest morbidity and disease typically induce a more or less protective immunity very slowly. Reasons for this include poor immunogenicity of individual antigens, poor protective immunity of major antigens, antigenic variation (protozoa), antigen polymorphism, immune evasion, immunomodulation of effector responses, and/or the requirement for a threshold amount of antigen which is released more easily upon treatment than from natural parasite death [10Woolhouse M.E.J. Hagan P. Seeking the ghost of worms past.Nat. Med. 1999; 5: 1225-1227Crossref PubMed Scopus (94) Google Scholar, 11Gupta S. et al.Acquired immunity and postnatal clinical protection in childhood cerebral malaria.Proc. Biol. Sci. 1999; 266: 33-38Crossref PubMed Scopus (39) Google Scholar, 12Good M.F. Vaccine-induced immunity to malaria parasites and the need for novel strategies.Trends Parasitol. 2005; 21: 29-34Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar, 13Yazdanbakhsh M. Sacks D.L. Why does immunity to parasites take so long to develop?.Nat. Rev. Immunol. 2010; 10: 80-81Crossref PubMed Scopus (36) Google Scholar, 14Mutapi F. et al.Age-related and infection intensity-related shifts in antibody recognition of defined protein antigens in a schistosome-exposed population.J. Infect. Dis. 2008; 198: 167-175Crossref PubMed Scopus (45) Google Scholar]. I&T approaches have overcome some of these parasite survival strategies. Several important characteristics that underlie their success are discussed below.The pathogen must be immunogenicParasites successfully controlled by I&T are immunogenic during natural infections. Echinococcus granulosus onchospheres provoke a high degree of protective immunity, which is the basis of a highly effective vaccine in lambs (90% protection [15Hashemitabar G.R. et al.Trials to induce protective immunity in mice and sheep by application of protoscolex and hydatid fluid antigen or whole body antigen of Echinococcus granulosus.J. Vet. Med. B: Infect. Dis. Vet. Public Health. 2005; 52: 243-245Crossref PubMed Scopus (14) Google Scholar]) and offering great potential as a human parasite vaccine [16Lightowlers M.W. Vaccination against hydatid disease.Dev. Biol. (Basel). 2002; 110: 81-87PubMed Google Scholar]. By contrast, vaccine development against Fasciola hepatica and Fasciola gigantica is hampered by their inability to induce immunity in their natural hosts, even after repeated infections, suggesting low immunogenicity of these flukes [2Meeusen E.N. Piedrafita D. Exploiting natural immunity to helminth parasites for the development of veterinary vaccines.Int. J. Parasitol. 2003; 33: 1285-1290Crossref PubMed Scopus (35) Google Scholar]. Parasites might be immunogenic but still infect the host if the host is unable to recognize the pathogen or mount a protective immune response during the parasite's immune-susceptible period. For example, infective stages of schistosomes, filarids, and hookworms are susceptible to immune attack but migrate and mature before effective immune responses develop. Subsequent infections may be prevented but only after the initial parasites become established [17Wilson R.A. Coulson S.R. Strategies for a schistosome vaccine: can we manipulate the immune response effectively?.Microbes Infect. 1999; 1: 535-543Crossref PubMed Scopus (27) Google Scholar]. Furthermore, adult schistosomes avoid the host's protective immunity through evasive mechanisms such as rapid membrane turnover, host mimicry, and masking themselves with host proteins [18Wilson R.A. Virulence factors of schistosomes.Microbes Infect. 2012; 14: 1442-1450Crossref PubMed Scopus (30) Google Scholar].In the CPS and PfSPZ–CVac studies, the timing of drug treatment allows full development of the liver stage parasites, thereby increasing the number and diversity of parasite antigens. It also eliminates the parasites before the onset of disease [19Roestenberg M. et al.Protection against a malaria challenge by sporozoite inoculation.N. Engl. J. Med. 2009; 361: 468-477Crossref PubMed Scopus (453) Google Scholar] and prevents inhibition of anti-liver stage cellular immunity that would otherwise occur during blood stage infections [20Mota M.M. et al.Migration of Plasmodium sporozoites through cells before infection.Science. 2001; 291: 141-144Crossref PubMed Scopus (393) Google Scholar]. Additionally, with the increased complexity of whole parasite antigens against parasite stages for which protective immunity might not otherwise develop, I&T offers great potential for strain-transcending protection.However, protozoan parasites can vary the antigens seen by host immune systems through mechanisms including transcriptional and epigenetic control (in situ switching, e.g., P. falciparum or Giardia lamblia) or through gene conversion (unidirectional recombination, e.g., Trypanosoma brucei and Babesia bovis) [21Craig A. Antigenic Variation. Elsevier, 2003Google Scholar]. I&T may overcome antigenic variation and immune avoidance by inducing immunity to many antigens of several parasite strains/variants. Such broad coverage is very challenging to achieve with a recombinant vaccine, even if it is multivalent, such as the AMA1 [22Kusi K.A. et al.Humoral immune response to mixed PfAMA1 alleles; multivalent PfAMA1 vaccines induce broad specificity.PLoS ONE. 2009; 4: e8110Crossref PubMed Scopus (62) Google Scholar] or MSP-1 [23Cowan G.J. et al.A malaria vaccine based on the polymorphic block 2 region of MSP-1 that elicits a broad serotype-spanning immune response.PLoS ONE. 2011; 6: e26616Crossref PubMed Scopus (18) Google Scholar] vaccine candidates. To date, antigenic switching has not been demonstrated in helminths, although a micro-exon mechanism for potentially generating antigenic variation is present in the schistosome genome [24DeMarco R. et al.Protein variation in blood-dwelling schistosome worms generated by differential splicing of micro-exon gene transcripts.Genome Res. 2010; 20: 1112-1121Crossref PubMed Scopus (74) Google Scholar].Inducing protective effector, rather than regulatory responsesIndividuals infected naturally with schistosomes or malaria parasites eventually develop effector responses that may confer protection despite also stimulating regulatory responses. Schistosome infection intensities are associated with the balance between protective and regulatory responses, which is affected by host age [25Nausch N. et al.Regulatory and activated T cells in human Schistosoma haematobium infections.PLoS ONE. 2011; 6: e16860Crossref PubMed Scopus (48) Google Scholar]. An often overlooked aspect of protective immunity is how effector responses surpass regulatory responses during natural infection and progress to long-lived memory B and T cells. Understanding this phenomenon may help unlock the door to successful vaccine design.Not all immune responses result in parasite killing or resistance to re-infection. Indeed, some parasite evasive mechanisms may divert the immune system to respond against ‘decoy’ antigens. In Plasmodium, T cell mimotopes are protein variants of parasite antigens (altered peptide ligands) that prevent development of memory T cell effector functions of cytotoxic lymphocytes [26Plebanski M. et al.Immune evasion in malaria: altered peptide ligands of the circumsporozoite protein.Parasitology. 1997; 115: S55-S66Crossref PubMed Scopus (39) Google Scholar]. Similarly, carbohydrate epitopes on schistosome cercariae and egg antigens predominantly induce IgM and IgG2 antibodies, which are not as efficacious against schistosomulae as other antibody subclasses [27Butterworth A.E. et al.Immunity in human Schistosomiasis mansoni: cross reactive IgM and IgG2 anti-carbohydrate antibodies block the expression if immunity.Biochimie. 1988; 70: 1053-1063Crossref PubMed Scopus (72) Google Scholar, 28Capron A. et al.Development of a vaccine strategy against human and bovine schistosomiasis. Background and update.Trop. Geogr. Med. 1994; 46: 242-246PubMed Google Scholar] and skew the immune system towards anergy [29Everts B. et al.Schistosome-derived omega-1 drives Th2 polarization by suppressing protein synthesis following internalization by the mannose receptor.J. Exp. Med. 2012; 209: 1753-1767Crossref PubMed Scopus (181) Google Scholar]. Why the host maintains these ineffective responses is unknown but there may be homeostatic reasons for maintaining them [30Raberg L. et al.On the adaptive significance of stress-induced immunosuppression.Proc. Biol. Sci. 1998; 265: 1637-1641Crossref PubMed Scopus (364) Google Scholar]. Thus, the value of these responses must be considered before disregarding them entirely. Alternatively, certain responses may be regulatory and suppress protective immunity, such as the AgEm2 carbohydrate in E. granulosus that interferes with antigen presentation and cell activation [31Zhang W. et al.Mechanisms of immunity in hydatid disease: implications for vaccine development.J. Immunol. 2008; 181: 6679-6685PubMed Google Scholar].Amelioration of autoimmunity in rodents by Plasmodium suggests that blood stage parasites induce immunosuppression. This was confirmed in humans as blood stages of P. falciparum suppress T lymphocyte reactivity to malarial and unrelated antigens [32Ho M. et al.Antigen-specific immunosuppression in human malaria due to Plasmodium falciparum.J. Infect. Dis. 1986; 153: 763-771Crossref PubMed Scopus (140) Google Scholar]. The several immunosuppressive strategies employed by Plasmodium parasites include utilization of T cell mimotopes to inhibit T cell activation, induce anergy, or shift the T cell phenotype [33Casares S. Richie T.L. Immune evasion by malaria parasites: a challenge for vaccine development.Curr. Opin. Immunol. 2009; 21: 321-330Crossref PubMed Scopus (47) Google Scholar]; alteration of antigen presentation by impairing dendritic cell function and maturation [34Orengo J.M. et al.A Plasmodium yoelii soluble factor inhibits the phenotypic maturation of dendritic cells.Malar. J. 2008; 7: 254Crossref PubMed Scopus (15) Google Scholar]; and induction of regulatory T cells [35Jangpatarapongsa K. et al.Plasmodium vivax parasites alter the balance of myeloid and plasmacytoid dendritic cells and the induction of regulatory T cells.Eur. J. Immunol. 2008; 38: 2697-2705Crossref PubMed Scopus (76) Google Scholar]. By contrast, the P. falciparum I&T trial in humans resulted in equivalent or better protection than that produced by irradiated sporozoite immunizations [36Mellouk S. et al.Protection against malaria induced by irradiated sporozoites.Lancet. 1990; 335: 721Abstract PubMed Scopus (55) Google Scholar]. I&T exposes the host to all pre-erythrocytic stages, allowing effector responses to be mounted against a broader range of antigens, while limiting exposure to the pathogenic and immunosuppressive asexual blood stages [37Yayon A. et al.Stage-dependent effects of chloroquine on Plasmodium falciparum in vitro.J. Protozool. 1983; 30: 642-647Crossref PubMed Scopus (90) Google Scholar, 38Bejon P. et al.The induction and persistence of T cell IFN-γ responses after vaccination or natural exposure is suppressed by Plasmodium falciparum.J. Immunol. 2007; 179: 4193-4201PubMed Google Scholar]. In natural infections, people are typically infected with Plasmodium from a single mosquito bite and treated based on clinical symptoms or diagnosis, at which time the blood stage parasites may be suppressing pre-erythrocytic immunity. In successful Plasmodium CPS, the drug was administered prophylactically, including during inoculation of sporozoites from 15 mosquitoes [39Belnoue E. et al.Protective T cell immunity against malaria liver stage after vaccination with live sporozoites under chloroquine treatment.J. Immunol. 2004; 172: 2487-2495PubMed Google Scholar]. This requirement to curtail exposure to blood stage parasites for full protection is supported by development of protective acquired immunity in children receiving treatment that restricts the development of symptomatic malaria [40Sutherland C.J. et al.How is childhood development of immunity to Plasmodium falciparum enhanced by certain antimalarial interventions?.Malar. J. 2007; 6: 161Crossref PubMed Scopus (37) Google Scholar]. Thus, successful vaccination must overcome the effects of regulatory responses that are stimulated by certain parasite life cycle stages. I&T for Plasmodium has achieved this by minimizing immune exposure to immunosuppressive blood stage parasites. How or even if this is achieved in people who develop natural resistance to malaria is unclear.Experimental and natural helminth infections are associated with immunoregulatory responses that polarize CD4+ T cells towards a T helper 2 (Th2) phenotype (production of interleukins 4, 5, and 13, secretion of IgE and IgG4 by plasma cells, and activation of eosinophils and mast cells), and immunosuppress worm-specific [41Gopinath R. et al.Long-term persistence of cellular hyporesponsiveness to filarial antigens after clearance of microfilaremia.Am. J. Trop. Med. Hyg. 1999; 60: 848-853PubMed Google Scholar] and general [42Maizels R.M. et al.Helminth parasites – masters of regulation.Immunol. Rev. 2004; 201: 89-116Crossref PubMed Scopus (681) Google Scholar] immune responses. Helminth parasites modulate both innate and adaptive arms of the immune system, targeting both humoral and cellular responses [43Siracusano A. et al.Immunomodulatory mechanisms during Echinococcus granulosus infection.Exp. Parasitol. 2008; 119: 483-489Crossref PubMed Scopus (73) Google Scholar]. Regulatory responses are characterized by suppressive cytokines [interleukin (IL)-10 and transforming growth factor β (TGF-β)] produced by natural and adaptive regulatory T (Treg) cells [44Taylor M.D. et al.Removal of regulatory T cell activity reverses hyporesponsiveness and leads to filarial parasite clearance in vivo.J. Immunol. 2005; 174: 4924-4933PubMed Google Scholar, 45Wilson M.S. et al.Suppression of allergic airway inflammation by helminth-induced regulatory T cells.J. Exp. 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Med. 2007; 204: 273-283Crossref PubMed Scopus (472) Google Scholar, 49Loke P. et al.IL-4 dependent alternatively-activated macrophages have a distinctive in vivo gene expression phenotype.BMC Immunol. 2002; 3: 7Crossref PubMed Scopus (267) Google Scholar] (e.g., alternatively activated macrophages [50Jenkins S.J. Allen J.E. Similarity and diversity in macrophage activation by nematodes, trematodes, and cestodes.J. Biomed. Biotechnol. 2010; 2010: 262609Crossref PubMed Scopus (72) Google Scholar]). The influence of these regulatory responses on the development of resistance in human hosts is still under investigation. Cross-inhibition between effector CD4+ T cell subsets (Th1, Th2, and Th17) also means that effector cytokines [interferon (IFN)-γ, IL-4, and IL-21) are required to maintain a balanced acquired immune response [51Wilson M.S. et al.Suppression of murine allergic airway disease by IL-2:anti-IL-2 monoclonal antibody-induced regulatory T cells.J. Immunol. 2008; 181: 6942-6954PubMed Google Scholar, 52Babu S. et al.Alternatively activated and immunoregulatory monocytes in human filarial infections.J. Infect. Dis. 2009; 199: 1827-1837Crossref PubMed Scopus (77) Google Scholar], which is associated with protective immunity against infection/re-infection [53Lyke K.E. et al.HLA-A2 supertype-restricted cell-mediated immunity by peripheral blood mononuclear cells derived from Malian children with severe or uncomplicated Plasmodium falciparum malaria and healthy controls.Infect. Immun. 2005; 73: 5799-5808Crossref PubMed Scopus (21) Google Scholar, 54Allen J.E. Maizels R.M. Diversity and dialogue in immunity to helminths.Nat. Rev. Immunol. 2011; 11: 375-388Crossref PubMed Scopus (592) Google Scholar]. When schistosome infection is cleared by drug treatment, immune reactivity can increase shortly afterwards, presumably in response to: (i) antigen release from dead parasites [14Mutapi F. et al.Age-related and infection intensity-related shifts in antibody recognition of defined protein antigens in a schistosome-exposed population.J. Infect. Dis. 2008; 198: 167-175Crossref PubMed Scopus (45) Google Scholar], (ii) reversal of hyporesponsiveness [55Grogan J.L. et al.Elevated proliferation and interleukin-4 release from CD4+ cells after chemotherapy in human Schistosoma haematobium infection.Eur. J. Immunol. 1996; 26: 1365-1370Crossref PubMed Scopus (86) Google Scholar], or (iii) an increased effector T (Teff):Treg ratio [56Watanabe K. et al.T regulatory cell levels decrease in people infected with Schistosoma mansoni on effective treatment.Am. J. Trop. Med. Hyg. 2007; 77: 676-682PubMed Google Scholar]. Thus, success of I&T in human schistosomiasis may result partly from the treatment-induced increase in effector responses relative to regulatory responses.The effective dose: protective, non-pathological immune responsesQuantitative studies in human schistosomiasis show that immuno" @default.
• W1983201829 created "2016-06-24" @default.
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• W1983201829 date "2013-03-01" @default.
• W1983201829 modified "2023-10-16" @default.
• W1983201829 title "Infection and treatment immunizations for successful parasite vaccines" @default.
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• W1983201829 doi "https://doi.org/10.1016/j.pt.2013.01.003" @default.
• W1983201829 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3884123" @default.
• W1983201829 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/23415733" @default.
• W1983201829 hasPublicationYear "2013" @default.
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