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www.landesbioscience.com Human Vaccines 1205

SPECIAL FOCUS REVIEW: NEGLECTED VACCINESDEVELOPING WORLD SPECIAL FOCUS REVIEW: NEGLEC TED VACCINESDEVELOPING WORLD

complex, it is believed that human VL trials will follow any suc-cessful CL immunization program. Whether the same vaccinewill work against both forms of the disease is not clear at present.Literature reporting cross-protection between VL and CL speciesis scarce. Exposure to heat-killed L. donovanihas been shown toprotect against L. majorchallenge,14and recently immunizationwith the polyprotein KSAC with MPL-SE A as an adjuvant has

been reported to be effective against L. infantumand L. major.15The genomic analysis of three Leishmania species, which causedistinct disease pathologies, showed that L. major, L. brazilien-sisand L. infantumgenomes are highly conserved and have veryfew species-specific genes.16However, there is a high degree ofvariability in the cross-protective immunity induced by infec-tion with different Leishmania species17,18 and VL specific vac-cines may provide a more successful intervention. To compoundthe issue further is the fact that despite causing cutaneous dis-ease, the old and new world parasites, L. majorand L. mexicana/L. amazonensis, respectively, are markedly different.19There aredifferences in virulence factors between these species,20,21and insurvival capacity in the presence of Th1 responses.22These find-

ings highlight an interesting and poorly understood aspect ofparasite immunobiology, and may have connotations for the vac-cine development process for the old and new world leishmani-asis. Yet another challenge for the vaccine is to obtain protectionagainst VL even if it is efficacious against the different forms ofCL. Nevertheless, the mortality associated with VL suggests thatpriority should be given to anti-VL vaccine, but VL vaccinationstudies are hampered by the lack of a suitable animal model ofdisease.

Initially, vaccines composed of whole killed parasites havebeen proposed as both prophylactic and therapeutic vaccines. Thetherapeutic application may be particularly important in cases of

drug resistant disease. In general, the whole-cell, killed vaccineshave been rather poorly defined and variable in potency, hencethey have rendered inconclusive results.12In addition, it has beendemonstrated that inoculation of killed parasites into immunemice leads to a loss of infection induced immunity.23This situa-tion might be analogous to that observed in endemic areas, wheremany individuals with subclinical leishmaniasis were vaccinatedwith killed vaccines, which subsequently led to a loss of natu-rally acquired immunity and vaccination failure. Although thishypothesis has not been proven, it clearly demonstrates that thereare still many unknown aspects of the vaccine design that wouldneed to be resolved prior its use in clinics. Nevertheless, the tri-als completed so far demonstrated their good safety profile, and

despite poor prophylactic outcomes, showed encouraging resultsas therapeutic vaccines in South America and Sudan.

A variety of different molecules (summarized in Table 1) hasbeen tested as second-generation vaccines,13,24and these includedantigens such as surface expressed glycoprotein leishmaniolysin(gp63) delivered by a plethora of immunization regimens, how-ever, promising findings from animal models were overshadowedby mostly negative T-cell responses in humans.25Nevertheless,this molecule is still being considered a strong candidate for avaccine and recent studies demonstrated its protective efficacy ina mouse model in combination with Hsp70 26and in heterologous

on the observation that following lesion healing, an individual isresistant to reinfection. This method involved deliberate infec-tion of an individual using live parasites and has now been largelydiscontinued based on the grounds of quality control, parasitepersistence, emergence of HIV and ethical reasons, among theothers. The first-generation vaccines based on killed parasiteshave replaced leishmanization, but this type of vaccines have

shown poor efficacy in clinical trials and in general the tradi-tional vaccine approaches have worked poorly.12The focus is nowon the second generation vaccines including genetically modi-fied parasites, defined subunit vaccines or recombinant bacteriaand viruses expressing leishmanial antigens.11 So far, their effi-cacy in the field trials has not been reported. Leishmania vaccinedevelopment has proven to be a difficult and challenging task,which is mostly hampered by inadequate knowledge of parasitepathogenesis and the complexity of immune responses needed forprotection. These aspects are of key importance in the vaccinedevelopment process. These issues as well as issues of fundingand knowledge dissemination in antileishmanial vaccine pro-grams have been highlighted in a recent proposal for a research

agenda that stemmed from the International Symposium onLeishmaniasis Vaccines.13 In general, leishmaniasis is a diseaselinked to poverty, and is associated with malnutrition, poorhousing, illiteracy and lack of resources. Therefore, the targetpopulation for antileishmanial vaccine cannot afford the costof treatment, which surpasses a substantial percentage of house-hold income and would exert a significant financial burden onpeople in need for antileishmanial treatment. Hence, develop-ment of such a vaccine is considered unattractive to the industrydue to poor return of funds invested in research and develop-ment. Currently, leishmaniasis is considered to be endemic in 88countries, with 90% of VL cases occurring in Bangladesh, Brazil,

India, Nepal and Sudan, and 90% CL cases in Afghanistan,Brazil, Iran, Peru, Saudi Arabia and Syria. Therefore, popula-tions of these countries might be the best choices for implemen-tation of new vaccination programs since the burden of disease inthose countries is quite significant. In several foci of the diseasein Africa, the prevalence of infection can reach up to 5% and notreatment is available, therefore a successful vaccine would be thebest method of control. However, unlike African countries, Indiaand Brazil have developed strong vaccine industries in order toachieve self-sufficiency in vaccine supply, which might be benefi-cial to anti-leishmanial vaccine program implementation.

Overview of Vaccine Development

Leishmaniasis is a disease that is most likely to be controlled by asuccessful vaccination program. Evidence from studies in animalmodels, indicates that protection can be achieved upon immu-nization with various vaccine formulations, however, to datesuch vaccines have been disappointing when tested in the field.11Historically, CL has been the focus of vaccination attempts, asit has been known for centuries that people who resolve a pri-mary CL skin lesion are protected from further infections.Vaccination against VL has received limited attention comparedwith CL, and although the demands for a VL vaccine are more


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Table 1.Summary of vaccination approaches discussed in the text

Antigen Vaccine formulationVaccinated

species

Outcome of

vaccinationTargeted disease Reference

KSACpolyprotein (KMP11/SMT/A2/CPB) + monophosphoryl

lipid Amouse protection VL/CL 15

gp63 recombinant protein mouse no protection CL 132

recombinant proteinnon-human

primatepartial protection CL 133

native protein mouse protection CL 134

protein expressed in BCG mouse protection CL 135

protein expressed in Salmonella mouse protection CL 136

DNA vaccine mouse protection CL 137

DNA vaccine mouse partial protection CL 138

DC pulsed with native protein mouse protection CL 139

recombinant protein/DNA prime/boost mouse protection VL 27

HSP70 native proteins mouse protection VL 26

gp46/PSA-2 native protein mouse protection CL 30,32

recombinant protein mouse no protection CL 31

DNA vaccine mouse no protection CL 140


DNA vaccine mouse partial protection CL 138

recombinant protein + IL-12 mouse protection CL 34

p36/LACK DNA vaccine + protein expressed in vaccinia virus mouse protection CL 141

protein expressed in Listeria monocytogenes mouse partial protection CL 142

DNA vaccine mouse no protection VL 38

DNA vaccine + protein expressed in vaccinia virus mouse protection VL 143

DNA vaccine + protein expressed in vaccinia virus dog protection CVL 144


DNA vaccine + protein expressed in vaccinia virus mouse protection CL 145

DNA vaccine + protein expressed in Salmonella mouse protection CL 146



DC pulsed with native antigen mouse protection CL 139

recombinant protein fused with HIV TAT delivered in

pulsed DCmouse protection CL 37

CP recombinant protein mouse partial protection CL 148

A2, P4, P8 native antigen mouse partial protection CL 40

KMP-11 DNA vaccine hamster protection VL 41

DC pulsed with native antigen mouse protection CL 139

LCR1 protein expressed in BCG mouse partial protection VL 42

HASPB1 recombinant protein mouse protection VL 43

ORFF recombinant protein mouse partial protection VL 44

DNA vaccine + recombinant protein mouse protection VL 44

DNA vaccine mouse protection VL 149

P0 DNA vaccine mouse protection CL 45

PFR-2 DNA vaccine mouse protection CL 46

NH36 DNA vaccine mouse partial protection VL/CL 47

PPG recombinant protein hamster protection VL 48

CL, cutaneous leishmaniasis; VL, visceral leishmaniasis; ML, mucosal leishmaniasis; CVL, canine visceral leishmaniasis; DC, dendritic cells; BCG, Mycobac-

teriumbovisBacillus Calmette-Guerin.


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response toward detrimental Th2 responses,35however, suscep-tible BALB/c mice immunised with LACK had the ability tocontrol a subsequent infection with L. major.36Recently, a fusionof LACK with HIV-1 TAT transduction domain delivered indendritic cells has been shown to be superior to immunization

with LACK alone and improved disease outcome.37

Nevertheless,the protective efficacy of LACK has been mainly demonstrated inthe L. majormodel, and LACK failed to protect against visceralleishmaniasis.38

Other antigens tested against either CL or VL include amasti-gote cysteine proteases (CP),39cysteine proteinase A2 and amas-tigote membrane proteins P4 and P8,40kinetoplastid membraneprotein-11 (KMP-11),41amastigote LCR1,42hydrophilic acylatedsurface protein B1 (HASPB1),43 leishmanial antigen ORFF,44acidic ribosomal protein P0,45paraflagellar rod protein 2 (PFR-2),46NH36, a main component of the fucose-mannose ligand,47

prime-boost approach using DNA and recombinant protein.27Another vaccine candidate has been a GPI-anchored membraneprotein gp46 or Parasite Surface Antigen 2 (PSA-2), that belongsto a gene family present in all Leishmania species except L. bra-ziliensis.28PSA-2 is involved in macrophage invasion through the

interaction of its leucine rich repeats with complement receptor3.29 Immunization with the native polypeptides derived frompromastigotes protected mice against infection,30 but vaccina-tion with a recombinant protein derived from either promasti-gotes or amastigotes protein showed lack of protective efficacy.31Similarly, DNA vaccination conferred protection in mice whenused as either prophylactic32 or therapeutic vaccines.33 Anotherextensively tested antigen is the Leishmania homolog for recep-tors of activated C kinase (LACK) that is expressed through-out leishmanial life cycle.34 Immunization with LACK appearsto promote the expansion of IL-4 secreting T cells skewing the

Table 1.Summary of vaccination approaches discussed in the text

Antigen Vaccine formulationVaccinated

species

Outcome of

vaccinationTargeted disease Reference

ATP synthase

chain, -tubulin,

HSP70-related

protein 1

native protein in liposomes mice protection VL 49

-glutamylcysteinesynthetase recombinant protein mouse protection VL 50

P1 DNA vaccine, recombinant protein hamster partial protection VL 51

Leish-111f recombinant polyprotein mouse protection CL 53

recombinant polyprotein mouse protection VL 54

recombinant polyprotein dog no protection CVL 55

recombinant polyprotein + Glucantime dog protection CVL 56

Leish-110f recombinant polyprotein mouse protection CL/VL 57

Leish-F1 recombinant polyproteinhuman

Phase I

safe and immuno-

genicCL 150

recombinant polyprotein + sodium stibogluconatehuman

Phase I

safe and immuno-

genicML 60

recombinant polyprotein + meglumine antimoniate humanPhase I

safe and immuno-genic

CL 61

recombinant polyproteinhuman

Phase I

safe and immuno-

genicVL 59

maxadilan synthetic protein mouse protection CL 64

SP15 native protein/DNA vaccine mouse protection CL 65

LJM19 DNA vaccine hamster protection VL 66

dhfr-ts/ live attenuated parasites mouse protection CL 72

mouse no protection CL 73

cpa/ live attenuated parasites mouse protection CL 74

hamster protection CL 75

lpg2/ live attenuated parasites mouse protection CL 76

LdCen1/ live attenuated parasites mouse protection VL 81

PMM live attenuated parasites mouse protection CL 82

SIR2+/ live attenuated parasites mouse protection VL 83

CL, cutaneous leishmaniasis; VL, visceral leishmaniasis; ML, mucosal leishmaniasis; CVL, canine visceral leishmaniasis; DC, dendritic cells; BCG, Mycobac-

teriumbovisBacillus Calmette-Guerin.

(continued)


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an effective antileishmanial response might be linked to neutral-ization of saliva components.69However, recent insights into pro-tection induced by salivary gland components indicate that theprotective effect might be limited to a short-term exposure,70andthat the protective efficacy of saliva-based vaccine originating fromcolonized sand fly populations my be affected by variable responsesfollowing natural exposure.71

In view of disappointing outcomes from field trials of wholecell killed vaccines and the general inability of subunit vaccinesto trigger long-term immunity, the live-attenuated vaccine pro-vides an appealing alternative, but only a few attenuated strainshave been tested so far. Avirulent microorganisms can be gen-erated by a defined genetic alteration, eliminating the risk ofparasite reversion to the virulent phenotype. Vaccination withdihydrofolate reductase thymidylate synthase (dhfr-ts) knockoutparasites led to protection in a mouse model,72but failed in theprimate model.73Deletion of cysteine proteinases in L. mexicanaled to an attenuated strain capable of triggering partial protec-tion against challenge in animal models.74,75 These moderatelyencouraging results were thought to be due to rapid elimination

of parasites by the host, since knockout parasites were not persis-tent. Conversely, L. majorparasites lacking the lpg2gene persistedin mice without pathology and were able to confer protectionagainst infection,76 although required an adjuvant to be ableto protect resistant C57BL/6 mice.77However, over time thesemutants regained their ability to cause disease in the absence ofthe lpg2gene through an unknown compensatory mechanism,78suggesting that persistence may not be a desirable feature of alive-attenuated vaccine. It is already known that generation ofmemory cells during Leishmania infection does not require para-site persistence,79 therefore non-persistent attenuated mutantsmight offer a safer alternative. L. donovanicentrin null mutants

(LdCEN

-/-

) have been reported to have selective growth arrestin the amastigote stage of development, but were viable in cul-ture as promastigotes.80These mutants were unable to survive invitro in human macrophages and immunization with LdCen1-/-

knockouts protected mice against L. donovaniand L. brazilien-sis infections.81 We have also demonstrated that non-persistentphosphomannomutase (PMM) mutants were able to protect sus-ceptible mice against L. majorchallenge by early suppression ofIL-10 and IL-13 production and increased magnitude of T-cellresponses.82These parasites are viable in vitro, but do not sur-vive in macrophages or in vivo in mice, similarly to LdCEN -/-

parasites. The genetic attenuation does not necessarily require theproduction of null mutants. A single knockout of L. infantum

SIR2gene was sufficient to prevent amastigotes from undergoingintracellular replication in macrophages. Immunization with themutant triggered strong T-cell responses and conferred completeprotection in a VL mouse model.83A limitation of this approachis the presence of the second SIR2allele making reversion to viru-lence a likely occurrence. An interesting alternative to geneticallyattenuated strains is the use of non-pathogenic species such asL. tarentolaeas live vaccines, an approach that has been provensuccessful in mice against VL.84 The use of Leishamania non-pathogenic species might be equivalent to the role vaccinia virusplayed in eradication of smallpox.

and proteophosphoglycan (PPG).48 In addition, molecules suchas ATP synthase chain, -tubulin and heat shock 70-relatedprotein 1 precursor have been identified as novel vaccine can-didates.49 More recently, gamma-glutamylcysteine synthetase50and ribosomal P1 gene51have been shown to protect mice againstL. donovani.

To date, only one second generation vaccine, Leish-111f, has

been assessed in clinical trials.52 Initial immunization experimentsin a mouse model demonstrated that Leish-111f was able to pro-tect mice against L. major and L. amazonensis infection.53 Thereis some evidence that the Leish-111f vaccine can also induce par-tial protection against VL in animal models,54however, Leish-111ffailed to protect dogs against infection and did not prevent diseasedevelopment in a recent Phase III trial in dogs,55but was effectiveas therapeutic vaccine in combination with chemotherapy.56 Anoptimized version of the original construct, Leish-110f, has demon-strated strong immunogenicity and some protective efficacy againstL. infantumin mice,57and has been tested in dogs as a therapeu-tic vaccine in combination with chemotherapy and led to reducednumber of deaths and higher survival probability.58The Leish-111f

vaccine is moving forward into clinical trials as LeishF1, F2 and F3,and is being trialled in combination with the MPL-SE adjuvant. Arecent small scale clinical trial in a L. donovaniendemic area showedLeish-F1-MPL-SE was safe and well-tolerated in people regardlessof their prior VL exposure, and induced strong antigen-specificT-cell responses.59In addition, Leish-F1 has been shown to be safeand immunogenic when used in combination with pentavalentantimonials in CL and mucosal leishmaniasis patients.60,61HumanPhase I and II clinical trials of Leish-111f have been completed overthe past few years in Brazil, Peru, Columbia and India. New clinicaltrials of Leish-F2 are to be conducted against CL in Peru and VL inSudan (clinicaltrials.gov).

The sand fly injects Leishmania parasites in the presence ofsaliva, which contains a range of pharmacologically active mole-cules that can modulate hosts immune and inflammatory responsesand facilitate establishment of infection. For a number of years sali-vary gland antigens have been targeted as potential candidates forantileishmanial vaccine development, primarily against L. major.62Prior exposure of mice to bites of uninfected sand flies conferredprotection from L. major infection.63 Immunization with mol-ecules present in saliva, such as maxadilan64or a 15 kDa protein,SP15 65also induced protection against CL. It has been shown thatsalivary proteins, such as LJM19, protected hamsters from VL,66and immunization of dogs with salivary antigens led to the devel-opment of high IgG2 antibody levels and significant IFN pro-

duction.67

Peters et al.68

demonstrated that sand fly transmissionof parasites abrogates vaccine-induced protective immunity. Whilemice vaccinated with killed parasites were refractory to a needlechallenge, they were susceptible to the sand fly inoculum imply-ing that the protective responses in vaccinated animals were eithernot generated or not maintained. These data provide a rationalefor the inclusion of sand fly saliva components, which are specificto natural infection, in vaccine design. In support of this notion,it has been shown that children who underwent anti-VL delayedtype hypersensitivity (DTH) conversion also had increased titersof antibodies directed to sand fly saliva, suggesting that mounting


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re-activation of CD8+T cells is currently being developed againstVL (Paul Kaye, personal communication).

A relat ively new vaccine platform that has been recentlytested against leishmaniasis utilizes an engineered nanopar-ticle delivery system. A number of nanoparticle-based thera-peutics are currently in use in the clinic, several of which arebased on liposomes, which have low immunogenicity, excellent

safety profiles and established clinical-scale manufacturingprocess.124Such delivery system can also be used to carry anti-gens and make good vaccines.125Recently, various nanoparticlebased systems were used to deliver cysteine proteinases126 orsuperoxide dismutase B1 127and demonstrated feasibility of theapproach and exciting potential for developing new vaccinetechnology.

An antileishmanial vaccine faces a challenging task of induc-ing protective immunity. As parasites persist following naturalinfection providing a low level of sustained antigenic stimula-tion, the immunity that is induced by Leishmania is analogousto concomitant immunity, which puts a considerable constrainton vaccine efficacy. T-cell subsets contributing to such immunity

include CD4+T cells of the central memory79and effector Th1 128phenotypes, as well as CD8+T cells, which can play a critical rolein recall responses to secondary infection.129Therefore, an effica-cious vaccine would need to generate these subsets, but how togenerate these cells by vaccination remains a challenge. It is also atpresent unknown, which T cells may provide the best protectionand are most likely to survive long-term to fulfill their intendedrole. Recent studies suggest that the most protective CD4+T cellsare polyfunctional, capable of producing not just one, but severalcytokines.130CD4+ T cells of single specificity, secreting IFNonly, have limited capacity to provide durable protection againstLeishmania, whereas the ability of CD4+T cells to produce mul-

tiple cytokines (IFN

, TNF and IL-2) greatly increases the qual-ity of vaccine mediated responses.131In addition, elimination ofIL-10 promotes resistance, as this immunosuppressive cytokineappears to limit the generation of the protective T-cell subsetsfollowing vaccination.131Unfortunately, although there seem tobe clearly defined immunobiological goals for a vaccine, to datenone of the approaches have been successful in eliciting desirableprotective responses in humans.

Concluding Remarks

Preventive vaccines are recognized as the best and most cost-effective protection measure against pathogens, and are sav-

ing millions of lives every year across the globe. Leishmaniavaccine development has proven to be a difficult and challeng-ing task, which has been hampered an inadequate knowledgeof disease pathogenesis, the complexity of immune responsesneeded for protection and the cost of vaccine development. Theburden of the disease is concentrated in resource poor nations,and a lack of political will and philanthropic investment fur-ther aggravate the situation. However, the rise of biotechnol-ogy industries in endemic countries, such as India and Brazil,may provide an impetus for a vaccine development. There arealso new European based vaccine efforts including a synthetic

complexity of the parasite, the capacity to respond to several tar-gets may be a crucial prerequisite for a vaccine. Many candidateshave been selected based on the abundance, but this criteriondoes not necessarily correspond to their antigenicity. In termsof expression patterns, proteomic approaches provide valuableinformation for vaccine research, due to the importance of post-transcriptional regulation of gene expression. Improvements of

proteomic analysis, incorporating the use of subcellular fractionsseems to allow the identification of novel stage specific proteins.For example, the proteome-serological approach, can providea useful tool to identify highly antigenic, but poorly expressedproteins and provide a catalog of antigenic patterns as well asimmune response specificity patterns that may advance develop-ment of vaccines.111Proteomic approach combined with reversevaccinology112is also being employed in a search of new vaccinecandidates and thus far has successfully been used to identify twonovel antigens.113T-cell epitope prediction is yet another power-ful approach, that might accelerate antigen discovery and furtherrefinement of prediction tools will improve their reliability,114,115however, at this stage experimental verification of the candidates

is a necessity and a major limiting step considering a large num-ber of antigens that can be identified from such analyses.

Vaccine formulations will be pivotal for vaccine efficacy.Several strategies have been tested, but in general the tradi-tional approaches have worked poorly. Virally vectored vac-cines emerged as a very effective and eliciting robust responsesplatforms that might address the deficiencies of traditionaldelivery systems, particularly where cell mediated responses areneeded for protection.116 Recently, our group utilized a modelof recombinant influenza expressing a single, immunodomi-nant LACK

158173CD4 +T-cell peptide, and demonstrated that a

prime/boost approach resulted in considerable protection against

Leishmania in a mouse model and was associated with increasedIFNproduction by CD4+T cells (Kedzierska et al. manuscriptsubmitted). Influenza viruses are attractive candidates as vaccinevectors, with the approach being tried so far for HIV,117tubercu-losis,118malaria119and cancer.120These results point to the valueof recombinant influenza vector for Leishmania vaccination.Influenza viruses can be easily manipulated by a reverse genet-ics strategy121 to elicit prominent CD8+T-cell responses. Thus,the delivery of leishmanial epitopes in the context of influenzavector can facilitate the class I presentation in addition to classII presentation of a recombinant peptide. As the vector can bemanipulated by reverse genetics to include multiple epitopes, thisapproach has the capacity to generate broad protective responses

with the potential to overcome HLA restriction and provideimmunological coverage to the broader host population. A poten-tial obstacle for a vaccine based on a viral vector is safety. In caseof on influenza there is already a precedent in using live, tem-perature sensitive influenza virus in a FluMist vaccine approvedby the FDA (live-attenuated, intranasal vaccine).122 Moreover,the insertion of foreign sequences into the neuraminidase (NA)segment results in a virus that can express the recombinant pep-tide as part of the NA protein, but cannot release virus progenyfrom infected cells, rendering the virus highly attenuated.123Anadenovirus-based therapeutic vaccine targeting the induction/


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in research and development to move promising vaccine leadsalong the development pathway toward an effective and afford-able antileishmania vaccine.

Acknowledgements

I would like to thank Dr. Katherine Kedzierska for insightful andcritical review of the manuscript.

vaccine RAPSODI (www.fp7-rapsodi.eu) and a DNA basedLEISHDNAVAX (www.leishdnavax.org). New adjuvants arealso being developed and there are several clinical vaccine tri-als in progress and in planning.5Given the rapid progress inthe fields of parasite immunology and genomics, a successfulanti-Leishmania vaccine should be achievable sooner ratherthan later, however, there is a clear need for greater investment

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