Current Status of the Sm14/GLA-SE Schistosomiasis Vaccine: Overcoming Barriers and Paradigms towards the First Anti-Parasitic Human(itarian) Vaccine

Miriam Tendler, Marília S Almeida, Monica M Vilar, Patrícia M Pinto, Gabriel Limaverde-Sousa, Miriam Tendler, Marília S Almeida, Monica M Vilar, Patrícia M Pinto, Gabriel Limaverde-Sousa

Abstract

Schistosomiasis, a disease historically associated with poverty, lack of sanitation and social inequality, is a chronic, debilitating parasitic infection, affecting hundreds of millions of people in endemic countries. Although chemotherapy is capable of reducing morbidity in humans, rapid re-infection demonstrates that the impact of drug treatment on transmission control or disease elimination is marginal. In addition, despite more than two decades of well-executed control activities based on large-scale chemotherapy, the disease is expanding in many areas including Brazil. The development of the Sm14/GLA-SE schistosomiasis vaccine is an emblematic, open knowledge innovation that has successfully completed phase I and phase IIa clinical trials, with Phase II/III trials underway in the African continent, to be followed by further trials in Brazil. The discovery and experimental phases of the development of this vaccine gathered a robust collection of data that strongly supports the ongoing clinical phase. This paper reviews the development of the Sm14 vaccine, formulated with glucopyranosyl lipid A (GLA-SE), from the initial experimental developments to clinical trials including the current status of phase II studies.

Keywords: FABP; Sm14; schistosomiasis; vaccine.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Timeline: Sm14/GLA-SE anti-schistosomiasis vaccine - from discovery phase to final product. MAPA: Brazilian Ministry of Agriculture.

References

    1. Chitsulo L., Engels D., Montresor A., Savioli L. The global status of schistosomiasis and its control. Acta Trop. 2000;77:41–51. doi: 10.1016/S0001-706X(00)00122-4.
    1. Steinmann P., Keiser J., Bos R., Tanner M., Utzinger J. Schistosomiasis and water resources development: Systematic review, meta-analysis, and estimates of people at risk. Lancet Infect. Dis. 2006;6:411–425. doi: 10.1016/S1473-3099(06)70521-7.
    1. Osakunor D.N.M., Woolhouse M.E.J., Mutapi F. Paediatric schistosomiasis: What we know and what we need to know. PLoS Negl. Trop. Dis. 2018;12:e0006144. doi: 10.1371/journal.pntd.0006144.
    1. Poole H., Terlouw D.J., Naunje A., Mzembe K., Stanton M., Betson M., Lalloo D.G., Stothard J.R. Schistosomiasis in pre-school-age children and their mothers in Chikhwawa district, Malawi with notes on characterization of schistosomes and snails. Parasit. Vectors. 2014;7:153. doi: 10.1186/1756-3305-7-153.
    1. Bergquist R., van Dam G.J., Xu J. Diagnostic tests for schistosomiasis. In: Jamieson B.G.M., editor. Schistosoma: Biology, Pathology and Control. 1st ed. CRC Press; Boca Raton, FL, USA: 2016. pp. 401–439.
    1. Coura J.R., Amaral R.S. Epidemiological and control aspects of schistosomiasis in Brazilian endemic areas. Mem. Inst. Oswaldo Cruz. 2004;99:13–19. doi: 10.1590/S0074-02762004000900003.
    1. Barbosa C.S., Araújo K.C., Antunes L., Favre T., Pieri O.S. Spatial distribution of schistosomiasis foci on Itamaracá Island, Pernambuco, Brazil. Mem. Inst. Oswaldo Cruz. 2004;99:79–83. doi: 10.1590/S0074-02762004000900014.
    1. Schistosomiasis. [(accessed on 14 September 2018)]; Available online: .
    1. Ahuja A., Baird S., Hicks J.H., Kremer M., Miguel E. Economics of Mass Deworming Programs. In: Bundy D.A.P., de Silva N., Horton S., Jamison D.T., Patton G.C., editors. Child and Adolescent Health and Development. The International Bank for Reconstruction and Development/The World Bank; Washington, DC, USA: 2017.
    1. Guidelines for School-Based Deworming Programs. [(accessed on 5 September 2018)]; Available online: .
    1. WHO School Deworming at a Glance. [(accessed on 25 September 2018)]; Available online:
    1. Molina-Hernández V., Mulcahy G., Pérez J., Martínez-Moreno Á., Donnelly S., O’Neill S.M., Dalton J.P., Cwiklinski K. Fasciola hepatica vaccine: We may not be there yet but we’re on the right road. Vet. Parasitol. 2015;208:101–111. doi: 10.1016/j.vetpar.2015.01.004.
    1. Bergquist N.R., Colley D.G. Schistosomiasis vaccine: Research to development. Parasitol. Today. 1998;14:99–104. doi: 10.1016/S0169-4758(97)01207-6.
    1. WHO CEWG Demonstration Projects: Background and Process. [(accessed on 25 September 2018)]; Available online:
    1. Santini-Oliveira M., Coler R.N., Parra J., Veloso V., Jayashankar L., Pinto P.M., Ciol M.A., Bergquist R., Reed S.G., Tendler M. Schistosomiasis vaccine candidate Sm14/GLA-SE: Phase 1 safety and immunogenicity clinical trial in healthy, male adults. Vaccine. 2016;34:586–594. doi: 10.1016/j.vaccine.2015.10.027.
    1. Lustigman S., Geldhof P., Grant W.N., Osei-Atweneboana M.Y., Sripa B., Basáñez M.-G. A research agenda for helminth diseases of humans: Basic research and enabling technologies to support control and elimination of helminthiases. PLoS Negl. Trop. Dis. 2012;6:e1445. doi: 10.1371/journal.pntd.0001445.
    1. Tendler M., Almeida M., Simpson A. Development of the Brazilian anti-schistosomiasis vaccine based on the recombinant fatty acid binding protein Sm14 plus GLA-SE adjuvant. Front. Immunol. 2015;6 doi: 10.3389/fimmu.2015.00218.
    1. Scapin M., Tendler M. Immunoprecipitins in human schistosomiasis detected with adult worm antigens released by 3M KC1. J. Helminthol. 1977;51:71–72. doi: 10.1017/S0022149X00007276.
    1. Tendler M., Scapin M. The presence of Schistosoma mansoni antigens in solutions used for storing adult worms. Rev. Inst. Med. Trop. Sao Paulo. 1979;21:293–296.
    1. Scarpin M., Tendler M., Messineo L., Katz N. Preliminary studies with a Schistosoma mansoni saline extract inducing protection in rabbits against the challenge infection. Rev. Inst. Med. Trop. Sao Paulo. 1980;22:164–172.
    1. Tendler M., Scapin M., Tendler M., Scapin M. Schistosoma mansoni antigenic extracts obtained by different extraction procedures. Mem. Inst. Oswaldo Cruz. 1981;76:103–109. doi: 10.1590/S0074-02761981000200001.
    1. Tendler M., Lima A.O., Pinto R.M., Cruz M.Q., Brascher H.M., Katz N., Tendler M., Lima A.O., Pinto R.M., Cruz M.Q., et al. Immunogenetic and protective activity of an extract of Schistosoma mansoni. Mem. Inst. Oswaldo Cruz. 1982;77:275–283. doi: 10.1590/S0074-02761982000300006.
    1. Tendler M., Pinto R.M., Bambirra E.A., Cruz M.Q., Lima A.O., Tendler M., Pinto R.M., Bambirra E.A., Cruz M.Q., Lima A.O. Acquired resistance of mice against S. mansoni and lung granulomatous reaction induced by BCG. Mem. Inst. Oswaldo Cruz. 1983;78:147–151. doi: 10.1590/S0074-02761983000200003.
    1. Tendler M., Magalhães Pinto R., Côrtes M., Gebara G. Schistosoma mansoni: Comparative evaluation of different routes of experimental infection. Rev. Inst. Med. Trop. São Paulo. 1985;27:111–114. doi: 10.1590/S0036-46651985000300001.
    1. Tendler M., Pinto R.M., Lima A.O., Gebara G., Katz N. Schistosoma mansoni: Vaccination with adult worm antigens. Int. J. Parasitol. 1986;16:347–352. doi: 10.1016/0020-7519(86)90113-X.
    1. Tendler M. Schistosoma mansoni: Protective antigens. Mem. Inst. Oswaldo Cruz. 1987;82:125–128. doi: 10.1590/S0074-02761987000800021.
    1. Almeida M.S.S., Pinto R.M., Noronha D., Tendler M., Katz N., Almeida M.S.S., Pinto R.M., Noronha D., Tendler M., Katz N. Schistosoma mansoni—NZ rabbit-model: Resistance due to infection and active immunization with adult worm antigen. Mem. Inst. Oswaldo Cruz. 1987;82:233. doi: 10.1590/S0074-02761987000800043.
    1. Almeida M.S., Pinto R.M., Noronha D., Katz N., Tendler M. Curative and protective activity in rabbits after reinfection with Schistosoma mansoni: A new model of immunity? J. Parasitol. 1989;75:308–310. doi: 10.2307/3282780.
    1. Tendler M., Almeida M.S., Pinto R.M., Noronha D., Katz N. Schistosoma mansoni-New Zealand rabbit model: Resistance induced by infection followed by active immunization with protective antigens. J. Parasitol. 1991;77:138–141. doi: 10.2307/3282571.
    1. Tendler M., Pinto R.M., de Oliveira Lima A., Savino W., Katz N. Vaccination in murine schistosomiasis with adult worm-derived antigens: Variables influencing protection in outbred mice. Int. J. Parasitol. 1991;21:299–306. doi: 10.1016/0020-7519(91)90031-2.
    1. Tendler M., Pinto R.M., de Oliveira Lima A., Savino W., Katz N. Vaccination in murine schistosomiasis with adult worm derived antigens—II. Protective and immune response in inbred mice. Mem. Inst. Oswaldo Cruz. 1992;87:281–286. doi: 10.1590/S0074-02761992000500053.
    1. Moser D., Tendler M., Griffiths G., Klinkert M.Q. A 14-kDa Schistosoma mansoni polypeptide is homologous to a gene family of fatty acid binding proteins. J. Biol. Chem. 1991;266:8447–8454.
    1. Tendler M., Brito C.A., Vilar M.M., Serra-Freire N., Diogo C.M., Almeida M.S., Delbem A.C., Silva J.F.D., Savino W., Garratt R.C., et al. A Schistosoma mansoni fatty acid-binding protein, Sm14, is the potential basis of a dual-purpose anti-helminth vaccine. Proc. Natl. Acad. Sci. USA. 1996;93:269–273. doi: 10.1073/pnas.93.1.269.
    1. Angelucci F., Johnson K.A., Baiocco P., Miele A.E., Brunori M., Valle C., Vigorosi F., Troiani A.R., Liberti P., Cioli D., et al. Schistosoma mansoni fatty acid binding protein: Specificity and functional control as revealed by crystallographic structure. Biochemistry. 2004;43:13000–13011. doi: 10.1021/bi048505f.
    1. Pertinhez T.A., Sforça M.L., Alves A.C., Ramos C.R.R., Ho P.L., Tendler M., Zanchin N.I.T., Spisni A. Letter to the Editor: 1H, 15N and 13C resonance assignments of the apo Sm14-M20(C62V) protein, a mutant of Schistosoma mansoni Sm14. J. Biomol. NMR. 2004;29:553–554. doi: 10.1023/B:.
    1. Ramos C.R.R., Spisni A., Oyama S., Sforça M.L., Ramos H.R., Vilar M.M., Alves A.C., Figueredo R.C.R., Tendler M., Zanchin N.I.T., et al. Stability improvement of the fatty acid binding protein Sm14 from S. mansoni by Cys replacement: Structural and functional characterization of a vaccine candidate. Biochim. Biophys. Acta BBA-Proteins Proteom. 2009;1794:655–662. doi: 10.1016/j.bbapap.2008.12.010.
    1. Giera M., Kaisar M.M.M., Derks R.J.E., Steenvoorden E., Kruize Y.C.M., Hokke C.H., Yazdanbakhsh M., Everts B. The Schistosoma mansoni lipidome: Leads for immunomodulation. Anal. Chim. Acta. 2018;1037:107–118. doi: 10.1016/j.aca.2017.11.058.
    1. Rodríguez-Pérez J., Rodríguez-Medina J.R., García-Blanco M.A., Hillyer G.V. Fasciola hepatica: Molecular cloning, nucleotide sequence, and expression of a gene encoding a polypeptide homologous to a Schistosoma mansoni fatty acid-binding protein. Exp. Parasitol. 1992;74:400–407. doi: 10.1016/0014-4894(92)90202-L.
    1. Almeida M.S., Torloni H., Lee-Ho P., Vilar M.M., Thaumaturgo N., Simpson A.J.G., Tendler M. Vaccination against Fasciola hepatica infection using a Schistosoma mansoni defined recombinant antigen, Sm14. Parasite Immunol. 2003;25:135–137. doi: 10.1046/j.1365-3024.2003.00619.x.
    1. Study of Safety and Immune Response of the Sm14 Vaccine in Adults of Endemic Regions. [(accessed on 17 September 2018)]; Available online: .
    1. WHO Guideline on Country Pharmaceutical Pricing Policies. World Health Organization; Geneva, Switzerland: 2013. WHO Guidelines Approved by the Guidelines Review Committee.

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