Assessment of the Plasmodium falciparum Preerythrocytic Antigen UIS3 as a Potential Candidate for a Malaria Vaccine
Rhea J Longley, Benedict R Halbroth, Ahmed M Salman, Katie J Ewer, Susanne H Hodgson, Chris J Janse, Shahid M Khan, Adrian V S Hill, Alexandra J Spencer, Rhea J Longley, Benedict R Halbroth, Ahmed M Salman, Katie J Ewer, Susanne H Hodgson, Chris J Janse, Shahid M Khan, Adrian V S Hill, Alexandra J Spencer
Abstract
Efforts are under way to improve the efficacy of subunit malaria vaccines through assessments of new adjuvants, vaccination platforms, and antigens. In this study, we further assessed the Plasmodium falciparum antigen upregulated in infective sporozoites 3 (PfUIS3) as a vaccine candidate. PfUIS3 was expressed in the viral vectors chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) and used to immunize mice in a prime-boost regimen. We previously demonstrated that this regimen could provide partial protection against challenge with chimeric P. berghei parasites expressing PfUIS3. We now show that ChAd63-MVA PfUIS3 can also provide partial cross-species protection against challenge with wild-type P. berghei parasites. We also show that PfUIS3-specific cellular memory responses could be recalled in human volunteers exposed to P. falciparum parasites in a controlled human malaria infection study. When ChAd63-MVA PfUIS3 was coadministered with the vaccine candidate P. falciparum thrombospondin-related adhesion protein (PfTRAP) expressed in the ChAd63-MVA system, there was no significant change in immunogenicity to either vaccine. However, when mice were challenged with double chimeric P. berghei-P. falciparum parasites expressing both PfUIS3 and PfTRAP, vaccine efficacy was improved to 100% sterile protection. This synergistic effect was evident only when the two vaccines were mixed and administered at the same site. We have therefore demonstrated that vaccination with PfUIS3 can induce a consistent delay in patent parasitemia across mouse strains and against chimeric parasites expressing PfUIS3 as well as wild-type P. berghei; when this vaccine is combined with another partially protective regimen (ChAd63-MVA PfTRAP), complete protection is induced.
Trial registration: ClinicalTrials.gov NCT01465048.
Keywords: Plasmodium; UIS3; liver stage; malaria; sterile protection; synergy; vaccines.
Copyright © 2017 Longley et al.
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References
- Plowe CV, Alonso P, Hoffman SL. 2009. The potential role of vaccines in the elimination of falciparum malaria and the eventual eradication of malaria. J Infect Dis 200:1646–1649. doi:10.1086/646613.
- Cohen J, Nussenzweig V, Nussenzweig R, Vekemans J, Leach A. 2010. From the circumsporozoite protein to the RTS, S/AS candidate vaccine. Hum Vaccin 6:90–96. doi:10.4161/hv.6.1.9677.
- . 2015. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet 386:31–45. doi:10.1016/S0140-6736(15)60721-8.
- Reyes-Sandoval A, Rollier CS, Milicic A, Bauza K, Cottingham MG, Tang CK, Dicks MD, Wang D, Longley RJ, Wyllie DH, Hill AV. 2012. Mixed vector immunization with recombinant adenovirus and MVA can improve vaccine efficacy while decreasing antivector immunity. Mol Ther 20:1633–1647. doi:10.1038/mt.2012.25.
- Ewer KJ, O'Hara GA, Duncan CJ, Collins KA, Sheehy SH, Reyes-Sandoval A, Goodman AL, Edwards NJ, Elias SC, Halstead FD, Longley RJ, Rowland R, Poulton ID, Draper SJ, Blagborough AM, Berrie E, Moyle S, Williams N, Siani L, Folgori A, Colloca S, Sinden RE, Lawrie AM, Cortese R, Gilbert SC, Nicosia A, Hill AV. 2013. Protective CD8+ T-cell immunity to human malaria induced by chimpanzee adenovirus-MVA immunisation. Nat Commun 4:2836. doi:10.1038/ncomms3836.
- Trimnell A, Takagi A, Gupta M, Richie TL, Kappe SH, Wang R. 2009. Genetically attenuated parasite vaccines induce contact-dependent CD8+ T cell killing of Plasmodium yoelii liver stage-infected hepatocytes. J Immunol 183:5870–5878. doi:10.4049/jimmunol.0900302.
- O'Hara GA, Duncan CJ, Ewer KJ, Collins KA, Elias SC, Halstead FD, Goodman AL, Edwards NJ, Reyes-Sandoval A, Bird P, Rowland R, Sheehy SH, Poulton ID, Hutchings C, Todryk S, Andrews L, Folgori A, Berrie E, Moyle S, Nicosia A, Colloca S, Cortese R, Siani L, Lawrie AM, Gilbert SC, Hill AV. 2012. Clinical assessment of a recombinant simian adenovirus ChAd63: a potent new vaccine vector. J Infect Dis 205:772–781. doi:10.1093/infdis/jir850.
- Ogwang C, Kimani D, Edwards NJ, Roberts R, Mwacharo J, Bowyer G, Bliss C, Hodgson SH, Njuguna P, Viebig NK, Nicosia A, Gitau E, Douglas S, Illingworth J, Marsh K, Lawrie A, Imoukhuede EB, Ewer K, Urban BC, Hill AVS, Bejon P, MVVC Group . 2015. Prime-boost vaccination with chimpanzee adenovirus and modified vaccinia Ankara encoding TRAP provides partial protection against Plasmodium falciparum infection in Kenyan adults. Sci Transl Med 7:286re285. doi:10.1126/scitranslmed.aaa2373.
- Longley RJ, Salman AM, Cottingham MG, Ewer K, Janse CJ, Khan SM, Spencer AJ, Hill AV. 2015. Comparative assessment of vaccine vectors encoding ten malaria antigens identifies two protective liver-stage candidates. Sci Rep 5:11820. doi:10.1038/srep11820.
- Spielmann T, Fergusen DJ, Beck HP. 2003. etramps, a new Plasmodium falciparum gene family coding for developmentally regulated and highly charged membrane proteins located at the parasite-host cell interface. Mol Biol Cell 14:1529–1544. doi:10.1091/mbc.E02-04-0240.
- Matuschewski K, Ross J, Brown SM, Kaiser K, Nussenzweig V, Kappe SH. 2002. Infectivity-associated changes in the transcriptional repertoire of the malaria parasite sporozoite stage. J Biol Chem 277:41948–41953. doi:10.1074/jbc.M207315200.
- Kaiser K, Matuschewski K, Camargo N, Ross J, Kappe SH. 2004. Differential transcriptome profiling identifies Plasmodium genes encoding pre-erythrocytic stage-specific proteins. Mol Microbiol 51:1221–1232. doi:10.1046/j.1365-2958.2003.03909.x.
- Limbach K, Aguiar J, Gowda K, Patterson N, Abot E, Sedegah M, Sacci J, Richie T. 2011. Identification of two new protective pre-erythrocytic malaria vaccine antigen candidates. Malar J 10:65. doi:10.1186/1475-2875-10-65.
- Le Roch KG, Zhou Y, Blair PL, Grainger M, Moch JK, Haynes JD, De La Vega P, Holder AA, Batalov S, Carucci DJ, Winzeler EA. 2003. Discovery of gene function by expression profiling of the malaria parasite life cycle. Science 301:1503–1508. doi:10.1126/science.1087025.
- Mueller AK, Labaied M, Kappe SH, Matuschewski K. 2005. Genetically modified Plasmodium parasites as a protective experimental malaria vaccine. Nature 433:164–167. doi:10.1038/nature03188.
- Tarun AS, Dumpit RF, Camargo N, Labaied M, Liu P, Takagi A, Wang R, Kappe SH. 2007. Protracted sterile protection with Plasmodium yoelii pre-erythrocytic genetically attenuated parasite malaria vaccines is independent of significant liver-stage persistence and is mediated by CD8+ T cells. J Infect Dis 196:608–616. doi:10.1086/519742.
- Mikolajczak SA, Jacobs-Lorena V, MacKellar DC, Camargo N, Kappe SH. 2007. L-FABP is a critical host factor for successful malaria liver stage development. Int J Parasitol 37:483–489. doi:10.1016/j.ijpara.2007.01.002.
- Sharma A, Yogavel M, Akhouri RR, Gill J, Sharma A. 2008. Crystal structure of soluble domain of malaria sporozoite protein UIS3 in complex with lipid. J Biol Chem 283:24077–24088. doi:10.1074/jbc.M801946200.
- Storch J, Thumser AE. 2010. Tissue-specific functions in the fatty acid-binding protein family. J Biol Chem 285:32679–32683. doi:10.1074/jbc.R110.135210.
- Longley RJ, Halbroth BR, Ewer KJ, Hill AV, Spencer AJ. 2015. Identification of immunodominant responses to the Plasmodium falciparum antigens PfUIS3, PfLSA1 and PfLSAP2 in multiple strains of mice. PLoS One 10:e0144515. doi:10.1371/journal.pone.0144515.
- Sauzet JP, Perlaza BL, Brahimi K, Daubersies P, Druilhe P. 2001. DNA immunization by Plasmodium falciparum liver-stage antigen 3 induces protection against Plasmodium yoelii sporozoite challenge. Infect Immun 69:1202–1206. doi:10.1128/IAI.69.2.1202-1206.2001.
- Yadava A, Nurmukhambetova S, Pichugin AV, Lumsden JM. 2012. Cross-species immunity following immunization with a circumsporozoite protein-based vaccine for malaria. J Infect Dis 205:1456–1463. doi:10.1093/infdis/jis220.
- Sheehy SH, Spencer AJ, Douglas AD, Sim BK, Longley RJ, Edwards NJ, Poulton ID, Kimani D, Williams AR, Anagnostou NA, Roberts R, Kerridge S, Voysey M, James ER, Billingsley PF, Gunasekera A, Lawrie AM, Hoffman SL, Hill AV. 2013. Optimising controlled human malaria infection studies using cryopreserved parasites administered by needle and syringe. PLoS One 8:e65960. doi:10.1371/journal.pone.0065960.
- Todryk SM, Pathan AA, Keating S, Porter DW, Berthoud T, Thompson F, Klenerman P, Hill AV. 2009. The relationship between human effector and memory T cells measured by ex vivo and cultured ELISPOT following recent and distal priming. Immunology 128:83–91. doi:10.1111/j.1365-2567.2009.03073.x.
- Matuschewski K. 2013. Murine infection models for vaccine development: the malaria example. Hum Vaccin Immunother 9:450–456. doi:10.4161/hv.23218.
- Butler NS, Schmidt NW, Vaughan AM, Aly AS, Kappe SH, Harty JT. 2011. Superior antimalarial immunity after vaccination with late liver stage-arresting genetically attenuated parasites. Cell Host Microbe 9:451–462. doi:10.1016/j.chom.2011.05.008.
- Douradinha B, van Dijk MR, Ataide R, van Gemert GJ, Thompson J, Franetich JF, Mazier D, Luty AJ, Sauerwein R, Janse CJ, Waters AP, Mota MM. 2007. Genetically attenuated P36p-deficient Plasmodium berghei sporozoites confer long-lasting and partial cross-species protection. Int J Parasitol 37:1511–1519. doi:10.1016/j.ijpara.2007.05.005.
- Mauduit M, Gruner AC, Tewari R, Depinay N, Kayibanda M, Chavatte JM, Franetich JF, Crisanti A, Mazier D, Snounou G, Renia L. 2009. A role for immune responses against non-CS components in the cross-species protection induced by immunization with irradiated malaria sporozoites. PLoS One 4:e7717. doi:10.1371/journal.pone.0007717.
- Good MF, Reiman JM, Rodriguez IB, Ito K, Yanow SK, El-Deeb IM, Batzloff MR, Stanisic DI, Engwerda C, Spithill T, Hoffman SL, Lee M, McPhun V. 2013. Cross-species malaria immunity induced by chemically attenuated parasites. J Clin Invest 2013:66634. doi:10.1172/jci66634.
- Bergmann-Leitner ES, Mease RM, De La Vega P, Savranskaya T, Polhemus M, Ockenhouse C, Angov E. 2010. Immunization with pre-erythrocytic antigen CelTOS from Plasmodium falciparum elicits cross-species protection against heterologous challenge with Plasmodium berghei. PLoS One 5:e12294. doi:10.1371/journal.pone.0012294.
- Guebre-Xabier M, Schwenk R, Krzych U. 1999. Memory phenotype CD8(+) T cells persist in livers of mice protected against malaria by immunization with attenuated Plasmodium berghei sporozoites. Eur J Immunol 29:3978–3986.
- Morrot A, Hafalla JC, Cockburn IA, Carvalho LH, Zavala F. 2005. IL-4 receptor expression on CD8+ T cells is required for the development of protective memory responses against liver stages of malaria parasites. J Exp Med 202:551–560. doi:10.1084/jem.20042463.
- Berenzon D, Schwenk RJ, Letellier L, Guebre-Xabier M, Williams J, Krzych U. 2003. Protracted protection to Plasmodium berghei malaria is linked to functionally and phenotypically heterogeneous liver memory CD8+ T cells. J Immunol 171:2024–2034. doi:10.4049/jimmunol.171.4.2024.
- Nganou-Makamdop K, van Gemert GJ, Arens T, Hermsen CC, Sauerwein RW. 2012. Long term protection after immunization with P. berghei sporozoites correlates with sustained IFNgamma responses of hepatic CD8+ memory T cells. PLoS One 7:e36508. doi:10.1371/journal.pone.0036508.
- Reyes-Sandoval A, Wyllie DH, Bauza K, Milicic A, Forbes EK, Rollier CS, Hill AV. 2011. CD8+ T effector memory cells protect against liver-stage malaria. J Immunol 187:1347–1357. doi:10.4049/jimmunol.1100302.
- Reyes-Sandoval A, Berthoud T, Alder N, Siani L, Gilbert SC, Nicosia A, Colloca S, Cortese R, Hill AV. 2010. Prime-boost immunization with adenoviral and modified vaccinia virus Ankara vectors enhances the durability and polyfunctionality of protective malaria CD8+ T-cell responses. Infect Immun 78:145–153. doi:10.1128/IAI.00740-09.
- Good MF, Doolan DL. 2010. Malaria vaccine design: immunological considerations. Immunity 33:555–566. doi:10.1016/j.immuni.2010.10.005.
- Tine JA, Lanar DE, Smith DM, Wellde BT, Schultheiss P, Ware LA, Kauffman EB, Wirtz RA, De Taisne C, Hui GS, Chang SP, Church P, Hollingdale MR, Kaslow DC, Hoffman S, Guito KP, Ballou WR, Sadoff JC, Paoletti E. 1996. NYVAC-Pf7: a poxvirus-vectored, multiantigen, multistage vaccine candidate for Plasmodium falciparum malaria. Infect Immun 64:3833–3844.
- Forbes EK, Biswas S, Collins KA, Gilbert SC, Hill AV, Draper SJ. 2011. Combining liver- and blood-stage malaria viral-vectored vaccines: investigating mechanisms of CD8+ T cell interference. J Immunol 187:3738–3750. doi:10.4049/jimmunol.1003783.
- Pichyangkul S, Tongtawe P, Kum-Arb U, Yongvanitchit K, Gettayacamin M, Hollingdale MR, Limsalakpetch A, Stewart VA, Lanar DE, Dutta S, Angov E, Ware LA, Bergmann-Leitner ES, House B, Voss G, Dubois MC, Cohen JD, Fukuda MM, Heppner DG, Miller RS. 2009. Evaluation of the safety and immunogenicity of Plasmodium falciparum apical membrane antigen 1, merozoite surface protein 1 or RTS,S vaccines with adjuvant system AS02A administered alone or concurrently in rhesus monkeys. Vaccine 28:452–462. doi:10.1016/j.vaccine.2009.10.022.
- Grifantini R, Finco O, Bartolini E, Draghi M, Del Giudice G, Kocken C, Thomas A, Abrignani S, Grandi G. 1998. Multi-plasmid DNA vaccination avoids antigenic competition and enhances immunogenicity of a poorly immunogenic plasmid. Eur J Immunol 28:1225–1232. doi:10.1002/(SICI)1521-4141(199804)28:04<1225::AID-IMMU1225>;2-6.
- Jiang G, Charoenvit Y, Moreno A, Baraceros MF, Banania G, Richie N, Abot S, Ganeshan H, Fallarme V, Patterson NB, Geall A, Weiss WR, Strobert E, Caro-Aquilar I, Lanar DE, Saul A, Martin LB, Gowda K, Morrissette CR, Kaslow DC, Carucci DJ, Galinski MR, Doolan DL. 2007. Induction of multi-antigen multi-stage immune responses against Plasmodium falciparum in rhesus monkeys, in the absence of antigen interference, with heterologous DNA prime/poxvirus boost immunization. Malar J 6:135. doi:10.1186/1475-2875-6-135.
- Mullarkey CE, Boyd A, van Laarhoven A, Lefevre EA, Veronica Carr B, Baratelli M, Molesti E, Temperton NJ, Butter C, Charleston B, Lambe T, Gilbert SC. 2013. Improved adjuvanting of seasonal influenza vaccines: preclinical studies of MVA-NP+M1 coadministration with inactivated influenza vaccine. Eur J Immunol 43:1940–1952. doi:10.1002/eji.201242922.
- Epstein JE, Tewari K, Lyke KE, Sim BK, Billingsley PF, Laurens MB, Gunasekera A, Chakravarty S, James ER, Sedegah M, Richman A, Velmurugan S, Reyes S, Li M, Tucker K, Ahumada A, Ruben AJ, Li T, Stafford R, Eappen AG, Tamminga C, Bennett JW, Ockenhouse CF, Murphy JR, Komisar J, Thomas N, Loyevsky M, Birkett A, Plowe CV, Loucq C, Edelman R, Richie TL, Seder RA, Hoffman SL. 2011. Live attenuated malaria vaccine designed to protect through hepatic CD8(+) T cell immunity. Science 334:475–480. doi:10.1126/science.1211548.
- Aguiar JC, Bolton J, Wanga J, Sacci JB, Iriko H, Mazeika JK, Han ET, Limbach K, Patterson NB, Sedegah M, Cruz AM, Tsuboi T, Hoffman SL, Carucci D, Hollingdale MR, Villasante ED, Richie TL. 2015. Discovery of novel Plasmodium falciparum pre-erythrocytic antigens for vaccine development. PLoS One 10:e0136109. doi:10.1371/journal.pone.0136109.
- Romero P, Maryanski JL, Corradin G, Nussenzweig RS, Nussenzweig V, Zavala F. 1989. Cloned cytotoxic T cells recognize an epitope in the circumsporozoite protein and protect against malaria. Nature 341:323–326. doi:10.1038/341323a0.
- McConkey SJ, Reece WH, Moorthy VS, Webster D, Dunachie S, Butcher G, Vuola JM, Blanchard TJ, Gothard P, Watkins K, Hannan CM, Everaere S, Brown K, Kester KE, Cummings J, Williams J, Heppner DG, Pathan A, Flanagan K, Arulanantham N, Roberts MT, Roy M, Smith GL, Schneider J, Peto T, Sinden RE, Gilbert SC, Hill AV. 2003. Enhanced T-cell immunogenicity of plasmid DNA vaccines boosted by recombinant modified vaccinia virus Ankara in humans. Nat Med 9:729–735. doi:10.1038/nm881.
- Hodgson SH, Ewer KJ, Bliss CM, Edwards NJ, Rampling T, Anagnostou NA, de Barra E, Havelock T, Bowyer G, Poulton ID, de Cassan S, Longley R, Illingworth JJ, Douglas AD, Mange PB, Collins KA, Roberts R, Gerry S, Berrie E, Moyle S, Colloca S, Cortese R, Sinden RE, Gilbert SC, Bejon P, Lawrie AM, Nicosia A, Faust SN, Hill AV. 2015. Evaluation of the efficacy of ChAd63-MVA vectored vaccines expressing circumsporozoite protein and ME-TRAP against controlled human malaria infection in malaria-naive individuals. J Infect Dis 211:1076–1086. doi:10.1093/infdis/jiu579.
- Franke-Fayard B, Trueman H, Ramesar J, Mendoza J, van der Keur M, van der Linden R, Sinden RE, Waters AP, Janse CJ. 2004. A Plasmodium berghei reference line that constitutively expresses GFP at a high level throughout the complete life cycle. Mol Biochem Parasitol 137:23–33. doi:10.1016/j.molbiopara.2004.04.007.
- Hafalla JC, Bauza K, Friesen J, Gonzalez-Aseguinolaza G, Hill AV, Matuschewski K. 2013. Identification of targets of CD8(+) T cell responses to malaria liver stages by genome-wide epitope profiling. PLoS Pathog 9:e1003303. doi:10.1371/journal.ppat.1003303.
- Bejon P, Andrews L, Andersen RF, Dunachie S, Webster D, Walther M, Gilbert SC, Peto T, Hill AV. 2005. Calculation of liver-to-blood inocula, parasite growth rates, and preerythrocytic vaccine efficacy, from serial quantitative polymerase chain reaction studies of volunteers challenged with malaria sporozoites. J Infect Dis 191:619–626. doi:10.1086/427243.
- Salman AM, Mogollon CM, Lin JW, van Pul FJ, Janse CJ, Khan SM. 2015. Generation of transgenic rodent malaria parasites expressing human malaria parasite proteins. Methods Mol Biol 1325:257–286. doi:10.1007/978-1-4939-2815-6_21.
- Jacobs-Lorena VY, Mikolajczak SA, Labaied M, Vaughan AM, Kappe SH. 2010. A dispensable Plasmodium locus for stable transgene expression. Mol Biochem Parasitol 171:40–44. doi:10.1016/j.molbiopara.2009.12.009.
- Lin JW, Annoura T, Sajid M, Chevalley-Maurel S, Ramesar J, Klop O, Franke-Fayard BM, Janse CJ, Khan SM. 2011. A novel 'gene insertion/marker out' (GIMO) method for transgene expression and gene complementation in rodent malaria parasites. PLoS One 6:e29289. doi:10.1371/journal.pone.0029289.
- Janse CJ, Franke-Fayard B, Mair GR, Ramesar J, Thiel C, Engelmann S, Matuschewski K, van Gemert GJ, Sauerwein RW, Waters AP. 2006. High efficiency transfection of Plasmodium berghei facilitates novel selection procedures. Mol Biochem Parasitol 145:60–70. doi:10.1016/j.molbiopara.2005.09.007.
- Menard R, Janse C. 1997. Gene targeting in malaria parasites. Methods 13:148–157. doi:10.1006/meth.1997.0507.
- Orr RY, Philip N, Waters AP. 2012. Improved negative selection protocol for Plasmodium berghei in the rodent malarial model. Malar J 11:103. doi:10.1186/1475-2875-11-103.
- Janse CJ, Ramesar J, Waters AP. 2006. High-efficiency transfection and drug selection of genetically transformed blood stages of the rodent malaria parasite Plasmodium berghei. Nat Protoc 1:346–356. doi:10.1038/nprot.2006.53.
- Epstein JE. 2013. Taking a bite out of malaria: controlled human malaria infection by needle and syringe. Am J Trop Med Hyg 88:3–4. doi:10.4269/ajtmh.2013.12-0715.
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