Generation of a Peptide Vaccine Candidate against Falciparum Placental Malaria Based on a Discontinuous Epitope
Abstract
:1. Introduction
2. Materials and Methods
2.1. Synthetic Peptide Design and Conjugation
2.2. Animal Immunizations
2.3. ELISAs
2.4. Statistical Analysis
3. Results
3.1. N10-C22 Is the Minimal Epitope for 3D10 Recognition, but Does Not Elicit Cross-Reactive Antibodies
3.2. 3D10 Recognizes a Discontinuous Epitope in SD1
3.3. Immunization with SD1CLIPS Elicited Cross-Reactive VAR2CSA Antibodies
3.4. Fine Specificity and Avidity of Anti-SD1CLIPS Antibodies in Individual Mice
3.5. SD1CLIPS Elicits Cross-Reactive Antibodies in a Rabbit
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Fried, M.; Duffy, P.E. Maternal malaria and parasite adhesion. J. Mol. Med. 1998, 76, 162–171. [Google Scholar] [CrossRef]
- Fried, M.; Domingo, G.J.; Gowda, C.D.; Mutabingwa, T.K.; Duffy, P.E. Plasmodium falciparum: Chondroitin sulfate A is the major receptor for adhesion of parasitized erythrocytes in the placenta. Exp. Parasitol. 2006, 113, 36–42. [Google Scholar] [CrossRef] [PubMed]
- Gamain, B.; Trimnell, A.R.; Scheidig, C.; Scherf, A.; Miller, L.H.; Smith, J.D. Identification of multiple chondroitin sulfate A (CSA)-binding domains in the var2CSA gene transcribed in CSA-binding parasites. J. Infect. Dis. 2005, 191, 1010–1013. [Google Scholar] [CrossRef] [Green Version]
- Salanti, A.; Dahlback, M.; Turner, L.; Nielsen, M.A.; Barfod, L.; Magistrado, P.; Jensen, A.T.; Lavstsen, T.; Ofori, M.F.; Marsh, K.; et al. Evidence for the involvement of VAR2CSA in pregnancy-associated malaria. J. Exp. Med. 2004, 200, 1197–1203. [Google Scholar] [CrossRef] [PubMed]
- Salanti, A.; Staalsoe, T.; Lavstsen, T.; Jensen, A.T.; Sowa, M.P.; Arnot, D.E.; Hviid, L.; Theander, T.G. Selective upregulation of a single distinctly structured var gene in chondroitin sulphate A-adhering Plasmodium falciparum involved in pregnancy-associated malaria. Mol. Microbiol. 2003, 49, 179–191. [Google Scholar] [CrossRef] [PubMed]
- Mordmuller, B.; Sulyok, M.; Egger-Adam, D.; Resende, M.; de Jongh, W.A.; Jensen, M.H.; Smedegaard, H.H.; Ditlev, S.B.; Soegaard, M.; Poulsen, L.; et al. First-in-human, Randomized, Double-blind Clinical Trial of Differentially Adjuvanted PAMVAC, A Vaccine Candidate to Prevent Pregnancy-associated Malaria. Clin. Infect. Dis. 2019, 69, 1509–1516. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sirima, S.B.; Richert, L.; Chene, A.; Konate, A.T.; Campion, C.; Dechavanne, S.; Semblat, J.P.; Benhamouda, N.; Bahuaud, M.; Loulergue, P.; et al. PRIMVAC vaccine adjuvanted with Alhydrogel or GLA-SE to prevent placental malaria: A first-in-human, randomised, double-blind, placebo-controlled study. Lancet Infect. Dis. 2020, 20, 585–597. [Google Scholar] [CrossRef]
- Chene, A.; Gangnard, S.; Guadall, A.; Ginisty, H.; Leroy, O.; Havelange, N.; Viebig, N.K.; Gamain, B. Preclinical immunogenicity and safety of the cGMP-grade placental malaria vaccine PRIMVAC. EBioMedicine 2019, 42, 145–156. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gnidehou, S.; Mitran, C.J.; Arango, E.; Banman, S.; Mena, A.; Medawar, E.; Lima, B.A.S.; Doritchamou, J.; Rajwani, J.; Jin, A.; et al. Cross-Species Immune Recognition Between Plasmodium vivax Duffy Binding Protein Antibodies and the Plasmodium falciparum Surface Antigen VAR2CSA. J. Infect. Dis. 2019, 219, 110–120. [Google Scholar] [CrossRef]
- Mitran, C.J.; Mena, A.; Gnidehou, S.; Banman, S.; Arango, E.; Lima, B.A.S.; Lugo, H.; Ganesan, A.; Salanti, A.; Mbonye, A.K.; et al. Antibodies to Cryptic Epitopes in Distant Homologues Underpin a Mechanism of Heterologous Immunity between Plasmodium vivax PvDBP and Plasmodium falciparum VAR2CSA. mBio 2019, 10. [Google Scholar] [CrossRef] [Green Version]
- Pandey, M.; Ozberk, V.; Langshaw, E.L.; Calcutt, A.; Powell, J.; Batzloff, M.R.; Rivera-Hernandez, T.; Good, M.F. Skin infection boosts memory B-cells specific for a cryptic vaccine epitope of group A streptococcus and broadens the immune response to enhance vaccine efficacy. NPJ Vaccines 2018, 3, 15. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Mitchell, D.A.J.; Dupuy, L.C.; Sanchez-Lockhart, M.; Palacios, G.; Back, J.W.; Shimanovskaya, K.; Chaudhury, S.; Ripoll, D.R.; Wallqvist, A.; Schmaljohn, C.S. Epitope mapping of Ebola virus dominant and subdominant glycoprotein epitopes facilitates construction of an epitope-based DNA vaccine able to focus the antibody response in mice. Hum. Vaccines Immunother. 2017, 13, 2883–2893. [Google Scholar] [CrossRef] [PubMed]
- Bajic, G.; Maron, M.J.; Adachi, Y.; Onodera, T.; McCarthy, K.R.; McGee, C.E.; Sempowski, G.D.; Takahashi, Y.; Kelsoe, G.; Kuraoka, M.; et al. Influenza Antigen Engineering Focuses Immune Responses to a Subdominant but Broadly Protective Viral Epitope. Cell Host Microbe 2019, 25, 827–835. [Google Scholar] [CrossRef] [PubMed]
- Bangaru, S.; Lang, S.; Schotsaert, M.; Vanderven, H.A.; Zhu, X.; Kose, N.; Bombardi, R.; Finn, J.A.; Kent, S.J.; Gilchuk, P.; et al. A Site of Vulnerability on the Influenza Virus Hemagglutinin Head Domain Trimer Interface. Cell 2019, 177, 1136–1152. [Google Scholar] [CrossRef]
- Watanabe, A.; McCarthy, K.R.; Kuraoka, M.; Schmidt, A.G.; Adachi, Y.; Onodera, T.; Tonouchi, K.; Caradonna, T.M.; Bajic, G.; Song, S.; et al. Antibodies to a Conserved Influenza Head Interface Epitope Protect by an IgG Subtype-Dependent Mechanism. Cell 2019, 177, 1124–1135. [Google Scholar] [CrossRef]
- George, M.T.; Schloegel, J.L.; Ntumngia, F.B.; Barnes, S.J.; King, C.L.; Casey, J.L.; Foley, M.; Adams, J.H. Identification of an Immunogenic Broadly Inhibitory Surface Epitope of the Plasmodium vivax Duffy Binding Protein Ligand Domain. mSphere 2019, 4. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Chen, E.; Salinas, N.D.; Huang, Y.; Ntumngia, F.; Plasencia, M.D.; Gross, M.L.; Adams, J.H.; Tolia, N.H. Broadly neutralizing epitopes in the Plasmodium vivax vaccine candidate Duffy Binding Protein. Proc. Natl. Acad. Sci. USA 2016, 113, 6277–6282. [Google Scholar] [CrossRef] [Green Version]
- Jones, G.L.; Edmundson, H.M.; Spencer, L.; Gale, J.; Saul, A. The use of maleimidocaproyloxysuccinimide to prepare malarial peptide carrier immunogens. Immunogenicity of the linking region. J. Immunol. Methods 1989, 123, 211–216. [Google Scholar] [CrossRef]
- Timmerman, P.; Puijk, W.C.; Meloen, R.H. Functional reconstruction and synthetic mimicry of a conformational epitope using CLIPS technology. J. Mol. Recognit. 2007, 20, 283–299. [Google Scholar] [CrossRef]
- Chen, S.W.; Van Regenmortel, M.H.; Pellequer, J.L. Structure-activity relationships in peptide-antibody complexes: Implications for epitope prediction and development of synthetic peptide vaccines. Curr. Med. Chem. 2009, 16, 953–964. [Google Scholar] [CrossRef]
- Van Regenmortel, M.H. What is a B-cell epitope? Methods Mol. Biol. 2009, 524, 3–20. [Google Scholar] [CrossRef] [PubMed]
- Amoah, L.E.; Abagna, H.B.; Akyea-Mensah, K.; Lo, A.C.; Kusi, K.A.; Gyan, B.A. Characterization of anti-EBA175RIII-V in asymptomatic adults and children living in communities in the Greater Accra Region of Ghana with varying malaria transmission intensities. BMC Immunol. 2018, 19, 34. [Google Scholar] [CrossRef] [PubMed]
- Ssewanyana, I.; Arinaitwe, E.; Nankabirwa, J.I.; Yeka, A.; Sullivan, R.; Kamya, M.R.; Rosenthal, P.J.; Dorsey, G.; Mayanja-Kizza, H.; Drakeley, C.; et al. Avidity of anti-malarial antibodies inversely related to transmission intensity at three sites in Uganda. Malar. J. 2017, 16, 67. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Adjah, J.; Fiadzoe, B.; Ayanful-Torgby, R.; Amoah, L.E. Seasonal variations in Plasmodium falciparum genetic diversity and multiplicity of infection in asymptomatic children living in southern Ghana. BMC Infect. Dis. 2018, 18, 432. [Google Scholar] [CrossRef] [Green Version]
- Anders, R.F. Multiple cross-reactivities amongst antigens of Plasmodium falciparum impair the development of protective immunity against malaria. Parasite Immunol. 1986, 8, 529–539. [Google Scholar] [CrossRef]
- Cadman, E.T.; Abdallah, A.Y.; Voisine, C.; Sponaas, A.M.; Corran, P.; Lamb, T.; Brown, D.; Ndungu, F.; Langhorne, J. Alterations of splenic architecture in malaria are induced independently of Toll-like receptors 2, 4, and 9 or MyD88 and may affect antibody affinity. Infect. Immun. 2008, 76, 3924–3931. [Google Scholar] [CrossRef] [Green Version]
- Ibison, F.; Olotu, A.; Muema, D.M.; Mwacharo, J.; Ohuma, E.; Kimani, D.; Marsh, K.; Bejon, P.; Ndungu, F.M. Lack of avidity maturation of merozoite antigen-specific antibodies with increasing exposure to Plasmodium falciparum amongst children and adults exposed to endemic malaria in Kenya. PLoS ONE 2012, 7, e52939. [Google Scholar] [CrossRef] [Green Version]
- Jain, D.; Salunke, D.M. Antibody specificity and promiscuity. Biochem. J. 2019, 476, 433–447. [Google Scholar] [CrossRef]
- Leoratti, F.M.; Durlacher, R.R.; Lacerda, M.V.; Alecrim, M.G.; Ferreira, A.W.; Sanchez, M.C.; Moraes, S.L. Pattern of humoral immune response to Plasmodium falciparum blood stages in individuals presenting different clinical expressions of malaria. Malar. J. 2008, 7, 186. [Google Scholar] [CrossRef] [Green Version]
- Ferreira, M.U.; Kimura, E.A.; De Souza, J.M.; Katzin, A.M. The isotype composition and avidity of naturally acquired anti-Plasmodium falciparum antibodies: Differential patterns in clinically immune Africans and Amazonian patients. Am. J. Trop. Med. Hyg. 1996, 55, 315–323. [Google Scholar] [CrossRef]
- Tutterrow, Y.L.; Salanti, A.; Avril, M.; Smith, J.D.; Pagano, I.S.; Ako, S.; Fogako, J.; Leke, R.G.; Taylor, D.W. High avidity antibodies to full-length VAR2CSA correlate with absence of placental malaria. PLoS ONE 2012, 7, e40049. [Google Scholar] [CrossRef]
- Babakhanyan, A.; Fang, R.; Wey, A.; Salanti, A.; Sama, G.; Efundem, C.; Leke, R.J.; Chen, J.J.; Leke, R.G.; Taylor, D.W. Comparison of the specificity of antibodies to VAR2CSA in Cameroonian multigravidae with and without placental malaria: A retrospective case-control study. Malar. J. 2015, 14, 480. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Saveria, T.; Oleinikov, A.V.; Wiliamson, K.; Chaturvedi, R.; Lograsso, J.; Keitany, G.J.; Fried, M.; Duffy, P. Antibodies to Escherichia coli-expressed C-terminal domains of Plasmodium falciparum variant surface antigen 2-chondroitin sulfate A (VAR2CSA) inhibit binding of CSA-adherent parasites to placental tissue. Infect. Immun. 2013, 81, 1031–1039. [Google Scholar] [CrossRef] [Green Version]
- Doritchamou, J.Y.; Herrera, R.; Aebig, J.A.; Morrison, R.; Nguyen, V.; Reiter, K.; Shimp, R.L.; MacDonald, N.J.; Narum, D.L.; Fried, M.; et al. VAR2CSA Domain-Specific Analysis of Naturally Acquired Functional Antibodies to Plasmodium falciparum Placental Malaria. J. Infect. Dis. 2016, 214, 577–586. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Thompson, E.A.; Ols, S.; Miura, K.; Rausch, K.; Narum, D.L.; Spangberg, M.; Juraska, M.; Wille-Reece, U.; Weiner, A.; Howard, R.F.; et al. TLR-adjuvanted nanoparticle vaccines differentially influence the quality and longevity of responses to malaria antigen Pfs25. JCI Insight 2018, 3. [Google Scholar] [CrossRef] [PubMed]
- Phillips, B.; Van Rompay, K.K.A.; Rodriguez-Nieves, J.; Lorin, C.; Koutsoukos, M.; Tomai, M.; Fox, C.B.; Eudailey, J.; Dennis, M.; Alam, S.M.; et al. Adjuvant-Dependent Enhancement of HIV Env-Specific Antibody Responses in Infant Rhesus Macaques. J. Virol. 2018, 92. [Google Scholar] [CrossRef] [Green Version]
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Mitran, C.J.; Higa, L.M.; Good, M.F.; Yanow, S.K. Generation of a Peptide Vaccine Candidate against Falciparum Placental Malaria Based on a Discontinuous Epitope. Vaccines 2020, 8, 392. https://doi.org/10.3390/vaccines8030392
Mitran CJ, Higa LM, Good MF, Yanow SK. Generation of a Peptide Vaccine Candidate against Falciparum Placental Malaria Based on a Discontinuous Epitope. Vaccines. 2020; 8(3):392. https://doi.org/10.3390/vaccines8030392
Chicago/Turabian StyleMitran, Catherine J., Lauren M. Higa, Michael F. Good, and Stephanie K. Yanow. 2020. "Generation of a Peptide Vaccine Candidate against Falciparum Placental Malaria Based on a Discontinuous Epitope" Vaccines 8, no. 3: 392. https://doi.org/10.3390/vaccines8030392