Corradin Giampietro, Group leader
Giampietro Corradin graduated in chemistry at the University of Padua and received his PhD degree in chemistry from the University of California, Santa Barbara, after completion of a thesis on the structure and function of cytochrome c. After a post-doctoral position in biochemistry at Dartmouth Medical School, Hanover, New Hampshire, he continued his training in molecular immunology at the National Jewish Hospital, Denver, Colorado. He joined the Institute of Biochemistry in 1979 where he was an Associate Professor. For the last 15 years the main focus of his laboratory has been the elucidation of the immunological mechanisms of protection in malaria using well-defined animal models. In addition, development of vaccine candidates has been actively pursued by introducing new and faster approaches for the identification, production and development of novel malaria vaccine candidates.
MALARIA: SEARCH OF ANTIGENS FOR THE DEVELOPMENT OF PROTECTIVE VACCINES
Malaria is a world-wide parasitic disease which affects millions of people especially young children and pregnant women. Among the measures directed toward the prevention of this disease, vaccines represent a cost-effective approach. Identification of molecules important in the elicitation of a protective immune response and their use in experimental animals to be followed by testing in human volunteers has been a constant goal of our laboratory.
Malaria is a parasitic disease transmitted during the blood meal of infected mosquitoes, which inoculate sporozoites into the mammalian host. Within minutes, sporozoites invade hepatocytes and develop into merozoites intracellularly by asexual schizogony. The merozoites then invade red blood cells, producing the various symptoms associated with the disease. The life cycle is completed when gametocytes are ingested during the blood meal of the mosquito vectors. Upon repeated infections, partial antibody-dependent immunity directed against the erythrocytic stage is elicited in humans.
Protective immunity against malaria can be obtained by immunizing mice and humans with irradiation-attenuated sporozoites. This immunity is the result of the effect of neutralizing antibodies recognizing free sporozoites in the blood stream and of CD4+ and CD8+ T cells which prevent the development of the parasite hepatic forms. Experiments performed in B cell deficient mice have demonstrated that, despite the absence of anti-sporozoite antibodies, protection is induced by irradiated sporozoite immunization. This suggests that T cells specific for proteins present in the intracellular hepatic stage play a predominant role in protection. Therefore, one of the aims in malaria vaccine research is to mimic the protective immune response induced by injection of irradiated sporozoites.
The impossibility of culturing sporozoites outside the mosquitos renders this vaccination approach impracticable on a large scale. Thus, considerable effort has been devoted to the identification of highly antigenic sporozoite derived antigens, which can substitute for the whole sporozoite in the design of anti-malaria vaccines. A second target of vaccine intervention is represented by the erythrocytic stage of the parasite and its specific antigens.
Our approach to vaccine development involves the use of long polypeptides containing various B, T-helper, and T-cytotoxic epitopes. The use of longer antigen fragments will also provide epitopes capable of binding to the various MHC class I and II molecules, thus overcoming the MHC restriction observed in response to shorter epitopes. This approach has lead to numerous malaria phase I clinical trials in record time.
While this work continues in order to optimize the vaccine formulation to be used in further clinical trials, the availability of the P. falciparum genome provides an ideal basis from which to identify new proteins associated with protective immune responses. To this effect, we performed a selection of new antigens using a genome-wide approach complemented with high-throughput peptide synthesis. We first identified potential protein antigens present on the surface of asexual malaria blood stages through bioinformatics and published transcriptome and proteome analysis. Amongst the proteins identified, we selected those that contain protein regions, which are relatively short (30-50 amino acid residues) and structurally stable as isolated fragments or longer unstructured regions ( up to 100 amino acids). All selected antigens were then tested in ELISA assay using a panel of sera from donors living in different malaria endemic areas. Recognition of these synthetic antigens varied from few to 100 %, thus identifying a number of new potential vaccine candidates.
Affinity purified antibodies recognize the infected red blood cells and are immunogenic in mice. Further characterization of these proteins using mouse specific or affinity purified human antibodies is underway. In order to select the most appropriate protective antigens, a series of assays like antibody dependent cytotoxic inhibition (ADCI) and growth inhibition assay (GIA) are being employed to determine the biological properties of purified antibodies. Results obtained to date demonstrate that our bioinformatics/chemical synthesis approach can lead to the identification of new proteins that can be targets of potential vaccines and/or drugs in a very short time frame (2 years, see reference Olugbile et al.). In addition, the antigen selection mechanism is of general application, and can be applied to any other pathogen where protection is mediated by antibodies.
- Arama C, Assefaw-Redda Y, Rodriguez A, Fernández C, Corradin G, Kaufmann SH, Reece ST, Troye-Blomberg M. Heterologous prime-boost regimen adenovector 35-circumsporozoite protein vaccine/recombinant Bacillus Calmette-Guérin expressing the Plasmodium falciparum circumsporozoite induces enhanced long-term memory immunity in BALB/c mice. Vaccine 2012 Jun 8;30(27):4040-5. doi: 10.1016/j.vaccine.2012.04.029. Epub 2012 Apr 19.
- Bernabeu M, Lopez FJ, Ferrer M, Martin-Jaular L, Razaname A, Corradin G, Maier AG, Del Portillo HA, Fernandez-Becerra C. Functional analysis of Plasmodium vivax VIR proteins reveals different subcellular localizations and cytoadherence to the ICAM-1 endothelial receptor. Cell Microbiol. 2012 Mar;14(3):386-400. doi: 10.1111/j.1462-5822.2011.01726.x. Epub 2011 Dec 28.
- Corradin G, Céspedes N, Verdini A, Kajava AV, Arévalo-Herrera M, Herrera S. Malaria vaccine development using synthetic peptides as a technical platform. Adv Immunol. 2012;114:107-49. doi: 10.1016/B978-0-12-396548-6.00005-6.
- Kulangara C, Luedin S, Dietz O, Rusch S, Frank G, Mueller D, Moser M, Kajava AV, Corradin G, Beck HP, Felger I. Cell biological characterization of the malaria vaccine candidate trophozoite exported protein 1. PLoS One. 2012;7(10):e46112. doi: 10.1371/journal.pone.0046112. Epub 2012 Oct 8.
- Olugbile S, Villard V, Bertholet S, Jafarshad A, Kulangara C, Roussilhon C, Frank G, Agak GW, Felger I, Nebie I, Konate K, Kajava AV, Schuck P, Druilhe P, Spertini F, Corradin G. Malaria vaccine candidate: design of a multivalent subunit α-helical coiled coil poly-epitope. Vaccine. 2011 Sep 16;29(40):7090-9. doi: 10.1016/j.vaccine.2011.06.122. Epub 2011 Jul 29.
- Arévalo-Herrera M, Soto L, Perlaza BL, Céspedes N, Vera O, Lenis AM, Bonelo A, Corradin G, Herrera S. Antibody-mediated and cellular immune responses induced in naive volunteers by vaccination with long synthetic peptides derived from the Plasmodium vivax circumsporozoite protein. Am J Trop Med Hyg. 2011 Feb;84(2 Suppl):35-42. doi: 10.4269/ajtmh.2011.09-0507.
- Arévalo-Herrera M, Vera O, Castellanos A, Céspedes N, Soto L, Corradin G, Herrera S. Preclinical vaccine study of Plasmodium vivax circumsporozoite protein derived-synthetic polypeptides formulated in montanide ISA 720 and montanide ISA 51 adjuvants. Am J Trop Med Hyg. 2011 Feb;84(2 Suppl):21-7. doi: 10.4269/ajtmh.2011.10-0110.
- Herrera S, Fernández OL, Vera O, Cárdenas W, Ramírez O, Palacios R, Chen-Mok M, Corradin G, Arévalo-Herrera M. Phase I safety and immunogenicity trial of Plasmodium vivax CS derived long synthetic peptides adjuvanted with montanide ISA 720 or montanide ISA 51. Am J Trop Med Hyg. 2011 Feb;84(2 Suppl):12-20. doi: 10.4269/ajtmh.2011.09-0516.
- malERA Consultative Group on Vaccines. A research agenda for malaria eradication: vaccines. PLoS Med. 2011 Jan 25;8(1):e1000398. doi: 10.1371/journal.pmed.1000398.
- Coppi A, Natarajan R, Pradel G, Bennett BL, James ER, Roggero MA, Corradin G, Persson C, Tewari R, Sinnis P. The malaria circumsporozoite protein has two functional domains, each with distinct roles as sporozoites journey from mosquito to mammalian host. J Exp Med. 2011 Feb 14;208(2):341-56. doi: 10.1084/jem.20101488. Epub 2011 Jan 24.
- Stubbs J, Olugbile S, Saidou B, Simpore J, Corradin G, Lanzavecchia A. Strain-transcending Fc-dependent killing of Plasmodium falciparum by merozoite surface protein 2 allele-specific human antibodies. Infect Immun. 2011 Mar;79(3):1143-52. doi: 10.1128/IAI.01034-10. Epub 2010 Dec 28.
- Corradin G, Kajava AV, Verdini A. Long synthetic peptides for the production of vaccines and drugs: a technological platform coming of age. Sci Transl Med. 2010 Sep 22;2(50):50rv3. doi: 10.1126/scitranslmed.3001387.
- Maestre A, Muskus C, Duque V, Agudelo O, Liu P, Takagi A, Ntumngia FB, Adams JH, Sim KL, Hoffman SL, Corradin G, Velez ID, Wang R. Acquired antibody responses against Plasmodium vivax infection vary with host genotype for duffy antigen receptor for chemokines (DARC). PLoS One. 2010 Jul 15;5(7):e11437. doi: 10.1371/journal.pone.0011437.
- Olugbile S, Habel C, Servis C, Spertini F, Verdini A, Corradin G. Malaria vaccines - The long synthetic peptide approach: Technical and conceptual advancements. Curr Opin Mol Ther. 2010 Feb;12(1):64-76.
- Corradin G, Kajava AV. Malaria vaccine: why is it taking so long? Expert Rev Vaccines. 2010 Feb;9(2):111-4. doi: 10.1586/erv.09.154.
- Bongfen SE, Ntsama PM, Offner S, Smith T, Felger I, Tanner M, Alonso P, Nebie I, Romero JF, Silvie O, Torgler R, Corradin G. The N-terminal domain of Plasmodium falciparum circumsporozoite protein represents a target of protective immunity. Vaccine. 2009 Jan 7;27(2):328-35. doi: 10.1016/j.vaccine.2008.09.097. Epub 2008 Nov 5.
- Dostert C, Guarda G, Romero JF, Menu P, Gross O, Tardivel A, Suva ML, Stehle JC, Kopf M, Stamenkovic I, Corradin G, Tschopp J. Malarial hemozoin is a Nalp3 inflammasome activating danger signal. PLoS One. 2009 Aug 4;4(8):e6510. doi: 10.1371/journal.pone.0006510.
- Gondeau C, Corradin G, Heitz F, Le Peuch C, Balbo A, Schuck P, Kajava AV. The C-terminal domain of Plasmodium falciparum merozoite surface protein 3 self-assembles into alpha-helical coiled coil tetramer. Mol Biochem Parasitol. 2009 Jun;165(2):153-61. doi: 10.1016/j.molbiopara.2009.01.015. Epub 2009 Feb 10.
- Audran R, Lurati-Ruiz F, Genton B, Blythman HE, Ofori-Anyinam O, Reymond C, Corradin G, Spertini F. The synthetic Plasmodium falciparum circumsporozoite peptide PfCS102 as a malaria vaccine candidate: a randomized controlled phase I trial. PLoS One. 2009 Oct 2;4(10):e7304. doi: 10.1371/journal.pone.0007304.
- Flueck C, Frank G, Smith T, Jafarshad A, Nebie I, Sirima SB, Olugbile S, Alonso P, Tanner M, Druilhe P, Felger I, Corradin G. Evaluation of two long synthetic merozoite surface protein 2 peptides as malaria vaccine candidates. Vaccine. 2009 May 5;27(20):2653-61. doi: 10.1016/j.vaccine.2009.02.081. Epub 2009 Mar 6.
- Kulangara C, Kajava AV, Corradin G, Felger I. Sequence conservation in Plasmodium falciparum alpha-helical coiled coil domains proposed for vaccine development. PLoS One. 2009 May 25;4(5):e5419. doi: 10.1371/journal.pone.0005419.
- Olugbile S, Kulangara C, Bang G, Bertholet S, Suzarte E, Villard V, Frank G, Audran R, Razaname A, Nebie I, Awobusuyi O, Spertini F, Kajava AV, Felger I, Druilhe P, Corradin G. Vaccine potentials of an intrinsically unstructured fragment derived from the blood stage-associated Plasmodium falciparum protein PFF0165c. Infect Immun. 2009 Dec;77(12):5701-9. doi: 10.1128/IAI.00652-09. Epub 2009 Sep 28.
- Romero JF, Ciabattini A, Guillaume P, Frank G, Ruggiero P, Pettini E, Del Giudice G, Medaglini D, Corradin G. Intranasal administration of the synthetic polypeptide from the C-terminus of the circumsporozoite protein of Plasmodium berghei with the modified heat-labile toxin of Escherichia coli (LTK63) induces a complete protection against malaria challenge. Vaccine. 2009 Feb 18;27(8):1266-71. doi: 10.1016/j.vaccine.2008.12.010. Epub 2008 Dec 26.
- Toure-Balde A, Perlaza BL, Sauzet JP, Ndiaye M, Aribot G, Tall A, Sokhna C, Rogier C, Corradin G, Roussilhon C, Druilhe P. Evidence for multiple B- and T-cell epitopes in Plasmodium falciparum liver-stage antigen 3. Infect Immun. 2009 Mar;77(3):1189-96. doi: 10.1128/IAI.00780-07. Epub 2009 Jan 12.
|Ahou Mireille Amiah||Trainee|