Riccardo Cortese[edit]

Riccardo Cortese (Siena, Italy, March 29, 1944 - Basel, Switzerland, April 27, 2017) was an Italian scientist, entrepreneur, and innovator in the field of gene expression, drug discovery and genetic vaccines. His work led to the development of novel therapeutic strategies for the prevention and cure of viral infections, including HIV, HCV, Ebola and RSV. He pioneered a novel platform technology based on simian adenoviral vectors for prophylactic and therapeutic vaccines, and authored more than 300 publications in peer reviewed journals in the field of gene expression, transcriptional control, molecular virology and immunology.

Scientific career[edit]

Riccardo Cortese received his medical degree in 1968 from the University of Naples, Italy. Shortly after, he joined the lab of Bruce Ames at the University of California Berkeley as a PhD student, where he studied transcriptional regulation and RNA post-transcriptional modification in bacteria. In 1973, he returned to Naples as an Assistant Professor at the Institute of Biochemistry of the II Medical School, where he pursued research efforts investigating post-transcriptional modifications of tRNA, dealing in particular with tRNA pseudouridylation (1-3)

In 1976 he took a post-doctoral position at the MRC Laboratory of Molecular Biology in Cambridge, England, where he forged lasting professional relationships with leading figures in Molecular Biology, including Max Perutz, John Gurdon, Fred Sanger and Sydney Brenner. While at the MRC, his research focus was the maturation of tRNAs in eukaryotic systems (4-7).

In 1979 Cortese was recruited as Group Leader at the EMBL-Heidelberg, and subsequently established and directed the Gene Expression Programme (now the Genome Biology Unit).

During this period, Cortese and his lab published numerous seminal papers on the transcriptional regulation of RNA polymerase III-transcribed genes (8-13) and on liver-specific gene expression. To identify gene products enriched in the liver, he undertook the first ever direct DNA sequencing experiment on tissue-specific cDNAs libraries (14).

In 1990, Cortese left EMBL to found and direct the Istituto di Ricerche di Biologia Molecolare (IRBM) in Pomezia (Rome, Italy), a joint venture between Merck and Sigma Tau, where he remained until 2006. In 2000, Merck bought out the shares it did not own in IRBM, making it a fully owned subsidiary.

At IRBM, Cortese created an internationally renowned research center with approximately 200 employees. IRBM’s research focus was the development of drugs and vaccines for the treatment of infectious diseases. He used Phage display technology to isolate peptides for diagnostic and vaccination purposes (15-22; for complete listing see Pubmed).

A substantial research effort at IRBM was in drug discovery aimed at identifying inhibitors of the hepatitis C virus (HCV), a virus that had been recently discovered but not yet fully characterized. The work at IRBM elucidated key features of the HCV replication cycle (23-25) and infection mechanisms (26) and positioned the IRBM among the leading research centers in the field of HCV. This work would later inform the development of a novel class of antiretroviral agents, HIV integrase inhibitors, and ultimately of an approved drug product, Isentress, the first anti-integrase of HIV to reach the market (^27-30)

In his last years at IRBM, Cortese oversaw the development of a new approach to vaccines based on chimpanzee adenoviral vectors (31). This became the founding idea of Okairos, a biotech company that he founded in 2007 upon leaving IRBM.

With Okairos, Cortese made major scientific contributions, establishing a successful pipeline of candidate vaccines against HCV, malaria, RSV and Ebola. These vaccines were tested in animal models and in clinical trials, demonstrating safety and immunogenicity (32-40).

The success of Okairos led to its acquisition by Glaxo-Smith Kline (GSK) in 2013; from that date the company changed its name to ReiThera, and continued independent work in the further development and manufacture of viral vector-based therapeutics and vaccines.

In 2015, Cortese founded a new company, Nouscom, dedicated to the generation of anti-cancer vaccines.

Cortese passed away in Basel, Switzerland on April 27, 2017 of metastatic cancer. He is survived by his wife of almost 50 years, Karen Jonkman, his daughter Irene, son Maurizio and five grandchildren.

Academic and professional recognitions[edit]

1991 Borgia Prize (awarded for innovative research in the field of gene expression)
First Chairman of the Italian Life Science Federation (FISV)
Chairman of the Scientific Advisory Board of the Institute of Genetics and Biophysics (IGB), Naples, Italy
Chairman of the User Committee of the CNR Genetic Engineering project
Coordinator of the National Commission for the Human Post-Genome organized by the Ministry of the University and Scientific Research (MURST), Italy
Member of the Academia Europaea (Pan-European Academy of Sciences Humanities and Letters)
Associate foreign member of the Academie des Sciences, 2002, France
Member of the Commission for the Project on the Stem Cell Research organized by the Ministry of Health, Italy
Elected Member of the Council of the European Molecular Biology Organization
Member of the Board of the European School of Molecular Medicine
Member of the Scientific Advisory Board of the S. Raffaele Hospital, Rome, Italy
Member of the Scientific Advisory Board of the University of Rome, Campus Biomedico, Rome, Italy
Member of the Scientific Advisory Board of the Italian College of Applied Molecular Medicine
Member of the Editorial Board of: The EMBO Journal; the European Journal of Biochemistry; Biotech Techniques; The European Journal of Genetics, Biological Chemistry, Combinatorial Chemistry.
Member of the Board of MolMed SPA
Editor of a volume “Combinatorial Libraries”, Walter De Gruyer, Berlin New York, 1996

Selected References[edit]

Singer C.E., Smith G.R., Cortese R. and Ames B.N. Mutant tRNAHis ineffective in repression and lacking two pseudouridine modifications. Nature New Biology 238, 72-74 (1972).
Cortese R., Kammen H.O., Spengler S.J. and Ames B.N. Biosynthesis of pseudouridine in transfer Ribonucleic Acid. Journal of Biological Chemistry 249, 1103-1108 (1974).
Cortese R., Landsberg R., Von Der Haar R.A., Umbarger H.E. and Ames B.N. Pleiotrophy of hisT mutants blocked in pseudouridine synthesis in tRNA: leucine and isoleucine-valine operons. Proc. Natl. Acad. Sci. USA 71, 1857-1861 (1974).
Melton D.A., Cortese R. Transcription of cloned tRNA genes and the nuclear partitioning of a tRNA precursor. Cell 18, 1165-1172 (1979).
Cortese R., Harland R., Melton D. Transcription of tRNA genes in vivo: Single-stranded compared to double-stranded templates. Proc. Natl. Acad. Sci. USA 77, 4147-4151 (1980).
Melton D.A., De Robertis E.M., Cortese R. Order and intracellular location of the events involved in the maturation of a spliced tRNA. Nature 284, 143-148 (1980).
Ciampi M.S., Melton D.A., Cortese R. Site-directed mutagenesis of a tRNA gene: base alterations in the coding region affect transcription. Proc. Natl. Acad. Sci. USA 79, 1388-1392 (1982).
Ciliberto G., Castagnoli L., Melton D.A., Cortese R. Promoter of a eukaryotic tRNAPro gene is composed of three noncontiguous regions. Proc. Natl. Acad. Sci. USA 79, 1195-1199 (1982).
Ciliberto G., Traboni C., Cortese R. Relationship between the two components of the split promoter of eukaryotic tRNA genes. Proc. Natl. Acad. Sci. USA 79, 1921-1925 (1982).
Traboni C., Ciliberto G., Cortese R. A novel method for site-directed mutagenesis: its application to an eukaryotic tRNAPro gene promoter. EMBO Journal 1, 415-420 (1982).
Dente L., Fasano O., Costanzo F., Traboni C., Ciliberto G., Cortese R. A prokaryotic tRNATyr gene, inactive in Xenopus laevis oocytes, is activated by recombination with a eukaryotic tRNAPro gene. EMBO Journal 1, 817-820 (1982).
Ciliberto G., Raugei G., Costanzo F., Dente L., Cortese R. Common and interchangeable elements in the promoters of genes transcribed by RNA polymerase III. Cell 32, 725-733 (1983).
Traboni C., Ciliberto G., Cortese R. Mutations in Box B of the promoter of a eucaryotic tRNAPro gene affect rate of transcription, processing, and stability of the transcripts. Cell 36,179-187 (1984).
Costanzo F., Castagnoli L., Dente L., Arcari P., Smith M., Costanzo P., Raugei G., Izzo P., Pietropaolo T.C., Bougueleret L., Cimino F., Salvatore F., Cortese R. Cloning of several cDNA segments for human liver proteins. EMBO Journal 2, 57-61 (1983).
Folgori A., Tafi R., Meola A., Felici F., Galfré G., Cortese R., Monaci P., Nicosia A. A general strategy to identify mimotopes of pathological antigens using only random peptide libraries and human sera. EMBO Journal 13, 2236-2243 (1994).
Cortese R., Monaci P., Nicosia A., Luzzago A., Felici F., Galfré G., Pessi A., Tramontano A. and Sollazzo M. Identification of biologically active peptides using random libraries displayed on phage. Current Opinion in Biotechnology 6, 73-80 (1995).
Meola A., Delmastro P., Monaci P., Luzzago A., Nicosia A., Felici F., Cortese R., Galfré G. Derivation of vaccines from mimotopes. Immunologic properties of Human Hepatitis B Virus Surface Antigen mimotopes displayed on filamentous phage. J. Immunol. 154, 3162-3172 (1995).
Martin F., Toniatti C., Salvati A.L., Ciliberto G., Cortese R., Sollazzo M. Coupling protein design and in vitro selection strategies: improving specificity and affinity of a designed β-protein IL-6 antagonist. Journal of Molecular Biology 255, 86-97 (1996).
Galfré G., Monaci P., Nicosia A., Luzzago A., Felici F., Cortese R. Immunization with Phage-Displayed Mimotopes. In: Methods in Enzymology, J. N. Abelson ed., vol. 267, ch. 6, pp. 109- 115 (1996).
Mecchia M., Casato M., Tafi R., Filocamo G., Bonomo L., Fiorilli M., Cortese R., Migliaccio G., Nicosia A. Nonrheumatoid IgM in Human Hepatitis C Virus-Associated Type II Cryoglobulinemia Recognize Mimotopes of the CD4-Like LAG-3 Protein. J. Immunol. 157, 3727-3736 (1996).
Cortese I., Tafi R., Grimaldi L.M.E., Martino G., Nicosia A., Cortese R. Identification of peptides specific for cerebrospinal fluid antibodies in multiple sclerosis by using phage libraries. Proc. Natl. Acad. Sci. USA 93, 20, 11063-11067 (1996).
Puntoriero G., Meola A., Lahm A., Zucchelli S., Bruni Ercole B., Tafi R., Pezzanera M., Mondelli M.U., Cortese R., Tramontano A., Galfré G., Nicosia A. Towards a solution for hepatitis C virus hypervariability: mimotopes of the hypervariable region 1 can induce antibodies cross-reacting with a large number of viral variants. EMBO Journal 17, 13, 3521-3533 (1998).
Failla C., Tomei L., De Francesco R. Both NS3 and NS4A are required for proteolytic processing of hepatitis C virus nonstructural proteins. J Virol. 68, 3753-3760 (1994).
Behrens S.E., Tomei L., De Francesco R. Identification and properties of the RNA-dependent RNA polymerase of hepatitis C virus. EMBO J.15,12-22 (1996).
Steinkühler C., Biasiol G., Brunetti M., Urbani A., Koch U., Cortese R., Pessi A., De Francesco R. Product inhibition of the hepatitis C virus NS3 protease. Biochemistry. 37, 8899-8905 (1998).
Scarselli E., Ansuini H., Cerino R., Roccasecca RM., Acali S., Filocamo G., Traboni C., Nicosia A., Cortese R., Vitelli A. The human scavenger receptor class B type I is a novel candidate receptor for the hepatitis C virus. EMBO J 2002;21:5017-25.
Summa V, Petrocchi A., Pace P., Matassa V.G., De Francesco R., Altamura S., Tomei L., Koch U., Neuner P. Discovery of alpha,gamma-diketo acids as potent selective and reversible inhibitors of hepatitis C virus NS5b RNA-dependent RNA polymerase. J Med Chem. 47, 14-7 (2004).
Summa V., Petrocchi A., Matassa V.G., Taliani M., Laufer R., De Francesco R., Altamura S., Pace P. HCV NS5b RNA-dependent RNA polymerase inhibitors: from alpha,gamma-diketoacids to 4,5-dihydroxypyrimidine- or 3-methyl-5-hydroxypyrimidinonecarboxylic acids. Design and synthesis. J Med Chem. 47(22),, 5336-5339 (2004).
Petrocchi A., Koch U., Matassa V.G., Pacini B., Stillmock K.A., Summa V. From dihydroxypyrimidine carboxylic acids to carboxamide HIV-1 integrase inhibitors: SAR around the amide moiety. Bioorg Med Chem Lett. 17,350-353 (2007).
Hazuda DJ., Anthony NJ., Gomez RP., Jolly SM., Wai JS., Zhuang L., Fisher TE., Embrey M., Guare JP. Jr, Egbertson MS., Vacca JP., Huff JR., Felock PJ., Witmer MV., Stillmock KA., Danovich R., Grobler J., Miller MD., Espeseth AS., Jin L., Chen IW., Lin JH., Kassahun K., Ellis JD., Wong BK., Xu W., Pearson PG., Schleif WA., Cortese R., Emini E., Summa V., Holloway MK., Young SD. A naphthyridine carboxamide provides evidence for discordant resistance between mechanistically identical inhibitors of HIV-1 integrase. Proc. Natl. Acad. Sci. USA 101, 11233-11238 (2004)
Folgori A., Capone S., Ruggeri L., Meola A., Sporeno E., Bruni Ercole B., Pezzanera M., Tafi R., Arcuri M., Fattori E., Lahm A., Luzzago A., Vitelli A., Colloca S., Cortese R., Nicosia A. A T-cell based HCV vaccine eliciting effective immunity against heterologous virus challenge in chimpanzees. Nat Med 12, 190-197 (2006).
Barnes E., Folgori A., Capone S., Swadling L., Aston S., Kurioka A., Meyer J., Huddart R., Smith K., Townsend R., Brown A., Antrobus R., Ammendola V., Naddeo M., O'Hara G., Willberg C., Harrison A., Grazioli F., Esposito ML., Siani L., Traboni C., Oo Y., Adams D., Hill A., Colloca S., Nicosia A., Cortese R., Klenerman P. Novel Adenovirus-Based Vaccines Induce Broad and Sustained T Cell Responses to HCV in Man. Sci Transl Med., 4, 115 (2012).
Colloca S., Barnes E., Folgori A., Ammendola V., Capone S, Cirillo A., Siani L., Naddeo M., Grazioli F., Esposito ML., Ambrosio M., Sparacino A., Bartiromo M., Meola A., Smith K., Kurioka A., O’Hara G.A., Ewer K. J., Anagnostou N., Bliss C., Hill AVS., Traboni C., Klenerman P., Cortese R., Nicosia A. Vaccine Vectors Derived from a Large Collection of Simian Adenoviruses Induce Potent Cellular Immunity Across Multiple Species. Sci Transl Med. 2012, 4:115.
Stanley DA., Honko AN., Asiedu C., Trefry JC., Lau-Kilby AW., Johnson JC., Hensley L., Ammendola V., Abbate A., Grazioli F., Foulds KE., Cheng C., Wang L., Donaldson MM., Colloca S., Folgori A., Roederer M., Nabel GJ., Mascola J., Nicosia A., Cortese R., Koup RA., Sullivan NJ. Chimpanzee adenovirus vaccine generates acute and durable protective immunity against ebolavirus challenge. Nat Med. 20, 1126-1129 (2014).
Swadling L., Capone S., Antrobus RD., Brown A., Richardson R., Newell EW., Halliday J., Kelly C., Bowen D., Fergusson J., Kurioka A., Ammendola V., Del Sorbo M., Grazioli F., Esposito ML., Siani ., Traboni C., Hill A., Colloca S., Davis M., Nicosia A., Cortese R., Folgori A., Klenerman P., Barnes E. A human vaccine strategy based on chimpanzee adenoviral and MVA vectors that primes, boosts, and sustains functional HCV-specific T cell memory. Sci Transl Med. 2014 Nov 5;6(261):261ra153.doi: 10.1126/scitranslmed.3009185.
Ledgerwood J.E., DeZure A.D., Stanley D.A., Coates E., Novik L., Enama ME., Berkowitz NM., Hu Z., Joshi G., Ploquin A., Sitar S., Gordon IJ., Plummer SA., Holman LA., Hendel CS., Yamshchikov G., Roman F., Nicosia A., Colloca S., Cortese R., Bailer RT., Schwartz RM., Roederer M., Mascola JR., Koup RA., Sullivan NJ., Graham BS.; the VRC 207 Study Team. Chimpanzee Adenovirus Vector Ebola Vaccine. Epub 2014 Nov 26 2014 Nov 26 N Engl J Med 2017 Mar 9;376(10):928-93 doi: 10.1056/NEJMoa1410863.
Ewer K., Rampling T., Venkatraman N., Bowyer G, Wright D, Lambe T., Imoukhuede E.B., Payne R., Fehling S.K., Strecker T., Biedenkopf N., Krähling V., Tully C.M., Edwards N.J., Bentley E.M., Samuel D., Labbé G., Jin J., Gibani M., Minhinnick A., Wilkie M., Poulton I., Lella N., Roberts R., Hartnell F., Bliss C., Sierra-Davidson K., Powlson J., Berrie E., Tedder R., Roman F., De Ryck I., Nicosia A., Sullivan N.J., Stanley D.A., Mbaya O.T., Ledgerwood J.E., Schwartz R.M., Siani L., Colloca S., Folgori A., Di Marco S., Cortese R., Wright E., Becker S., Graham B.S., Koup R.A., Levine M.M., Volkmann A., Chaplin .P, Pollard A.J., Draper S.J., Ballou W.R., Lawrie A., Gilbert S.C., Hill A.V A Monovalent Chimpanzee Adenovirus Ebola Vaccine - N Engl J Med. 2016 Apr 28;374(17):1635-46. doi: 10.1056/NEJMoa1411627. Epub 2015 Jan 28. PMID: 25629663.
Green C.A., Scarselli E., Sande C.J., Thompson A.J., De Lara C.M., Taylor K.S., Haworth K., Del Sorbo M., Angus B., Siani L., Di Marco S., Traboni C., Folgori A., Colloca S., Capone S., Vitelli A., Cortese R., Klenerman P., Nicosia A., Pollard A.J. Chimpanzee adenovirus- and MVA-vectored respiratory syncytial virus vaccine is safe and immunogenic in adults. Sci Transl Med. 2015 Aug 12;7(300):300ra126. doi: 10.1126/scitranslmed.aac5745.
Swadling L., Halliday J., Kelly C., Brown A., Capone S., Ansari M.A., Bonsall D., Richardson R., Hartnell F., Collier J., Ammendola V., Del Sorbo M., Von Delft A., Traboni C., Hill A.V., Colloca S., Nicosia A., Cortese R., Klenerman P., Folgori A., Barnes E. Highly-Immunogenic Virally-Vectored T-cell Vaccines Cannot Overcome Subversion of the T-cell Response by HCV during Chronic Infection. Vaccines. 2016 Aug 2;4(3):27. doi: 10.3390/vaccines4030027. PMID: 27490575.
Capone S., Brown A., Hartnell F., Sorbo M.D., Traboni C., Vassilev V., Colloca S., Nicosia A., Cortese R., Folgori A., Klenerman P., Barnes E., Swadling L. Optimising T cell (re)boosting strategies for adenoviral and modified vaccinia Ankara vaccine regimens in humans. NPJ Vaccines. 2020 Oct 12;5:94. doi: 10.1038/s41541-020-00240-0. eCollection 2020. PMID: 33083029.