Rino Rappuoli#

Fields of research#

• Diphtheria and CRM197. Characterization of the phages carrying the gene coding for diphtheria toxin, the nucleotide sequence of the toxin gene and several genes coding for non toxic mutants. CRM197, one of the mutants characterized is now carrier of many conjugate vaccines.

• Pertussis. Cloning and sequencing of the genes coding for the five subunits of pertussis toxin (1986), its side directed mutagenesis (1998), and the construction of a Bordetella pertussis strain producing a non toxic form of pertussis toxin (1989). The vaccine containing this molecule was tested in phase I (1989-90), phase II (1991-2) and phase III (1993-95) efficacy trials. The vaccine showed high efficacy against clinical disease, it was licensed in Italy and Europe and used in humans since 1993. The mutant form of pertussis toxin used in the vaccine represents the first protein constructed by rational drug design that has been approved for human use.

• Meningoccocal conjugate vaccines. Development and clinical tests of the first conjugate meningococcal vaccines. In 1991-1993 phase I-II clinical trials started in The Gambia, United Kingdom, and the United States. The promising results in phase II studies encouraged the Public Health Laboratory Service (PHLS) in the United Kingdom to start a program for the clinical development of a conjugate vaccine against meningococcus C. In 1999-2000 the vaccine was licensed in the UK, and by 2001 had eliminated most of the meningococcal C cases in the UK. Tetravalent conjugate vaccines to cover four strains (MenACYW) were developed and licensed worldwide.

• Mucosal adjuvants. Technologies developed for pertussis were applied to design non toxic derivatives of cholera and Escherichia coli enterotoxins. The systematic study of many non toxic derivatives of these toxins resulted in the selection of two non toxic mutants (LTK63 and LTR72) which are today believed to be the most promising mucosal adjuvants available.

• Helicobacter pylori. Development of the first mouse model and the classification of the clinical isolates into pathogenic and less pathogenic strains (type I and II, respectively). Cloning, characterization and sequencing of several important antigens such as the Vacuolating cytotoxin (VacA), the cytotoxin-associated immunodominant antigen (CagA). Discovery of a Type IV secretion apparatus, which injects the protein CagA into the host cells, which in turn phosphorylates the bacterial protein. A vaccine based on the major antigens entered the clinical development, however after a successful phase I it was put on hold, mainly for commercial reasons.
• Cellular microbiology. In 1996 the review “Cellular Microbiology Emerging” (Science; 271: 315-316) by Cossart P, Boquet P, Normark S, Rappuoli R coined the term “Cellular Microbiology” to formalize the marriage between cell biologists and microbiologists. The new discipline was adopted by the scientific community and has since given vent to a series of meetings with this title, to the founding of a scientific journal, and to the publication of two textbooks.

• Adjuvant: Contributed to the licensing of the MF59 adjuvant for human use. Today, MF59 is a leading candidate for many vaccines, including pandemic influenza. In 2016 the MF59 adiuvanted influenza vaccine was licensed by the FDA for vaccination of the elderly in the USA.

• Reverse vaccinology and meningococcus B. Collaborating with Craig Venter at TIGR and Richard Moxon at Oxford University to sequence the genome of serogroup B meningococcus with the idea of using this new technology to find novel antigens and develop a vaccine which had not been solved for decades using conventional technologies. The genomic approach to vaccine development was named reverse vaccinology and resulted in the discovery of Bexsero, the first vaccine able to provide coverage against meningococcal serogroup B in infants and adolescents, which was approved by the European Medicinal Agency in November 2012. In January 2015 the US Food and Drug Administration (FDA) granted approval of Bexsero in adolescents and young adults from 10 years through 25 years of age. The data from the national immunization program in the UK confirm the very high efficacy of the vaccine in preventing meningococcal B disease.

• Pandemic influenza. Demonstrated that any pandemic influenza caused by the virus H5 can be prevented by MF59-adjuvanted vaccine, independently of the virus used for vaccination.

• Neglected disease - GVGH Institute: Conceived and designed a non profit institute to develop vaccines against neglected diseases. . The institute has access to all technologies and know-how available at the GSK Vaccines company. So far GVGH developed a conjugate vaccine for typhoid fever and is presently in clinical development with a Shigella vaccine supported by a grant from the Gates Foundation.

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