Profile of Rino Rappuoli

PROFILE Profile of Rino Rappuoli ino Rappuoli grew up in the shadow of what he describes as a testament to the devastating impact of infectious disease: Rthe unfinished wall of the Siena Cathe- dral in Siena, Italy. When the plague hit the city in 1348, it slashed the popula- tion from 100,000 to 30,000. ‘‘It basically shut down one of the most powerful economies of the time, and that momen- tum was lost forever. I see it as an example of what could happen today with pandemic influenza,’’ says Rappuoli, whose current research focuses on developing a vaccine for avian influenza. Rappuoli, currently the Global Head of Vaccines Research for Novartis Vaccines & Diagnostics (Siena, Italy), was elected as a foreign associate of the National Academy of Sciences in 2005. He has spent his career developing vaccines for pertussis, meningitis, and Helicobacter pylori and is jointly responsible for engineering the carrier protein used in many conjugate vaccines. He is credited with launching the field of reverse vaccinology, the first fruits of which are revealed in his Inaugural Article in this issue of PNAS Rino Rappuoli (1), where he describes a universal vaccine for serogroup B meningococcus. fellowship at Siena’s Sclavo Research to Alwin Pappenheimer, who became a Bucolic Beginnings Center, the Italian vaccine institute that mentor to Rappuoli. ‘‘He was one of Rappuoli was born in 1952, in Radicofani, had been developing and producing vac- the fathers of microbiology and immun- Italy, a village 40 miles south of Siena. cines for almost a century. ology....Heisanother person who really When he was 11, his family moved closer shaped my career,’’ says Rappuoli. Microbiology in America to Siena, enabling Rappuoli to attend high At Harvard Medical School, Rappuoli school in the city. He spent weekends and Almost immediately after joining the joined Murphy and Pappenheimer in summers helping his father produce Chi- institute, Rappuoli left to take on a their search for a new diphtheria vac- anti, the region’s signature red wine. As project in the United States. He knew cine. The project stemmed from work college approached, Rappuoli was torn that to work at the cutting edge of vac- Pappenheimer had done in 1972 (2, 3). between the desires to study poetry or cine science he needed to learn new Pappenheimer had mutagenized the science. ‘‘I chose science,’’ says Rappuoli. techniques in molecular biology and ge- diphtheria toxin gene and isolated a mu- ‘‘The moon landing and the sense of im- netic engineering. In 1979, he spent four tant with a single amino acid change. pending scientific revolution probably in- pivotal months at The Rockefeller Uni- This minute tweak rendered the mole- fluenced my thinking.’’ versity (New York, NY) as a visiting cule, called CRM197, nontoxic and ideal Rappuoli pursued his undergraduate scientist in the laboratory of Emil as a diphtheria vaccine. ‘‘This was a big studies at the University of Siena but Gotschlich, who pioneered meningococ- change in thinking because instead of yearned to experience science outside of cal vaccine studies in the 1960s. ‘‘He is using chemicals to detoxify the toxin, Italy. Wanderlust led him to Washington probably one of the smartest scientists you could modify the gene, and the bac- University in St. Louis, MO, where he I’ve ever met and probably the person teria would produce a molecule you studied bacterial mutagenesis during the who had the greatest impact on me,’’ wanted already to go for you. It is per- summer vacation after his third year of says Rappuoli. ‘‘He would just tell me haps the first example of rational design college. More important than the re- about science . how to approach the of natural molecules to yield efficient search, however, were his observations of problem and spend a lot of time teach- therapeutics or vaccines,’’ says Rappuoli. ing me. Sometimes you meet a person the bountiful conditions American scien- Conjugate Vaccines tists enjoyed. ‘‘In Italy, the theoretical who changes the way you think.’’ training was good, but the technology gap In 1980, Rappuoli spent a year at Har- In 1981, Rappuoli returned to Sclavo Re- was huge,’’ says Rappuoli, ‘‘and molecular vard Medical School (Boston, MA) in the search Center in Italy and launched his biology was 5 or 6 years behind the laboratory of John Murphy, who worked own laboratory. He continued his collabo- United States.’’ on Corynebacterium diphtheriae, which ration with Murphy and Pappenheimer After graduation, Rappuoli remained causes diphtheria. Murphy introduced at the University of Siena, where he Rappuoli to bacterial genetics and the This is a Proﬁle of a recently elected member of the National earned a Ph.D. in biological sciences for world of bacterial toxins, and he helped Academy of Sciences to accompany the member’s Inaugural his NMR studies of proteins and tissue Rappuoli learn new techniques in microbi- Article on page 10834. membranes. In 1978, he was offered a ology. Murphy also introduced Rappuoli © 2006 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0604892103 PNAS ͉ July 18, 2006 ͉ vol. 103 ͉ no. 29 ͉ 10831–10833 Downloaded by guest on September 28, 2021 and was charged with mass-producing States and Europe to shift from use of the cloned the H. pylori toxin, identified the CRM197. He succeeded in 1982, using old pertussis vaccine to the new acellular mechanism of action, and made a vac- classical genetics, but CRM197 was never one. ‘‘That was a milestone in vaccination cine that went into clinical trials. But by used for a diphtheria vaccine. The current because it was a switch from traditional the end of Phase I studies, commercial diphtheria vaccine was developed in and whole-cell killed-bacterial vaccines to interest in the vaccine was low. has been in use since 1924. ‘‘That’s the more sophisticated, modern purified vac- Although the work did not yield a vaccine that we still use today,’’ says Rap- cines,’’ Rappuoli says. vaccine, Rappuoli found that H. pylori puoli, ‘‘in large part because regulatory The development of the pertussis first attached to the eukaryotic cell and agencies and companies did not want to vaccine was particularly satisfying for Rap- then injected toxin directly through a change something that had been working puoli. In 1993, Italy adopted the use of hole in the membrane. ‘‘It was a totally for a century.’’ Thus, CRM197 was not the new vaccine, and within 2 years the new mechanism,’’ he says (6). Chiron, pursued as a diphtheria vaccine. disease was essentially eliminated. ‘‘So which was acquired by the pharmaceuti- However, CRM197 found an even that is basically one of the most beautiful cal company Novartis, has continued to broader application than for diphtheria. things that can happen if you do my probe the basic biology of the microbe. During the 1980s, other vaccine makers job....That’s been my motivation ever ‘‘We are starting to understand how were developing conjugate vaccines for since,’’ Rappuoli says. bacteria can cause cancer at the molecu- Hemophilus influenzae. Research by lar level, but we don’t have the full story John B. Robbins had established that Eliminating Serotype C Meningococcus yet,’’ says Rappuoli. The H. pylori toxin linking a polysaccharide to a carrier pro- ‘‘The next [vaccine] I thought I could triggers molecular changes in the cell tein could transform it into a powerful tackle with my team was meningococcus,’’ that resemble early stages of cancer. vaccine. Robbins suggested to Rappuoli says Rappuoli. Five primary serotypes ex- The work has led to many productive that CRM197 might make a good car- ist for Neisseria meningitides, the bacteria partnerships, including one with long- rier. ‘‘You vaccinate an infant with a responsible for meningitis and septicemia: time collaborator and fellow National polysaccharide, and there is absolutely A, B, C, Y, and W135. Rappuoli knew Academy of Sciences member Stanley no response. You link the polysaccha- from Gotschlich that capsule polysaccha- Falkow, a microbiologist at Stanford ride to a protein [such as CRM197], and rides were protective against serotype C. University (Stanford, CA) (7, 8). the response is dramatic. It’s the basis of That knowledge had been used to pro- As Rappuoli studied bacterial patho- many vaccines to date,’’ explains Rap- duce the meningococcal C vaccine, but genesis, he became increasingly aware puoli. Today, Rappuoli estimates that that microbiologists were growing bacte- every child in the United States and Eu- ria under artificial conditions that barely rope probably receives four or five vac- Eradicating whooping mimicked the real situations when these cinations with CRM197. It is a carrier microbes encountered humans. ‘‘We re- molecule for vaccines such as H. influen- cough in Italy was “one alized that some very important viru- zae, pneumococcus, and meningococcus. lence factors are not expressed when of the most beautiful you study the bacteria under those New Generation of Vaccines conditions,’’ says Rappuoli. He and his As with diphtheria, the new generation of things that can happen colleagues coined the term ‘‘cellular mi- vaccines against pertussis (whooping crobiology’’ to signal to the scientific cough) was made from a toxin that had if you do my job.” community, mainly to cell biologists and been deactivated with formaldehyde. ‘‘I microbiologists, that these two disci- didn’t waste any time doing that. I cloned plines should fuse into one. The idea, and sequenced the gene for pertussis the vaccine was not effective in infants. In which was published in a short essay in toxin and did what Pappenheimer had 1989, encouraged by promising results of Science, was immediately popular (9). A done 15 years before with diphtheria,’’ the first conjugate of CRM197 with H.

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