QNAS

QnAs with Rino Rappuoli QNAS

Prashant Nair, Science Writer

From Edward Jenner’s breakthrough discovery in 1796 that inoculating an eight-year-old boy with cow- pox sores protected him against smallpox, the field of vaccinology has come a long way. Today, de- sign often begins with researchers scouring the DNA sequences of pathogens to exhume buried targets that might trigger a robust immune response in peo- ple. Once identified, such targets become the focus of vaccine development. To be sure, most licensed vac- cines are still manufactured by laboriously growing large batches of entire pathogens or their parts in vats of animal cells or chicken eggs, which serve as vaccine factories. But that approach is slowly yielding to ge- nome-guided methods. For example, efforts to target the relatively unchanging stalk of a protein on the surface of the flu virus have energized the search for a universal flu vaccine in recent years. Such a vaccine would render moot the virus’ notorious knack for evading the human immune system through con- stant mutation, and a handful of vaccine candi- Rino Rappuoli. Image courtesy of GlaxoSmithKline. dates are poised to enter clinical trials. Among the pioneers of the genome-guided approach to vaccine of meningitis. There are five serogroups of the bacte- development is National Academy of Sciences mem- rium Neisseria meningitidis, and we were well on our ber Rino Rappuoli, Chief Scientist at GlaxoSmithKline way toward conjugate for all serogroups but B (GSK) Vaccines in , . At the 2016 Keystone Symposium on Translational Vaccinology for Global using the traditional approach. This approach relied on Health, Rappuoli traced the history of a new era in a sugar capsule that surrounds the bacterium. But the ’ vaccine development that has come to be defined by structural similarity of the serogroup B s sugar coat to a undergirding advances in genetics and structural bi- polysaccharide found in human tissues meant that we ology. Rappuoli spoke to PNAS about the long road could not use our traditional approach for serogroup B. to this new generation of vaccines. PNAS: So you developed a “reverse” vaccine that has PNAS: More than a decade ago, you coined the term become something of a poster-child for genome- “reverse vaccinology” to describe a nontraditional ap- guided vaccine design. How was it designed? proach to vaccine design. Can you explain how the ap- proach differs from conventional vaccine development? Rappuoli: Around this time, Craig Venter (1) published the complete genome sequence of a bacterium in Rappuoli: The concept of reverse vaccinology dates Science magazine, and that led to the thinking that back to around 1996. From the beginning of vaccina- instead of purifying components of pathogens grown ’ tion s history, vaccines were made by growing patho- in the laboratory, we might begin with the genome gens and then either killing and injecting them or sequence of the pathogens and produce the compo- making live, attenuated versions of the pathogens for nents of interest. I asked Venter whether he would be inoculation. The polio virus vaccines—the Salk and Sa- willing to sequence the genome of meningococcus B, bin vaccines—are well-known examples of vaccines made in this way. The other way to make vaccines was and we started a collaboration. This was the first time by purifying components of pathogens that would that a vaccine was made by beginning with informa- elicit an immune response. All of these approaches tion in a computer rather than with pathogens grown meant that the pathogens had to be grown in the lab- in the laboratory. So we termed this backward ap- oratory. In the mid-1990s, we realized that these clas- proach “reverse vaccinology.” sical approaches to vaccination were not working for one important pathogen, the meningococcus B bacte- PNAS: How long did it take for the vaccine to be rium, which accounts for almost half of all known cases licensed?

www.pnas.org/cgi/doi/10.1073/pnas.1620659114 PNAS Early Edition | 1of3 Downloaded by guest on September 30, 2021 Rappuoli: We began the project in 1996, and by 2000 these advances have the potential to yet again change we had sequenced the bacterial genome and identi- the pace of vaccine development. fied the candidate antigens that we wanted to focus on. We published the findings in Science (2). For PNAS: Structural biology, for example, has enabled the next 13 years, we did all of the work to translate rapid strides toward a universal flu vaccine, and several the findings into a product for the market. In 2013, the tantalizing preclinical findings have been published. vaccine was approved by the European Medicines From your perch at the helm of one of the world’s fore- Agency, as well as in Canada and Australia. The US most pharmaceutical companies, do these efforts Food and Drug Administration approval followed in hold promise? 2015, with a designation of breakthrough therapy. Rappuoli: In the case of , we can look in people PNAS: When the vaccine was launched, it was not who have had the flu for antibodies to both circulating readily embraced by health economists in the United and past strains of the virus. It turns out that these so- Kingdom. What were the reasons behind the initial called broadly neutralizing antibodies recognize a portion skepticism and eventual acceptance? of the hemagluttinin (HA) antigen on the flu virus that was previously considered unimportant for vaccine develop- Rappuoli: Meningococcal disease has a high inci- ment. Subsequently, X-ray crystallography of this portion, dence in the United Kingdom, and there was a lot of called the stem region, and the monoclonal antibodies awareness about the severity and toll of the disease that bind to it, revealed important structural clues for among parents, pediatricians, as well as Public Health vaccine development. Now the focus is on antibodies England [a government agency tasked with evaluating that target the antigen’s stem. That said, the studies in this the cost-effectiveness of new drugs and vaccines to area are still mostly in the preclinical stage: more specif- safeguard public health]. Despite its severity, the ically, at the stage where the immunogens are being disease is rare, compared with many other childhood designed, with the hope of launching clinical trials in illnesses. So the UK’s Joint Committee on Vaccination the next couple of years. Those trials will prove whether and Immunization, another government group that in- the approach based on the HA stem is a viable one. cludes health economists, determined that the vac- cine was not cost-effective at any price. But there PNAS: Although childhood vaccines no doubt play was a lot of outcry from advocates, including parents vital roles in safeguarding public health, vaccines for the of affected children, arguing that the committee’s ini- elderly have not received nearly the same attention. Do tial conclusion was flawed. A year later, the same com- elderly populations represent an area of unmet medical mittee revised their recommendation, saying that need from the perspective of vaccine development? when all factors were considered, the vaccine was cost-effective at a low price. That recommendation Rappuoli: Only recently have people begun to think served as the basis for the government’s decision to about the usefulness of vaccines for the elderly. When give the vaccine to newborn children in the United people age, they may become susceptible to diseases Kingdom. In October 2016, almost a year after the against which they were once vaccinated, such as vaccine began to be administered to newborn chil- tetanus, pertussis, meningococcus, pneumococcus dren, Public Health England published a report in etc. So in an aging society we may have to explore The Lancet showing greater than 80% effectiveness the need for conventional vaccines for the elderly. against the disease in vaccinated individuals in the Another growing concern among elderly populations UK (3). is due to increasing antimicrobial resistance, particularly hospital-acquired infections. That’s an- PNAS: In your talk, you described a new generation of other area of unmet medical need where reverse vac- techniques that have together ushered in yet another cinology 2.0 might play a crucial role. Finally, it is not era in vaccine development: reverse vaccinology 2.0, far-fetched to envision a future in which cancer vac- as it were. Can you describe some of these advances? cines are used to delay or perhaps prevent the onset of cancer in aging populations, complementary to the Rappuoli: Today, genome sequencing has advanced current focus on treatments and cures. exponentially, compared with the 1990s. Today’sre- Until recently, the thinking has been that vaccines verse vaccinology approach involves sequencing doz- are not very efficacious at preventing disease in the ens of strains of the same species of organism obtained elderly because of their relatively weakened immune from a range of habitats worldwide to represent the responses. The influenza vaccine is often cited as an vast diversity of antigens that could inform vaccine de- example. But our recent studies with the recombinant velopment. Also, proteomics methods allow us to char- herpes zoster vaccine have shown, for example, that acterize the entire range of proteins expressed by a administering the vaccine with the AS01 adjuvant pathogen of interest. Moreover, 20 years ago, deter- can help maintain its efficacy even in 90-year-old mining the structure of proteins was an arduous and individuals (4). time-consuming task; today, we can determine the structure of a large number of antigens using high- PNAS: Thereactiveapproachtovaccinedevelopment throughput, high-resolution analytical techniques. The for emerging infectious diseases is now widely recognized other major advance in biotechnology is our ability to as an impediment to pandemic readiness and has spurred isolate human monoclonal antibodies from protected, prominent initiatives, such as the Coalition for Epidemic immune people in a high-throughput fashion. Together, Preparedness Innovations (CEPI), a public–private alliance

2of3 | www.pnas.org/cgi/doi/10.1073/pnas.1620659114 Nair Downloaded by guest on September 30, 2021 funded by the Wellcome Trust and the Bill and Melinda CEPI was one initiative that resulted from this Gates Foundation to fund early-stage trials of neglected meeting and is poised to make inroads toward the vaccine candidates. The Ebola vaccine is a familiar case in goal. But there are a handful of other such initiatives. point; by the time the vaccine tests got under way, the AtGSK,forexample,wemadeasimilarproposalto epidemic had begun to wane. Are you involved in CEPI or partner with the public sector and create a biopre- similar initiatives? paredness organization (BPO), in which we would contribute our know-how and resources for targets Rappuoli: Already around 1999, there was enough selected by the public sector on a no-cost/no-loss data to make a vaccine for Ebola, but because it was basis (and the public sector would assume the not cost-effective back then, there was no push to running costs of such an organization). Talks are manufacture and test it. The epidemic that ensued ongoing to determine whether CEPI and BPO should was a global wake-up call. There were a handful of be merged, and deliberations are likely to happen in experts who convened at the World Economic Forum Davos early next year. The hope is that we can get in Davos at the beginning of 2016 to address the commitments from various governments for such need for preparedness for emerging epidemics. a combined initiative.

1 Fleischmann RD, et al. (1995) Whole-genome random sequencing and assembly of Rd. Science 269(5223): 496–512. 2 Pizza M, et al. (2000) Identification of vaccine candidates against serogroup B meningococcus by whole-genome sequencing. Science 287(5459):1816–1820. 3 Parikh SR, et al. (2016) Effectiveness and impact of a reduced infant schedule of 4CMenB vaccine against group B meningococcal disease in England: A national observational cohort study. The Lancet 388(10061):2775–2782. 4 Cunningham AL, et al. (2016) Efficacy of the herpes zoster subunit vaccine in adults 70 years of age or older. N Engl J Med 375:1019–1032.

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