In April 2014, GlaxoSmithKline and Novartis inked a megadeal unlike any in biopharmaceutical history. First, the two created a joint venture consumer healthcare business. A second part of the deal involved GSK divesting its marketed oncology portfolio and related R&D activities to its AKT inhibitor, as well as the granting of commercialization partner rights for future oncology products to Novartis for $16 billion. (For more on this, be sure to check out Is Oncology Back At GSK? Did It Ever Leave? on page 25). The third component included GSK’s acquisition of the Novartis global vaccines business (excluding influenza vaccines) for $5.25 billion, an amount nearly equal to the unit’s total sales revenue for 2015 ($5.38 billion)!
And although the company has been in the vaccine business for a long time, the increased responsibility that results from supplying vaccines to 90 percent of the world’s countries is an obligation Luc Debruyne, president of GSK Vaccines, does not take lightly. “When it comes to vaccines, if you don’t have scale, you just can’t be operationally effective,” says Debruyne. With over 16,000 people, three R&D centers, and 17 manufacturing sites making up GSK’s vaccine business, the company certainly has scale. Following Debruyne’s participation as a speaker at this year’s BIO International Convention, he took time out to share how the Novartis vaccine integration has been going, as well as why GSK sees vaccines as a growth opportunity — when so many others don’t.
WHY THE MASS EXODUS FROM THE BUSINESS OF VACCINES
Despite the global value of vaccines currently exceeding $34 billion (a number expected to reach nearly $100 billion by 2025), more companies have been opting to exit rather than enter the business of vaccinology (e.g.. two-thirds of the world’s vaccines are supplied by just four companies — GSK, Merck, Pfizer, and Sanofi Pasteur). Even countries are exiting the vaccine business. “Today, [June 7, 2016], it was announced that AJ Biologics was acquiring Denmark’s state-owned SSI vaccine production business,” shares Debruyne. “Back in 2012, the Netherlands Vaccine Institute was sold.”
According to Debruyne, the reason for the exodus of companies and small countries from vaccines is that to be profitable requires huge capital investments. “To give you an idea,” he shares, “over the last 10 years, GSK has invested $4 billion in vaccine infrastructure.” Another barrier to remaining in or entering into vaccinology is the lengthy timelines. “We’ve invested a total of £700 million (≈ $932 million) in two facilities in Belgium for pertussis and inactivated polio virus (IPV),” he explains. “The groundbreaking was in 2009, and the first commercial vaccine won’t roll out until 2018. Few companies or countries can afford to invest so much capital and wait so long before seeing any type of return. You really need to be the size of a company like GSK, with a diversity of revenue streams, to be able to make those types of large investments with long-time horizons.” GSK Vaccines began integrating the acquired Novartis vaccines business in 2015 and in May of that year stated it expected to reach a 30+ percent margin by 2020 (on mid- to high-single-digit sales growth on a CAGR basis at constant exchange rates). Some analysts estimate the profit margins for vaccines at Big Pharma companies to range between 10 and just over 40 percent. And although the business of vaccines is big money, when compared to the trillion-dollar worldwide biopharmaceutical industry, it represents a mere 2 to 3 percent.
Some argue that many companies have shied away from vaccines to focus on developing more-profitable drugs, because, historically, vaccines have been produced at relatively low prices and sold with low profit margins. But there are many pros to being in the business of vaccines. From a human health standpoint, “Nothing but clean drinking water can compete with vaccines as far as overall societal value,” Debruyne attests. “One dollar of investment in vaccines returns $44 to society.” A study looking at the benefits of vaccination in the United States between 1994 and 2013 estimated direct cost net savings of $295 billion and $1.38 trillion in total societal costs (i.e., the total cost to a society that includes private costs plus any external costs).
Luc Debruyne (right) with Life Science Leader Chief Editor Rob Wright
ONE COMPANY’S BARRIER CAN BE ANOTHER’S COMPETITIVE ADVANTAGE
Though there are many factors that make vaccines tricky (e.g., live vaccines can be troublesome to manufacture) and other barriers to entry (e.g., public agencies buying vaccines at capped prices), for those that know what they are doing, these same challenges can prove to be a competitive advantage. For example, in the U.S., Merck is the only company licensed to offer the measles vaccine and, consequently, has a captive market with about 50 percent of the purchases of its measles, mumps, and rubella (MMR) combination vaccine being made via the government’s Vaccine for Children Program.
“Unlike in pharma where you have to make back your profit before loss of patent exclusivity and generic incursion, in vaccines there are no patent cliffs to fall off,” Debruyne shares. “Most of the 39 vaccines GSK has on the market were discovered 20 years ago.” There’s an extra layer of complexity beyond that of pharmaceuticals. “In vaccines, we’re talking about living viruses — bacteria,” he emphasizes. “For instance, if you know anything about malaria, it’s caused by a parasite, which is genetically complex. So producing a vaccine against malaria, which took us 30 years, is much more involved than producing monoclonal antibodies.”
Debruyne notes that when Novartis owned the vaccine business, they were actually losing money. “But our commercial model is completely different,” he states. “Theirs was a single unit with its own commercial structure, and they didn’t have the power to negotiate.” Because vaccines are a public health issue, ministries of health are usually very interested in negotiating with vaccine manufacturers. According to Debruyne, the GSK model uses general managers who have the whole portfolio of company products at their disposal, not just vaccines. “We have country executive boards,” he says. “As such, for a government, there is only one GSK, and public health is very high on their negotiation agenda.” For example, for bacterial meningitis B, GSK had the vaccine, the data, and even approval in Europe. “The U.K. has the highest epidemiology of meningitis B. Just four weeks after we [GSK] closed the deal [with Novartis], we signed a partnership agreement with the U.K. government on a fair price. The U.K. is on track to vaccinate nearly 700,000 infants every year, and this effort will generate effectiveness data for other countries,” says Debruyne.
WHY GSK IS GOING AGAINST THE VACCINE EXODUS CRAZE
Debruyne has seen his share of M&As throughout his 30-plus-year career. And although he admits that M&As always require a big effort to successfully integrate, he views the Novartis acquisition as being quite unique because it involved three separate components. “We had a clear objective for why we wanted to acquire Novartis vaccines,” he says. “Of course, this was part of a much bigger deal with the consumer healthcare joint-venture creation and the oncology swap, but for years we realized we were held captive by Novartis with regard to their production of diphtheria tetanus (DT) in Marburg, Germany. As a vaccine manufacturer, to be dependent on the most important component necessary to manufacture key products is not a good place to be.”
Though DT was an important component of the deal with Novartis, there were other elements to consider, such as getting one of the industry’s top vaccine minds, Rino Rappuoli, Ph.D., who invented the reverse vaccinology process that resulted in the development of the first meningococcal B (MenB) vaccine, BEXSERO. (For more on this, be sure to read How GSK Vaccines’ CSO Solved The Unsolvable — The Story Of Reverse Vaccinology on page 28). “But they also had their GMMA [generalized modules for membrane antigens] technology, as well as their self-amplifying mRNA [messenger ribonucleic acid] platforms,” Debruyne attests. “GSK’s goal wasn’t to take on the assets and then kick out all the infrastructure. It wasn’t just the complementary science that made the deal so appealing. It was the scientists — the people.” Another reason the Novartis vaccine acquisition made such good business sense was the United States was an area, at least when it came to vaccines, where GSK had been lagging. “With the Novartis acquisition, we immediately laid our hands on the BEXSERO and MENVEO, so we now have the full alphabet of meningitis vaccines that cover A, B, C, W, and Y [meningitis strains],” he says. Although GSK had two of its own legacy meningitis vaccines — Nimenrix and Mencevax (divested to Pfizer in June 2015 to meet concerns raised by antitrust regulators) — these covered the same meningitis strains (i.e., A, C, W-135, and Y). And while available in 61 and 79 countries respectively, neither legacy vaccine was approved for the states. “Nimenrix might be in the U.S. by 2021 or 2022,” he affirms. “The acquisition of the Novartis assets gave us immediate access to the U.S. and allowed us to accelerate our U.S. market focus.” Beyond access to the U.S., Debruyne believes the science and scientists gained from Novartis would allow GSK to also accelerate its own vaccine innovation. But as is often the case when it comes to successful integration during an M&A, it is the people component that can be the most challenging.
DON’T BE ARROGANT DURING AN INTEGRATION
With any M&A, there’s always the chance for duplication. For example, GSK and Novartis both had respiratory syncytial virus (RSV) programs. “RSV is an unmet medical need killing many babies just after they are born,” explains Debruyne. “During the integration, we used our best scientists to determine the best RSV program to take forward and tried to make clear choices.” He says vaccine R&D programs, such as RSV, were integrated at a moderate speed, taking 12 to 15 months, while integration of commercial operations were done more rapidly, lasting 6 to 9 months. “With regard to manufacturing, a key objective was business continuity,” he says. “Doctors and governments don’t want to be told that you can’t deliver a vaccine on time because you are integrating two large companies. Integrating sounds straightforward, but it’s not that easy, as global supply networks are usually long-term agreements.” For this reason, integration of the Novartis vaccine manufacturing operations is deliberately being done slowly. According to Debruyne, multinational corporations can sometimes be arrogant when it comes to M&A integration. “They look at it and say, ‘I know how to do this. Just plug their system into ours and run with it.’ When it comes to manufacturing, you can lose a lot and make errors by not taking the time to understand how things operate.”
The downside of taking too much time during integration is the impact on employees. “As leaders, we often think we need to tell employees all of the specific details regarding an M&A. But what they really want to know is if they will have a job, will it be the same as what they have been doing, and who will be their boss.” Communications is a challenge, and something Debruyne admits to always being able to improve upon, especially during an integration. “When you are assigning and selecting employees, if you are not careful, it can take on a tone that’s overly transactional,” he states. “But you have to keep in mind: Of 10 people who may have to leave a company, at least nine are very good at what they do.” To better facilitate communication during the integration, Debruyne split his management team in two — one group focused only on the integration process, and the other dedicated to executing the day-to-day business operations. He retained oversight across the two groups. During the acquisition, Debruyne constantly reminded his team of the business objectives behind the integration (e.g., accelerate access to the U.S. market). He says in situations like this, it is always good to remind yourself — and your team — why you did the acquisition in the first place. Remember what the principles of the integration were, and stay focused on always executing on those. For example, he talks about the challenge of integrating two disparate ERP (enterprise resource planning) systems. “Yes, you want to go to one system, but for quality and business continuity purposes, you can’t just block each other [i.e., the two companies that are merging] from having access to each ERP,” he states. “That’s why we decided, for the time being, to let each system run separately. The biggest challenge of an integration isn’t the hard wiring, but how an organization is wired culturally.”
When asked what, if anything, he would do differently during the integration, Debruyne replies, “Communicate.” GSK’s vaccine president believes they did a great job on communicating to the people coming on board from Novartis. However, where they misstepped was with the folks from GSK. “We viewed the integration as being very synergistic and knew that most of GSK’s vaccine employees wouldn’t be touched,” he explains. “But they didn’t know this and were watching us give lots of attention to the newcomers. We shouldn’t have taken our GSK teams for granted.” Debruyne says, with hindsight, that is one reason why the company is now reinvesting in employee communication and engagement efforts.
One thing he would not do differently is constantly reminding employees of GSK’s values. “I never started a meeting without mentioning our corporate values — TRIP: transparency, respect for people, integrity, and patients,” he attests. “Getting people to focus on values is very helpful during the employee appointment and selection process. When people leave a company, how they are treated is reflected back on those who stay. You need people who are inspired to bring their very best. If an employee recently had a friend let go as a result of an M&A, and their perception is that person wasn’t valued, it can be very demotivational.” Debruyne says that how you treat people is the shadow your company casts, and that shadow not only impacts employee retention, but future recruitment as well.
Alex Hoos, M.D., Ph.D., SVP, Therapeutic Area Head for Oncology R&D and Head of Immuno-Oncology, GSK
Axel Hoos, M.D., Ph.D., is probably one of the biggest names in cancer drug development. After all, his scientific leadership not only led to a new paradigm for how to create cancer immunotherapies, but his development of ipilimumab while at Bristol-Myers Squibb (BMS) helped launch the entire immuno-oncology (IO) field! That being said, when the Wall Street Journal ran the April 22, 2014, headline, “Glaxo Exits Cancer Drugs,” one has to wonder if Hoos (who joined the company in 2012 and is the SVP, therapeutic area head for oncology R&D and head of immuno-oncology) suddenly regretted his most recent career move. If GSK was truly exiting oncology drug development, would they still need him? While Hoos attests, “Oncology is back at GSK,” the truth of the matter is that it actually never left. Though the mammoth deal included GSK shedding its marketed oncology portfolio and related R&D activities for $16 billion to Novartis, it also included a contractual obligation called a right of first negotiation (ROFN). This basically means that if GSK files an oncology R&D program for regulatory approval, it needs to first be shown to Novartis. In other words, despite various media outlets arguing to the contrary, GSK isn’t walking away from one of biopharmaceutical’s biggest and fastest-growing markets (i.e., cancer drugs), but, instead, transforming its oncology R&D engine.
OUT WITH THE OLD — TO FOCUS ON THAT WHICH IS NEW
Sometimes it is tough to let things go, especially when it means getting rid of revenue-generating oncology assets. But if you want to be able to focus on oncology’s R&D future, a divestiture can add more than just billions of dollars to your books. “You are not only shedding products that are on the market. You are removing some commercial and development infrastructure,” Hoos explains. One of the benefits of the GSK oncology divestiture to Novartis is it provides focus. “GSK is not going to reenter research areas that were just divested (i.e., targeted therapy discovery and development),” he states. This is good, because in the field of oncology there are constantly new mechanisms being explored, with the biggest and fastest-growing being IO. “This is where GSK wants to place its bets,” Hoos affirms.
In addition to IO and epigenetics, GSK also plans to focus on cell and gene therapy (CGT). But because CGT is highly complex, it requires a different business approach. “Technically, CGT is immunotherapy,” he clarifies. “However, from an infrastructure perspective, it is very unique, because to make it work, it requires many diverse resources.” This is why GSK opted not to have cell and gene therapy R&D initiatives subsumed under immunotherapy or immuno-oncology, but established its own parallel unit within the Oncology Therapeutic Area.
Another benefit Hoos sees from divesting the marketed oncology medicines is that it gives GSK the room to come up with new waves of innovation, as those former medicines are no longer taking up the resources. “When you think about how much money goes into product lifecycle management (PLM) [i.e., marketing, label expansion] relative to discovery and development [i.e., R&D], it can be a significant portion of your overall budget,” he says. Hoos notes that the divestiture also eliminated internal R&D competition. “When I arrived at GSK, new oncology discovery performance units (DPUs) [which are discussed in detail later in this article] were competing for resources with other, more-established parts of the business (e.g., small molecules for tyrosine-kinase inhibition and BRAF and MEK inhibitors),” he states.
When Hoos landed at GSK, throughout the biopharmaceutical industry, “generation two” of immuno-oncology R&D was well under way. As his previous work at BMS (i.e., ipilimumab) represented “generation one,” if he wanted to build something from scratch, GSK would basically have to skip working on a generation of IO drug development. “There were at least 15 PD-1s being developed,” he shares. “As all the PD-1 and PD-L1-blocking agents represented IO generation two, we knew that everyone else was pretty much already there.” Rather than try to play generation two catch-up, GSK instead opted to focus on generation three via its DPU approach.
HOW GSK CREATES SMALL BIOTECHS WITHIN A BIG PHARMA
Although the transaction was complex (as well as expensive), because GSK sold its marketed-oncology products for a premium (i.e., 10 times their annual sales), the company is able to reinvest some of those funds and basically “rebuild” its oncology business, which it is doing using DPUs. “The DPU model is actually one of the things that attracted me to GSK, because it enables you to be more entrepreneurial with a focus on one area of science,” Hoos states. At GSK, a DPU is treated like a small biotech company within the structure of a large pharma.
The process of creating a DPU — which GSK/Hoos did for immuno-oncology — involves developing a business plan that is presented to governance for review and, if approved, funded for a three-year cycle. “While a DPU may have some touchpoints to assess if it’s working or not, like a small biotech, you are in charge of your own budget and deliverables, and the structure allows you to work beyond just doing in-house discovery,” he states.
For example, if building in an area of science where there exists a technology that would benefit the DPU’s vision, the DPU can make an acquisition, develop an in-licensing deal, or create a partnership that enables it to build a portfolio. “We do a lot of option deals with milestones, and, if achieved, we can opt to buy the technology,” he attests. This is why Hoos views the DPU approach as an excellent means of de-risking R&D. “It allows you to work closely with other companies that have specific expertise, rather than spending a lot of money up front to acquire it, thereby diversifying what you are able to do.”
A DPU head — functioning like a CEO of a biotech —can build their own team, recruiting either internally or from GSK or outside the company. For example, the immuno-oncology DPU began with 15 GSK employees, most of whom came to the unit without having previous IO experience. “This is because the generation three IO area we were trying to build did not yet exist,” Hoos says. Today, the IO DPU consists of 85 employees, not all of whom came from within GSK. The other two areas of GSK oncology science (i.e., epigenetics and cell and gene therapy) are also set up as DPUs with their own heads. However, after the closing of the Novartis transaction, GSK is now rebuilding the Oncology Therapeutic Area with these three DPUs as building blocks. While GSK’s structure results in DPUs being treated like stand-alone, small biotechs, unlike a small biotech, these DPUs have the resources that only a Big Pharma can provide.
THE FOUR PILLARS OF GSK’S DIVERSIFIED ONCOLOGY R&D PIPELINE
There is no question that Hoos is interested in creating at GSK the same kind of transformational drug he worked on at BMS. “Right now, I’m focused on building something that is different and diversified,” he says. The first part — or “pillar” — of the plan to create the immuno-oncology R&D pipeline was to establish a set of checkpoint modulating antibodies of the third generation. Two of these are already in the clinic — an agonistic antibody against OX40 [CD134] and an agonistic antibody against the inducible co-stimulator (ICOS).
The second pipeline pillar is bispecific antibodies (i.e., putting two targets into one molecule). “Instead of having the antibody bind to one thing, you can have an antibody bind two things, and with that you end up having a combination therapy in one molecule,” he reiterates. While this is still in the discovery science phase, Hoos attests to GSK working on three different platforms of bispecific antibodies.
The third pillar involves small molecules. “We are leveraging our small molecule expertise and focusing it on immunotherapy targets, which is basically an unused area,” he says. Last year Hoos and three of his colleagues (Jerry Adams, James Smothers, and Roopa Srinivasan) wrote an article (Big Opportunities for Small Molecules in Immuno-oncology) published in Nature Reviews (July 2015) about how to use small molecules in immunooncology. He says the article was well-received and sets a framework under which small molecules can be used to make medicines in immuno-oncology. To that end, GSK has developed a set of new small molecule immunooncology targets and anticipates these moving into the clinic within the next 18 months.
“The fourth pillar is actually the most challenging, as well as the most exciting — cell therapy,” he says. While cell therapy is currently being attempted by many players using different approaches, at GSK it is viewed as an immuno-oncology component that needs its own infrastructure. “When I started at GSK, we built a group within the IO DPU that did cell therapy,” he shares. “But now that this area is reaching critical mass, it really needs to be its own DPU if it is going to be successful, and that’s what we are just starting to do.” To create next-generation cellular medicines, GSK Oncology is using a modular approach with multiple technologies integrated on a central platform. This approach includes different cell carriers, targeting receptors (CARs, T-cell receptors), signaling cascades, immune checkpoint or cytokine genes, supply chain technologies, and other components. Academic and industry partners also contribute key knowledge and technologies to the central R&D effort at GSK.
After the Novartis transaction was announced, many people thought GSK had just exited the hottest therapeutic category — oncology. Hoos doesn’t see it that way, though. He believes GSK seized this opportunity to transform its oncology R&D engine. “Immuno-oncology is clearly transformational, as are the checkpoint modulating antibodies currently being marketed,” he avows. For GSK to transform oncology, it meant striving to be a leader in the next generation of immuno-oncology products. “It has taken us almost four years to build the current pipeline of more than 15 immuno-oncology assets, and we just put the first drugs into the clinic,” he concludes. Targets and modalities were chosen to create synergies and enable novel combination therapies that may deliver transformational effects for patients. The focus remained on generation-three assets (OX40, ICOS, TCR-Ts) and not duplicating generation-two assets (PD-1, PD-L1, IDO, CD-19 CAR-T).
Rino Rappuoli, Ph.D., Chief Science Officer, GSK Vaccines
Rino Rappuoli, Ph.D., was faced with what many considered an unsolvable puzzle. The chief science officer for GSK Vaccines wanted to discover a vaccine for a serogroup B (MenB) of meningococcal meningitis that is responsible for nearly 50 percent of all worldwide cases of the disease. “Once you have seen one case of meningococcal meningitis, you don’t want to see another, and, unfortunately, I’ve seen too many,” he laments. “The mortality rate is as high as one in four.” Decades of research — as well as an unexpected encounter with a world-renowned geneticist — ultimately led Rappuoli to a solution he called reverse vaccinology.
SOLVING THE MenB PROBLEM REQUIRED SOMETHING REVOLUTIONARY
In the early 1990s, Rappuoli had developed the conjugate vaccine solution that would work for meningococcus strains A, C, Y, and W. And though his success led to a vaccine that helped to dramatically reduce the incidence of meningitis C (MenC) in the U.K., he knew the same approach was not going to work for MenB, because of B’s peculiar characteristic. “Unlike vaccines developed for serogroups A, C, W, and Y that induce an immune response against the polysaccharide capsule surrounding the bacterium, the capsular polysaccharide of MenB is structurally similar to certain abundant human glycoproteins,” he explains. “Therefore, if you try the same approach in developing a vaccine for MenB, you run the risk of causing autoimmune damage, as the MenB pathogen mimics host molecules.” In other words, the body’s immune system views the B antigen as something that is supposed to be there and, as such, won’t raise an immune response.
Rino Rappuoli, Ph.D., Chief Science Officer, GSK Vaccines
“While many other groups continued to try to solve the MenB problem, I basically shut down the program, as it seemed useless to work on if we didn’t have a technical solution,” he states. It appeared something revolutionary was needed in order to proceed. In 1995, in what Rappuoli describes as a lucky break, he stumbled across a Science magazine article in which Craig Venter had published the first genome sequence of a living organism. For the first time in human history, scientists were able to read what was required to make a living organism. And while Rappuoli thought this new technology might be the solution for what had previously seemed impossible (i.e., developing a MenB vaccine), he admits it took him about a year to fully conceptualize how. “I was trying to decide if I should learn how to sequence a genome,” he explains. “I calculated that for me and my team to become experts in mapping the necessary genome to solve MenB, it would take three to five years. In the end, I thought, ‘Why should I learn something that other people can already do?’” So the vaccinologist decided to go talk to Venter.
Around 1996, Rappuoli visited Venter at The J. Craig Venter Institute (formerly know as The Institute for Genomic Research), and asked if he would be willing to sequence the meningococcus B genome. Venter’s first reaction was, “Why should I do another bacterium when we’ve already done it?” Rappuoli suspected this might be his answer, as he knew mapping the bacterial genome was one small step toward eventually mapping the human genome. So he proceeded to tell Venter about the terrible disease that kills young children and adolescents that had no remedy. “I said, ‘If you sequence meningococcus B, we might be able to actually make a vaccine,’ and that got him to turn around,” he attests. “Fifteen minutes later, we were collaborating and have been ever since.” This allowed Rappuoli and his team to focus on their core knowledge of how to make vaccines instead of trying to learn how to sequence a genome — which would have wasted a lot of time.
OVERCOMING RESISTANCE AND SKEPTICISM TO REVERSE VACCINOLOGY
Rappuoli’s concept of reverse vaccinology involved taking an entire pathogenic genome and screening it. Using bioinformatics, the goal was to find genes with desirable attributes that would make good vaccine targets. As Rappuoli presented the concept of reverse vaccinology, he quickly realized that it caused two problems — external scientific skepticism and internal scientist resistance. And while overcoming outsider cynicism was an eventual goal, in order to successfully do so first required defeating insider reluctance. “At the time, biology was done very differently,” Rappuoli relates. “Prior to reverse vaccinology, every person working in biology, either in the company or an academic lab, was basically one person, one protein, one project.” But because Rappuoli’s proposal involved identifying potentially 600 proteins, under the traditional model (i.e., one person = one protein) this equated to needing 600 postdocs — each working on their own protein. That wasn’t possible, because at the time when Rappuoli was trying to realize his reverse vaccinology idea, he was working at Chiron Corporation, a small biotech based in Emeryville, CA. So he pulled the team together and said, “Now we’re going to work differently, like a chain, with one person working on the first piece, someone else the second, and so on.” But his team’s reaction was not one of receptivity. “We aren’t here to be your technicians,” they said. “We are scientists here to do our own experiments in an independent way.” According to Rappuoli, it took six months of meetings and convincing just to overcome this internal scientific sentiment.
Around seven months into the new research approach, the team was finally to a point of being able to analyze the genome, and that’s when things started to really get exciting. For example, in studying the MenB genome, they found 2,158 genes. While the team predicted that 600 had the potential to make good vaccine candidates, they ended up expressing 350, which was still significant, considering that up to this point everyone had been expressing just one at a time. From there, the team began testing the serum on mice and, within six months, had discovered 91 new proteins on the surface of the bacteria. “Prior to this, all of the microbiologists in the world had discovered only 13,” he says excitedly. Though the team didn’t yet know which of these was going to end up making a vaccine, they had discovered something nobody else had, which galvanized them. “From that point on, I did not have to push them, as they were actually pushing me,” Rappuoli attests.
In the beginning of the project, he says they rarely spoke about reverse vaccinology outside of the organization. However, the scientist recalls presenting at a Neisseria (meningitidis) Conference where he first encountered external skepticism to reverse vaccinology. “I presented data explaining how we were using genomics to get new proteins, which was a very revolutionary concept,” he reflects. “At the end, I didn’t get any questions. But I do remember a comment, which was basically, ‘Let’s wait and see what happens.’” He says when it comes to overcoming external skepticism, the more data you publish, the more people start to believe. That being said, it wasn’t until after the MenB vaccine (BEXSERO) was approved in Europe (2013) and the U.S. (2015) that skeptics really started to believe.
COULD REVERSE VACCINOLOGY RESULT IN A NOBEL PRIZE?
As the conversation with Dr. Rappuoli winds down, I ask if he has ever thought that his work on reverse vaccinology might result in a Nobel Prize. “No,” he responds quickly. “My priority in developing vaccines wasn’t winning an award but dealing with a severe disease. My passion for focusing on meningitis was nurtured from my training at Rockefeller University under Emil Gotschlich.” According to Rappuoli, there is not a tradition of Nobel Prizes being awarded for successful vaccine development. In fact, in the 121-year history of the award, only one vaccine scientist has ever been awarded the Nobel Prize for physiology or medicine (i.e., Max Theiler for his work on developing a Yellow Fever vaccine). But awards aren’t what give the GSK Vaccines chief science officer satisfaction. It’s simply protecting people from disease. “We are eager to see the U.K. results, where all of the newborns have been immunized, to get a feel for the impact the BEXSERO vaccine is having on the disease,” he says. Thus far, the best results come from the Canadian region with the highest incidence of meningococcus B. “In May 2014, the Saguenay-Lac-Saint-Jean region in Quebec began vaccinating the entire population from two months to 20 years of age with BEXSERO,” he explains. “Since they began immunization and up to the last report a few months ago, they’ve had no more cases of MenB in those who have had the vaccine.” Results like these, more than Nobel Prizes, reinforce that his effort to pioneer reverse vaccinology was time well spent.
SECURING SUPPLY REQUIRES LOOKING OUTSIDE YOUR INDUSTRY
You are probably aware of the serialization initiative being undertaken to improve the security of the biopharmaceutical industry’s global supply chain. However, until serialization becomes a global reality, to help ensure the safety of GSK vaccines in areas ripe with counterfeit drugs, GSK partnered with nontraditional industry companies (e.g., Vodafone) for solutions. “If you are in Mozambique, an area where we completed a pilot program, you can just scan the bar code of a vaccine vial with your mobile phone, and you will know exactly if it is a GSK vaccine or not,” explains Luc Debruyne, president of GSK Vaccines. But the collaboration goes beyond just ensuring product authenticity. The one-year pilot, supported by the Save the Children charity, also registered mothers on a ministry of health database that could alert them to the availability of vaccinations, as well as allow them to schedule appointments via text messaging. At the same time as the creation of the GSK/Vodafone partnership, the mobile communications giant also created a deal with Gavi, the Vaccine Alliance, to help collect information about how many children have been vaccinated, while also providing reminders to users of when vaccine boosters are due.
“We have 115 active scientific collaborations,” Debruyne boasts. “As our ambition is to be leading the industry in the world of vaccines, it requires more than developing internal skills and expertise. It means enabling scientists to be able to see opportunities faster than anyone else.” While collaborations certainly help GSK in its global health mission, they also provide employees increased visibility outside the walls of their own organization.
HOW GSK IS PREVENTING R&D INITIATIVES FROM BECOMING KNOWLEDGE SILOS
“What often happens at Big Pharma companies is you unintentionally end up siloing certain activities,” says Axel Hoos, M.D., Ph.D. “This was something we recognized not long ago. Perhaps you have oncology and infectious diseases therapeutic areas that share certain features and work on mechanisms that are similar, but may not know what each other is doing. So what do you do to break down those silos?” For GSK the approach was to create an overarching R&D focus based on immunology because “the immune system basically has universal mechanisms that can be applied in other R&D areas,” explains Hoos, who is GSK’s SVP therapeutic area head for oncology R&D and head of immuno-oncology.
The immunology framework designed to cross-pollinate R&D ideas (aka break down silos) and share knowledge throughout GSK is called the Immunology Summit, and it includes external academic experts and entrepreneurs who serve as advisors. While immunology is a core GSK focus (e.g., vaccines), it is important in many other areas as well. “You can apply that universal mechanism to cancer, an infectious disease threat, bacteria, as well as a virus,” he asserts. “Perhaps a PD-1 could work in HIV and doesn’t have to be restricted to just oncology.” According to Hoos, out of the eight GSK therapeutic areas, immunology touches almost all of them. So why not seize it as an opportunity to cross-pollinate and elevate ideas?
COLLABORATING WITH CRAIG VENTER PROVES TRANSFORMATIONAL
“I know a lot of people who have started companies, but I don’t know a lot of people like Craig Venter,” says GSK Vaccines Chief Science Officer Rino Rappuoli. After his work on genomics, Venter became interested in synthetic biology and wished to explore the possibility of using it to develop vaccines. “When he first suggested this, I told him this was just another one of his crazy ideas,” laughs Rappuoli, suddenly finding himself thrust into the role of scientific skeptic. “For the first two years, using synthetic biology as a means to develop vaccines wasn’t really a fit,” he affirms. “However, in the third year, things started to gel.” In 2013, Rappuoli’s team began working on a new potentially pandemic avian influenza strain (H7N9) that had been identified in China. It was Easter Sunday, and the Chinese CDC had just posted on its website the sequence of the two genes that were part of the H7N9 vaccine. The way vaccine seeds are usually made is a strain is identified, isolated, and sent to one of the three government centers in the world that make vaccine seeds. From there, scientists working at places like the CDC in Atlanta use the identified strain to try to make a vaccine (typically a three- to six-month process) and, once completed, give the seed to a manufacturer for commercial production. On the Monday after Easter, Venter, working in La Jolla, CA, synthesized the two genes from nucleotides. “He shipped us what we needed via express mail, and by Thursday of that same week, we had the first viruses popping up in the lab,” Rappuoli says. By Saturday, Rappuoli’s team had the necessary seed to make a vaccine. Using synthetic biology, Venter and Rappuoli converted what was typically a six-month process to about five days. “That gives you an idea of how transformational things can be when you decide to collaborate with Craig [Venter],” he concludes.