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The Story of Gardasil

Eliav Barr, Ph.D.
Barry Buckland, Ph.D.
Kathrin Jansen, Ph.D.

 

“You did it!”

 

That’s how Drs. Kathrin Jansen, Eliav Barr, and Barry Buckland learned in 2001 that they had a real winner on their hands. That was the “Aha!” moment for the inventors of Gardasil®, just the second prophylactic cancer vaccine ever and the very first vaccine against cervical cancer. That cry—accompanied by a smile, but no details—signaled a great deal to the scientists, however.

 

The long-awaited interim results of Gardasil’s first clinical trial, communicated behind closed doors to Dr. Edward M. Scolnick, then president of Merck Research Laboratories, were astounding. The proof-of-concept study of a monovalent vaccine against human papillomavirus (HPV) 16, the most common strain found in cervical cancers, demonstrated vaccine efficacy of 100 percent: “All 41 cases of new HPV-16 infection, including [all] nine cases of HPV 16—related cervical intraepithelial neoplasia, occurred among the placebo recipients,” a New England Journal of Medicine article later reported.

 

Given the randomized, double-blind nature of the study, Dr. Scolnick, the speaker above, could not share the results with his research scientists, leaving them somewhat mystified. But they were euphoric nonetheless—in the hallway outside Dr. Scolnick’s office, they danced, cried and hugged. Alas, another 260 weekends would come and go before their work on Gardasil was complete and the vaccine approved.

 

In recognition of the personal qualities they clearly brought to their work—their determination, brilliance, passion and creativity—as well as the important scientific and technological contributions they made to Gardasil’s discovery, Drs. Jansen, Barr, and Buckland are receiving the 2009 Discoverers Award. This annual honor is the pharmaceutical industry’s highest scientific honor.

 

 

Pharmaceutical Research and Manufacturers of America (PhRMA) President and CEO, Billy Tauzin (right) with the 2009 Discoverers Award recipients, Eliav Barr, Ph.D., Barry Buckland, Ph.D., and Katherin Jansen, Ph.D. at the 2009 PhRMA Discoverers Award dinner in San Antonio, Texas.

 

It Seemed Unimaginable

The idea that cancer could not only be caused by a virus, but also be prevented with a vaccine, was once thought novel, controversial and, in some quarters, maybe even ridiculous. In the 1970s and 1980s, Harald zur Hausen of Germany established a link between HPV and cervical cancer, work that took him ten years to complete and won him a Nobel prize just last year. Subsequent research by the Australian Ian Frazer demonstrated the potential of synthesizing virus-like particles (VLPs) from recombinantly expressed HPV capsid protein to resemble actual viral particles. While zur Hausen’s and Frazer’s advances did not immediately overturn the then current dogma about cervical cancer’s cause, it gave an enormous boost to efforts to find a vaccine. The hunt was on.

 

In time, the discovery of Gardasil became one of the most eagerly awaited vaccine discoveries in recent memory. When word of the monovalent vaccine’s astounding efficacy got out in 2002, interest and excitement in the new vaccine soared; likewise, Gardasil fever heightened again when the results of Phase III studies of a quadrivalent HPV (6, 11, 16, and 18) vaccine were reported. When FDA approval finally came in June of 2006, the promise of Gardasil was widely celebrated—from coast to coast, hemisphere to hemisphere, its discovery was called a “miracle.”

 

“This is the biggest breakthrough since the invention of the Pap test,” said Dr. Mark Einstein, gynecologic oncologist at Montefiore Medical Center in New York. 

 

About the Discoverer of the HPV Cancer Link

 

“Harald zur Hausen went against current dogma and postulated that oncogenic human papilloma virus (HPV) caused cervical cancer, the second most common cancer among women. He realized that HPV-DNA could exist in a non-productive state in the tumors and should be detectable by specific searches for viral DNA. He found HPV to be a heterogeneous family of viruses. Only some HPV types cause cancer. His discovery has led to characterization of the natural history of HPV infection, an understanding of mechanisms of HPV-induced carcinogenesis, and the development of prophylactic vaccines against HPV acquisition.”


– The Nobel Assembly at Karolinska Institutet (2008)

The reasons are obvious. Half a million women worldwide are diagnosed with cervical cancer annually; killing one-quarter of a million

women every year, it is the second leading cause of cancer death in women. In the United States, where routine Pap testing has made a serious dent in cervical cancer rates, “11,999 women were told that they had cervical cancer in 2005, and 3,924 women died from the disease,” according to the U.S. Centers for Disease Control and Prevention.

 

Moreover, 50 percent of all cervical cancers are caused by one strain (HPV 16), and 70 percent are caused by just two (HPV 16 and 18). HPV 16 also causes 80 percent of all HPV-related noncervical cancers as well.

 

In addition, HPV is the most common sexually transmitted infection. More than one out of four women ages 24 to 29 in the United States, estimates found, were infected by HPV. Researchers estimated that in 2000, there were approximately 6.2 million new cases of HPV infections among Americans aged 15–44. According to The New York Times, as many as 20 million Americans could be infected annually.

Considering 70 percent of all cervical cancer deaths are caused by only two virulent HPV strains targeted by Gardasil, its discovery and regulatory approval were a very big deal—for mothers, daughters, grandmothers, not to mention husbands and brothers and the rest of humankind.

 

“As a physician and as a woman, I think this is a phenomenal breakthrough,” Dr. Gloria A. Bachmann, director of the Women’s Health Institute at the Robert Wood Johnson Medical School, said when Gardasil’s final trial results were released. “This is the first breakthrough in eliminating a significant cause of cancer, and it promises to take this entire chapter out of women’s lives.”

 

Newsweek in June 2006 may have stated it best: “Until recently, it seemed unimaginable: a vaccine that could prevent cancer? But last week the Food and Drug Administration approved a vaccine intended to do just that.”

 

The Genesis of Gardasil

When their work began on an HPV vaccine in the 1990s, each of this year’s winners was in his or her own way an outsider. It’s difficult though to imagine a better team of individuals, with their different experiences, specializations, and perspectives, to lead a complex, global, multi-disciplinary project to invent a new vaccine.

 

Perhaps author Malcolm Gladwell was right: “There are times when being an outsider is precisely what makes you a good insider.”

  • Dr. Eliav Barr, who led the team that designed and implemented the complex clinical program for Gardasil, grew up in Israel, moved to Michigan when he was 11, and trained to become a cardiologist. He began his career at Merck in cardiovascular research, only switching to vaccines and infectious diseases in 1998. "I had an interest in public health,” Dr. Barr said, “and a desire to do something that would impact medical practice on a large scale. I learned from my years in cardiovascular research that it’s better to prevent, than to treat, as important as that is. “As an outsider, I was able to come to the field without a lot of preconceptions. There is great value in cross-fertilization.”
  • Dr. Kathrin Jansen, who established and led the basic research program for a HPV vaccine and later on led the product development team for Gardasil, was born in East Germany and raised and educated in West Germany. She began her research career, not as a virologist, but as a microbiologist studying carbon assimilation in anaerobic bacteria. “I always liked vaccines as a concept,” Dr. Jansen said. “They are prophylactic; you’re not waiting to treat the disease—you prevent it. “Everything I had done up to this point in my career was excellent training for developing vaccines. I looked at the field as an outsider and pulled all my experiences together and chose an approach that ultimately was right.”
  • Dr. Barry Buckland, who led the teams that developed and scaled up the vaccine processes from the small-scale clinical lots to manufacturing scale production, was born and raised in the United Kingdom, where he captained his rugby team. Dr. Buckland is a biochemical engineer who works among virologists, biologists, biochemists, chemists, and physicians. “We built a world class group in bioprocess R&D who were aware of all the latest process engineering and analytical advances coming from the broader biotechnology industry,” Dr. Buckland said. “We were in a perfect position to apply these advances to the proposed HPV vaccine.”

Pre-Clinical Phase

As a young child, Dr. Jansen already possessed two prerequisites of a scientific mind. “I was curious, and I loved biology and nature,” she said. “I was fascinated by what was crawling around me and always brought them home. Literally.”

 

One of her first experiments was to observe her pet canary flying from its perch in the living room to the kitchen counter whenever someone opened the cookie jar. Decades later her curious mind and love of science put her on a road that would eventually lead to Merck’s HPV vaccine research team. In particular, her familiarity with the hepatitis B vaccine and her experience as a yeast expression specialist convinced her that an HPV vaccine was achievable. “I am convinced I can make this work because it is not much different than the hepatitis B vaccine,” Dr. Jansen told her boss at the time. “I know exactly how to go about this.”

 

But before a single needle was stuck in anyone’s arm, there was much basic research to be done to understand HPV natural history. Moreover, several important decisions had to be made.

In Their Words


“I never imagined that I would be so fortunate to lead a program that resulted in a product with such a significant positive impact on human health.”


– Dr. Kathrin Jansen

 

In 1993 Dr. Jansen established the basic research program for the HPV vaccine. Five years later, Dr. Barr and Dr. Jansen created the HPV Vaccine FUTURE Steering Committee, an international academic/pharmaceutical research group whose mission was to solve the remaining questions about HPV natural history, as well as demonstrate the safety profile, efficacy, and immunogenicity of a HPV vaccine.1

 

While the foundations for Gardasil had been put in place by zur Hausen, Frazer, and others, the clinical course of HPV from point of infection to point of cancer had not been fully established. Using the technology developed by Frazer and drawing on both her own work with yeast expression and experiences in biochemistry and immunology, Dr. Jansen and her team of virologists, molecular biologists, and microbiologists, in collaboration with excellent epidemiologists in the field, made several important findings that filled in gaps in HPV natural history.

 

Perhaps her most important contribution to Gardasil’s discovery was her success in persuading her colleagues at Merck to make the vaccine in yeast, rather than insect cells. Yeast offered several key advantages. For one thing, it had a track record: Merck had been using Saccharomyces cerevisiae for years to make its very effective hepatitis B vaccine (Recombivax®). Moreover, yeast expression is scalable, meaning that enough vaccine supply could be generated to supply the world’s need. Yeast products are safe, and ultimately yeast proved very efficient in producing VLPs that generated a potent immune response to HPV virions.

 

“I had said from the get-go that we can make this product in yeast because I believed it was the best, fastest, and most efficient way to do it,” Dr. Jansen said.

 

“A crucial starting point was the development of a cell-based expression system that was stable over many generations and produced large amounts of high-quality VLPs,” Dr. Buckland explained in a 2005 article. “The decision to use Saccharomyces cerevisiae as the expression host for intracellular VLPs was excellent in this regard.”2

 

The choice of VLPs as antigen also had several advantages. Unlike most vaccines, which contain killed viruses or bacteria (or weak versions thereof) to generate an immune response, Gardasil does not contain any virus, dead or alive. Rather, it relies on these viral look-alikes: hollowed out particles that are synthesized in yeast from HPV L1 protein (which has all the information to create a look-alike) to resemble an HPV virion. The VLPs in Gardasil trick the body into generating antibodies to ward off HPV infections.

 

“For all intents and purposes the particle looks and behaves like a virus, but it does not have infectious nucleic acid,” Dr. Jansen explained.

 

For each of the four HPV strains, Dr. Jansen’s team had to perfect making VLPs recombinantly in yeast, and in each case they had to overcome major scientific obstacles. For example, even though HPV 11 made VLPs “beautifully,” Dr. Jansen said, HPV 6, which is very close in sequence to HPV 11, did not. It had zero expression. The solution was to tinker with HPV 11’s DNA, changing only those amino acids that distinguish HPV 11 from six.

 

Later, Jansen and her colleagues made another key decision in choosing the adjuvant, which is a sort of a vaccine booster rocket that helps stimulate the immune system. Specifically, they found that VLPs formulated on aluminum adjuvant were able to induce much higher concentrations (or titer) of antibodies than other kinds of adjuvants or VLPs by themselves.

 

In 1993 the pre-clinical proof-of-concept study designed and led by Dr. Jansen unambiguously demonstrated the efficacy of a prophylactic HPV vaccine in animals. Its potential for use in humans now demonstrated, the team turned to the next phase of the discovery process.

 


Clinical Trials

Dr. Barr brought a unique life view and intensity to his leadership role on the HPV Vaccine program. Not only was he shaped by the career DNA he inherited and absorbed at home, his father being a cardiologist and his mother, an intensive care unit nurse, his surroundings influenced him tremendously.

 

“What shaped me the most was living in a volatile world,” Dr. Barr said. “Life so close to the Middle East is intense—there’s a desire to be aware of one’s environment and to be able to control what you’re doing.

 

“My parents taught me that to be successful, you had to be ‘A, No. 1’— you had to believe that life was a calling.”

 

Dr. Barr wore several hats on the HPV vaccine program. In addition to leading the clinical development of the vaccine, he also developed the public health/implementation research strategy for the HPV vaccine. A major practical consideration in the development of any vaccine is the take-up rate once it’s on the market. The success of a vaccine depends on getting the entire population covered as quickly as possible.

 

“With any new vaccine, you need a good reason to put a needle in a healthy person’s arm,” Dr. Barr said.

 

An additional complicating factor was that the vaccine wasn’t intended for children, who are vaccinated in well baby visits and annual exams, but for teenagers, as well as young women.

 

“How do you get ornery people—who either don’t go to the doctor very often, believe in their own immortality, or try not to listen to their parents— vaccinated?” Dr. Barr asked.

 

“To a young person for whom the risk of cancer is too remote, the vaccine has to provide some immediate benefit.”

 

The solution was a to develop a quadrivalent vaccine—literally, four vaccines in one—that targeted four dangerous or nasty HPV strains: HPV 16 and 18, which cause 70 percent of all cervical cancers, and HPV 6 and 11, which cause 90 percent of all genital warts. A vaccine against the former, it was believed, would greatly enhance the vaccine’s appeal to the public and, thus, the take-up rate. Genital warts are a painful and an especially embarrassing condition that is quite common. Nor are they inconspicuous to partners. There was also an unintended consequence: The choice of a quadrivalent vaccine also enhanced its cost-effectiveness, since the cost of treating genital warts, which often requires three or four treatments, is very high.

 

Dr. Barr also led the discussions with the FDA, European Medicines Agency, and the World Health Organization regarding Gardasil’s basis for licensure and supervised the submissions and discussions with regulatory agencies. Besides in the United States, he had a hand in Gardasil’s gaining expedited approvals in Canada, Australia, New Zealand, and the European Union.

 

It was his role in conducting Gardasil’s mammoth, complex clinical trials, however, that perhaps stands out the most.

Conducted in parallel with the HPV 16 trial was a groundbreaking study that added significantly to our knowledge of HPV natural history. Published in two peer review medical journals, the results demonstrated the pathologic sequence from the point of genital exposure to HPV to the point of development of Cervical intraepithelial neoplasia 3 (the most severe grade of dysplasia).

 

Just consider the numbers: A total of 25 clinical trials involving more than 30,000 subjects worldwide and 150 clinical centers in 34 countries on 5 continents.

  • The first, the 2001 HPV proof-of-concept study mentioned earlier, demonstrated the efficacy of the monovalent HPV 16 vaccine. Dr. Jansen, her clinical colleagues at Merck, and Dr. Laura Koutsky, an epidemiologist and collaborator on the project from the University of Washington, designed the study and established diagnostic tools for the detection of HPV in clinical specimens. The trial involved 2,400 young women from 16 centers in the United States.
  • One of the two Phase III trials3 demonstrated Gardasil’s cancer-fighting capability unambiguously. In this randomized, double-blind trial involving 12,167 young women in 13 countries, the quadrivalent HPV (6, 11, 16, 18) vaccine “was highly effective (98%) in preventing HPV-16–related and HPV-18–related cervical intraepithelial neoplasia (CIN) grade 2 or 3 and adenocarcinoma in situ.”4 Just one woman in the vaccine group developed one of these conditions, as compared to 42 in the placebo group.5
  • A second Phase III trial6 involving 5,455 young women at 62 study sites in 16 countries had equally impressive results. “The HPV vaccine was 100% effective …in preventing vaginal, vulvar, perineal, and perianal intraepithelial lesions or warts.”7 Also found was a reduction in the overall rates of anogenital diseases, regardless of cause.8

None of this would have been possible without Dr. Buckland and his team of 70 chemical engineers, chemists, and technicians. Over many years, the team supplied Dr. Barr tens of thousands of doses, both monovalent and quadrivalent, for the various clinical trials. A process, it should be emphasized, that is far easier said than done—whatever process Dr. Buckland designed to produce clinical supplies had to be scalable, as is discussed below.

 

Nor would it have been possible without Dr. Jansen’s contribution to the clinical trials. More than 150,000 specimens were examined by Dr. Jansen’s lab to measure HPV infection and immunology; and over 15,000 biopsies were evaluated to assess HPV-related cervical and genital pathology.

 


Making the Vaccine

As captain of his rugby team, young Barry Buckland learned “not to be too cautious.” Considering the high-wire act he was required to perform years later as Merck’s lead on process development and manufacturing, that was an invaluable lesson. The fundamental challenge he and his team faced was to design a process for making thousands of vaccines for clinical trials that “can be scaled up and run reproducibly in a manufacturing environment to make tens of millions of doses per year.” Moreover, advances in process development and scale-up had to be incorporated into the clinical program for all four strains. On top of that, Dr. Buckland’s team had to be able to prove to regulators at the end that the vaccines made at opposite ends of the discovery process were essentially the same.

 

“Whatever process was used in Phase I had to incorporate the basic building blocks for the future manufacture of Gardasil,” Dr. Buckland said.

Above and beyond the challenge of designing a process that was scalable, Dr. Buckland and his team faced a range of scientific challenges peculiar to the discovery of Gardasil.

 

In Their Words


“This was a dream project. The innovative technical elements we incorporated into the process for making clinical supplies worked, the technical transfer to manufacturing went well, and the factory we built performed.”

 

– Dr. Barry Buckland

“The biggest challenge was to get yeast that was stable, had good expression levels, and would last the life of the program, which could be more than 30 years,” Dr. Buckland said. “Moreover, a separate yeast strain had to be made for each HPV strain in the vaccine.”

 

Working with Dr. Jansen and the yeast engineering group, Dr. Buckland’s fermentation team developed the culture medium components and fermentation processes. They also played a major part in the selection of yeast strains.

 

But it may have been the purification team that solved the biggest problem with initial HPV vaccines. After VLPs were released from inside the yeast (by dropping pressure to break open the yeast), they lacked stability. In a technological breakthrough, Buckland and his team produced VLPs with both more stable structures and improved immunogenicity by disassembling and reassembling VLPs for types 6, 11 and 16 in vitro. The result: VLPs that were more similar to the natural HPV particles.

 

One of the last steps in the Gardasil discovery process was the construction of manufacturing facilities. By necessity, that step cannot wait until regulatory approval—months and lives would be lost while the manufacturing infrastructure was being built. So work on building a plant began even before all the clinical trial data was in, and it was completed before Gardasil received FDA approval. Finally, Dr. Buckland had to prove to regulators that the vaccine made in the plant was virtually identical to the one tested in clinical studies. To that end, his team performed an extensive analytical characterization of the vaccine and assembled a comprehensive regulatory package describing the chemistry, manufacturing, and controls.

 

Gardasil Today

Since June 2006, over 36 million doses have been distributed globally, including 19 million in the U.S. Currently, more than 8 million young girls and women in the United States have received their first dose; through December 2007, approximately 74 percent of vaccine recipients have received their second dose and approximately 54 percent, the full course.9

 

Gardasil is now approved for the prevention of cervical, vulvar and vaginal cancers caused by HPV types 16 and 18; genital warts caused by HPV types 6 and 11; and precancerous or dysplastic lesions caused by HPV types 6, 11, 16 and 18 in girls and young women 9 through 26 years of age.10 Just weeks after Gardasil received FDA approval in 2006, the Advisory Committee on Immunization Practices recommended the vaccine for use in girls and women age 9–26.

 

Beyond the cancers caused by HPV 16 and 18, Gardasil has been shown to reduce incidence of cervical pre-cancers or non-invasive cervical cancer caused by 10 additional types of HPV.11 These 10 types are responsible for more than 20 percent of cervical cancer cases throughout the world.

 

In the developing world, Merck is working with governments and nongovernmental organizations to make Gardasil available. Through its Gardasil Access Program, Merck will donate at least 3 million doses over five years in under-resourced communities. Last year the program named eight GAVI-eligible countries to be the first recipients of Gardasil.12 Moreover, Merck is providing the vaccine to the public sectors in these countries at no-profit prices.13

 

The discovery of Gardasil was a major breakthrough—in the estimation of many “the top medical advance for 2006.”14 It represented a major paradigm shift in medical practice, as well as a major public health achievement. A cancer vaccine was invented. As important, the vaccine prompted a major shift in medical practice to the benefit of a large percentage of the population. The evidence: not only regulatory approvals in 108 countries, including the United States, E.U., Mexico, Australia, Canada, New Zealand, Peru, Brazil, Singapore, Korea and many countries in Africa, but take-up rates of as high as 70-80 percent in some countries.15

 

It is human nature to take great achievements like this for granted. That would be a major mistake here, as it is with most new drug discoveries. Besides many lost weekends and evenings and time with friends and family, this year’s winners, scientifically speaking, scaled cliffs, and traversed mountains and rivers to invent Gardasil.

 

Beyond the toil and time, was it not a little luck that brought these three scientists together for a decade or more? One could say the stars were all aligned—consider this: Available to Drs. Jansen, Barr and Buckland were brilliant, dedicated scientists and an extraordinary research infrastructure, a capability built by Merck’s corporate management and the leadership of Merck Research Laboratories.

 

“These seasoned scientists knew the art and science of making vaccines,” Dr. Barr said. “They really knew how to make high quality biologics and vaccines.”

Also available were the financial resources to answer basic research questions and achieve and prove this complex vaccine’s efficacy, safety, and immunogenicity; the vision to create a global and transparent research team to optimize collaboration and productivity; and the courage to roll the dice on a few occasions.

 

Finally, there was their humanity. These individuals became research scientists to prevent diseases and the pain, suffering, and loss of life left in their wake. They became research scientists to make the world a better place.

 

This story about the discovery of Gardasil will close with a bear hug, this one recently given Dr. Jansen by her neighbor. This gesture is a simple reminder of what drug discovery ultimately is all about.

 

“Thank you for all the lives you will save,” the neighbor told Dr. Jansen, wrapping her arms around her.

 

Leaning back, the neighbor, a mother of two daughters, asked, “Don’t you know how much you have done for all of humankind?”

 


References

 

1The FUTURE committee was also tasked to lay the groundwork for long-term public health research to monitor the impact of Gardasil on cancer rates in developed and

developing countries.


2Barry C. Buckland, “The process development challenge for a new vaccine,” Nature Medicine Supplement (April 2005), p. S17.

 

3Termed FUTURE II. For more information see The FUTURE II Study Group, “Quadrivalent Vaccine against Human Papillomavirus to Prevent High-Grade Cervical

Lesions,” N. Engl. J. Med. (May 10, 2007), pp. 1915-1927.

 

4Ibid., p. 1923.

 

5Vaccine efficacy was also demonstrated among women from all four geographic regions represented in the trial and for all ethnic or racial groups.

 

6Termed FUTURE I.

 

7Suzanne M. Garland, M.D. et al., “Quadrivalent Vaccine against Human Papillomavirus to Prevent Anogenital Diseases,” N. Engl. J. Med. (May 10, 2007), p. 1932.

 

8In September 2008, the FDA approved Gardasil for the prevention of vaginal and vulvar cancers caused by HPV types 16 and 18. The basis was data from a combined

analysis of three trials involving more than 15,000 young women and showing that the vaccine was 100 percent effective in preventing vaginal and vulvar pre-cancers associated with HPV types 16 or 18.

 

9Source: Merck & Co.

 

10In November 2008, Merck announced that GARDASIL had demonstrated efficacy (90%) in preventing HPV-related disease in males in a still-ongoing Phase III Study.

 

11According to data presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy in 2007.

 

12The 72 Global Alliance for Vaccines and Immunization-eligible countries have gross national income per capita below $1,000.

 

13www.merck.com/corporate-responsibility/access/access-vaccines-immunization/approach.html

 

14St. Louis Post-Dispatch, among other newspapers. Also called one of “the best new inventions of 2006” (The Dallas Morning News); and “a big medical

advance” (Associated Press).

 

15Source: Merck & Co.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


 



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