The history of the vaccine against human papillomavirus (HPV) is also the story of the extraordinary commitment of the Wilhelm SanderFoundation. Over a period of 50 years, HPV research has run like a common thread through the Foundation’s funding portfolio – from Harald zur Hausen’s bold hypothesis in the 1970s to the global use of a vaccine which prevents cancer before it develops. With 249 funded projects, accounting for ten per cent of the Foundation’s total portfolio, it is clear that this is not merely an episode in cancer research, but an outstanding chapter in scientific progress.

PART 1 A SUSPICION BECOMES A CERTAINTY

The starting point of our story is impressive in its simplicity. In the 1970s, the virologist Harald zur Hausen recognised a striking epidemiological pattern: cervical cancer and genital warts exhibited surprisingly similar patterns of spread. What was merely a statistical observation to others was to become a groundbreaking hypothesis: it was not just fate or heredity, but viruses that could be primarily responsible for the development of cancer. For this discovery, zur Hausen was awarded the Nobel Prize in Medicine in 2008.

The Wilhelm Sander Foundation was involved from the very beginning – placing its trust in something that was entirely uncertain in 1975. In line with its mission to promote innovative cancer research, it recognised the potential of this virological hypothesis at an early stage and appointed the future Nobel laureate Harald zur Hausen as a founding member of its Scientific Advisory Board – at that time still Director of the Institute of Virology at the University of Erlangen, and later long-serving Scientific Director and Chairman of the Executive Board of the German Cancer Research Centre in Heidelberg (1983–2003). This connection was based less on planning than on trust in a researcher and his questions: the Foundation was prepared to persevere with this research without knowing where it would lead.

PART 2 BASIC RESEARCH AS A FOUNDATION

The 1980s and 1990s were decades of basic research. Which genes does the virus use to infect a cell? How can it hide within the body to trigger chronic viral infections? How does a chronic viral infection eventually develop into cancer? These questions drove research forward, and the Wilhelm Sander Foundation was a reliable partner in this work. It enabled researchers to work over the long term on a topic that was initially still controversial, the practical benefits of which were not yet foreseeable.

Key figures during this phase were researchers at the DKFZ in Heidelberg who worked closely with Harald zur Hausen. In particular, Lutz Gissmann, Matthias Dürst and Elisabeth Schwarz deserve special mention.

The Heidelberg network was more than just a geographical concentration of research teams. Prof. Dr Martin Müller of the DKFZ emphasises the crucial role of application-oriented research – an approach which, however, offers no guarantee of success. “Most developments come to an end without ever reaching the market,” says Müller. “But if there were no applied research, no progress in this direction would be possible at all.” What set the Heidelberg network apart, in particular, was its perseverance and continuity. Zur Hausen stood out for his keen interest in the finer details of research: “Almost every morning he would come into the department and discuss the latest findings with the staff.”” Gissmann’s strength, in turn, lay in his international reputation and his personal connections with colleagues worldwide. “This led to a wide range of collaborations,” recalls Müller. PhD students, for example, were able to undertake research placements in other laboratories.

Thomas Iftner in Erlangen was already carrying out pioneering work on HPV biology as early as the late 1980s. All this work took place within an ecosystem that the Wilhelm Sander Foundation actively helped to shape. Particularly noteworthy was the continuity and long-term strategic approach in the composition of the Scientific Advisory Board. Alongside Harald zur Hausen, Bernhard Fleckenstein and, later, Ralf Bartenschlager were also active on the board – all of them leading virologists and experts in molecular virology.

PART 3 THE PATH TO THE VACCINE – A MARATHON, NOT A SPRINT

The entire development of the HPV vaccine was more like a marathon than a sprint. Right up until the 1990s, it was considered technically impossible to grow papillomaviruses in cell cultures. Science needed persistent researchers and courageous funders who believed in the breakthrough.

The work of Gissmann and Dürst played a key role: they had characterised HPV16 isolates from pre-malignant lesions – that is, from lesions in which HPV16 was not integrated into the genome. These isolates were shared with the National Institutes of Health (NIH) and, to this day, form the basis for all HPV-VLP vaccines worldwide.

In the early 1990s, various research groups began producing the main structural proteins of the HPV virus (L1 capsid protein) in such a way that they spontaneously assembled into virus-like particles – ideal for a vaccine. However, this did not work for HPV16. The problem was solved by a team of Austrian virologists led by Reinhard Kirnbauer: after analysing an HPV16 clone that had been isolated by the DKFZ, they corrected a mutation in the standard isolate at position 202, whereupon particle formation was successful. A reminder that, in research, tiny details can make the difference between success and failure.

This breakthrough paved the way for practical application. The first clinical trial took place in 1996. As early as the early 2000s, extensive clinical trials involving around 25,000 young women showed that the vaccine worked. In 2006, the regulatory authorities approved the first HPV vaccine.

PART 4 MARTIN MÜLLER AND THE FUTURE OF THERAPY

Whilst prophylactic vaccines were gaining ground, a new generation of researchers was pursuing a different question: how can a disease caused by HPV still be prevented or cured even after infection?

Martin Müller of the DKFZ continues to focus on this question to this day. His research group is developing combined prophylactic and therapeutic vaccines – an approach known as ‘post-exposure prophylaxis’. Whilst the excellent VLP vaccines have a critical weakness – they only protect against HPV infection – therapeutic vaccines are intended to help people whose bodies are already infected with HPV or who have already developed early-stage lesions. Müller’s research aims to bridge this gap.

The Wilhelm Sander Foundation has been supporting Müller’s research group for many years in the development of these combined vaccine strategies. This demonstrates once again the Foundation’s focus on facilitating ambitious, highly innovative projects with a translational approach.

PART 5 AN UNPRECEDENTED SUCCESS STORY

The reality today is impressive: the HPV vaccine is one of the most successful vaccines ever developed. In countries with high vaccination coverage, the incidence of precancerous cervical lesions has fallen by up to 90 per cent. High-risk HPV infections are suppressed before they can develop into precancerous lesions. Yet HPV-related cancer poses a significant health problem: every year in Germany, around 6,000 women and 1,700 men are diagnosed with HPV-associated cancers. However, for many of those affected, this type of cancer has now become preventable through vaccination before it develops.

This is the often-cited ‘From Bench to Population Prevention’ story that medical professionals and virologists had been working towards. Fundamental discovery → deeper understanding → technical innovation → clinical validation → global application. Rarely is this path followed so clearly and so comprehensively. And the Wilhelm Sander Foundation was involved throughout all these phases.

However, the path from the laboratory to global application was anything but straightforward. Martin Müller emphasises that this transition was a gradual process and cannot be attributed to a sudden ‘Eureka moment’. A crucial milestone was reached when major pharmaceutical companies snapped up the available licences for VLP technology worldwide – at which point it became clear that commercial development might be possible. Yet there were considerable doubts: how effective would the vaccines really be? Were strong antibody responses in the mucous membranes required? These questions could only be answered through extensive clinical trials. When Merck and GlaxoSmithKline ‘took the reins’, as Müller puts it, the dynamic changed: suddenly, these companies dominated HPV conferences, whilst keeping their internal developments under wraps until the results were published. But progress was being made.

In Germany, the vaccine initially met with considerable resistance. A group of 17 renowned German clinicians expressed fundamental concerns: they argued that we should first wait and see whether the vaccine actually prevented cervical cancer – a question that would take years or even decades to answer. The overall value of the vaccine was also called into question. Harald zur Hausen responded with an excellent and well-reasoned counter-argument, which appeared, amongst other places, in the *Frankfurter Allgemeine Zeitung*. This scientific debate demonstrates that even a brilliant idea faces a long and contentious path to acceptance in medical practice.

PART 6 THE PORTFOLIO OF A VISIONARY FOUNDATION

A look at the 249 projects that the Wilhelm Sander Foundation has funded in the field of oncogenic viruses and HPV prevention over a period of 50 years reveals an extraordinary strategic commitment. Accounting for ten per cent of the total funding portfolio, this research focus is remarkably well represented. This underlines both the scientific continuity and the deep conviction that this research is pioneering.

What makes this research focus unique within the portfolio? It is the ‘common thread’ – the clearly discernible arc stretching from the virological discovery (HPV as a cause of cancer) through to biological elucidation (How does the virus cause cancer?) and on to preventive solutions (How do we protect the population?), and beyond to new therapeutic approaches. Whilst other funding areas tend to be structured according to medical specialisms, this strand tells a scientific story with a clear beginning, traceable progress and questions that remain open for the future.

PART 7 WHAT REMAINS TO BE DONE? NEW HORIZONS AND INTERDISCIPLINARITY

The current funding of projects such as that led by PD Dr Thorsten Rieckmann at the University Medical Centre Hamburg-Eppendorf demonstrates that the Wilhelm Sander Foundation not only supports basic HPV research aimed at optimising vaccines, but is also investigating entirely new clinical applications. It is important to note that HPV-associated tumours are not limited to the cervix. They also develop in the oropharyngeal region, the vagina, the anus and other sites – in both women and men.

Whilst Rieckmann is exploring new therapeutic approaches, Prof. Dr Frank Stubenrauch of the Eberhard Karls University of Tübingen is working on the scientific fundamentals: he is investigating how HPV persists and how chronic infections lead to the development of cancer. The Wilhelm Sander Foundation has funded several of his basic research projects. His work reveals the molecular mechanisms that preventive and therapeutic strategies ultimately target – and thus forms the basis for the clinical approaches that Rieckmann and others are currently advancing.

It is also noteworthy that the Wilhelm Sander Foundation is currently funding several parallel research approaches into head and neck cancers, including the work of Prof. Dr Anna Dubrovska (see also the article ‘Inside the Tumour’ in this issue) on overcoming immune suppression in these tumours. This demonstrates how the Foundation tackles problems from different angles in order to develop innovative therapeutic solutions.

PART 7 WHAT REMAINS TO BE DONE? NEW HORIZONS AND INTERDISCIPLINARITY

The current funding of projects such as that led by PD Dr Thorsten Rieckmann at the University Medical Centre Hamburg-Eppendorf demonstrates that: The Wilhelm Sander Foundation not only funds basic research into HPV to optimise vaccines, but also investigates entirely new clinical applications. It is important to note that HPV-associated tumours are not limited to the cervix. They also occur in the oropharyngeal region, the vagina, the anus and other sites – in both women and men.

Whilst Rieckmann is exploring new therapeutic approaches, Prof. Dr Frank Stubenrauch of the Eberhard Karls University of Tübingen is working on the scientific fundamentals: he is investigating how HPV persists and how chronic infections lead to the development of cancer. The Wilhelm Sander Foundation has funded several of his basic research projects. His work reveals the molecular mechanisms that preventive and therapeutic strategies ultimately target – and thus forms the basis for the clinical approaches that Rieckmann and others are currently advancing.

It is also noteworthy that the Wilhelm Sander Foundation is currently funding several parallel research approaches into head and neck cancers, including the work of Prof. Dr Anna Dubrovska (see also the article ‘Inside the Tumour’ in this issue) on overcoming immune suppression in these tumours. This demonstrates how the Foundation approaches problems from different angles in order to develop innovative therapeutic solutions.

PART 8  AN ANNIVERSARY MESSAGE – PATIENCE AND A LONG-TERM APPROACH

To mark the Wilhelm Sander Foundation’s anniversary, the HPV story conveys a message on several levels. It demonstrates that long-term investment in basic research pays off – if not always quickly, then certainly in the long run and with a significant impact. It illustrates the power of collaboration between researchers worldwide. And it underlines how important it is for foundations to invest in areas where the practical benefits are not yet immediately apparent.

Frank Stubenrauch sums up the need for this patience: “Basic research is a slow process and is characterised by setbacks. That is why you need to be patient, curious and have funders such as the Wilhelm Sander Foundation who support basic research over the long term.”

What further sets the foundation apart is its efficiency, despite its long-term focus. Stubenrauch emphasises: “A key advantage of funding from the Wilhelm Sander Foundation is the relatively short time between the submission of an application and a decision. This makes it possible to implement new ideas quickly.” Thorsten Rieckmann summarises why this is valuable: “Foundations such as the Wilhelm Sander Foundation are fundamental building blocks in research funding, enabling ambitious projects to be pursued with scientific precision and depth.”

The success story of the HPV vaccine impressively demonstrates the unique role that private foundations can play. They not only support established mainstream research, but also have the courage to invest in hypotheses in people who think outside the box, who persist with questions even when the answers are still years away. Although cervical cancer has not yet been completely eradicated, in countries with high vaccination rates it has become a preventable cancer within the foreseeable future. The Wilhelm Sander Foundation has played a significant part in making this a reality.