HPV vaccines: what remains to be done?

Abstract

Interview by Lauren Constable, Commissioning Editor

Harald zur Hausen studied medicine at the Universities of Bonn, Hamburg and Düsseldorf (Germany) and received his MD in 1960. After a period of 3 years as a senior scientist at the Institute of Virology of the University of Würzburg (Germany), he was appointed in 1972 as Chairman and Professor of Virology at the University of Erlangen-Nürnberg (Germany). In 1977 he moved to a similar position at the University of Freiburg. From 1983 until 2003 zur Hausen was appointed Scientific Director of the Deutsches Krebsforschungszentrum (German Cancer Research Center) in Heidelberg before retiring from this position in 2003. During the early 1980s he was involved in the isolation of HPV-16 and HPV-18 from cervical cancer biopsies and hypothesized that cervical cancer was caused by papillomaviruses. This led to a better understanding of the mechanism of HPV-mediated carcinogenesis and eventually to the development of preventative vaccines against HPV-16 and HPV-18. He received the Nobel Prize for Medicine, 2008 for his discovery of human papillomaviruses causing cervical cancer. In addition, zur Hausen has received a number of other national and international awards, among them the Robert-Koch-Prize; the Charles S Mott Prize of the General Motors Cancer Research Foundation; the Federation of the European Cancer Societies Clinical Research Award; the Paul-Ehrlich-Ludwig Darmstätter-Prize; the Jung-Prize, Hamburg, the Charles Rudolphe Brupbacher Prize, Zürich; the Prince Mahidol Award, Bangkok, the Raymond Bourgine Award, Paris; the Coley-Award, New York; the Life Science Achievement Award of the American Association for Cancer Research, San Diego; and the German Special Order of Merit with Star. He received 16 honorary MD and PhD doctorates from the Universities of Chicago (USA), Umeå (Sweden), Prague (Czech Republic), Salford (UK), Helsinki (Finland), Erlangen-Nürnberg (Germany), Würzburg (Germany), Ferrara (Italy), Buenos Aires (Argentina), Madrid (Spain), Melbourne (Australia), Salerno (Italy), Los Angeles (CA, USA), Bucaramanga (Colombia), Besancon (France) and Jerusalem (Israel).

▪ Your suggestion that cervical cancer might be caused by human papillomavirus went against the consensus of the time. How did you arrive at that hypothesis?

My hypothesis was based on several aspects: first, in the 1930s, Richard E Shope and Peyton Rous had previously demonstrated the potential carcinogenicity of a papillomavirus infection, the cottontail rabbit papillomavirus [1]. Thus, this demonstrated that papillomaviruses could be cancerogenic.

The second point originated from the analysis of the literature on malignant conversion of genital warts. Since I myself had seen in the electron microscope typical papillomavirus particles in some genital warts, I was alarmed by some anecdotal reports in the literature, covering the past 100 years, on the occasional malignant conversion of genital warts into squamous cell carcinomas. This, indeed, led me to the speculation that the virus may be more aggressive at the cervical site.

The third point originated from our analysis of cervical cancer biopsies for herpes simplex type 2 DNA. Since the end of the 1960s this virus had been considered the main carcinogenic agent for cervical cancer [2,3]. We entirely failed to demonstrate herpes simplex type 2 DNA in cervical cancer biopsies. Thus, in 1972, we started an intensive program on the search and characterization of papillomavirus in genital warts, and its potential role in cervical cancer.

▪ The award of half of the Nobel Prize in Medicine, 2008 to yourself for the “discovery of human papillomaviruses causing cervical cancer” has undoubtedly increased awareness the link between infectious agents and human of cancer. How do you think the currently approved HPV vaccines will affect the prevalence of HPV-linked cancers in the next 10–15 years?

First of all, I believe that the approved HPV vaccines will have a measurable effect on high-risk precursor lesions for cervical cancer. This already became visible in the first studies conducted in Australia [4,5]. Vaccines containing the antigens of HPV-6 and -11 have also been shown to be highly effective against genital warts. As far as HPV in cancers are concerned, their average latency period is between 15 and 25 years following primary infection. Since the first clinical trial only started 8 or 9 years ago, we will still have to wait for at least one additional decade. I foresee, however, that within this period of time a reduction in the rate of cervical cancer will take place in the vaccinated population. Unfortunately, this will only be seen in those individuals who have been vaccinated prior to the primary infection. Based on the present vaccine protocol, we can anticipate that approximately 70% of cervical cancers are preventable by vaccination. This percentage might be slightly higher, because there also exists a cross-reactivity with types 31, 33, and 45 of the HPV-16 and -18 antigens.

▪ It has been reported that 93% of anal cancers are associated with HPV. The US FDA recently approved Gardasil^® for use in males and females aged 9–26 to prevent anal cancer. What other patient groups or cancers do you believe HPV vaccines should be indicated for?

I believe that the approval of a vaccine by the US FDA in males and females also has the potential to prevent anal cancer. In addition, approximately a quarter to a third of oropharyngeal cancers are probably also preventable by vaccination. I am personally arguing very strongly for the vaccination of boys, not only to prevent cancers linked to HPV occurring in males, but also due to the transmission of the virus by males to females. Only an extensive program to vaccinate both genders could lead to an eradication of the high-risk HPV types within a foreseeable period of time.

▪ In the past, some have noted that pharmaceutical companies were reluctant to invest in the research and development of vaccines against oncogenic etiological agents. Do you think that there is now an adequate amount of investment in the development of these vaccines?

For the companies involved I believe that there is sufficient investment in the development of these vaccines. Octovalent and nonavalent vaccines are currently in preparation. There is also a rising interest in preparing a group-specific vaccine based on a group-specific antigenic epitope in the L2 protein. To my knowledge, there are also additional companies now working on the preparation of vaccines. The major problem at this stage is the price, which is difficult to afford particularly for resource-restrained countries.

▪ Recently, a collaborative effort between pharmaceutical companies and the government of Rwanda was announced that plans to help make HPV vaccination affordable in this country. Some believe that vaccination in developing countries is worthwhile but in developed countries, where screening rates are high, screening is more suitable as opposed to vaccination. What are your thoughts on this?

An affordable vaccine for Rwanda is one major step forward. I believe that the contributions of the vaccine at a low price, as recently announced specifically for parts of the developing world, will be of great help. Clearly, the vaccination is most needed in the developing world where cervical cancer rates are very high. It is, however, needed in resource-rich countries as well where it prevents the appearance of high-risk precursor lesions. They frequently require surgical intervention, which would be prevented by vaccination. For example, even in developed countries, precursor lesions requiring surgical intervention exceed the incidence of cervical cancer frequently by a factor of 20. In Germany, we have approximately 6000–6500 cases of cervical cancer annually, but according to data of health insurances, approximately 140,000 surgical interventions for precursor lesions. The risk for side effects (in particular for subsequent pregnancies) amounts to 2–7%, according to the same sources. For these reasons vaccination is also an important issue for affluent and well screened societies.

▪ In terms of vaccination policy, what do you feel needs to be implemented in order to facilitate the eradication of cervical cancer globally?

Global policy for HPV vaccination would, of course, be of great advantage. I foresee, however, that this is not possible to develop. Thus, advocacy of the vaccine, teaching the respective health ministries, health officials, physicians, parents and teachers about the importance of the vaccine should be conducted as much as possible globally.

▪ In the past decade, what research in the area of oncogenic agents and their vaccines do you think has most significantly changed the field or will change the field in years to come?

Clearly, the research on hepatitis B virus, and also on high-risk papillomaviruses most significantly changed the field. Consequently, we anticipate a remarkable reduction in the rate of hepatocellular carcinomas, as well as of cervical cancer within a foreseeable period of time.

▪ In your opinion, how far are we from the development of a therapeutic HPV vaccine?

Unfortunately, as far as therapeutic HPV vaccines are concerned, progress has been relatively slow. It is likely that effective vaccines could be developed faster for very early lesions or for persistent infections than for advanced lesions. More research is required here.

▪ Many important issues of tumor virology remain unresolved and exciting new ones are emerging from recent discoveries. Which of these do you feel is the most significant in terms of future research directions?

The development of vaccines against hepatitis C virus infections, against HIV, if possible, and also against Helicobacter pylori and Schistosoma infections remains extremely important. I feel, however, that in general more research needs to be carried out in tumor virology. We can presently estimate that approximately 21% of human cancers are linked to infections. Personally, I am convinced that this rate will increase in the future.

▪ In the coming decade, what other links between viruses and cancer might you expect to see confirmed?

I suspect that, in particular, cancers of the hematopoietic system may be more linked to infectious diseases than we presently consider them to be. In addition, there are some hints that may point to a viral involvement of colorectal cancers as well. If those suspicions would turn out to be true, the global cancer rate linked to infections would immediately jump up to approximately 35%.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.