HPV Vaccination, from theory to practice: An interview with Margaret Stanley

Prof Margaret Stanley is the Emeritus Professor of Epithelial Biology in the Division of Cellular and Molecular Pathology at the University of Cambridge, Department of Pathology. She has a lifetime award for contribution to research on cervical cancer and cervical precancers from the American Society for Colposcopy and Cytopathology (ASCCP) and a lifetime award for achievement from the International Papillomavirus Society. In 2004 she was awarded the OBE for services to Virology.

You’ve predicted this for many years, but this must nevertheless be a great day for you – to see your life’s work result in hundreds of women being prevented from getting cervical cancer – and that’s just the tip of the iceberg. How do you feel?

Absolutely elated, in many ways. I’ve been in this business a long time, and when I started as a postdoc my project was to look at the cytogenetics of biopsies of CIN3 and compare them to invasive cancers. At that time, we couldn’t do much about it. We couldn’t do cone biopsies on the precancers. Back then, for invasive cancers we had treatments which are not too different than what they are now. Radiotherapy was the primary option, but the women usually presented late so mortality was high. We’ve gone from that, diagnosing the disease, to now, where we can prevent it. That’s really an extraordinary leap in anyone’s lifetime. Globally, though, there are still hundreds of thousands of women who are still getting the disease, getting no treatment, and dying. Helping them is the next big step.

You have had a key role in the development and implementation of HPV immunisation. What was your proudest moment?

The publication of Laura Koutsky which showed that the HPV type 16 VLPs (Virus-like particles) vaccine prevented persistent infection. That was a landmark moment, not only because getting a vaccine to the VLP stage is difficult, but also because a lot of the pharmaceutical companies involved were unsure it would work. Additionally, when the randomised control trial in 2006 further supported our findings – I was euphoric.

Can you tell us something about the development of the HPV vaccines? What were the key steps? Who were the personalities involved?

The first VLPs were generated by Jian Zhou, who worked at Cambridge in Lionel Crawford’s lab. He was absolutely obsessed with the idea that you had to make a lot of the coat protein L1. He came to Cambridge to work with Lionel and with Geoff Smith, who developed the vaccinia recombinant system. Jian was talented, but the best person in the lab was his wife, Xiao Yi Sun who had green fingers and excelled at the technically tricky experiments we were undertaking. The two of them together were an extraordinary team. Jiang was what I would describe as a ‘quick and dirty’ scientist. His note keeping wasn’t magnificent, and when he would go to the freezer, he would just pick out a specimen – no one was ever quite sure which one he had picked.

The Tiananmen Square Massacre (June Fourth Incident) happened when Jian was a post-doc with us, and it made him stateless. The British government wouldn’t give asylum status to Tiananmen Square refugees, but Australia would. Ian Frazer, an Australian HPV researcher was on sabbatical with me in Cambridge at the time, and offered Jian a position in Australia, where he would be accepted as an asylum seeker. Jian struck gold when he got to Queensland and made the first VLP. Bob Rose and Bob Garcea in the US were also making VLPs, but they were using HPV 6 not 16. Jian and Ian presented their work at a meeting in Seattle, and that was the first publication explaining that we could make a VLP from the coat protein of HPV. Making that VLP was a key moment.

You have been a strong proponent of vaccinating boys as well as girls, but these results suggest that cervical cancer can virtually be eliminated by vaccinating girls only. Do you still think it’s important to vaccinate boys?

If preventing cervical cancer is your only objective, then you can argue that immunising girls is enough. However, you have to immunise more than 80%, ideally 85-90% for that effect to happen. You have to do it in a sustained fashion, so every year you’re immunising girls rather than just cohorts, so there’s no chance for reinfection. The UK and particularly Scotland have done this very well, with an average of about 85% coverage every year. If you’re looking at HPV in a wider perspective, so other HPV-related cancers which are in men as well as in women, you won’t be able to eliminate the virus without vaccination of both sexes. Globally, I believe that unless you vaccinate boys, you won’t be able to reach the WHO target of eliminating cervical cancer.

The original HPV vaccination programme was based on three doses of the vaccine. The current programme on just two. Increasingly there is evidence that a single dose may be sufficient. What is your view?

The evidence is strong that a single dose is enough to prevent persistent infection. There are a couple of caveats here. In the UK style programme, which is given to 12-year-olds, one dose should be enough. We have evidence from Indian studies, that the protection lasts for at least 10 years. Other trials in African show that one dose works, but there’s not been the time for follow-up yet. Everything so far is saying that one dose is going to be as effective as two or three doses, at least for the first 10 years. My argument is always that one dose for both boys and girls will give you a far more dramatic effect than two doses just for girls. I think one dose will increasingly be used, and if there’s any evidence to the contrary you can provide a second dose as a booster shot. For most of the world, however, this is not a question of one or two doses, but a question of one or zero doses.

Few countries have as high uptake of the HPV vaccine as the UK. What can be learnt and what needs to be done to ensure cervical cancer is brought under control globally?

The UK planned the introduction of the HPV for a long time before it was rolled out. The architect of the British HPV immunisation programme, David Salisbury, pulled together a range of scientists and researchers to help with planning. Social psychologists were conducting small trials about how parents would feel having a vaccine to prevent something sexually transmitted, for instance. So we collected a lot of information about who the target audience should be, and what sort of education and information should be put out there. You can’t always do this in developing countries, but you can make sure that the people who matter in terms of information are on side. Further to that, you need to make it as easy as possible to access the vaccine. Any problems that arise after the vaccine programme has started need to be dealt with very quickly – think ‘when’ something will happen, not ‘if’.

The current HPV vaccines are all prophylactic, what do you think the prospects for a therapeutic HPV vaccine are?

We know from natural infection in animals, and producing vaccines for them, that therapeutic vaccines against infection, or a wart, is possible. If you’re looking at the cancer process – so precancer, invasive cancers – this is looking more at personalised medicine. The precancer and cancer that arises in one person will be different to another. To succeed here you have to know what the generics are across people, with regards to cervical cancer. So, I’m gloomy about vaccines for cancers and precancers, but I’m more optimistic about vaccines which target infection. 90% of HPV infections go away, but if you’re 25, you don’t want to have to wait a couple of years to find out if it’s gone away. An injection to treat it might be a better way.

Looking back over your career, are you pleased that you decided to work on cervical cancer and HPV infection? What advice would you give to a young researcher today?

In short, I am pleased! I started because I was really interested in this field, and I’ve stayed really interested in it this whole time. What advice would I give? Loyalty is a grossly over-emphasized characteristic. More optimistically, it’s what I just said. Do something you’re interested in, follow your passion.


Additional Reading:

Further information regarding the history of the development of the HPV Vaccine.

Cervical cancer rates reduced by 87% in women vaccinated against HPV, English study confirms


The views expressed are those of the author. Posting of the blog does not signify that the Cancer Prevention Group endorse those views or opinions.

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