本田財団レポート No.133
第 30 回本田賞授与式 記念講演（2009 年 11 月 17 日）「免疫を通じたがんの予防 ― その過去・現在・未来」
オーストラリア・クイーンズランド大学
プリンセス・アレクサンドラ病院
ディアマンティナ・がん・免疫学・代謝薬協会局長

イアン・フレイザー博士

Cancer Prevention through Immunization– Past, Present and Future
Commemorative lecture at the 30th Honda Prizeawarding ceremony on the 17th November 2009

Dr. Ian Hector FRAZER
Director, Diamantina Institute for Cancer, Immunology and Metabolic Medicine
The University of Queensland
Princess Alexandra Hospital, Australia

イアン ・ フレイザー博士
オーストラリア・クイーンズランド大学
プリンセス・アレクサンドラ病院
ディアマンティナ・がん・免疫学・代謝薬協会局長
Director, Diamantina Institute for Cancer,
Immunology and Metabolic Medicine
The University of Queensland
Princess Alexandra Hospital, Australia

Dr. Ian Hector FRAZER■生まれ
1953年1月6日
■学 歴
1974年
1977年
1988年
■職 歴
1977年
1978年
1980年
1981～85年
1989～99年
1989～93年
1991年～現在
1994年～現在
■受賞歴
2006年

2007年

2008年

2009年
■現公職
1988年～
1989年～
2002年～
2003年～
2004年～

スコットランド・グラスゴー市生まれ(56歳)＊オーストラリア人■Born
6th January 1953, Glasgow, Scotland (Nationality : Australian)

エジンバラ大学病理学部卒業（スコットランド）
エジンバラ大学医学部卒業（スコットランド）メルボルン大学医学部博士課程修了■Qualifications
1974 Bachelor of Science (Hons) Pathology, University of Edinburgh,
Scotland1977 Bachelor of Medicine and Bachelor of Surgery, University of
Edinburgh, Scotland
1988 Doctor of Medicine, The University of Melbourne

ルードランズ病院常駐幹部（スコットランド・ハディントン市）
王立病院腎臓医療班常駐幹部（スコットランド・エジンバラ市）
王立病院腎臓医療班研修医（スコットランド・エジンバラ市）
メルボルン・ウォルター・エリーザ・
ホール協会上席研究員
ブリスベン・プリンセス・アレクサンドラ
病院局長
クイーンズランド大学医学部内科助教授
クイーンズランド大学がん免疫学研究所(現ディアマンティナ協会)局長
クイーンズランド大学医学部教授■Biographical details
1977 House Officer, Roodlands Hospital, Haddington, Scotland
1978 Senior House Officer, Medical Renal Unit, Royal Infirmary,
Edinburgh, Scotland
1980 Registrar, Medical Renal Unit, Royal Infirmary, Edinburgh,
Scotland
1981-1985 Senior Research Officer, Walter and Eliza Hall Institute,
Melbourne
1985-1999 Director, Div. of Clinical Immunology, Princess Alexandra
Hospital, Brisbane
1989-1993 Associate Professor, Department of Medicine, Universityof Queensland
1991-present Director, Centre for Immunology and Cancer Research(Now the Diamantina Institute), University of Queensland
1994-present Professor, Department of Medicine, University of
Queensland

ニューヨークがん研究協会ウィリアム・
コーリー・メダル、王立病理医科大学名
誉研究者賞、今年のオーストラリア人、
今年のクイーンズランド州人
ノバーティス賞（臨床免疫学・リオデジャ
ネイロ）、国際偉業サミット金賞、国際生命賞（科学研究分野）、メルク・シャープ・ハワード・フローレイ・メダル、ク
ラニーズロス賞（科学技術工学アカデミー）
バルザン賞（予防薬）、ラマシオッティ・メダル、（オーストラリア）総理大臣賞（科学）、米皮膚病学アカデミー・リアグラバー
皮膚病理学賞
オーストラリア医学協会金賞、ゴールド
ハロルド医薬健康賞
王立エジンバラ医学校・特別研究員
オーストラリア王立病理医学校・特別研究員
オーストラリア企業役員協会・特別研究員
オーストラリア科学技術工学アカデミー・特別研究員
オーストラリア科学アカデミー・特別研究員■Selected awards
2006: William Coley Medal, Cancer Research Institute, N. Y.,
Distinguished Fellowship Award, Royal College of Pathologists,
Australian of the Year, Queenslander of the Year.
2007: Novartis Prize for Clinical Immunology, Rio de Janeiro,
Golden Plate recipient, International Achievement Summit,
International Life Award for Scientific Research, Merck Sharp &Dohme Howard Florey Medal, Clunies Ross Award, Academy ofTechnological Sciences and Engineering.
2008: Balzan Prize for Preventative Medicine, Ramaciotti Medal,(Australian) Prime Minister's Prize for Science, American Academyof Dermatology Lila Gruber Award for Dermatology.
2009: Australian Medical Association Gold Medal, Winner of theGold Harold Health & Medicine Award■Fellowships
Royal College of Physicians of Edinburgh, since 1988,
Royal College of Pathologists of Australia, since 1989,
Australian Institute of Company Directors, since 2002,
Australian Academy of Technological Science and Engineering,
since 2003,
Australian Academy of Science, since 2004

このレポートは、2009 年 11 月 17 日 東京、帝国ホテルにおいて行われた第 28 回本田賞授与式記念講演の要旨をまとめたものです。
This report is the gist of the commemorative lecture at the twenty eighth Honda Prize Awarding Ceremony on the 17th November
2009 Imperial Hotel, Tokyo.

Cancer Prevention through Immunization– Past, Present and Future
Cancer is a challenge for the 21st Century
Ian Hector FRAZER

Fig 1

Fig 2
〈Fig 2〉 In Australia, cancer is now the commonest cause of death. The International
Cancer Prevention Union suggests that by 2050 cancer will also be the commonest cause ofdeath worldwide, as the common cancers, with the exception of breast and cervical cancer, are30

predominantly diseases of over 50 year olds and we are all living longer. The solution to thechallenge of cancer in the 21st century must therefore firstly be to ensure we do everything we
can to prevent cancer. We have the knowledge already to prevent over 70% of cancer if weavoid smoking, obesity, excessive exposure to sunlight, excess consumption of alcohol and those
infections we know cause cancer. We also know that we can cure over 50% of cancer, which isgood news, because when I was a medical student it was only 10% of cancer that could be cured.
We have the ability, for some cancers, to detect the disease early, and the chances are that in
the future we will do better in this area, as risk profiling for people who are at particular risk of
specific cancers will help us to work out who we should target for vigilant screening.

Fig 3〈Fig 3〉 Globally, the burden of cancer is unevenly distributed with the majority of cancers
occurring in the developed world. This is largely because we live longer in the developed
world and therefore are more at risk. Cancers like cervical and breast cancer, on the other
hand, are commoner in the developing world because these are cancers which occur in people
under the age of 50, and the risk factors for cancer there are higher, and the ability to preventthe disease is less.

31Fig 4〈Fig 4〉 The critical challenge for the 21st century will be to find methods of preventing thepredicted increase in cancer in the developing world, where expensive treatments are unlikely
to be available. Prevention is obviously the best hope. Through behaviour change such as
reduction in smoking, by removing carcinogens from the environment, for example arsenicfrom drinking water, and by reducing the risk of infection through vaccination we can prevent
many cancers relatively cheaply on a global basis. Early detection through screening is not
likely to become available in the developing world in the near future - it will however remain amainstay of cancer prevention for those cancers for which an effective screen is available in thedeveloped world. Screening for cervical cancer through PAP smears, screening for earlymalignancy through breast cancer screening and screening for genetic risk markers such as
BRCA-1 and BRCA-2 will be the mainstay of early detection of cancer risk in the developed
world. Definitive treatment for cancer is well known and I will not speak further about thatexcept to point out that as you go down the list from surgery to immunotherapy the cost ofthese treatments increases substantially and the new immunotherapeutics such as Etanercept
and Rituximab will be not only very useful, and therefore very widely used, but also very
expensive. Of course, it is critically important that we also remember about palliation for
those with uncurable cancer and one of the major challenges that we face is that in many of thecountries in the developing world. Where cancer is common and very little can be done fortreatment, there is no available opiate analgesia for palliation.

32

Fig 5〈Fig 5〉 Today I am going to speak particularly about the prospects for preventing theinfections that are responsible for cancer, and how we can use the body’s immune system toprevent and control these infections. Infection causes over 20% of the global cancer burden- viruses contribute the largest part of that - papillomavirus and hepatitis B virus at the top of
the list. Of course, and particularly in Japan, we must not forget about Helicobacter, abacterium which is responsible for 5% of the global cancer burden, and particularly for gastriccancer. The pathogens in green on the slide are ones for which we already have vaccines,
while the ones in yellow are ones where vaccines are under development, and these are where
the major breakthroughs in the 21st century are likely to emerge. I am going to talkparticularly today about human papillomavirus associated cancers, and while most of the talkwill be about cervical cancer because this is the cancer most commonly associated with humanpapillomavirus infection, I would like to remind you that there is also a burden of disease due
to papillomavirus at other sites particularly other anagenital cancers and cancers of the headand neck. These problems are not unique to women - they also occur in men. As for most of
the pathogens on this list, infection with Papillomavirus is common, and as for all of them,cancer is a rare consequence of the common infection.

33

Fig 6〈Fig 6〉 A little bit about papillomaviruses. These are very common viruses and there are
now recognized to come in over 200 different varieties. They are double standard DNA
viruses, which mean that they are genetically stable and do not change much with time. They
only can replicate in skin. They are very much species specific and, unusually amongst
viruses, they do not kill the cells they infect but rather promote cell growth and proliferation,
conveying a risk of cancer development. There are 4 major groups of these viruses in humans.
One major group is responsible for cutaneous warts which all of us get and which do not turninto cancer. An equally common group produce genital warts: again these do not turn into
cancer. A third group are responsible for genital cancer, termed A7 and A9, of which HPV
types 16 and 18 are the commonest. These viruses produce little visible disease apart fromthe risk of cancer. The fourth group is associated with skin cancer, and includes HPV types 5
and 8, also beta viruses. These viruses are very common, and infection only rarely produces
cancer.

34

Fig 7〈Fig 7〉 Infection with all papillomaviruses is extremely common - this graph shows thegradual accumulation of new papillomavirus infection amongst young people after the onset of
sexual activity and you can see that over a period of 3 years after the onset of sexual activity
more than half of this particular population acquired one or other of the papillomaviruses
responsible for cervical cancer risk.

Fig 8〈Fig 8〉 Unsurprisingly, the greatest instance of new genital papillomavirus infections are inyoung adults, but it is worth pointing out that this risk of acquiring new genital papillomavirus
infections exist throughout life albeit at lower frequency, and there is no time of life when there
is no further risk on a community basis. Men also get human papillomavirus infections and35

also therefore human papillomavirus associated cancers.

Fig 9〈Fig 9〉 These are data for tonsillar cancer and you can see that both males and females
have a significant risk of tonsillar cancer, and this is increasing. The interesting thing is thatthe increased risk is due to the increased risk of papillomavirus associated tonsillar cancer.
There are two groups of people at risk for tonsillar cancer: elderly males who smoke and drink
too much alcohol - these cancers are not increasing in prevalence, and younger men and women
who acquire HPV infection and who do not have smoking or alcohol consumption as a risk
factor. The papillomavirus associated tonsillar cancers are the ones that are increasing.

Fig 1036

〈Fig 10〉 When it comes to prevention of human papillomavirus infection, Harold zur
Hausen led the way by demonstrating in the early 1980’s that papillomaviruses were
responsible for cervical cancer. He had the advantage of the new technology of molecularbiology which enabled categorization of these viruses and the recognition that there were notjust one or two papillomaviruses but over 20, some of which were associated with cervicalcancer. That gave rise to the idea that it was possible to prevent papillomavirus infection andtherefore papillomavirus associated cancers. Unfortunately these viruses could not be grownin the laboratory, precluding the normal approach for development of vaccines. In 1990, mycolleague, the late Dr Jian Zhou, and I came up with the technology for making papillomavirus
virus-like particles using recombinant DNA technology. The L1 protein assembles itself into
these particles that you can see in the picture which look just like the virus and consist of 360
copies of the L1 protein. Fortunately for us the process of the assembly of the L1 proteins into
the virus like particles happened automatically and produced highly immunogenic virus likeparticles.

Fig 11〈Fig 11〉 We achieved this by cloning the genetic information for the virus out of the lesion
and demonstrating that we could express that protein in vitro using the recombinant DNA
technology so long as this was done in eukaryotic cells, and the gene expression started fromthe appropriate place in the gene. The net result was the production of virus like particles.
These virus like particles combined with adjuvant became the basis of the vaccines that are
now available to help prevent cervical cancer.

37

Fig 12〈Fig 12〉 Of course there was a considerable amount of clinical research work that had to bedone between the development of the virus like particle technology in 1990 and the availabilityof the vaccines in 2005. That work involved some 2,000 scientists worldwide; 60,000 womentaking part in clinical trials and the expenditure of about USD $1.5 billion. So, clearly most of
the work that was done on the development of these vaccines was done by others. What has
emerged are two very conventional vaccines based on virus like particles and alum adjuvant,which produce neutralizing antibody and give long term protection against infection. The
major difference between the two vaccines is that one prevents the two virus infections which
are most commonly responsible for cervical cancer and the other additionally prevents 2 HPV
infections which are responsible for genital warts.

Fig 1338

〈Fig 13〉 So, given that these vaccines are now available there are some questions that you
should ask yourself including: do these vaccines work, are they safe, how long should
protection last, whom should we vaccinate and what do we still need to know? I will attempt
to answer these questions over the remainder of the talk.

Fig 14〈Fig 14〉 The first important observation is that, against the right criteria, these vaccines
are extremely effective. These data show the efficacy of the vaccines for preventing diseasecaused by the virus types in the vaccine in a woman who had not previously been exposed tothese virus types so this is if you like an ideal situation and in this ideal situation cervicalpre-cancer is prevented with 100% efficacy in the majority of the trials.

Fig 1539

〈Fig 15〉 Of course, in the real world quite a bit of cervical cancer, about a third, is due tovirus types that are not in the vaccine. Therefore in the next slide you can see data showingthat there is a steady accumulation of pre cervical cancer in the unvaccinated population andthat this occurs with reduced frequency in the vaccinated population, but not with zerofrequency. The green arrow shows the reduction in disease burden due to vaccination. The
red arrow shows residual disease due to papillomavirus infection with virus types that are notin the vaccine. For this reason vaccines are a part of the process of cervical cancer prevention
and will be used along with cervical cancer screening - the PAP smear program, to help ensurethat women stay clear of this disease. Of course, the green arrow represents the major publichealth benefit that prevents one operation for cervical pre-cancer per 1,000 women per year inAustralia, if the vaccines are used universally.

Fig 16〈Fig 16〉 There is another limitation on the use of the vaccine. This is a complicated slide
but it shows basically in the first data box the efficacy of the vaccine for preventing cervicalpre-cancer in women who have never seen the virus before, and as I have shown you previously
this efficacy is about 100%. The red box shows the efficacy of the vaccine in women who havealready seen the virus, they have no disease but the virus is already there and as you can see
here the vaccine efficacy is essentially zero. So, the vaccines have to be given to women before
they become exposed to the virus because once they already have the virus there is notherapeutic effect from giving vaccination.

40

Fig 17〈Fig 17〉 These vaccines are also effective in men and data shown on this slide here are forthe prevention of genital warts in men vaccinated with the quadrivalent vaccine which also
prevents genital warts and while the efficacy is a little bit less than for cervical cancer
prevention, genital warts are prevented with at least 85% efficacy.

Fig 18〈Fig 18〉 Why would you bother vaccinating men? Well, the most obvious reason is
because men get HPV associated cancer - about 10% of the global cancer burden caused bypapillomaviruses is in men. The second reason is because immunizing men reduces the risk
for their female partners - if they don’t have the disease they can’t pass it on. The third
reason is because generalized immunization across the whole community will rapidly reduce41the overall burden of papillomaviruses in the community and therefore papillomavirus
associated disease. Of course, the ultimate decision as to whether to vaccinate men is basedon cost efficacy and if all women are vaccinated then the added value for vaccinating men isrelatively small but if less than 70% of the female population is vaccinated then vaccinating
men as well significantly increases the protection for both men and women frompapillomavirus associated cancer.

Fig 19〈Fig 19〉 Are these vaccines safe?

Fig 2042

〈Fig 20〉 The extensive phase 3 clinical trials looked at the local side effects from vaccination
and as with any vaccine there is a local pain and swelling to be expected at the site ofvaccination in at least a small percentage of people vaccinated. This is not due to thepapillomavirus - it is due to the adjuvant aluminum that makes the immune system switch onin response to immunization. As you can see, the placebo in the vaccine gives similar side
effects whereas a saline placebo without adjuvants is relatively pain free. However, theseeffects are common and to be expected with all vaccinations. Rarer events are determined in
post licencing studies. Over 40 million women worldwide have been immunized now.
Amongst 27 million doses delivered over 12 months in the United States there were 12,000
reported adverse events. Most were not related to vaccination - and mostly they were notserious. Fainting was the commonest vaccine associated adverse event and a significant
number of head injuries and broken noses resulted from fainting and falling. However,serious vaccine associated adverse events were pretty much limited to anaphylaxis and thefrequency with which anaphylaxis occurred about 1 in a million is exactly the same as has beenreported for most other vaccines. These vaccines will be given to young women of an age when
they might become pregnant so pregnancy safety becomes critically important. Of course,
women who take part in clinical trials should not become pregnant and are told to takeappropriate contraceptive advice but nevertheless out of 12,000 women who took place inclinical trials, 1,244 became pregnant. There was a rumour indeed going around that thesevaccines might be causing pregnancy but fortunately the placebo group did equally well at
becoming pregnant showing that it was not the vaccine but just normal behaviour that allowed
the pregnancies to occur. These data allow examination of the risk of adverse events due tovaccination and the risk of adverse events in the vaccine and placebo group were identical with
about 3.6% of women developing an abnormal outcome from pregnancy and serious congenitalabnormalities were equally frequent in the vaccine and placebo recipients.

43

Fig 21〈Fig 21〉 How long should vaccine protection last?

Fig 22〈Fig 22〉 We don’t really know the mechanism for protection against infection although we
believe strongly that it is antibody, and therefore if we use antibody as a surrogate measure wecan see from the data here that in fact antibody titres induced by vaccination, shown in theyellow circles, are high initially after vaccination and fall quite steeply over the first two years
during which there may be a tenfold reduction of antibody levels. Thereafter the induced
antibody levels plateau and there is no evidence of decline. Exactly why that should happen
is uncertain but the bottom line is that the antibody responses are well above the backgroundlevel that you see in natural infection for at least 5 years after immunization with all the44

evidence suggesting that this will carry on for the lifetime for the woman. So, it is reasonable
to expect long term protection although clearly it is important that we continue to survey toensure that that is achieved.

Fig 23〈Fig 23〉 So, what do we need to know for the future? Well, there are a number of issues
that I could cover including whether we could get broader coverage against different types of
HPV infections through increasing the number of HPV types in the vaccine, how we can bestdeliver these vaccines in the high risk countries where resources are limited, how longprotection will last, whether we can develop therapeutic vaccines, whether we can determine
who is at particular risk of HPV associated cancer and therefore more effectively target
immunotherapy and whether we can develop vaccines for other cancers caused bypapillomaviruses including particularly skin cancer.

45

Fig 24〈Fig 24〉 The data suggests quite strongly that there is some cross protection against HPV
types that are not in the vaccines in women who have been vaccinated. These data show
several different HPV types there is some partial protection. Of course, I have already shown
you that the protection is not absolute and this is important because it is the reason that wehave to carry on screening. We can add further HPV types to the vaccine and a 10 valentvaccine is now under early stage clinical trial.

Fig 25〈Fig 25〉 We are doing active research on immunization in high risk countries because werecognize that one of the critical parts of getting this vaccine where it is needed is to ensure it
is made available in countries where there currently aren’t the resources to enable purchaseand distribution of the vaccine.

46

Fig 26〈Fig 26〉 Worldwide the vaccine is licensed in over 100 countries - mostly for men andwomen, but in some countries only for women. The Government sponsored immunization
programs however, are limited to a rather smaller number of countries. Australia was one of
the first and has now immunized all girls between the ages of 12 and 25 with better than 80%
coverage. Most of the European countries, Canada and some parts of America currently haveprograms underway and the real challenge is for the developing world who have their licencebut are not being used. The Companies that make the vaccine are themselves putting
considerable effort into ensuring that the vaccines are made available in the developing world
free of charge or at much reduced cost and along with the Gates Foundation are planning todeliver vaccine across most of the developing world. The most critical thing will be to develop
programs which can effectively and sustainably deliver vaccines in these countries because thevaccines are designed to be given to 12 year olds shortly before they become sexually active andwe have no vaccine programs targeted at this group at present.

47

Fig 27〈Fig 27〉 For that reason we are now doing field studies of vaccine delivery in Vanuatu andin Nepal. Let me share a little of the data from Vanuatu. Vanuatu are a group of Islands
some 2 hours flying time from Brisbane in Australia. The 50 Islands have a population of
250,000 and only 5 Doctors although they manage to have 91 Parliamentarians. There is only
one vaccine fridge for the whole islands based in Port Vila and reliable electricity outside ofPort Vila does not exist.

Fig 28〈Fig 28〉 The problem clinically is that over 5% of apparently healthy 30 year old Vanuatu
women have cervical pre-cancer and 1% of them are walking the streets with cervical cancer.
So we set up a trial where we decided that we would try to deliver the vaccine to 12 year olds in48

this part of the world. The challenge being is that 12 year olds have generally left school in
Vanuatu and we wanted to ensure that we could get them back for the 3 shots that they are
required to have for protection. We tested out the hypotheses that giving a silicone wrist band- one of these coloured bracelets, with a reminder on the band that they should return for theirsecond and third vaccination would improve the chances that they would complete all threevaccine courses. This trial is currently underway.

Fig 29〈Fig 29〉 This is us educating the Vanuatu children under a Banyan tree in the north part of
Efate Island along with their parents who are seen in the background there.

Fig 3049

〈Fig 30〉 We have done 2 rounds of vaccination, immunized over 900 school girls in the firstround and virtually completed the second round of vaccination. Fortunately there is little loss
to follow up and almost every girl immunized who received the first vaccine, of course the third
vaccine which is six months after the first two will be the challenging one and we should be
able to report on how that has done at the end of this year.

Fig 31〈Fig 31〉 My major research interest these days is in developing therapeutic vaccines totreat the very many people who are already infected with these viruses who are not likely
therefore to benefit from a prophylactic vaccine.

Fig 3250

〈Fig 32〉 The challenge with this is that most people who develop these infections resolve theinfections spontaneously although we know that a resolution is impaired with immune
suppression and the virus induces particular proteins in the cells that it infects and vaccines
can raise really good immune responses against these proteins in both animals and humansubjects although, unfortunately the immune responses in human have not yet been shown toclear infection even though the animal models seem to suggest that they should.

Fig 33〈Fig 33〉 I got into this area many years ago, indeed the first study that I did looking at theconnection between papillomavirus infection and immunosuppresion and what we showed wasthat immunosupression increased risk of anal pre - cancer amongs HIV and HPV infected
males. These studies have subsequently been confirmed and extended to show that what
actually the immunosupression does is prevent clearance of the infection, so that HIV positive
individuals take twice as long to clear the infection on average and a third of people who are
HIV positive never clear the infection in comparison with HIV negative subjects where most of
the infections clear and half of infections clear within a year. Even if the infection does notclear, the immune system is clearly interested in persisting infection.

51

Fig 34〈Fig 34〉 These pictures from Connie Trimble at John Hopkins University show a cervicalpre-cancer lesion and normal epithelium - the normal epithelial is on the right and the cervicalpre-cancer lesion is on the left. What you can see is a significant immune cell infiltrate into
the cervical pre-cancer lesion even though this lesion is not cleared. So, the question really is
why do some people get persisting infection with human papillomavirus. It is not the virus
because people have looked at the sequence of the virus and persisting and non persistinglesions and the viruses are the same. It does not appear to be the environment because no
epidemiological study has shown anything which increases your risk of persisting infection bymore than double and yet clearly the risk of persisting infection in some individuals is verymuch higher than in others. So, it must presumably therefore be genetic and it is likely thatgenes pre - disposed to the risk of persisting infection.

52

Fig 35〈Fig 35〉 We undertook a study to see if we could clear people of persisting papillomavirus
infection using an immunotherapy for patients with recurrent warts. In a randomized double
blended placebo controlled study we demonstrated that the addition of immunotherapy toconventional destructive therapy for genital warts significantly increased the chances of wart
virus clearance over the course of the study so long as one or other of the two larger doses ofvaccine were used. These preliminary findings, not yet published, suggested immunotherapy
may have something to offer in the clearance of infection but clearly we are not getting 100%
clearance for the data that I showed you here.

Fig 36

Fig 37〈Fig 36〉〈Fig 37〉 To understand who is at particular risk of persisting infection andtherefore might benefit from immunotherapy we have undertaken a study looking at thegenetic pre-disposition in people who have persisting infection.

53

Fig 38〈Fig 38〉 We selected 750 women with high grade pre-malignant lesions of the cervix andmatched them up with control subjects from random population of healthy individuals.
Basically both groups were typed for genetic polymorphisms across the genome in a so called
genome wide association study.

Fig 39〈Fig 39〉 This study is underway but what I will report here is the findings with a limited
number of pilot markers where we used genes where we thought that polymorphisms might beassociated with persisting infection. Of the 12 genes that we trialled in fact 2 came up
positive. One gene of our 2 is a gene which encodes for a protein whose absence is associatedwith persisting HPV infections as shown by Professor Gerard Orth some years ago. A variant54

in this gene significantly increases the risk of persisting the papillomavirus infection.
Similarly another gene ERAP 1 which is associated with peptide processing in the
Endoplasmic Reticulum is associated with persisting infection. A full study is underway
looking across every gene in the genome and hopefully some results from this will be available
next year.

Fig 40〈Fig 40〉 Finally, I would like to talk about preventing skin cancer through papillomavirus
infection. Gerard Orth back in 1980, about the same time as Harald zur Hausen was
describing the association between papillomaviruses and cervical cancer, showed that at least
some skin cancers were due to papillomaviruses as well.

Fig 4155

〈Fig 41〉 Immunosuppresion has always been known to increase the risk of squamouscancer of the skin and the genetic variation in the EV gene which I talked about previously
increases risk too. We know that most people carry multiple papillomaviruses of the beta
papillomavirus family in their normal hair follicles so everybody is exposed to the virus and we
also know that while papillomaviruses are very rarely found in the squamous cancers in theskin it is quite possible for papillomavirus to cause cancer through a hit and run mechanism.
In cattle, bovine papillomaviruses are confirmed to give rise to oesophageal cancers in the
cattle but while the virus is necessary it is never present in the cancers themselves.

Fig 42〈Fig 42〉 We also know that immuno suppression in humans is significantly associated witha risk of not only the cancers in the cervix and vulva that we know are papillomavirus
associated but also squamous skin cancers with a relative risk of over 1,000. So there is asmoking gun suggesting that papillomaviruses might be responsible for skin cancer.

56

Fig 43〈Fig 43〉 The problem is, of course, that the papillomaviruses responsible for the skincancer are not the same types as in the cervical cancer vaccine so a new vaccine will be needed
including the beta papillomaviruses.
A trial to prove that such a vaccine might work would be rather difficult however since thevirus infections are acquired in early childhood and the cancers don’t occur until late adult life
and therefore an efficacy trial would last the life time of the individual, would cost a large
amount of money and would not be feasible.

Fig 44〈Fig 44〉 So, our alternative approach is to demonstrate that immunotherapy against
HPV infection is effective at preventing skin cancer in a group of patients who are at high risk.
The high risk group that we wish to examine is patients who are about to undergo renal57

transplantation because we know that 5% or more of them will develop skin cancer in the first
3 years after they become immunosupressed. Basically, we will immunise them withimmunotherapy targeted at HPV5, 8 or 20 and wait to see what happens with the incidence ofskin cancer over the following 5 years. If we showed a significant reduction in the skin cancer
due to papillomavirus infection this would be sufficient to justify a trial of a prophylactic
vaccine.

Fig 45〈Fig 45〉 So, in conclusion I have told you that papillomavirus associated cancer can beprevented through vaccination; that we can prevent cervical cancer at the moment throughuniversal immunization; that vaccines are not therapeutic for existing infection although weare developing these at the moment and therefore administration of these for cervical cancer isbest for pre - teen boys and girls and we need to carry on screening but the big challenge is to
get these vaccines into the developing world where they are really needed. Immunotherapy
routinely for papillomavirus infection we require significant and heroic intervention which
would not be acceptable for pre-malignant disease. On the other hand it can be used as a
proof of principle to demonstrate that a prophylactic vaccine might be effective against skincancer.
Similar strategies for the other infections associated with cancer will be necessary to enableeffective prevention of the cancers through immunization.
Thank you for your time.

■ This report can be viewed in the Honda Foundation’s website.
You may not use the proceedings for the purposes other than personal use without the express
written consent of The Honda Foundation.

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