Why a vaccine against papillomavirus?
Cervical cancer is still a public health problem
In France, 60 women fall victim and 20 others are killed by this disease every week. It is the second cause of cancer after breast cancer in young women from 20 to 40 years of age. With a first frequency peak at 40 years, this cancer affects women at an age when they have considerable family, professional and social responsibilities. In poor countries with no healthcare structure, the disease is without doubt more frequent and more frightening. High-risk papillomavirus strains are the sole cause, alone insufficient but necessary for the development of pre-cancers and cancers of the cervix and, more rarely, of the anus, vulva and vagina. High-risk papillomavirus strains are the sole cause, alone insufficient but necessary for the development of pre-cancers and cancers of the cervix and, more rarely, of the anus, vulva and vagina. The impact of papillomavirus infection in the population is considerable. More than one woman in two has been exposed to HPV during her life, 10% are chronic carriers and, of them, one woman in five risks developing cervical cancer in the absence of screening or in the event of inadequate screening. A major consideration in the research and development of HPV vaccines is the number of viral strains to be included in immunogenic agents. Existing epidemiological studies are fairly convincing in attributing to each viral strain the proportion of cervical cancers for which they are responsible. It is clear that the benefit achieved decreases after four viral strains, while manufacturing costs increase. However, the potential impact of HPV vaccination requires complex models which incorporate variables affecting the natural history of cervical cancer in various countries and depending on different scenarios. HPV 16 and 18 are responsible for 70% of cervical cancers worldwide. There are geographical variations in the distribution of these viruses associated with cervical cancer, as in Europe and the United States, they cause two-thirds of cancers yet, in sub-Saharan Africa, just half. Compared with other papillomavirus strains associated with cancer, these two types are recognised as the main agents associated with an elevated risk of developing pre-cancerous and cancerous lesions (in the absence of early detection). The causal link with this cancer is very powerful compared with other cancer risk factors such as smoking for lung cancer, or infection with hepatitis B virus for liver cancer. Moreover, type 16 papillomavirus is that for which natural immunity is the least active, as HPV 16 infection is persistent, and thus active, more often than infections with other viral strains. While exposure to these viruses is dominant during initial sexual activity at a young age, it can continue in the adult. It is essential to realise that diseases caused by these viruses usually occur around the age of 30 in the case of pre-cancers and around the age of 40 in the case of cervical cancer. In 2002, worldwide, there were an estimated 492,800 cases of cancer of the uterus, 16,000 cases of cancer of the vulva, 27,300 cases of cancer of the anus, 8,200 of mouth cancer and 6,200 cases of naso-pharyngeal cancer attributed to HPV.
Early detection, insufficient secondary prevention with a strong emotional impact
In the past, the only possible prevention for cervical cancer was based on the early detection of abnormal cells taken from the surface of the cervix by means of a smear. These cells, which have integrated the papillomavirus, are altered and the smear is used to detect them while they are still at a benign stage. Colposcopy then allows any lesion to be identified and its treatment to be programmed. This so-called “secondary” preventive action, when it occurs without fail, is always successful in protecting against the disease. In developed countries, where early detection by smear is, by and large, established, this preventive action has proved its efficacy as, since it was introduced in the 1950s, a 70% reduction in the frequency of cervical cancer has been recorded compared with the era when this screening was not in place. This has transformed the cancer from a fatal disease into a rare pathology in rich countries. However, it remains a major public health issue in poor countries where there is no - or at least no effective - screening organisation; two-thirds of cervical cancers are found in these countries. In our countries, where screening and information about cervical cancer prevention is widespread, the disease is still a reality even though it is thought to be preventable. The disease has not been eradicated in any country with organised screening. The main reasons for this are the complexity of the screening process: difficulties in ensuring optimum coverage of the screened population and raising women´s awareness of their responsibility to undergo regular screening due to the incomplete performance of the smear. This cancer is sometimes observed because the treatment following an abnormal smear has been inappropriate. Despite the considerable success that the smear has achieved in preventing the disease, it has not lived up to the hopes that could be expected of it in terms of a large-scale reduction in the frequency of this cancer. Furthermore, the emotional consequences inherent in screening must not be ignored. The announcement of an abnormal smear comes as a shock to the women concerned: for them, it is synonymous with cancer. The surgical treatments for dysplasia, although they have been simplified, are still a trauma for many women because they are an affront to their most intimate privacy. The repercussions can sometimes have major consequences for couples if the physician has not clearly explained the particular features of this sexually-transmitted disease.
Genital warts: a sexually transmitted disease common in young people
HPV 6 and 11 are responsible for 90% of genital condyloma acuminata, lesions which are always benign and never responsible for cancer and are observed in as many men and women, often between the ages of 15 and 25 years. The disease, which has been on the increase for twenty years now, and although not serious and always benign, is difficult to treat. It is characterised by a high rate of reoccurrence, and has a major psychological impact whether for a single individual or within a couple. It is clear, therefore, that by mobilising the immune system to form a barrier to this virus, it becomes possible to protect women from pre-cancers which can result from the infection, and to do so remarkably effectively. All these arguments constitute powerful reasons for developing HPV vaccination based on these viral strains. The fact that cervical cancer is the ultimate consequence of chronic papillomavirus infection provides an extraordinary opportunity for preventing the disease by vaccination. A vaccine to prevent these viral strains, i.e. able to protect against pre-cancerous and cancerous lesions, should save lives, reduce anxiety and costly procedures, and would thus be of major individual and collective benefit.
History of the vaccination
Twenty-five years of research and the combined efforts of numerous teams were needed to produce these vaccines. The odyssey started with the identification of the causal agent (HPV) of cervical cancer during the 1970s, followed by large epidemiological cohorts which showed the major risk of cervical cancer attributed to high-risk HPV, and the carcinogenic role of these viruses on the host cells. Then came the use of the viral test in clinical practice to optimise treatment and screening. All these stages have influenced the research, work and efforts of the entire scientific community over the past ten years. Richard Reichman, Robert Rose and William Bonnez, from the University of Rochester in the United States, started their work on the papillomavirus in the early 1980s, but at that time there was no question of a vaccine: these virologists hoped to develop a test which would allow doctors to detect the presence of the microorganism in the blood of their patients and to determine its genotype. In fact, while infection with HPV 16 and 18 can result in cancer, infection with HPV 6 and 11, which are benign, cause genital warts, the “coxcombs” described by Hippocrates. But to study the immune reactions associated with human papillomavirus, a sufficient quantity of the virus was needed, yet it is very difficult to cultivate. William Bonnez offered to collect warts growing on cows´ udders, excrescences caused by the bovine equivalent of HPV. The idea was to purify them and to put them in the presence of the blood of two groups of volunteers: people who had had genital warts and “controls” who had never had sexually-transmitted HPV. The team imagined that the proteins of the bovine virus would attract the anti-papillomavirus antibodies produced by infected people, which would enable them to be identified. The researchers would then be able to invent a screening test for these antibodies. A blood collection was thus started... from American nuns and priests (once a questionnaire had confirmed their chastity!) The experiment was a failure. The bovine virus was too far away from its human counterpart to make the antibodies react. During this time, John Kreider and his colleagues at the hospital of Pennsylvania made progress in cultivating the virus. In 1985, they incubated freshly-circumcised human foreskins with fragments of genital warts. They then grafted these foreskins onto immuno-suppressed mice. This technique allowed them to observe the natural infection of grafts with HPV 11 and to recover a substantial quantity of this virus. For a long time, the practical development of vaccines against HPV was problematic as these viruses are difficult to reproduce in cell culture. Attenuated live vaccines from this production process would have contained potentially carcinogenic viral genes, which stood in the way of their use as a preventive measure for women in good health. Progress in research was made once it was possible to produce a recombinant protein of the virus´s envelope in mammalian cells. Attention thus turned to the development of sub-unitary vaccines, based on the production of a protein which makes up the viral envelope, the L1 protein. Initial attempts to produce this protein from bacteria failed as the purified protein was, in most cases, malformed and did not cause sufficient antibody production in animal models. Progress came with the discovery of the phenomenon of the unfolding and spontaneous self-assembly of the L1 envelope protein. It was observed that, once produced, this protein had a spontaneous capacity for self-organisation to form a spherical envelope just like that of the virus. This was a major discovery. These virus-like particles were very similar to the virus but did not contain its genetic material. Thus, injected into animals or humans, they did not cause the disease, as this protein does not carry the DNA of the papillomavirus: on the other hand, they triggered an immune reaction strong enough to eliminate the virus. It is from this important innovation, based on the production of VLPs (virus-like particles), i.e. viral particles which mimic the virus, that the principle of vaccination against papillomavirus was born. These particles, without being infectious as they do not contain any genetic material, fool the immune system which recognises them as viruses that produce high levels of antibodies, but without generating the disease. A number of clinical trials on anti-HPV vaccines based on VLP have been conducted over the past five years. VLPs have a strong immunogenic power at doses of 10 to 50 micrograms after three intra-muscular injections. Side-effects associated with the vaccination are rare.
Principles of preventive HPV vaccination, natural immunity and vaccine-induced immunity
Natural immunity against HPV: biological inequality
The principle of contracting certain infectious diseases, in particular viral ones, is to acquire a sufficient immune defence to protect individuals in the event of any new exposure. Thus, chickenpox or measles are only caught once, as the antibodies produced by the first infection are sufficient to protect the individual against subsequent infection. Papillomavirus infection is characterised by insufficient natural immunity that does not always protect against further exposure to the virus.
Under natural conditions, the sexually-transmitted virus arrives on the surface of the cervix in contact with the cells. The favoured target of the virus is the transformation zone of the cervix in the deepest and easily-accessible cells of the cervix, at the junction zone between the outer (malpighian) and the inner (glandular) linings.
- Malpighian epithelium
- Glandular epithelium
Figure 23: Junction between the two linings of the cervix, the favoured place for penetration of HPV
From here, the virus - in its inactive state in the cell - triggers a reaction by the immune system to get rid of it. Two immune mechanisms are then set in motion.
- Presentation of viral antigen
- T-lymphocyte-mediated cytotoxicity
- Antibody synthesis
- Sub-epithelial blood vessels
- Lymphoid organs
- Infected epithelial cell
- Antigen-presenting cell
- Major histocompatibility complex
- Tumour necrosis factor cx
Figure 24: Mechanism of natural immunity to HPV infection
Firstly, so-called humoral immunity involves immune cells called B-lymphocytes. These cells produce antibodies which will exude to the surface of the cervix. These antibodies are called neutralising´as they act as guards at the surface of the cervix to neutralise and eliminate any papillomavirus which may come into contact with them. Another immune reaction occurs which involves immune cells called T-lymphocytes, cells which have the particular characteristic of eliminating viruses inside the cell, as they have memorised their antigens.
Neutralising antibodies are therefore present at the surface of the cervix, acting as guards preventing HPV from coming into contact with the cervix and penetrating the deep cells of the lining. The memory immune cells spring into action and eliminate viruses if they should already be inside the cells.
In papillomavirus infection under natural conditions, this immune process is not effective, as it varies greatly from one individual to the next. This explains why the neutralising antibodies on the surface of the epithelium are not adequate: the immune barrier on the surface of the cervix is permeable and the immune memory not very active. This is why a papillomavirus infection is sometimes not eradicated naturally; lesions can be produced once again, and the infection re-appear. It is said that the papillomavirus infection is characterised by its immune tolerance.
Non-infectious recombinant vaccines, prepared from purified virus-like particles (VLPs) of the main L1 protein of the HPV envelope, cause a strong humoral immunity reaction (production of antibodies), a reaction which is far superior to that of the natural immunity, hence their efficacy. The results of clinical trials identify three situations:
Woman never exposed to the HPV types in the vaccine: this is the case of young girls before the onset of sexual activity. This is the situation where vaccination has proved to be completely effective.
- L1: major protein of the capsid
- Transformation zone
- Cervical mucus
- Region coding for L1
- L1 produced in yeast or recombinant baculovirus
- L1 protein
- L1 pentamer
- Virus-like particles or VLPs
Figure 25: How the vaccine works in a woman never exposed to HPV
The preventive HPV vaccination, based on L1 VLPs, achieves a very high production of neutralising antibody. These antibodies concentrate on the surface of the cervix in the mucus which covers it, forming a veritable protective layer which prevents any newly-arriving papillomavirus from penetrating the cells. This immunological barrier, which is impermeable to papillomavirus, is how this vaccination works. This indicates that HPV vaccination is effective above all for women who have never been exposed to the virus or, at least, do not have any virus present at the time of vaccination. In young women who have never been exposed and who we know have never had sex, vaccination produces sufficiently large quantities of neutralising antibodies to enable them to eliminate the newly- arrived virus and to protect them. This is why this vaccination is sensible for young girls before the onset of sexual activity. However, this situation can also be encountered among adult women.
This protection is, of course, provided only against the virus strains contained in the vaccine and not for all the others.
Woman exposed to the HPV types in the vaccine who has not produced any lesions: uncertain or zero efficacy.
- L1: major protein of the capsid
- Transformation zone
- Cervical mucus
- Region coding for L1
- L1 produced on yeast or recombinant baculovirus
- L1 protein
- L1 pentamer
-Virus-like particles or VLPs
Figure 26: How the vaccine works in a woman already exposed to HPV
(virus present inside the cell)
This situation, which can be observed at any age, is still being assessed. There are two possible situations:
Woman in whom the virus has produced lesions: zero vaccine efficacy
In this case, the preventive vaccine has no effect on the lesions caused by the viruses contained in the vaccine. It is not a therapeutic vaccination.
The parameters for evaluating the efficacy of vaccines
Available study results relate to the monovalent HPV 16 vaccine, bivalent HPV 16 and 18 vaccine and the quadrivalent HPV 16-18-6-11 vaccine. Phase 2 and 3 studies have evaluated tolerance and immunogenicity (measurement of antibody level) going back over five years . Vaccine efficacy is measured on the basis of viral and lesional indicators, i.e. the momentary or incident infection, persistent HPV infection, CINs - in particular high-grade lesions - and cancer, (although with regard to the latter, it is difficult to provide a judgement on the current basis of a five-year period). With the quadrivalent vaccine, which also contains strains 6 and 11 responsible for condyloma acuminata, the protective effect for these lesions was also measured.
The following important points need to be borne in mind:
- the results available from current studies going back five years relate only to naïve young populations under 25 years of age, i.e. never exposed to the viruses contained in the vaccine. Evaluations on virus carriers and on adults are underway;
- the analysis relates to the efficacy specific to the viral strains contained in the vaccines, i.e. strains 16 and 18 ( Cervarix®) and 16-18-6-11 (Gardasil®). It is, of course, essential to consider this effect in relation to the overall efficacy for lesions associated with all HPV strains;
- it has been possible to measure additional protection in the form of potential cross-immunity for other viral strains not contained in the vaccines;
- with regard to the immunity produced by the vaccines, the minimum level of antibodies which would provide protection is not known. The level of neutralising antibodies is best correlated to vaccine efficacy in young naïve women never exposed to the virus; the same cannot currently be said for women already exposed or infected;
- protection is only known to last for five years, and the need for boosters will be examined following a vaccine experiment covering ten to twenty years;
- trials are currently under way to answer many unresolved questions.
Two powerful vaccines
Two vaccines have been widely evaluated in huge international clinical trial programmes:- the Merck vaccine (Gardasil®) commercialised and distributed in Europe by Sanofi Pasteur MSD. This is a quadrivalent recombinant vaccine using the L1 VLPs of HPV 16, 18, 6 and 11. It contains a universal additive, aluminium, a substance always used with the active principle in the vaccine that has the effect of potentiating the immune reaction. It is indicated in the prevention of CIN and cervical dysplasia, rarer lesions of the vagina and the vulva and cancers associated with these viral strains, and also genital warts (condyloma acuminate). In September 2006, it was granted its European commercialisation authorisation and has been available in French pharmacies since 23 November 2006. It is indicated for young women from 9 to 26 years of age, by intra-muscular administration, following a schedule of 0, 2 and 6 months;
- the Glaxo Smith Kline vaccine (Cervarix®) is a bivalent recombinant vaccine comprising the L1 VLPs of HPV 16 and 18. The GSK vaccine is intended to prevent CIN, cervical cancer and cancer at other sites associated with HPV 16 and 18. It contains an original additive, called AS04, which is presented as a new immuno-stimulant for humoral immunity. This vaccine is positioned as a preventive measure for pre-cancers and cancers of the cervix. It is administered by intra-muscular route following a schedule of 0, 1 and 6 months. To date, this vaccine is still awaiting its European approval and is not yet available.
What do the results of clinical trials teach us?
In France, we have coordinated the clinical trials of the two vaccines and have attended numerous meetings of international experts within the two laboratories and in independent institutional and scientific groups.
Although the commercial stakes are considerable, we want here to provide independent objective information based solely on published data and data presented in scientific and consensus conferences without making any claims, it being understood that the research is making progress and new results are expected every year.
For both vaccines, large-scale clinical trials indicate that tolerance is satisfactory after five years of evaluation. No major incident has so far been reported following vaccination. Few patients have left clinical trials because of side-effects.
Local side-effects (redness at the point of injection, swelling, pain, itching) are reported at less than 1% and with no significant difference from the placebo group.
General effects (fever and rash) are reported but without any marked difference from the patients given placebo. To our knowledge, no studies have been published about pregnant women. Studies on animals have not shown any harmful effects. As a precautionary measure, this vaccination is not to be recommended during pregnancy. Breast-feeding does not seem to be a contraindication.
Specific immunological tests for each type of vaccine have enabled the level of neutralising antibodies produced for each type of HPV in the vaccine to be measured. The follow-up is five years. These methods are particular to each vaccine and cannot be used routinely.
In short, the two vaccines trigger a strong immune reaction. In the naïve population never exposed to the HPV strains in the vaccine, a major production of neutralising antibodies is observed with a maximum peak in the seventh month, based on the schedule of three vaccine injections. This is called sero-conversion, i.e. the massive production of antibodies in women who did not have any at the start of the study. Sero-conversion is observed with regard to the neutralising antibodies for HPV 16 and 18 for Cervarix® and 16, 18, 6 and 11 for Gardasil®. The antibody level falls over time but remains significantly elevated for up to five years in the monitoring period, in particular for HPV 16. The neutralising antibody levels after natural infection is much lower than those produced by the vaccine.
There are no studies which directly compare the immune reactions to the two vaccines. The data are thus separate for each type of vaccine.The scale of the immune reaction is dependent on age. For both vaccines, it is greater where the vaccination is given to youngsters under 15 years of age. This indicates the potential of vaccination in adolescents. However, it has been demonstrated that the Gardasil® vaccine generates a high antibody level even in the adult. Similar data are also available for Cervarix®. Clinical efficacy remains stable for both vaccines after a five-year monitoring period. This appears to indicate that other mechanisms are probably involved in long-term clinical protection.
For both vaccines in a population which has never been exposed to these viruses, i.e. young people under 25 years of age, the scale of the vaccine-induced immune reaction is perfectly correlated with 100% efficacy for the viral strains contained in each of the vaccines. In those already exposed to these viruses but without the associated lesions, the vaccines trigger a stronger immune reaction than the natural infection, but the clinical efficacy is at its maximum where the recipient is a young woman who has previously managed to eliminate the virus, and is incomplete or zero for those who still have latent virus in their cells. Papillomavirus types 16 and 18 have similarities with other strains of HPV. One might therefore think that vaccination with certain types of HPV VLPs would provide protection from other viral strains closely related to those in the vaccines.
For both vaccines, a significant and durable increase is indeed observed in the level of antibodies against certain HPV strains not contained in the vaccines. This is called cross-immunisation. At present, there are no data about any correlation with clinical efficacy for lesions associated with these other types of virus not contained in the vaccine. In short, the immune antibody reaction produced by the two vaccines is robust and durable for a five-year monitoring period. It is correlated with a remarkable clinical efficacy in young women exposed to these viruses, the vaccines for which provide absolute protection against the pre-cancerous lesions associated with these viral strains.
Efficacy of HPV vaccines: preventive, not therapeutic
Quadrivalent vaccine for strains 6, 11, 16, 18 (Gardasil®)
The double-blind placebo-controlled clinical trials involved 20,541 women aged from 16 to 26 years and covered a five-year period. Efficacy on persistent infections due to HPV 16, 18, 6 and 11, dysplastic lesions of the cervix (CIN), the vagina (VaIN) and the vulva (VIN) of all grades, and condyloma acuminata was evaluated. The preventive efficacy of Gardasil® in young populations not previously exposed to the vaccine´s viruses is perfectly demonstrated.
* In women not infected by the strain or strains of HPV contained in the vaccine
The results are reported in table 1.
Table 1: Efficacy results of quadrivalent vaccine for strains 6, 11, 16 and 18 on CINs, dysplasias of the vagina and the vulva and condyloma acuminata
The efficacy of Gardasil® on CIN1, 2 and 3 lesions or associated lesions of the vulva and the vagina, including condyloma acuminate, due to HPV 16, 18, 6 and 11 ranges from 95.2% to 100% depending on the protocol. For viral persistence, defined as the presence of the same virus following a twelve-month interval, prevention efficacy ranges from 93.3% to 100%, depending on the protocol.
* In women with a prior or current lesion
No protection has been demonstrated against the disease caused by the HPV strains which the women were carrying at the start of the study and / or of which they had scars from a prior infection. However, if the infection before the vaccination was only from one or more of the HPV strains in the vaccine, clinical protection could be observed for lesions caused by the other viral strains contained in the vaccine.
Bivalent vaccine for strains 16, 18 (Cervarix®)
Table 2: CIN efficacy results of the bivalent vaccine
1. The population is defined in accordance with the protocol as follows: women receptive to different HPV types including women vaccinated for a period of six months, those who were given the three vaccines, and those who did not show significant changes to the protocol.
2. Modified after Harper et al., Lancet, 2004, 364: 1757
3. Modified after Harper et al., Lancet, 2006, 367: 9518
The first multicentre, randomised, double-blind, placebo-controlled study was conducted in Brazil, Canada and the United States. Approximately 1,100 women aged from 15 to 25 years were selected and evaluated at 27 and 54 months following vaccination. All the women were naïve at inclusion but had previously been exposed to these viruses and had a normal smear.
Compared to the placebo, for current or incident infections, efficacy ranges from 91.5 (strains 16 and 18) to 100% (strain 16). For persistent infections, efficacy reaches 100% (strains 16 and 18). For smear abnormalities associated with these viral strains, efficacy is 93%. For CINs associated with these viral strains, efficacy is 100%. It is important to note that these results, analysed at 27 months, were the same five years later.
In terms of immune reaction, a strong sero-conversion is observed with very high neutralising antibody levels for HPV 16 and 18 in the seventh month: compared to natural infection, the antibody levels with the vaccines are 80 to 100 times higher. High antibody levels remained constant through to analysis at five years.
The phase 3 programme, which started in 2003, involved over 20,000 women from 10 to 25 years and over 25 years. The objective was to identify the optimum ages for vaccination, and also vaccination tolerance and long-term efficacy.
According to a recent study, preliminary results show that the bivalent vaccine confers cross-protection for existing so-called incident infections against viral strains similar to HPV 16 and 18. Women vaccinated with the type 16 and 18 vaccine are protected from infections and CINs associated with these viruses, but also against existing HPV 45 infections (94.2%) and HPV 31 infections (54.2%). However, there are no results about clinical efficacy.
Preliminary results show that women of any age, whether or not exposed to viral strains 16 and 18, have a fairly strong immune reaction following vaccination. If these data are confirmed clinically, vaccination at any age would be extremely sensible for women not exposed to the virus.
Key questions about preventive HPV vaccination
Compared with hepatitis B vaccination, likewise involving a cancer-risk virus, the results could be remarkable. In Africa and in Southwest Asia, 10% of children are affected by hepatitis B. An intensive vaccination programme started in 1984, targeting the newborn. In 1992, the prevalence of hepatitis B in children fell from 10.5 to 1.7%, showing a reduction by a factor of 4 in the frequency of liver cancer. In 2010, a 0.1% hepatitis B rate is projected for children, i.e. a 99% reduction in carriers and a major decrease in the disease.
|>= 70% reduction in cervical cancers||Major delayed impact on cancer.
The vaccine will save lives.
|>= 50% reduction in abnormal smears||Significant early impact on screening.|
|Reduction in HPV pathologies:
dysplasia / condyloma
|Early impact on treatment (follow-up, treatments, costs).|
|Limitation of HPV infection||Major impact on the spread of the infection and the reduction in the risk of the disease.|
|Improvement in the quality of life||Psychological and emotional impact, both for the individual and the couple.|
Immunisation against HPV will have a major impact in poor countries where 70% of cervical cancer cases are observed every year and where early screening is non-existent or ineffective. HPV 16 and 18 vaccines would prevent 70% of cases of cervical cancer. However, given the natural history of HPV infection, the measurable effect on cervical cancer would only be perceptible quite some time later, i.e. on average around twenty years after the introduction of a vaccination programme (figure 27). In rich countries, the impact on screening parameters will be quickly observed: a 90% reduction in the frequency of HPV 16 and 18 infection; smear abnormalities down by approximately 50%; the number of CIN cases cut in half and cases of CIN3 down by 65%. The significant reduction in the level of abnormal smears will be perceptible in a short space of time, on average within three to five years. Because the majority of cervical cancers are associated with HPV 16 and 18, the level of protection against deaths by this cancer could rise above the 90% mark.
The younger the population vaccinated, the longer the interval before an effect on HPV infection and cancer is observed. This idea needs to be taken into account when deciding on the ideal age for vaccination, given that the incidence peaks for cervical cancer are observed at 40 and at 60 years.
With the Gardasil® vaccine, a 90% reduction in genital warts is expected in young people within a short period. And, above all, the impact of the reduction in abnormal smears and associated treatments on the quality of life must not be overlooked.
Impact projection studies, Cost-Benefit of HPV vaccines
From simulations carried out with recent mathematical models, it appears that, in the context of cervical cancer prevention, thanks to the practice of screening by smear, early vaccination provides an opportunity for reducing the frequency of pre-cancerous lesions by 55% and cervical cancer by 75%, and dividing by 4 the absolute risk of cervical cancer over a lifetime. The models suggest the benefit of mass vaccination before 26 years and targeted or individual vaccination in those over 26 years. The strategy of vaccination at 11-13 years, with a vaccination catch-up system for 14-26 year-olds, is without doubt the strategy which will enable, in the very long term, the greatest number of cases of dysplasia or cancer associated with HPV 16 and 18 to be avoided. Nonetheless, the scenario of vaccinating girls between 15 and 17 years, with a catch-up system for 18 to 25 year-olds, is better if the age of vaccination is compared with that of exposure to the risk of HPV infection and the associated lesions. These same models indicate a benefit of HPV vaccination combined with screening after 26 years of age.
Mathematical simulation models indicate that the combination of an HPV vaccination programme with cervical cancer screening has a potential impact on the cost-benefit situation in developed countries. The models indicate that prevention based on the HPV vaccine alone would reduce but not eliminate cervical cancer. In fact, there is no serious demonstration that HPV vaccines can replace screening programmes. However, it is more plausible to envisage a cervical cancer prevention programme based on large-scale primary prevention for young people (vaccination) and secondary prevention (screening) in older women, the benefits of which would certainly be greater than those offered by the current situation. Studies indicate that strategies combining vaccination and screening by smear have a better cost-benefit ratio than strategies based solely on screening by smear. The most striking benefit seems to be focused on a suitable balance between three-yearly screening starting at the age of 25 years together with vaccination between 9 and 26 years. As HPV vaccination generates a greater significant reduction for HSIL smears than for LSIL smears, it would then be possible to envisage less aggressive procedures for the latter than we currently perform.
Use of HPV vaccines
Who can benefit from the HPV vaccine
- 9 to 26 year-olds: the best individual and collective benefit
Studies show that, to be as effective as possible, vaccination against the most common HPV strains for cervical cancer prevention must be undertaken before the age of 26 years. If it is established that the vaccine performs best if it is offered collectively to pre-adolescents and adolescents before the onset of sexual activity (not exposed, or naïve to, HPV), it is probable that, on an individual level, a benefit is also expected for older women not exposed to these viruses. The average age of the start of sexual activity is falling in industrialised countries. In Europe, it is estimated to be 17 years. However, many young girls have sex for the first time a lot earlier than this. The introduction of an HPV vaccine for young adolescents would necessitate a programme of education for young people and their parents. The acceptance of and motivation for the vaccine will be greater after 18 years. The first contraception consultation provides a good opportunity for discussion of the subject. But this population is difficult to mobilise by campaign. One of the objectives of this method lies in the potential for action on incident and latent infections, thereby reducing the risk of lesion development or transmission.
At these ages vaccination offered on the basis of viral status is not indicated.
After the age of 26 years, in response to an individual request, it will certainly be essential to distinguish between women not exposed to HPV, who would certainly gain individual benefit from vaccination, and women exposed to HPV, where limited efficacy for recent infections and zero for women having a prior infection are anticipated. Virological tests would enable this status to be established today and serology will probably do so tomorrow. In any event, preventive HPV vaccination is not effective where HPV lesions are already present. This presupposes that at least one smear is carried out before any individual request for vaccination in a woman over 26 years of age, and preferably one smear and one viral test to rule out an infection with one or more of the viral strains contained in the vaccine at the time of vaccination.
- Which sex: girls or boys?
In terms of cervical cancer prevention and limitation of the spread of the infection, there are insufficient data and there is currently no clear answer to this question. Although vaccinating boys would certainly have an impact in limiting the disease, cervical pre-cancers and cancers caused by high-risk HPV are diseases associated with the immune potential of each woman. Vaccinating both sexes would necessitate greater financial resources, and it will, of course, be necessary to demonstrate the cost-benefit of this approach. It remains to be shown that, in the context of cervical cancer prevention, an effective vaccine for women would not necessitate vaccinating men. In fact, to prevent the disease, it would appear wiser to concentrate resources on broad vaccine coverage for young girls rather than vaccinating boys and girls indiscriminately. This issue may evolve as we now know that the young boy´s immune response following vaccination is just as strong as the young girl´s. While vaccines have demonstrated their efficacy in the mucous environment (cervix), no data are available about protection in the cutaneous environment in man (penis).
However, with the quadrivalent vaccine (Gardasil®) including HPV 6 and 11 providing a real benefit in terms of prevention of condyloma acuminata, a benign disease as widespread in boys as in girls between 15 and 25 years of age, it is of very real interest for young boys.
Period of protection
The period we can currently look back over is approximately five years. Randomised studies with the quadrivalent HPV 16-18-6-11 vaccine (Gardasil®) and the bivalent 16 and 18 vaccine (Cervarix®) show that sero-conversion* is high after 3 injections. Depending on the viral strain, neutralising antibodies remain 50 to 100 times higher than those found with natural infection. In the phase 3 study with the quadrivalent vaccine, the neutralising HPV 16, 18, 6 and 11 antibodies were measured at 36 months. While the level of antibodies remains significantly elevated at 36 months for HPV 16 and falls for HPV 18, HPV 6 and HPV 11, for anti-HPV 6 antibodies, immunisation seems quite clearly superior between 9 and 15 years, rather than after the age of 16 years, justifying the introduction of vaccination for pre-adolescents and adolescents. In the future, immunological competition depending on the number of viral strains associated with the vaccine will need to be examined. We do not currently know the precise correlation between the minimum level of neutralising antibodies and the protective effect. However, to date, as levels of neutralising antibodies remain at a high plateau for five years following vaccination, we can anticipate long-lasting protection. A booster effect (immunological reactivation) could possibly occur with new natural exposure, but this has yet to be demonstrated. Long-term studies will show whether booster injections are necessary. It has already been demonstrated that a booster injection at six months triggers a very strong antibody protection, testifying to an excellent immune memory. This does not call into question the efficacy of the vaccines.
Do high-risk groups need to considered?
If one high-risk group needs to be considered, it is that of the immuno-suppressed: HIV positive, in auto-immune diseases, patients taking immuno-suppressants. With regard to HIV-positive people, the introduction of tritherapy has enabled immunity to be restored making these high-risk individuals equal to immune-competent individuals with regard to cervical cancer. However, recurrent HPV pathologies of the genital tract, cases which do not respond to conventional treatments, and multi-focal and multi-centre lesions are still a reality in this context. The efficacy of vaccination in the immuno-suppressed has nonetheless yet to be demonstrated. If it is effective, HPV vaccination will probably also have to be considered for immunoo-suppressed individuals, in particular those who are HIV-positive. It could be offered too before an immuno-suppressant treatment is given for transplantation, or in the event of an auto-immune disease. However, these are marginal cases. Because cervical cancer is a disease which can potentially affect any sexually-active woman, and because the cause is an individual's inability to produce an immune response, HPV vaccination is only feasible and can only be offered for high-risk groups. This approach would have only a partial effect in poor countries and a minor and imperceptible benefit in developed countries.
Vaccination recommended or plainly necessary?
The commercialisation process includes essential stages in France. Commercialisation approval is given by the European Drug Agency: Gardasil® received it in September 2006 and that for Cervarix® is expected in 2007. There is a particular decision-making process.
Recommendations are then formulated by the Technical Vaccination Committee (Comité Technique des Vaccinations - CTV) which puts forward proposals about the target populations to be vaccinated and who would benefit from vaccination. A decision is made as to whether or not to include this prevention in vaccination programmes.
The dossier is passed to the Ministry of Health which examines the consequences for France, proposing a reimbursement sum which is passed to health insurers. The Ministry of Health makes the final decision based on public health, economic and political factors.
Although cervical cancer is a public health issue with a priority for action which varies from one country to another, questions remain as to the directions national agencies will take in recommending this vaccination or not. It would not be acceptable for there to be inequality of access to this vaccination in our country. Approaches which are overly cautious or not wholehearted would have a negative impact both for health professionals and for women.
While a recommendation for this vaccination goes in the right direction, will it be individual or proposed in the context of a collective programme (in particular for young girls)?
It already seems evident that individual and opportunistic vaccination would have a barely-perceptible protective effect against cervical cancer.
This is an expensive vaccine. In the USA and Canada, it costs 120 dollars per injection, i.e. 360 dollars for all three. Gardasil® is offered at 140 euro per injection from its launch in November 2006, i.e. 420 euro for the three injections. It is, of course, more expensive than the usual vaccines but it is a vaccine with a high added value. In our country, it is essential to ensure that there are no inequalities in access to prevention. We will not achieve a major reduction in cervical cancer if this vaccine is reserved for those who can afford it. Even more importantly: this vaccination needs to be promoted in poor countries as their need is greatest.
The impact of this vaccine among professionals and the public will be directly linked to the message which accompanies it: vaccine to prevent a sexually-transmitted disease or to protect against cervical cancer, or both? It is essential to be attentive to the perception of the message. While clinical trials confirm protection against CINs, will it be acceptable to offer these vaccines with the primary objective of avoiding HPV infection? The message “anti-cancer” would clearly have greater impact among women over 30 years of age, whereas “vaccine to protect against a sexually-transmitted disease” would have more impact among younger people.
Surveys indicate good acceptance by professionals and the public alike.
Promotion and Education
One of the barriers to the uptake of an HPV vaccine is the lack of information and the misconceptions which circulate about HPV infection and its links with cervical cancer. Various surveys among the general public show that over 80% of women have not the slightest idea about the cause of cervical cancer. The commercialisation of an HPV vaccine will clearly bolster educational and information campaigns about the causes of the disease, and highlight the means available to prevent it. A broad public education and professional information programme is one of the essential prerequisites for the development of a vaccination programme. The messages need to be clear and unambiguous. A distinction needs to be drawn between relatively frequent and asymptomatic HPV infection in the general population, and its rare consequences, namely pre-cancer and cancer of the cervix. The anxiety which could be generated in women who know they are carriers of an oncogenic virus is one of its perverse effects. It will be dissipated by clear, unambiguous messages to avoid psychological catastrophes on an individual level or between couples.
In any event, it is important to ensure that complacency does not set in with regard to the prevention of sexually-transmitted infections and screening, which absolutely must be maintained at its normal frequency.
It is already acknowledged that vaccination education campaigns will bear fruit in terms of screening and attendance for screening. This synergy will be the best way to eradicate the disease. The history of vaccination shows us that it has been the victim of its own success. Reticence and resistance must not be under-estimated. Vaccination, which is an intrusive procedure, is for the individual in good health. Although recommended, the individual must always seek the advice of her doctor. It is hardly surprising that vaccination, even where obligatory, has always met with opposition. In this regard, France is one of the developed countries in which anti-vaccination movements are best organised, tending to come from the lay community, whereas anti-vaccination leagues worldwide tend to stem from religious sects. Some people also think that society is organised today, as if by reaction, around a “magnification” of science. Those opposing vaccination tend to base their arguments on individual liberty and rely on others being vaccinated instead of them. The recent controversy and fears about anti-hepatitis B vaccination in France can teach us a great deal in this regard.
It must be borne in mind that the regulatory agencies in France with ANSM (Agence nationale de sécurité du médicament et des produits de santé) and throughout the world, in particular the World Health Organization (WHO), constantly monitor the conditions of manufacture and use of vaccines and demand large-scale clinical trials. Unexpected side-effects are recorded and reported. Even in developed countries, vaccination coverage is generally inadequate.
The educational programme must endeavour to overcome resistance and explain what is at stake.
Carrying out a vaccination campaign: essential role of compliance
In public health terms, participation in the vaccination programme is, as for screening, crucial. Mathematical models indicate that with an HPV 16 and 18 vaccine, 90% effective for cancers associated with these viral strains, protection against cervical cancer would stand at just 25% with 40% coverage of the population, 38% with 60% and 51% with 80% coverage of the population. The performance of cervical cancer prevention thus depends on the viral strains associated with the vaccine and the scope of participation.
While mammography appears to reduce deaths due to breast cancer in over one third of cases, screening by smear in the developed countries provides protection against cervical cancer. It is logical to think that a programme-based HPV vaccination and screening will increase protection and will reduce mortality from cervical cancer more significantly, in the order of 90%. If we accept that smears prevent 70% of deaths by cervical cancer and that the HPV 16 and 18 vaccine is 90% effective in preventing deaths by this cancer, the combination of HPV vaccination and screening would prevent 90% of deaths from cancer.
Screening strategies in the era of vaccination
One of the most hotly-debated subjects today concerns the future strategies and development of algorithms so that primary prevention (vaccination) and secondary prevention (screening) can co-exist in the various countries. Cervical cancer is a rare event following HPV infection. However, as the success of screening relies on the rigorous conditions of its implementation and, in particular, on the stringent yet still risky compliance with a regular frequency and a strict calendar based on smears every two or three years from the age of 20 to 70, the introduction of vaccination for cervical cancer prevention would provide additional security guaranteeing optimum protection. There must be no opposition [competition?] between vaccination and screening. Vaccination is to be regarded as an additional safety measure to screening. Screening and vaccination are two complementary and synergetic preventive measures.- In the unvaccinated population, screening by smear with or without HPV testing will continue as an essential measure for cervical cancer prevention.
- In the vaccinated population, prevention strategy scenarios are currently being studied.
Trials are currently underway to measure the benefit of vaccination in the adult.
Under 26 years of age, a broad vaccination programme without prior conditions and continuation of screening from 20 years of age in accordance with the usual recommendations. Over 26 years of age, by individual request:
- a genotyping HPV test (HPV 16-18-6-11) would be offered;
- for subjects HPV-negative to HPV 16, 18, 6, 11, vaccination is possible and screening by smear and / or an HPV test after three years would be indicated;
- if HPV-positive (16-18-6-11) at the age of the start of screening, a smear and treatment or suitable follow-up would be offered. In the absence of lesions, there are currently no data about the benefit of vaccination.
It is anticipated that participation in the vaccination programme will be gradual, increasing over the next forty years.
Major benefits of preventive HPV vaccines: vaccination associated with screening, the new standard for cervical cancer prevention
In countries where screening exists, a significant reduction in the incidence of abnormal smears, colposcopies and biopsies, treatments and follow-ups is anticipated. And the fall in costs associated with this screening will be perceptible in just a short time. A decrease in the number of cervical cancer cases in high-risk populations who do not have the benefit of screening and in those who are screened (30% of invasive cervical cancers, approximately 1,000 cases in France every year) would be one of the major impacts of this new strategy. The cost-benefit associated with these new programmes would need to be evaluated in comparison with conventional strategies based on the screening smear. Possible changes to screening recommendations are already anticipated. Offering an HPV vaccine associated with fewer regular screening procedures, and starting screening at a higher age, is one option for which the cost-benefit ratio needs to be evaluated. The potential risk to compliance and the risk of neglecting screening by women reassured by the “protective” effect of the vaccine also need to be considered. Any possible confusion in the minds of the public between screening and vaccination needs to be avoided. This is why vaccination programmes will certainly be associated with the education, information and promotion of cervical cancer screening. Vaccination and screening will be closely linked to optimise the benefits of prevention.
In poor countries where there is no screening or no effective screening, the impact on cancer will be evident but only quite some time later. The promotion of mass screening by simple methods should therefore continue. Even if vaccination programmes have proven their efficacy in these countries, the difficulties in organising them must not be under-estimated: high cost of product, formulations not suitable for mass vaccination (three injections, cold chain etc.). Other routes of administration are being studied (oral or nasal) which may meet the specific conditions of these populations.
What are the responses to the individual vaccination of adult women?
It has not been demonstrated that these vaccines are less effective in women not exposed to HPV. However, the very principle of the preventive vaccination is to produce neutralising antibodies in the cervical mucus forming a protective lining on the surface of the cervix; this immunological barrier prevents the virus from penetrating following exposure by sexual contact. This would indicate that vaccination would only be effective at the stage before the virus penetrates the epithelium. Phase 3 studies will enable these questions to be answered more precisely. It will be difficult to exclude these women, who are generally more motivated, although vaccination has no impact on prevalent and latent HPV infection. In adults as a whole, less benefit is expected from vaccination. It is estimated at 40% for high-grade dysplasia associated with the vaccine´s viral strains and 25% for dysplasia of any viral strain. It could protect against other viral strains not contained in the vaccine (cross-protection). Vaccination would reduce persistence by preventing self-contamination. It could control the dissemination of the infection. The economic impact of these approaches should of course be evaluated. By reducing diseases associated with HPV, the impact on quality of life is undeniable.
Studies in progress will provide clarification about the natural history of the disease and give answers which epidemiological studies have not yet delivered. Multiple HPV infections affect over 30% of the population. The natural history of these combined infections is not known. In the absence of intervention, is cervical cancer the consequence of the persistent or latent infection, or rather of a recently-acquired incident infection later in life?
Nor do we know whether the current vaccines would be likely to select and favour the emergence of other viral genotypes hitherto very rarely implicated in this cancer. The preliminary results of trials with the quadrivalent vaccine do not show the development at five years of any new HPV infections more frequent in the vaccinated group compared with the placebo group.
It will take some time to provide rational responses to all these questions, taking into account the economic constraints of each country. This should not hold back the promotion of these vaccines.
Large-scale vaccination and simplified screening will probably become the new standards for cervical cancer prevention. Recommendations about screening methods and tools will certainly evolve in the era of vaccination. The combination of screening and HPV vaccination will be able to guarantee those accepting it almost 100% protection. We already know that the absence of vaccination for women who do not undergo regular screening will be a lost opportunity in the face of the disease. In France, the cost-benefit ratio of this approach now needs to be evaluated in terms of public health although current models support this strategy.
In poor countries, HPV vaccination will clearly provide a considerable benefit to populations which, in any event, do not have access to traditional screening.
It will be some years yet before vaccination is included in an accepted large-scale prevention strategy. During this period, it will be essential to remain vigilant about gynaecological monitoring so as not to relax the efforts already made in optimising screening and thus run the risk of seeing the re-emergence of this much-feared disease.
Preventive vaccination against papillomavirus with a view to preventing condyloma, pre-cancers and cancers of the cervix is a major innovation for the health of women. For the first time, it is possible to protect oneself against a solid tumour.
This is also a victory in the war which has been waged since the introduction of the screening smear to defeat the disease, over fifty years ago.It opens up a new era in the prevention of cancer. However, the history of vaccination is surprisingly littered with obstacles. Even if the acceptance of this vaccination already seems fairly good, the anti-cancer dimension is a high added value. Preventive vaccination of the cervix has to rely on an understanding of what is at stake. It is essential to avoid the injustice of vaccination not being available to those who are in the greatest need of it; millions of young women continue to fall victim to this potentially fatal disease which can now be prevented by vaccination combined with screening.
Victory is within our reach. We have a very real hope of seeing the disease disappear if proactive and concrete action is taken by our healthcare decision-makers.