Human papillomaviruses (HPVs) are DNA viruses, in which the DNA is surrounded by a capsid consisting of one ‘major’ (L1) and one ‘minor’ (L2) protein. There are a very large number of antigenically distinct types. Information regarding the number of types varies but there are at least 120 Citation[1]. Of those, approximately 30 types infect the human genital tract.
Human papillomavirus is one of the most common sexually transmitted diseases. Viral exposure can result in asymptomatic or symptomatic primary infection with genital warts (condyloma accuminata), which can be smooth, round, raised or flat and can occur as single or multiple growths that resemble cauliflower. The incubation period is 1 to several months. They afflict men and women alike. Approximately 90% of all condylomas are caused by HPV types 6 and 11 Citation[2]. HPV infections are so common that exposure usually occurs soon after sexual debut. Approximately 90% of primary infections are asymptomatic. Condylomas can heal spontaneously, usually after several months to years, or become chronic. Long-lasting or chronic genital warts can be cosmetically disturbing and result in a disturbed sexual life and severe psychologic suffering. In a large Northern European study Citation[3], 11% of women aged 18–45 years had experienced genital warts. Of all participants in the study, 1.3% had had genital warts during the preceding year.
Carcinoma of the cervix is the second most common form of cancer among women worldwide. More than 500,000 cases occur every year with a case–fatality rate of at least 50%. Although the incidence and case–fatality rate are highest in developing countries with no screening programs, the disease burden is also great in industrialized countries. The American Cancer Society estimates that 11,000 cases, with 3900 deaths, will occur in the USA in 2008, and in the 27 member states of the EU the total number of cases in 2004 was estimated to be 34,000 with 16,000 deaths Citation[4]. Furthermore, cervical cancer is, in contrast to many other malignant diseases, a disease of relatively young women with a majority of cases occurring between 35 and 50 years, leading to many years of active life lost.
Cervical cancer is caused by persistent infection with HPV. The time from infection of carcinoma in situ to invasive cancer is 20–40 years. Approximately 70% of all cases of cervical cancer are due to the most oncogenic types, 16 and 18 Citation[2,5]. Several other HPV types are also oncogenic but each of these types contributes a maximum of a few percent to the total burden of cervical cancer Citation[2,5].
The oncogenic types 31 and 45 are immunologically related to types 16 and 18. This raises hope, supported by a recent publication, that up to 80% of cervical cancer cases might be prevented by a vaccine consisting of types 16 and 18 Citation[6].
Human papillomavirus type 16 and to a lesser extent, type 18, are related to cancer in the vulva, vagina, penis, anal region and oropharynx Citation[7–9]. There are many risk factors apart from HPV infection for these forms of malignancies. Most probably, HPV vaccines against types 16 and 18 will decrease the incidence of these malignancies but it is currently not possible to predict the magnitude of this decrease.
Two HPV vaccines have recently become available: Gardasil® (Sanofi Pasteur) and Cervarix® (GlaxoSmithKline). The active parts in both vaccines are recombinant L1 capsid from types 16 and 18, and in Gardasil there is also recombinant L1 from types 6 and 11. Both vaccines should be administered three-times, with intervals of 2 and 6 months and 1 and 6 months, respectively.
The literature on HPV and HPV vaccines is so extensive that it cannot be reviewed here. For efficacy data the reader is referred to the European Public Assessment Report Citation[101,102] and some recent publications Citation[5–12].
Briefly, both vaccines induce virus-neutralizing antibodies against types 16 and 18, which protect against HPV infection and viral persistence, a prerequisite for cancer development. Efficacy against cervical intraepithelial neoplasia (which precedes the development of cancer) has been demonstrated. The quadrivalent Gardasil also has a very high efficacy against genital warts, which would be the first public-health effect if this vaccine is used. The vaccines have no therapeutic effect against the virus types a recipient may be infected with before vaccination, thus, vaccination should start before onset of sexual activity, with the optimal time of vaccination being before the onset of puberty.
Efficacy against cervical cancer is, of course, not shown because it takes several decades for cancer to develop after HPV infection. It is, in my opinion, not realistic or necessary to wait for such a long time before decisions regarding HPV vaccinations are made since HPV vaccine efficacy against persistent HPV infection and cervical intraepithelial neoplasia have been convincingly shown.
HPV vaccines and their use have been intensely discussed in industrialized countries during the last few years. Opinions vary from general vaccination of both girls and boys or of girls alone, to no general vaccination at all.
The USA, Australia, many countries in Europe and a few countries in Asia recommend general HPV vaccination of prepubertal girls. The logistics of vaccine administration and of financing (public or private sector) vary widely between countries. Many countries that have started general vaccination of girls also support catch-up vaccination of adolescents and young women.
The main reason for hesitation about general HPV vaccination is certainly the cost of the vaccine. The costs of the vaccines vary somewhat between countries but are generally around €100 per dose (i.e., €300 per completely vaccinated individual). A large number of recent cost–benefit analyses from different countries unequivocally show that general HPV vaccination is a cost-effective way of preventing cervical cancer but, of course, the benefits will not be obvious until several decades have elapsed Citation[13–16]. Most of these analyses have focused on cervical cancer. If the quadrivalent vaccine is used, positive effects, both medico–ethical and economic, will be obvious within a few years, when the incidence of genital condylomas will decrease drastically.
Other reasons for hesitation about general HPV vaccination are the lack of knowledge about duration of protection, long-term effects of general vaccination (replacement of vaccine types with other types) and a hypothetical fear that general vaccination against one sexually transmitted disease will lead to increases in others, if sexual behavior changes with less motivation among HPV-vaccinated adolescents to use safe sexual practices. These reasons should, in my opinion, not delay the start of general HPV vaccination.
It is not necessary that vaccination before puberty induces life-long protection. It should be enough with 20–30 years, because infection with oncogenic HPV types at 35–45 years instead of 15–20 years of age would delay cancer development by 20 years and furthermore, sexual activity and number of partners decrease with age.
Replacement of the currently most common HPV types is a possible threat and it is more likely than not that mutations with new oncogenic types will arise in the future. This motivates continuous surveillance of HPV incidence, types and cervical and other HPV-related cancers in the same way as continuous surveillance of serotypes of pneumococci and rotavirus must be performed when new vaccines against those infections are rapidly introduced into national vaccination programs.
An important factor to consider for countries contemplating general HPV vaccination is the organization for vaccination and information to parents and adolescents. Most countries in the world have more or less well-functioning systems for infant vaccination and industrialized countries also for booster doses against some important infectious diseases. The HPV vaccine is the first vaccine that will be introduced with a primary vaccination of three doses in early adolescence. Thus, a new organization will be needed for vaccination and it will differ from country to country. In my home country, Sweden, the most realistic way to solve this is through the school healthcare system, which is currently responsible for diphtheria–tetanus–pertussis and measles–mumps–rubella booster vaccinations. For a successful HPV vaccination it will be necessary that vaccine costs, information and vaccination are sufficiently funded, preferably through government funding to the schools.
The question of whether both boys and girls or only girls should be vaccinated is unresolved. The situation has certain similarities with rubella vaccination. All countries with national programs for rubella vaccination include boys, even though boys have little to gain from being protected against this mild, self-limiting disease. The reason for vaccinating boys is to achieve herd immunity, so that women will have both individual protection and little risk of being exposed. The same reasoning is valid for HPV. If both girls and boys are vaccinated with a high vaccination rate, herd immunity for the oncogenic types will be achieved and women will be doubly protected. If the vaccine does not give individual protection for their life-time, herd immunity will probably still be maintained and one of the reasons for hesitation mentioned earlier (duration of individual protection) will be less relevant. In contrast to rubella vaccination, boys will also benefit from an individual HPV protection. Furthermore, the risk of other HPV-related cancers, such as anal and oropharyngeal cancer, will decrease. With the quadrivalent vaccine, boys will also be protected against condylomas.
In conclusion, the benefits of general HPV vaccination are, in my opinion, so large that general vaccination of both girls and boys is warranted. Sufficient resources must be given to cover the high vaccine costs, costs for a new organization for vaccination and costs for continuous surveillance. Mankind has always dreamed about ‘a vaccine against cancer’. There will never be one vaccine against cancer, because cancer comprises a wide range of diseases with different etiologies, but we now have a vaccine against one of the most common forms of cancer. Why not use it?
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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Websites
- Gardasil®: European Public Assessment Report www.emea.europa.eu/humandocs/Humans/EPAR/gardasil/gardasil.htm
- Ceravix®: European Public Assessment Report www.emea.europa.eu/humandocs/Humans/EPAR/cervarix/cervarix.htm