This document has been written by a group of experts and is a compilation of scientific data available within in the area of respective expert.
The document forms the background for the assessment of the National Board of Health and Welfare whether to include HPV vaccination in the Swedish vaccination programme or not.
The document is written in English to facilitate comparisons with similar studies from other countries.
The following text comprises brief summaries of different aspects of introducing the HPV vaccine in a vaccination program, as described in the chapters below. Questions on lack-of-knowledge are enclosed after some paragraphs, These questions are adapted from those identified by the ECDC in their evaluation of the HPV vaccine to be relevant to the Swedish situation.
What is the effect of the present preventive screening program?
In Sweden 80% of women in the targeted population participate in the preventive cervical cancer screening program and among them the cervical cancer morbidity is low - about 150 cancer cases and some 30 deaths per year. The rest of the cancers occur among women with inadequate screening participation. It is therefore especially important to gain vaccine coverage in these groups before they get infected.
In view of the effects of the screening program, the prevention of cervical cancer has to be seen as an entity, including both screening and vaccination. General vaccination is a long-term strategy and has to be coordinated with maintenance of current screening procedures, which effectively protects already infected women against all HPV types, including those not included in the vaccines.
Lack of knowledge
The following questions should be answered when the effects of a vaccineprogramme are monitored:
- What is the long term impact of HPV vaccines on participation in and outcome of screening programmes?
- What is the cost-effectiveness of cervical cancer prevention programmes that include both vaccination and screening, taking into account observed data on screening compliance after vaccination?
- Could screening programmes be modified once an increasing number of girls/women are vaccinated?
- What is the value of HPV testing as a primary screening tool in vaccinated cohorts?
What is the effect of the vaccine?
Both HPV vaccines available in the market demonstrate high protective efficacy (90-100%) in HPV naïve women against HPV 16/18-related cervical cancer, as measured by the surrogate endpoints CIN 2/3 and other relevant histological endpoints. Vaccine efficacy against CIN 2/3 due to HPV 16/18 in the intention-to-treat population, including women already infected with vaccine HPV types, is substantially lower, 44% after 3 years of follow-up after the first vaccine dose. Based on these data it is evident that vaccination is of greatest value in females not yet exposed to any of the vaccine HPV types. The value for boys remains to be proven and the added value to vaccinate both sexes will probably be low, if high vaccination coverage among girls is attained.
Serologic studies and mathematic modelling in theory supports that duration of protection will be sustained over many years. However, it is currently not possible to determine the exact duration. Both vaccines are well tolerated in all studied age-groups, with no differences in prepubertal girls as compared to young women, nor did the safety profile for Gardasil differ in prepubertal boys. The vaccines are non-live and it is therefore not likely that any major interference with other childhood vaccines given to the teenagers will be demonstrated.
Lack of knowledge
The following questions remain to be answered if the effects of a vaccineprogramme should be analysed further:
- Will exposure to an HPV virus after vaccination act as a natural booster?
- What is the role of cell-mediated immunity in the protection generated by the virus-like particle vaccines?
- What fraction of cancer incidence overall will be prevented by vaccinating against HPVs 16 and 18?
- What benefits might vaccination confer on adults who are already sero-positive to vaccine HPV types?
- Does co-administration of HPV vaccines with other vaccines administered to adolescents result in changed immunogenicity of the vaccines or changed side effect profiles?
- What will be the effect of vaccinating boys?
- If a vaccination-program has the effect that women are infected at an older age to what extent will infections cause cancer?
What is the disease burden?
The major disease caused by HPV is cervical cancer, which is mainly (70%) caused by HPV16 and 18. The disease burden is kept at comparatively low levels by the present screening program. Even so, there are on average 450 cases and 150 deaths from cervical cancer per year and an estimated 290 cases and 110 deaths of those are caused by HPV16 and 18.
HPV16/18 also cause a substantial proportion of other anogenital cancers (vulvar, vaginal, penile and anal) as well as oropharyngeal cancer, estimated at 150 cases and 80 deaths per year.
Altogether HPV16/18 is estimated to cause about 440 cases of cancer and about 190 cases of cancer deaths per year.
HPV16/18 is also a major cause of precursors to cervical cancer, causing about 2,600 cases of high-grade dysplasia and >5,000 cases of low-grade cervical lesions per year.
The major disease caused by HPV6 and 11 is condyloma acuminata (genital warts), which affects about 20,000-40,000 subjects each year.
Lack of knowledge
The following questions remain to be answered if the effects of a vaccineprogramme should be analysed further:
- Information on the exact proportion of different types of cancers that are caused by HPV 16 and 18 in Sweden
- Information on the exact proportion of precancerous lesions, in particular of the cervix, that are caused by HPV 6/11/16/18 in Sweden
- Information on the overall burden-of-disease of condylomas and recurrent repiratory papillomatosis and the exact proportion of this burden that is caused by vaccine-types of HPV in Sweden.
Assumed health-economic effect
The published health economic studies indicate, on the assumptions made, that HPV vaccination of 12-year old girls may have a cost effectiveness ratio within a wide range around a couple of hundred thousand SEK per LYS and a slightly lower cost per QALY. However, several assumptions are very uncertain. The sensitivity analyses showed that the results were sensitive to vaccine price, vaccination compliance, protective effect of the vaccine and discounting rate.
In Sweden it can be assumed that after a period of 50 years the combination of vaccination against HPV 16 and 18 and Pap smear screening would result in a total of 980 avoided cases of cervical cancer per year. This means that a further 230 cases of cervical cancer are approximately avoided per year compared with today. A third (77) of these cases is expected to correspond to premature deaths. Calculated as life years saved, 77 avoided deaths correspond to approximately 995 saved life years without discounting.
Health improvements achieved today are assumed to have a higher value for citizens than health improvements far into the future. This means that future health improvements have a lower value than those that can be achieved at present, which is calculated by means of discounting. 995 saved life years are equivalent to 191 saved life years at 3 percent discounting.
Lack of knowledge
The following issues remain to be answered if the effects of a vaccine programme should be analysed further (most of these are related to the effect of a vaccine programme):
- Define common quality-of-life scores, in order to be able to compare studies performed in different settings.
- Include other HPV-related diseases (genital warts, other cancers) in cost-effectiveness evaluation models, in order to fully value the impact of vaccination.
- Expand the use of worst case and best case scenarios, which are useful in order to establish the robustness of the underlying assumptions of the models.
Legal aspects
The legal basis for introducing HPV-vaccination in the Swedish child vaccination programme is found in the Swedish Communicable Diseases Act from 2004 and its ordinance. HPV-vaccination could be included in the child vaccination programme in a binding regulation. In order to ensure an effective implementation, regulati