Human papillomavirus (HPV) is a double stranded DNA virus, that infects squamous epithelia including the skin and mucosae of the upper respiratory and anogenital tracts. There are approximately 100 types of HPV, of which about 40 infect the genital tract (McCance, 2004). Although most infections are asymptomatic and self-limiting, genital infection by HPV is associated with genital warts and anogenital cancers in both men and women. HPV viruses are classified as either ‘high-risk’ or ‘low-risk’ types depending on their association with the development of cancer.
Genital HPVs are transmitted by sexual contact with an infected individual, primarily through sexual intercourse. The risk therefore, generally increases with the number of sexual partners, the introduction of a new sexual partner, and the sexual history of any partner. Studies of incident HPV infection based on HPV DNA detection demonstrate that acquisition of at least one type of HPV infection occurs soon after sexual debut with around 30% of women being infected within two years (Winer et al., 2003; Winer et al., 2008).
The use of condoms reduces but does not eliminate the risk of sexual trans-mission. Non-sexual routes of HPV transmission include vertical transmission from mother to newborn baby.
Persistent infection by high-risk HPV types is detectable in more than 99% of cervical cancers (Munoz et al., 2006). Of these high-risk types, HPV16 is responsible for more than 50% and HPV18 for more than 15% of all cervical cancers in Europe (Smith et al., 2007). A further 11 high-risk types have been described (WHO IARC, 2007).1 In addition to cervical cancer, HPV is causally associated with other less common cancers, which include cancer of the vulva, vagina, penis and anus, and some cancers of the head and neck (Parkin et al., 2006; Stanley, 2007).
The majority of high-risk HPV infections are transient and cause no clinical problems. Within one year, around 70% of new infections will clear and approximately 90% of new infections will clear within two years (Ho et al., 1998; Franco et al.,1999). The median duration of a new infection is eight months. Infection by multiple types is common. Persistent infection by a high-risk HPV type is the most important causal factor for the development of cervical pre-cancerous and cancerous lesions. Persistence and disease is more common for infections by HPV types 16 and 18 than for other high risk types. The time span between infection by HPV and the development of CIN3 or cervical cancer varies from one to ten years (Moscicki et al., 2006).
HPV infection is associated with 80-90% of all anal squamous cell cancers. HPV types 16 and 18 are found in most anal cancers (Munoz et al., 2006). The natural history of vaginal and vulval cancers is not completely understood. Although HPV infection is a risk factor for the development of vaginal or vulval lesions, unlike cervical cancer, only approximately 50% are associated with HPV infection (Munoz et al., 2006). Around 40% of cases of penile cancer are attributable to HPV infection (Rubin et al., 2001). For all sites, the evidence for a causal association and the percentage attributable to HPV infection, is greater for HPV types 16 and 18 than for other HPV types.
Low-risk HPV types are responsible for genital warts, which is the most common viral sexually transmitted infection in the UK (Fenton et al., 2004). HPV types 6 and 11 cause over 90% (75-90%) of all genital warts (Lacey et al., 2006; Garland et al., 2007). Genital warts appear from three weeks to eight months after primary infection (most commonly two to three months) (Oriel,1971). In the absence of treatment, up to 30% may clear the infection in the short term (Tyring et al., 1998; Edwards et al., 1998). The rate of spontaneous regression in the long term is not known. Treatments focus on removal of the warts, but do not necessarily eliminate infection, which may persist sub-clinically, and be a source of recurrence and continuing viral transmission. Genital warts are not life threatening, but they can cause significant morbidity.
HPV infection has been associated with cancerous and non-cancerous lesions outside the ano-genital area including laryngeal papillomas, (Stamataki et al., 2007) and some head and neck cancers (Psyrri et al., 2008).
Surveillance of HPV is complex due to the high proportion of asymptomatic infections, the variable presentation of the different viral types, and the long period between infection and disease.
A UK seroprevalence study in an unselected population showed that HPV prevalence was extremely low in girls aged 14 years but HPV infections rise sharply in the mid teens. Among 10 to 29-year-old women, 11%, 3%, 12% and 5% have evidence of ever having been infected by HPV types 6, 11, 16 or 18 respectively (Jit et al., 2007).
Information on the prevalence of high-risk HPV infection is available from a large cross-sectional study of women having routine cervical screening in the UK (Kitchener et al., 2006). This study found evidence of current high-risk HPV infection (indicated by the presence of HPV DNA) in 40% of women aged 20 to 24 years, declining with increasing age. Prevalence of any HPV type, and particularly of HPV 16 or 18, was higher in women who had abnormal cytology.
Information on incidence of genital warts comes primarily from people attending genitourinary medicine (GUM) clinics. Over 80,000 new cases of genital warts were diagnosed in GUM clinics throughout the UK in 2006 (HPA, 2007). Rates of diagnoses are highest in young men and women under 24 years.
Cervical cancer is the second commonest cancer of women worldwide, with approximately 500,000 new cases and 270,000 deaths annually (Munoz et al., 2006; Parkin et al., 2006).
The introduction of a national cervical screening programme in the UK has made a major contribution to the fall in the incidence and death rate from cervical cancer. Due to cervical screening in the UK, mortality rates fell approximately 60% between 1974 and 2004 (Peto et al., 2004).
A total of 2253 new cases of invasive cervical cancer were diagnosed in England in 2005 (National Statistics, 2007). The peak incidence occurred in women in their 30s with a second peak in women in their 60s-80s (i.e. women less likely to have benefited from cervical screening during their lifetimes; Figure 1). In the UK, the lifetime risk of developing cervical cancer is estimated as 1 in 116 (National Statistics, 2004). In the UK, approximately one third of women die within five years of the diagnosis of invasive cervical cancer (National Statistics, 2004).women in their 30s with a second peak in women in their 60s-80s (i.e. women less likely to have benefited from cervical screening during their lifetimes; Figure 1). In the UK, the lifetime risk of developing cervical cancer is estimated as 1 in 116 (National Statistics, 2004). In the UK, approximately one third of women die within five years of the diagnosis of invasive cervical cancer (National Statistics, 2004). There are certain groups of women who are reported to have low cervical screening rates, e.g. ethnic minority groups and women born in foreign countries (Webb et al., 2004; Thomas et al., 2005). More recently, there has been a fall in the number of young women taking up invitations for cervical screening (Department of Health, 2007). In addition to cervical cancer, HPV is also associated with other anogenital cancers. In the UK, anal cancer is rare, with around 800 cases diagnosed annually (National Statistics, 2004). Overall, anal cancer is more common in women than in men, but relatively high rates are found among men who have sex with men. In the UK, there are around 1200 cases of vulval and vaginal cancers per year. There are certain groups of women who are reported to have low cervical screening rates, e.g. ethnic minority groups and women born in foreign countries (Webb et al., 2004; Thomas et al., 2005). More recently, there has been a fall in the number of young women taking up invitations for cervical screening (Department of Health, 2007).women in their 30s with a second peak in women in their 60s-80s (i.e. women less likely to have benefited from cervical screening during their lifetimes; Figure 1). In the UK, the lifetime risk of developing cervical cancer is estimated as 1 in 116 (National Statistics, 2004). In the UK, approximately one third of women die within five years of the diagnosis of invasive cervical cancer (National Statistics, 2004). There are certain groups of women who are reported to have low cervical screening rates, e.g. ethnic minority groups and women born in foreign countries (Webb et al., 2004; Thomas et al., 2005). More recently, there has been a fall in the number of young women taking up invitations for cervical screening (Department of Health, 2007). In addition to cervical cancer, HPV is also associated with other anogenital cancers. In the UK, anal cancer is rare, with around 800 cases diagnosed annually (National Statistics, 2004). Overall, anal cancer is more common in women than in men, but relatively high rates are found among men who have sex with men. In the UK, there are around 1200 cases of vulval and vaginal cancers per year. In addition to cervical cancer, HPV is also associated with other anogenital cancers. In the UK, anal cancer is rare, with around 800 cases diagnosed annually (National Statistics, 2004). Overall, anal cancer is more common in women than in men, but relatively high rates are found among men who have sex with men. In the UK, there are around 1200 cases of vulval and vaginal cancers per year.women in their 30s with a second peak in women in their 60s-80s (i.e. women less likely to have benefited from cervical screening during their lifetimes; Figure 1). In the UK, the lifetime risk of developing cervical cancer is estimated as 1 in 116 (National Statistics, 2004). In the UK, approximately one third of women die within five years of the diagnosis of invasive cervical cancer (National Statistics, 2004). There are certain groups of women who are reported to have low cervical screening rates, e.g. ethnic minority groups and women born in foreign countries (Webb et al., 2004; Thomas et al., 2005). More recently, there has been a fall in the number of young women taking up invitations for cervical screening (Department of Health, 2007). In addition to cervical cancer, HPV is also associated with other anogenital cancers. In the UK, anal cancer is rare, with around 800 cases diagnosed annually (National Statistics, 2004). Overall, anal cancer is more common in women than in men, but relatively high rates are found among men who have sex with men. In the UK, there are around 1200 cases of vulval and vaginal cancers per year.
HPV vaccines are sub-unit vaccines made from the major protein of the viral-coat or capsid of HPV. Virus-like particles (VLPs) are prepared from either recombinant yeast or baculovirus infected cells that are derived from a type of moth. VLPs mimic the structure of the native virus but do not contain any viral DNA. There are currently two different HPV vaccine products. Cervarix® contains VLPs for two HPV types (16 and 18 – bivalent vaccine) and Gardasil® contains VLPs for four HPV types (6, 11, 16 and 18 – quadrivalent vaccine). The VLPs used in Cervarix® are adjuvanted by AS04 containing 3-O-desacyl-4'- monophosphoryl lipid A (MPL) adsorbed on aluminium hydroxide. The VLPs used in Gardasil® are adsorbed on amorphous aluminium hydroxyphosphate sulphate adjuvant.
The above vaccines do not contain thiomersal. They do not contain live organisms and cannot cause the diseases against which they protect.
HPV vaccines are highly effective at preventing the infection of susceptible women with the HPV types covered by the vaccine. In clinical trials, both vaccines are over 99% effective at preventing pre-cancerous lesions associated with HPV types 16 or 18 in young women (Harper et al., 2006; Ault et al., 2007). Current studies suggest that protection is maintained for at least six years. Based on the immune responses, it is expected that protection will be extended further; long term follow-up studies are in place. Some other high-risk HPV types are closely related to those contained in the vaccines, and vaccination has been shown to provide some cross-protection against infection by these types (Brown et al., 2007). Gardasil® is also 99% effective at preventing genital warts associated with vaccine types in young women (Barr et al., 2007).
Vaccines should be stored in the original packaging at +2°C to +8°C and protected from light. All vaccines are sensitive to some extent to heat or cold. Heat speeds up the decline in potency of most vaccines, thus reducing their shelf life. Effectiveness cannot be guaranteed for vaccines unless they have been stored at the correct temperature. Freezing may cause increased reactogenicity and loss of potency for some vaccines. It can also cause hairline cracks in the container, leading to contamination of the contents.
HPV vaccines are all supplied as suspensions of VLPs in pre-filled syringes. During storage, a white precipitate may develop and the vaccines should be shaken before use to form a white cloudy liquid.
* The schedule for CervarixR is based on that listed in the Australian SPC and differs from that currently listed in the European SPC for CervarixR in that it offers a more flexible schedule for the second dose. This schedule has been recommended by the Joint Committee on Vaccination and Immunisation (JCVI).
For planning purposes, a vaccination schedule of 0,1-2, 6 months is appropriate for both vaccines. All three doses should be given within a 12-month period. If the course is interrupted, it should be resumed but not repeated, ideally allowing the appropriate interval between the remaining doses.
If there is a high likelihood that the third dose of HPV vaccine cannot be given according to the recommended schedule, a third dose of CervarixR can be given three months after the second. This guidance only applies when there are significant challenges in scheduling the third dose to individuals. For example, where the third dose coincides with examinations or when the second dose is given late.
There is no clinical data on whether the interval between doses two and three can be reduced below three months. Where the second dose is given late and there is a high likelihood that the individual will not return for a third dose after three months or if, for practical reasons, it is not possible to schedule a third dose within this time-frame, then a third dose of Cervarix® can be given at least one month after the second dose.
Whenever possible, immunisations for all individuals should follow the recommended 0, 1-2, 6 month schedule.
This advice applies to those girls and young women who are eligible to receive HPV vaccination as part of the national HPV immunisation programme as described in the guidance issued by the Department of Health (PL/CMO/2008/4).
If an individual has started a course of Gardasil®, then this course should be completed by the original provider. In the rare instances where this is not possible, then the vaccination course can be completed with Cervarix® to three doses in total (such as one Gardasil® and two Cervarix® , or two Gardasil® and one Cervarix®). The course should be completed according to a vaccination schedule of 0, 1-2, 6 months.
There is no evidence on the interchangeability of the two HPV vaccine products, therefore this advice is based on clinical judgement. It is not advisable to complete a three dose course of Cervarix® following one or two doses of Gardasil® as there is no safety data on individuals who receive mixed courses of vaccines that could involve four or even five HPV vaccine doses.
The girl or young woman should be informed that Cervarix® will provide protection against cervical cancer, but not against genital warts.
Vaccines are routinely given intramuscularly into the upper arm or anterolateral thigh. This is to reduce the risk of localised reactions, which are more common when vaccines are given subcutaneously (Mark et al., 1999; Zuckerman, 2000; Diggle et al., 2000). However, for individuals who have a bleeding disorder, vaccines should be given by deep subcutaneous injection to reduce the risk of bleeding.
HPV vaccines can be given at the same time as other vaccines such as Td/ IPV, MMR and hepatitis B. The vaccines should be given at a separate site, preferably in a different limb. If given in the same limb, they should be given at least 2.5cm apart (American Academy of Pediatrics, 2006). The site at which each vaccine was given should be noted in the individual’s records.
Equipment used for vaccination, including used vials, ampoules, or partially discharged vaccines should be disposed of at the end of a session by sealing in a proper, puncture-resistant ‘sharps’ box according to local authority regulations and guidance in the technical memorandum 07-01 (Department of Health, 2006).
The objective of the HPV immunisation programme is to provide three doses of HPV vaccine to females before they reach an age when the risk of HPV infection increases and they are at subsequent risk of cervical cancer.
Prevention of HPV infection in those eligible for vaccination and in others outside of the routine programme should include advice on safer sex. All women, whether vaccinated or not, should be strongly encouraged to attend routine cervical screening at the scheduled age.
Cervarix® is licensed for individuals from ten years old and Gardasil® is licensed for individuals from nine years old. Vaccination is not routinely recommended for those aged nine to 12 years.
From September 2008, HPV vaccination is routinely recommended for all girls at 12 to 13 years of age (school year 8 or S2 in Scotland or school year 9 in Northern Ireland). The course of HPV vaccination should be administered according to the guidance given in the dosage and schedule section. If the course is interrupted then it should be resumed but not repeated, ideally allowing the appropriate interval between the remaining doses.
Initially, there will be a catch-up campaign where girls aged 14 to under 18 years will be offered the vaccination. From September 2009, girls in England, Wales and Northern Ireland aged 16 to 18 (school years 12 and 13 or school years 13 and 14 in Northern Ireland) will be offered the vaccine. From September 2010, girls aged 15 to 17 (school years 11 and 12 or school years 12 and 13 in Northern Ireland) will be offered the vaccine. In Scotland, the catch up programme will begin on 1 September 2008 with girls aged 16 to 17 (school years S5 and S6). Girls aged 14 to 16 (school years S4 and S5) will be vaccinated from September 2009, and girls who have incomplete or no immunisation will be offered vaccination from September 2010. The course of HPV vaccination should be administered according to the guidance given in the dosage and schedule section. If the course is interrupted then it should be resumed but not repeated, ideally allowing the appropriate interval between the remaining doses.
Vaccination is not routinely recommended for those aged 18 years or over.
Where a female in the target cohort aged over 12 and under 18 years presents with an inadequate vaccination history, every effort should be made to clarify what doses they have had. A female who has not completed the schedule should complete the vaccination course at the minimum interval (see above) where possible. Females coming to the UK from overseas may not have been offered protection against HPV in their country of origin and should be offered vaccination where appropriate. http://www.who.int/ vaccines/ globalsummary/immunization/scheduleselect.cfm [accessed Feb 2008].
There are very few individuals who cannot receive HPV vaccine. Where there is doubt, appropriate advice should be sought from an immunisation coordinator or consultant in health protection rather than withholding vaccination.
The vaccine should not be given to those who have had:
Yeast allergy is not a contraindication to the HPV vaccine. Even though one vaccine is grown in yeast cells, the final vaccine product does not contain any yeast (DiMiceli et al., 2006).
Minor illnesses without fever or systemic upset are not valid reasons to postpone immunisation. If an individual is acutely unwell, immunisation may be postponed until they have fully recovered. This is to avoid confusing the differential diagnosis of any acute illness by wrongly attributing any signs or symptoms to the adverse effects of the vaccine.
There is no known risk associated with giving inactivated/recombinant viral or bacterial vaccines or toxoids during pregnancy or whilst breast-feeding (Atkinson et al., 2008). Since inactivated vaccines cannot replicate they cannot cause infection in either the mother or the foetus. However, on a precautionary basis, HPV vaccine is not advised in pregnancy. If a woman finds out she is pregnant after she has started a course of HPV vaccine, she should complete her pregnancy before finishing the three-dose schedule. This precaution is not due to any known risk associated with giving HPV vaccine during pregnancy, but due to limited data. Limited data is available because pregnant women were specifically excluded from clinical trials of HPV vaccine. However, despite safeguards some women were inadvertently immunised whilst pregnant or shortly before becoming pregnant. No specific safety concerns have been identified for the outcome of pregnancy in the women who had been given HPV vaccine, or for fetal development, when compared with women who received placebo/control. Routine questioning about last menstrual period and/or pregnancy testing is not required before offering HPV vaccine.
Girls aged under 18 years in the target cohort who are known to be sexually active, including those who are or who have been pregnant, may still be susceptible to high-risk HPV and could therefore benefit from vaccination according to the UK schedule. If pregnant, they should be offered vaccine as soon as possible after pregnancy. If high-risk sexual activity continues during pregancy, and the opportunity for vaccination after pregnancy is uncertain, the benefit of vaccination during pregnancy is likely to outweigh any potential risk.
Termination of pregnancy following inadvertent immunisation should not be recommended. The available evidence on the use of HPV vaccine in pregnancy should be discussed with the potential parents.
Due to the relatively limited experience of HPV vaccine in pregnant women to date, it is important to record and follow up such cases of inadvertent administration during pregnancy to provide further data on the outcome. Surveillance of vaccination in pregnancy is being conducted by the Immunisation Department of the HPA Centre for Infections, to whom such cases in England and Wales should be reported via the website (http://www. hpa.org.uk) or by telephone (01788 540298 or 0208 327 7471). Cases in Scotland should be reported to Health Protection Scotland on 0141 300 1100, Immunisation Department. Cases in Northern Ireland should be reported to Communicable Disease Surveillance Centre of Northern Ireland on 028 90263765.
Individuals with immunosuppression or with HIV infection (regardless of CD4 counts) should be considered for HPV vaccines in accordance with the recommendations above. However, individuals who are immunosuppressed may not develop a full antibody response. Clinical trials to study the effectiveness of HPV vaccination in immunosuppressed individuals are in progress. Re-immunisation should be considered after treatment is finished and/or recovery has occurred. Specialist advice may be required.
Cervarix® and Gardasil® vaccines both carry a black triangle symbol (H). This is a standard symbol added to the product information of a vaccine during the earlier stages of its introduction, to encourage reporting of all suspected adverse reactions. Doctors, nurses, pharmacists or parents can report a suspected adverse reaction to the Commission on Human Medicines (CHM) using the Yellow Card reporting scheme (www.yellowcard.gov.uk).
The most common adverse reaction observed after HPV vaccine administration is mild to moderate short-lasting pain at the injection site. An immediate localised stinging sensation has also been reported.
Redness has also been reported at the injection site.
Other reactions commonly reported are headache, myalgia, fatigue, and low grade fever.
Syncope (vasovagal reaction), or fainting, can occur during vaccination, most commonly amongst adolescents. Some individuals may also experience panic attacks before vaccination. The clinical features of fainting and panic attacks are described in detail in Chapter 8 of the Green Book.
Fainting and panic attacks occurring before or very shortly after vaccination are not usually direct side effects (adverse reactions) of the vaccine but events associated with the injection process itself.
Only reactions suspected to be related to the vaccine (and not those associated with the injection process) should be reported via the Yellow Card Scheme. Please report the main diagnosis only as the suspected reaction (i.e. 'vasovagal syncope', 'faint' or 'panic attack'). Any signs or symptoms associated with these events (such as loss of consciousness, limb jerking or tingling, shallow/difficulty in breathing, hyperventilation etc) should not be reported as the suspected reaction but, if necessary, as 'additional information' in the Yellow Card (or via www.yellowcard.gov.uk).
Anaphylaxis is a very rare, recognised side effect of most vaccines and suspected cases should be reported via the Yellow Card Scheme (www. yellowcard.gov.uk). Chapter 8 of the Green Book gives detailed guidance on distinguishing between faints, panic attacks and the signs and symptoms of anaphylaxis. If a case of suspected anaphylaxis meets the clinical features described in Chapter 8, this should be reported via the Yellow Card Scheme as a case of 'anaphylaxis' (or if appropriate 'anaphylactoid reaction'). Cases of less severe allergic reactions (i.e. not including the aforementioned clinical features for anaphylaxis) should not be reported as anaphylaxis but as 'allergic reaction'.
HPV vaccine is supplied by Movianto UK Ltd (Tel: 0870 8711890) as part of the national childhood immunisation programme.
In Scotland, supplies should be obtained from local childhood vaccine-holding centres. Details of these are available from Scottish Healthcare Supplies (Tel: 0131 275 6154).
In Northern Ireland, supplies can be obtained from local childhood vaccine holding centres. Details of these are available from the regional pharmaceutical procurement service (Tel: 028 90552386).
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