18a: Human papillomavirus (HPV)

The disease

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, is related to 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 often occurs soon after sexual debut with almost 40% of women being infected within two years (Winer et al., 2003; Winer et al., 2008). Infection by multiple types is common (Cuschieri et al., 2004).
The use of condoms reduces but does not eliminate the risk of sexual transmission. 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 (Walboomers et al., 1999). Of these high-risk types, HPV16 is responsible for almost 60% 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 less common cancers at other sites, including cancer of the vulva, vagina, penis and anus, and some cancers of the head and neck (Parkin et al., 2006; Stanley, 2007, Psyrri et al., 2008).
The majority of HPV infections are transient and cause no clinical problems. Around 70% of new infections will clear within one year and approximately 90% will clear within two years (Ho et al., 1998; Franco et al., 1999). The median duration of a new infection is eight months. 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 varies from one to ten years, and longer for the development of invasive cancer (Moscicki et al., 2006).
The natural history of HPV-related cancers at other sites is less well understood. Although high-risk HPV infection is a risk factor for the development of vaginal or vulval lesions, unlike cervical cancer, only approximately 40% are associated with HPV infection (Munoz et al., 2006). HPV infection is associated with 80–90% of all anal squamous cell cancers and HPV types 16 and 18 are found in the majority of HPV-related anal cancers (Munoz et al., 2006). Around 40% of cases of penile cancer are attributable to HPV infection (Rubin et al., 2001). There is emerging evidence for an association between HPV and head and neck cancers. For all sites, the evidence for a causal association is greater for HPV types 16 and 18, than for other HPV types, and the majority of HPV related cancers are associated with types 16 and 18.
Low-risk HPV types are responsible for genital warts, which is the most commonly diagnosed viral sexually transmitted infection in the UK (Health Protection Agency (HPA), 2012). HPV types 6 and 11 cause the majority 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% of individuals 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 6 and 11 infection also causes laryngeal papillomas, (Stamataki et al., 2007) an infection of the upper respiratory tract.

History and epidemiology of the disease

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 was extremely infrequent in girls aged under 14 years but HPV infections rose sharply from the mid-teens. Among 10-to 29-year-old women, 11%, 3%, 12% and 5% had serological evidence of 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 England (Howell-Jones et al., 2010). This study found evidence of current high-risk HPV infection (indicated by the presence of HPV DNA) in 29% of women aged 25 to 29 years undergoing cervical screening, with prevalence declining with increasing age after 30 years. 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 90,000 new cases of genital warts were diagnosed in GUM clinics throughout the UK in 2009 (PHE, formerly the HPA, 2012). 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. It has been estimated that mortality rates fell approximately 60% between 1974 and 2004 in the UK due to cervical screening (Peto et al., 2004).
The national HPV immunisation programme was introduced in September 2008 with all girls in school year 8 in England (aged 12 to 13 years) offered vaccine against HPV infection, with a ‘catch-up’ campaign for girls aged from 14 years to less than 18 years.

Number of cases of newly diagnosed cervical cancer in England, 2009 (source: National Statistics, 2011).

A total of 2747 new cases of invasive cervical cancer were diagnosed in England in 2009 (National Statistics, 2011). The peak incidence occurred in women in their 30s with a second smaller peak in women in their 70s–80s (i.e. women less likely to have benefited from cervical screening during their lifetimes; Figure 18a.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, 2011).
There are certain groups of women reported to have low cervical screening rates, e.g. some ethnic minority groups and women born in foreign countries (Webb et al., 2004; Thomas et al., 2005). There has also been a downward trend in the number of young women taking up invitations for cervical screening since the mid-1990s (NHS Cervical Screening Review, 2011).
In the UK, anal cancer is rare, with around 850 cases diagnosed annually (National Statistics, 2011). 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.

The HPV vaccination

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 recombinant proteins grown in either yeast or baculovirus infected insect cells (the latter derive 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 in young women with no evidence of previous infection, both vaccines are over 99% effective at preventing pre-cancerous lesions associated with HPV types 16 or 18 (Harper et al., 2006; Ault et al., 2007; Lu et al., 2011). Current studies suggest that protection is maintained for at least ten 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., 2009; Lehtinen et al., 2012). Gardasil® is also 99% effective at preventing genital warts associated with vaccine types in young women (Barr et al., 2007).
Cervarix® was the HPV vaccine offered from September 2008 to August 2012 with Gardasil® being offered from September 2012 (Department of Health, 2011).
In March 2014 the Joint Committee on Vaccination and Immunisation (JCVI) advised that based on the latest immunological evidence (including Dobson et al., 2013; Safaeian et al., 2013), the efficacy and duration of protection in adolescents vaccinated using a two dose schedule administered as a prime and boost (separated by a minimum of 6 months) was likely to be the same as a three dose schedule. In 2013/14 both Gardasil and Cervarix received licensing approval from the European Medicines Agency (EMA) for a two dose schedule in adolescent girls (Summary of Product Characteristics (SPC) Gardasil, Cervarix). The two dose schedule for Gardasil is licenced for individuals aged 9 to and including 13 years of age and Cervarix is licenced for individuals aged 9 to and including 14 years of age. JCVI has agreed, however, to recommend a 2-dose schedule up to (and including) 14 years of age for both Cervarix and Gardasil. The WHO‘s Strategic Advisory Group of Experts (SAGE) on immunisation also recently reviewed the evidence on HPV immunisation schedules. Upon review of the evidence, SAGE also recommended a 2-dose schedule for girls, if vaccination is initiated prior to 15 years of age. A 3-dose schedule remains necessary if immunization is initiated after the girls’ 15th birthday (WHO,2014). The two dose schedule will be implemented in the UK programme for the routine vaccination cohort of females aged 11 to 13 years old (academic year 8 in England and Wales) from September 2014.

Storage

Vaccines should be stored in the original packaging at +2°C to +8°C (ideally aim for 5°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.

Presentation

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.

Dosage and schedule

The two vaccine products are not routinely interchangeable and, ideally, one vaccine product should be used for the entire course (see below). Following the introduction of Gardasil® in September 2012 as the vaccine for the national immunisation programme, there is no longer a supply of Cervarix® available for girls who started the schedule with Cervarix® but missed vaccinations to complete the course (see below: previous incomplete vaccination with Cervarix®.) As the Summaries of Product Characteristics for Cervarix® and Gardasil® allow flexibility in their administration the following are the recommended schedules for the UK programme.

Two dose schedule (for girls aged between nine years old and below 15 years of age)

Schedule for Gardasil® (containing HPV types 6,11,16,18)
  •  
    First dose of 0.5ml of Gardasil® HPV vaccine.
  •  
    Second dose of 0.5ml at least six to 24 months after the first dose.
Schedule for Cervarix® (containing HPV types 16,18)
  •  
    First dose of 0.5ml of Cervarix® HPV vaccine.
  •  
    Second dose of 0.5ml at least six to 24 months after the first dose.
For girls aged less than 15 years of age JCVI recommended a schedule of 0, 6–24 months for both vaccines. For planning purposes a schedule at 0, 12 months is appropriate for both vaccines. Local needs, however, should be considered when planning the programme. Any gap between doses of between six and 24 months is clinically acceptable. As long as the first dose was received before the age of 15 years the two dose schedule can be followed. If the course is interrupted, it should be resumed (using the same vaccine) but not repeated, even if more than 24 months have elapsed since the first dose.
Whenever possible, immunisations for all individuals should follow the recommended 0, 6–24 months schedule, but there is some clinical data that the interval between the two doses can be reduced to five months for Cervarix. For Gardasil® the minimum interval between the two doses should be 6 months.

Three dose schedule (for girls aged 15 years and above)

Schedule for Gardasil® (containing HPV types 6,11,16,18)
  •  
    First dose of 0.5ml of Gardasil® HPV vaccine.
  •  
    Second dose of 0.5ml at least one month after the first dose.
  •  
    A third dose of 0.5ml at least three months after the second dose.
Schedule for Cervarix® (containing HPV types 16,18)
  •  
    First dose of 0.5ml of Cervarix® HPV vaccine.
  •  
    Second dose of 0.5ml, one to two and a half months after the first dose.
  •  
    A third dose of 0.5ml at least five months after the first dose.
A vaccination schedule of 0, 1, 4–6 months is appropriate for both vaccines for girls commencing the course at age 15 years and above. All three doses should ideally be given within a 12-month period. If the course is interrupted, it should be resumed (using the same vaccine) but not repeated, ideally allowing the appropriate interval between the remaining doses.
Whenever possible, immunisations for all individuals should follow the recommended 0, 1, 4–6 month schedule. 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 can be given at least one month after the second dose. This applies to both Cervarix® and Gardasil®.

Previous incomplete vaccination with Cervarix® – advice for girls and young women covered by the national HPV vaccination programme

The advice below 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).
There is no longer a supply of Cervarix® available in the UK. For girls who started the schedule with Cervarix,® but did not complete the vaccination course, the course can be completed with Gardasil®. The course should be completed according to a vaccination schedule of 0, 1, 4–6 months or 0, 6–24 months, depending on the age of the girl when she received the first dose and whether 1 or 2 doses have already been given (see above). As there is no evidence on the interchangeability of the two HPV vaccine products, this advice is based on expert opinion and the high levels of antibody achieved after partial courses of both vaccines.
As there is no clear benefit and there are no safety data on individuals who receive mixed courses of four or more HPV vaccine doses, offering a full course of Gardasil® following a partial or complete course of Cervarix® is inadvisable.
As the primary purpose of the NHS immunisation programme is to protect against cervical cancer, it is not appropriate, to offer Gardasil® to those who have had a full course of Cervarix® with the aim of providing additional protection against genital warts.

Previous incomplete vaccination with Gardasil®– advice for girls and young women covered by the national HPV vaccination programme

Vaccination started before September 2014

If an individual has started a three dose course of Gardasil®, then this course should, where possible, be completed according to a vaccination schedule of 0, 1, 4–6 months. If the course is interrupted, it should be resumed (using the same vaccine) but not repeated, ideally allowing the appropriate interval between the remaining doses.
Two doses given less than 6 months apart should not be considered adequate to provide long term protection and a third dose should be given according to the guidance given in the dosage and schedule section.

Vaccination started after September 2014

As long as the first dose was received before the age of 15 years the two dose schedule should be followed. If an individual has started a two dose course of Gardasil, then this course should, where possible, be completed according to a vaccination schedule of 0, 6–24 months. If the course is interrupted, it should be resumed (using the same vaccine) but not repeated even if more than 24 months have elapsed since or even if the girl is then aged 15 years or more.

Administration

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, Influenza, MenC and hepatitis B. A trend of lower anti-HPV titres has been observed when Gardasil® is administered concomitantly with dTaP, dT/IPV and dTaP/IPV vaccines, though the clinical significance of this observation is unclear. 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.

Disposal

Equipment used for vaccination, including used vials, ampoules or syringes, should be disposed of by placing them in a proper, puncture-resistant ‘sharps’ box according to local authority regulations and guidance in Health Technical Memorandum 07-01: Safe management of healthcare waste (Department of Health, 2013).
 1Including types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 and 66

Recommendations for the use of the vaccine

The objective of the HPV immunisation programme is to provide two doses of HPV vaccine at least six months apart to females before they reach an age when the risk of HPV infection increases and puts them 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.

National HPV vaccination programme cohort

Females aged nine to 11 years

Cervarix® and Gardasil® are licensed for individuals from nine years old. Vaccination of girls of this age is not covered by the national HPV vaccination programme.

Females aged 11 to 18 years

HPV vaccination is routinely recommended for all girls at 11 to 14 years of age with the first dose offered in school year 8 in England and Wales, S1/S2 in Scotland, and school year 9 in Northern Ireland. The move to a two dose schedule in September 2014 allows flexibility around the schedule with the interval between the first and second dose from 6 months to 24 months (0, 6–24 months) and covers girls from 11 up to and including the age of 14 years (school year 8 to 9 or S1/S2 to S3 in Scotland or school year 9 to 10 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. For girls who miss starting a course of vaccination in the first target year, those less than 15 years of age should still start on a two dose schedule; those aged 15 or less than 18 years of age should start a three dose schedule.
Two doses less than 6 months apart should not be considered adequate to provide long term protection and a third dose should be given according to the guidance given in the dosage and schedule section.

Females aged 18 or over

Vaccination for females over the age of 18 years is not covered by the national HPV vaccination programme. However, for girls who commenced, but did not complete vaccination, it is reasonable to complete their HPV vaccination course after the age of 18 years.

Vaccination of females with unknown or incomplete immunisation status

Where a female in the target cohort aged over 11 and under 18 years presents with an inadequate vaccination history, every effort should be made to clarify what doses she has had and when she received them. A female who has started but did not complete the schedule before reaching the age of 18 years, should complete the vaccination course at the minimum interval (see above) where possible.
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.
Two doses less than 6 months apart should not be considered adequate to provide long term protection and a third dose should be given according to the guidance given in the dosage and schedule section.
Females coming to the UK from overseas and registered with a GP practice may not have been offered protection against HPV in their country of origin and should be offered vaccination if they are aged under 18 years. If they are aged 18 years or over, and commenced, but did not complete vaccination, it is reasonable to complete their HPV vaccination course.

Vaccination of boys and young men

Males of any age are not covered by the national HPV vaccination programme.

Contraindications

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:
  •  
    a confirmed anaphylactic reaction to a previous dose of HPV vaccine, or
  •  
    a confirmed anaphylactic reaction to any components of the vaccine.
Yeast allergy is not a contraindication to the HPV vaccine. Even though Gardasil® 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 any possible adverse effects of the vaccine.

Pregnancy and breast-feeding

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 absence of data. Limited data are available because pregnant women were specifically excluded from clinical trials of HPV vaccine. However, despite these exclusion criteria some women were inadvertently immunised whilst pregnant or shortly before becoming pregnant (many pregnant women have also now been vaccinated following the introduction of HPV vaccination programmes). No specific safety concerns have been identified in the women who have been given HPV vaccine, either for the outcome of pregnancy or fetal development, when compared with women who received a placebo or control vaccine. 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 infection 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 pregnancy, 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 prospective 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 at Public Health England (PHE) Colindale, 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 the Public Health Agency Duty Room (028 9055 3997).

Immunosuppression and HIV infection

There are limited data on 3 dose schedules in HIV infected populations. Although the immunogenicity and efficacy of HPV vaccines may be reduced in HIV infected females, they appear to be preserved (Toft et al., 2014). Lower GMTs have been observed in HIV infected subjects compared to non-HIV infected subjects of the same age for both vaccines (SPC Gardasil, Cervarix). However, the clinical relevance of these observations is unknown. Suboptimal immunogenicity of HPV vaccine in transplant patients has also been observed (Kumar et al., 2013).
There is no data on fewer than 3 doses among HIV-infected or immunocompromised populations. Therefore a 3-dose schedule should be offered to individuals who are known to be HIV-infected, including those on antiretroviral therapy, or are known to be immunocompromised at the time of immunization. This recommendation is endorsed by WHO SAGE. Re-immunisation should be considered after treatment is finished and/or recovery has occurred. Specialist advice may be required.
Further guidance is provided by the Royal College of Paediatrics and Child Health (http://www.rcpch.ac.uk/), the British HIV Association (BHIVA) immunisation guidelines for HIV-infected adults (BHIVA, 2008; http://www.bhiva.org/Immunization2008.aspx) and the Children’s HIV Association (CHIVA) immunisation guidelines (http://www.chiva.org.uk/professionals/health/guidelines/index.html).

Adverse reactions

As with all vaccines and medicines, healthcare professionals and parents/carers are encouraged to report suspected adverse reactions to the Medicines and Healthcare products Regulatory Agency (MHRA) using the Yellow Card reporting scheme (http://yellowcard.mhra.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.
A detailed list of adverse reactions associated with Cervarix® and Gardasil® is available in the Summary of Product Characteristics (SPC) for each vaccine, which are available from the EMAEMA website http://www.ema.europa.eu.
Syncope (vasovagal reaction), or fainting, can occur during any 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.

Reporting anaphylaxis and other allergic reactions

Anaphylaxis is a very rare, recognised side effect of most vaccines and suspected cases should be reported via the Yellow Card Scheme (www.mhra.gov.uk/yellowcard). 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’.

Supplies

  •  
    Cervarix® – manufactured by GlaxoSmithKline.
  •  
    Gardasil® – manufactured by Sanofi Pasteur MSD.
These vaccines are distributed in the UK by Movianto UK Ltd (Tel: 01234 248631) 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 Procurement, Commissioning & Facilities of NHS National Services Scotland (Tel: 0131 275 6725).
In Northern Ireland, supplies should be obtained from local childhood vaccine holding centres. Details of these are available from the Regional Pharmaceutical Procurement Service (Tel: 028 9442 4346).

References

American Academy of Pediatrics (2006) Vaccine Administration. In: Pickering LK (ed.) Red Book: 2006. Report of the Committee on Infectious Diseases. 26th edition. Elk Grove Village, IL: American Academy of Pediatrics, pp. 18–22.
Atkinson WL, Kroger AL, Pickering LK (2008) Section 1: General aspects of vaccination, Part 7: General immunization practices. In: Plotkin S, Orenstein W, Offit P (eds) Vaccines. 5th edition. Philadelphia: WB Saunders Company, pp 83–109.
Ault KA and FUTURE II Study Group (2007) Effect of prophylactic human papillomavirus L1 virus-like-particle vaccine on risk of cervical intraepithelial neoplasia grade 2, grade 3, and adenocarcinoma in situ: a combined analysis of four randomised clinical trials. Lancet 369(9576): 1861–8. [CrossRef] [PubMed]
Barr E, Tamms G (2007) Quadrivalent human papillomavirus vaccine. Clin Infect Dis 45(5): 609–17. [CrossRef] [PubMed]
British HIV Association (2008) British HIV Association guidelines for immunization of HIV-infected adults 2008. HIV Med 9(10): 795–848. http://www.bhiva.org/documents/Guidelines/Immunisation/Immunization2008.pdf. Accessed December 2013.
Brown D, Kjaer S, Sigurdsson K (2009) The impact of quadrivalent human papillomavirus (HPV; types 6, 11, 16, and 18) L1 virus-like particle vaccine on infection and disease due to oncogenic nonvaccine HPV types in generally HPV-naive women aged 16–26 years. J Infect Dis 199: 926–35. [CrossRef] [PubMed]
 

Cervarix Available at the electronic Medicines Compendium (eMC) http://www.medicines.org.uk/emc/default.aspx. Updated 07/01/2014.

Cuschieri KS, Cubie HA, Whitley MW (2004) Multiple high risk HPV infections are common in cervical neoplasia and young women in a cervical screening population. J Clin Pathol 57: 68–72. [CrossRef] [PubMed]
Department of Health (2013) Health Technical Memorandum 07-01: Safe management of healthcare waste. https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/167976/HTM_07-01_Final.pdf. Accessed December 2013.
Department of Health (2011) HPV vaccination programme switching to Gardasil from September 2012 http://webarchive.nationalarchives.gov.uk/20130107105354/http://immunisation.dh.gov.uk/hpv-vacc-prog-switch-to-gardasil-sept-2012/ Accessed: Feb. 2012.
Diggle L, Deeks J (2000) Effect of needle length on incidence of local reactions to routine immunisation in infants aged 4 months: randomised controlled trial. BMJ 321(7266): 931–3. [CrossRef] [PubMed]
DiMiceli L, Pool V, Kelso JM (2006) Vaccination of yeast sensitive individuals: review of safety data in the US vaccine adverse event reporting system (VAERS). Vaccine 24(6): 703–7. [CrossRef] [PubMed]
Dobson SR, McNeil S, Dionne (2013) Immunogenicity of 2 doses of HPV vaccine in younger adolescents vs 3 doses in young women: a randomized clinical trial. JAMA; 309 (17):1793–802. [CrossRef] [PubMed]
Edwards L, Ferenczy A, Eron L (1998) Self-administered topical 5% imiquimod cream for external anogenital warts. HPV Study Group. Human PapillomaVirus. Arch Dermatol 134(1): 25–30. [CrossRef] [PubMed]
Franco EL, Villa LL, Sobrinho JP (1999) Epidemiology of acquisition and clearance of cervical human papillomavirus infection in women from a high-risk area for cervical cancer. J Infect Dis 180(5): 1415–23. [CrossRef] [PubMed]
Gardasil Summary of Product Characteristics. Available at the electronic Medicines Compendium (eMC) http://www.medicines.org.uk/emc/default.aspx. Updated 03/04/2014.
Garland SM, Hernandez-Avila M, Wheeler CM (2007) Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 356(19): 1928–43. [CrossRef] [PubMed]
Harper DM, Franco EL, Wheeler CM (2006) Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet 367(9518): 1247–55. [CrossRef] [PubMed]
Ho GY, Bierman R, Beardsley L (1998) Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 338(7): 423–8. [CrossRef] [PubMed]
Howell-Jones R, Bailey A, Beddows S (2010) Multi-site study of HPV type-specific prevalence in women with cervical cancer, intraepithelial neoplasia and normal cytology, in England. Br J Cancer, 103(2): 209–16.  

Erratum in:

Br J Cancer (2010), 103(6): 928. [CrossRef] [PubMed]
HPA (2007) Testing times – HIV and other sexually transmitted Infections in the United Kingdom: 2007. Accessed: Feb. 2012.
HPA (2012) STI annual data tables. Accessed: Feb. 2012.
Jit M, Vyse A, Borrow R (2007) Prevalence of human papillomavirus antibodies in young female subjects in England. Br J Cancer 97(7): 989–91. [PubMed]
Joint Committee on Vaccination and Immunisation. (2014) Minute of the meeting on Tuesday 11 and Wednesday 12 February 2014 available at : https://www.gov.uk/government/groups/joint-committee-on-vaccination-and-immunisation#publications-and-statements.
Kumar D, Unger ER, Panicker G (2013), Immunogenicity of Quadrivalent Human Papillomavirus Vaccine in Organ Transplant Recipients. American Journal of Transplantation, 13: 2411–2417. [CrossRef] [PubMed]
Kitchener HC, Almonte M, Wheeler P (2006) HPV testing in routine cervical screening: cross sectional data from the ARTISTIC trial. Br J Cancer 95(1): 56–61. [CrossRef] [PubMed]
Lacey CJ, Lowndes CM, Shah KV (2006) Chapter 4: Burden and management of non-cancerous HPV-related conditions: HPV-6/11 disease. Vaccine 24 Suppl 3 S35–41. [CrossRef]
Lehtinen M, Paavonen J, Wheeler CM (2012) Overall efficacy of HPV-16/18 AS04-adjuvanted vaccine against grade 3 or greater cervical intraepithelial neoplasia: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial. Lancet Oncol, 13(1): 89–99.  

Erratum in:

Lancet Oncol (2012) Jan;13(1)e1. [CrossRef] [PubMed]
Lu B (2011) Efficacy and safety of prophylactic vaccines against cervical HPV infection and diseases among women: a systematic review and meta-analysis. BMC Infectious Diseases 11: 13. [CrossRef] [PubMed]
Mark A, Carlsson RM, Granstrom M (1999) Subcutaneous versus intramuscular injection for booster DT vaccination of adolescents. Vaccine 17 (15–16): 2067–72. [CrossRef] [PubMed]
McCance DJ (2004) Papillomaviruses. In: Zuckerman AJ, Banatvala JE, Pattison JR, Griffiths P, Schoub B (eds) Principles and practice of clinical virology. 5th edition. Wiley & Sons Ltd.
Moscicki AB, Schiffman M, Kjaer S (2006) Chapter 5: Updating the natural history of HPV and anogenital cancer. Vaccine 24 Suppl 3 S42–51. [CrossRef]
Munoz N, Castellsague X, de Gonzalez AB (2006) Chapter 1: HPV in the etiology of human cancer. Vaccine 24 Suppl 3 S1–S10. [CrossRef] [PubMed]
National Statistics (2011) Cancer registrations in England, 2009. Accessed: Feb. 2012.
National Statistics (2011) - Geographic patterns of cancer survival in England: Patients diagnosed 2002–2004, followed up to 2009 Accessed: Feb. 2012. NHS Cervical Screening Review 2011 Accessed: Feb. 2012.
Oriel JD (1971) Natural history of genital warts. Br J Vener Dis 47(1): 1–13. [PubMed]
Parkin DM, Bray F (2006) Chapter 2: The burden of HPV-related cancers. Vaccine 24 Suppl 3 S11–25. [CrossRef]
Peto J, Gilham C, Fletcher O (2004) The cervical cancer epidemic that screening has prevented in the UK. Lancet 364(9430): 249–56. [CrossRef] [PubMed]
Psyrri A, DiMaio D (2008) Human papillomavirus in cervical and head-and-neck cancer. Nat Clin Pract Oncol 5(1): 24–31. [CrossRef] [PubMed]
Rubin MA, Kleter B, Zhou M (2001) Detection and typing of human papillomavirus DNA in penile carcinoma: evidence for multiple independent pathways of penile carcinogenesis. Am J Pathol 159(4): 1211–18. [CrossRef] [PubMed]
Safaeian M, Porras C, Pan Y (2013). Durable antibody responses following one dose of the bivalent human papillomavirus L1 virus-like particle vaccine in the Costa Rica Vaccine Trial. Cancer Prev Res; 6(11):1242–50. [CrossRef]
Smith JS, Lindsay L, Hoots B (2007) Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update. Int J Cancer 121(3): 621–32. [CrossRef] [PubMed]
Stamataki S, Nikolopoulos TP, Korres S (2007) Juvenile recurrent respiratory papillomatosis: still a mystery disease with difficult management. Head Neck 29(2):155–62. [CrossRef] [PubMed]
Stanley M (2007) Prophylactic HPV vaccines: prospects for eliminating ano-genital cancer. Br J Cancer 96(9): 1320–3. [PubMed]
Thomas VN, Saleem T, Abraham R (2005) Barriers to effective uptake of cancer screening among Black and minority ethnic groups. Int J Palliat Nurs 11(11): 562, 564–71. [CrossRef] [PubMed]
Toft L, Storgaard M, Müller M Comparison of the immunogenicity and reactogenicity of Cervarix and Gardasil human papillomavirus vaccines in HIV-infected adults: a randomized, double-blind clinical trial. J Infect Dis. 2014 Apr 15;209(8):1165–73. [CrossRef] [PubMed]
Tyring S, Edwards L, Cherry LK (1998) Safety and efficacy of 0.5% podofilox gel in the treatment of anogenital warts. Arch Dermatol 134(1): 33–8. [CrossRef] [PubMed]
Walboomers JM, Jacobs MV, Manos MM (1999) Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol, 189: 12–19. [CrossRef] [PubMed]
Webb R, Richardson J, Esmail A (2004) Uptake for cervical screening by ethnicity and place-of-birth: a population-based cross-sectional study. J Public Health (Oxf) 26(3): 293–6. [CrossRef] [PubMed]
WHO IARC (2007) Human papillomaviruses. IARC Monographs on the evaluation of carcinogenic risks to humans.
WHO (2014) Summary of the SAGE April 2014 meeting. http://www.who.int/immunization/sage/meetings/2014/april/report_summary_april_2014/en/ (accessed May 2014)
Winer RL, Feng Q, Hughes JP (2008) Risk of female human papillomavirus acquisition associated with first male sex partner. J Infect Dis 197(2): 279–82. [CrossRef] [PubMed]
Winer RL, Lee SK, Hughes JP (2003) Genital human papillomavirus infection: incidence and risk factors in a cohort of female university students. Am J Epidemiol 157(3): 218–26. [CrossRef] [PubMed]
Zuckerman JN (2000) The importance of injecting vaccines into muscle. Different patients need different needle sizes. BMJ 321(7271): 1237–8. [CrossRef] [PubMed]

Number of cases of newly diagnosed cervical cancer in England, 2009 (source: National Statistics, 2011).

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