Human papillomavirus (HPV) is the most common sexually transmitted infection worldwide and causes cervical and other cancers.¹ HPV vaccine is a safe and effective vaccine that has been offered to girls in Ireland as part of a school-based programme since 2010. High vaccine uptake is key to the success of the HPV school vaccination programme. However, due to unsubstantiated safety concerns, a recent decline in vaccine uptake has been observed. This development is of concern to all involved in cancer prevention.

HPV and disease burden

HPV is a small double-stranded DNA virus.² It is spread by direct (usually sexual) contact with an infected person. Approximately 80% of women will have a HPV infection in their lifetime, usually in their late teens and early 20s.

More than 100 HPV types have been identified, of which 40 types can infect the genital tract.³ These are categorised according to their epidemiologic association with cervical cancer into high-risk (oncogenic) and low-risk (non-oncogenic) types. Most HPV infections clear naturally but some caused by high-risk HPV types may persist and progress to cancer. There are 13 high-risk types. In Europe, types 16 and 18 are responsible for over 70% of cervical cancers. Low-risk types 6 and 11 are associated with over 90% of genital warts.

In Ireland, the incidence rate of cervical cancer is 34% higher than the EU average.⁴ In Ireland, almost 300 women develop cervical cancer each year and almost 90 die from the disease. Furthermore, more than 7,500 women were diagnosed with high-grade cervical intraepithelial neoplasia (CIN) between September 1, 2014 and August 31, 2015.⁵

HPV is also a known cause of several other cancers including vulvar, vaginal, penile, oropharyngeal and anal cancers.¹ In 2016, the Centers for Disease Control and Prevention (CDC) in the US estimated that 91% of anal cancers, 75% of vaginal cancers, 69% of vulvar cancers, 70% of oropharyngeal cancers and 63% of penile cancers were attributable to HPV. 

HPV vaccine

There are three HPV vaccines currently available.³ These contain virus-like particles (VLPs) that are produced using recombinant DNA technology and are not live vaccines. Two HPV vaccines were licensed in 2006 – a bivalent vaccine (Cervarix) that protects against HPV types 16 and 18 and a quadrivalent vaccine (Gardasil) that protects against HPV types 6, 11, 16 and 18. A new 9-valent HPV vaccine (Gardasil 9) was licensed in 2014.

HPV4 vaccine (Gardasil) is used in the HSE HPV school vaccination programme.⁶ It can be given to females and males from nine years of age. Ideally, the vaccine should be administered before exposure to HPV at sexual contact. It is recommended for all girls aged 12-13 years.

The vaccine is known to induce a better immune response in girls aged between nine and 15 years compared with older teenage girls and young women (aged 16-26 years).^7,8 It is licensed to prevent premalignant genital (cervical, vulvar and vaginal) and anal lesions, and cervical and anal cancers causally related to HPV types 16 and 18.⁶

It provides protection against HPV types 6 and 11 that cause over 90% of genital warts in women and men. HPV4 vaccine (Gardasil) is over 99% effective in preventing CIN associated with HPV types 16 and 18 in young women and is 99% effective in preventing genital warts associated with HPV types 6 and 11.

HPV school vaccination programme

In 2010, HPV4 vaccine (Gardasil) was introduced routinely for all girls in first year of second level school and age-equivalent girls in special schools and those educated at home. Girls in second year and their age-equivalent counterparts who had not previously been targeted were also offered the vaccine. In September 2011, a catch-up programme was introduced with all girls in sixth year or equivalent from 2011 to 2014 offered the vaccine. 

Two doses, administered six months apart, are recommended for girls up to 14 years of age. Girls aged 15 years and older require three doses of the vaccine.

Immunity lasts for at least nine years and is likely to be long lasting. The need for a booster dose has not yet been determined.³

The target for uptake of two doses of HPV vaccine is ≥ 80%. However, in the academic year 2015/2016, this target was not met for the first time since commencement of the programme with uptake falling to 72%. ⁹

Vaccine safety

HPV vaccines are approved for use in over 100 countries, with more than 200 million doses distributed worldwide.⁶ It is used in over 25 European countries, Australia, the US and Canada. In Ireland, more than 660,000 doses have been distributed and more than 220,000 girls have been vaccinated. 

The safety of the HPV vaccine has been monitored for more than 10 years and is frequently reviewed by international bodies including the European Medicines Agency, the Global Advisory Committee on Vaccine Safety of the World Health Organization and the Centers for Diseases Control and Prevention. 

These bodies have continually reported that the vaccine is safe with no known long-term side-effects.^10,11,12

In Ireland, the Health Products Regulatory Authority (HPRA) continues to monitor the safety of HPV vaccine. All healthcare professionals and members of the public are encouraged to report any suspected adverse reactions/events associated with vaccination to the HPRA. 

There has been considerable media reporting about the alleged long-term side-effects of HPV vaccine with confusion between an adverse event (unfavourable sign, symptom or disease temporarily associated with but not necessarily caused by vaccination) and an adverse reaction (a known side-effect of vaccination with a causal relationship). 

The known side-effects are:

•
One in 10 develop pain, erythema and swelling at the injection site

•

One in 10 develop headache

•

One in 100 to 1 in 1,000 develop urticaria

•
Anaphylaxis occurs in one in one million

•
Syncope can occur after vaccination, especially in adolescents (girls are advised to sit down for 15 minutes to prevent this).⁶

The vaccine should not be given to individuals who have a history of anaphylaxis to a previous HPV vaccine or any of its ingredients or to pregnant women.³ 

There is no scientific evidence of an increase in chronic fatigue syndrome or any other long-term medical condition following the introduction of HPV vaccine in 2006.

Chronic fatigue syndrome (CFS) has been known for more than 200 years.⁶ It is three to four times more common in females and more common in adolescents. In Ireland, estimates suggested a prevalence rate of 0.2-0.4% (similar to that reported on other European countries) so at least 440-880 cases of CFS would be expected by chance among the 220,000 vaccinated girls. The numbers reported are much lower than expected.

Between June 2006 and September 2015, more than 80 million doses of Gardasil were distributed for use in the US, and there were 16 reports of premature ovarian failure and 13 reports of postural orthostatic tachycardia syndrome (POTS).¹⁰ There is no evidence to support a causal link between HPV vaccine and premature ovarian failure, POTS or complex regional pain syndrome (CRPS).^10,11,12

Impact of HPV vaccination

The impact of vaccination has been observed in several countries that have introduced a vaccination programme since 2006 and have maintained high vaccine uptake rates. Cases of high grade CIN have declined by 75% in Sweden and by more than 50% in Australia, Sweden and Scotland.^{13,14,15,16,17,18}

On August 29, 2016, Australian immunologist Prof Ian Frazer stated that after 10 years of HPV4 vaccine (Gardasil) use, “the number of new cases of cervical cancer in women has halved” in Australia.¹⁹

Since the vaccination programme began in Australia in 2007, there has been a 93% reduction in the number of diagnoses of genital warts in women aged up to 21 years.²⁰ A decrease in genital warts in heterosexual men has also been observed which may be attributed to the impact of herd immunity.

Cervical screening

Cervical screening is still necessary after vaccination as the HPV4 vaccine (Gardasil) only protects against 70% of cervical cancers (ie. those caused by HPV types 16 and 18). HPV vaccination is a preventive measure to be used in conjunction with cervical screening.

HPV vaccination is safe and effective and protects girls from developing cervical cancer in adulthood. The recommendation of a health professional has been shown to lead to increased vaccine uptake. 

All health professionals have an important role to play in the promotion of vaccination and informing the public as to its effectiveness and safety.

Breda Cosgrove is a specialist registrar in public health medicine at the National Immunisation Office (NIO), Manor Street Business Park, Dublin 7; and Anna Clarke is a consultant in public health medicine at the NIO with responsibility for the co-ordination of all national immunisation programmes and is a member of the National Immunisation Advisory Committee

References

1. Viens LJ, Henley SJ, Watson M, et al. Human Papillomavirus-Associated Cancers – United States 2008-2012. MMWR Morb Mortal Wkly Rep 2016; 65(26): 661-6
2. Centers for Disease Control and Prevention. Epidemiology and Prevention of Vaccine- Preventable Diseases. Washington DC: Public Health Foundation; 2015. Available from: https://www.cdc.gov/vaccines/pubs/pinkbook/rubella.html
3. National Immunisation Advisory Committee. Immunisation Guidelines for Ireland. Dublin: Royal College of Physicians of Ireland; 2016. Available from: http://www.hse.ie/eng/health/immunisation/hcpinfo/guidelines/chapter10.pdf
4. National Cancer Registry. Cancer in Ireland 1994-2014: Annual Report of the National Cancer Registry. Dublin: NCR; 2016
5. The National Cervical Screening Programme. CervicalCheck Programme Report 2014/2015. Dublin: National Screening Service; 2016
6. Health Service Executive National Immunisation Office. Human Papillomavirus (HPV) Vaccine Information [Internet]. Dublin: HSE; 2017 [updated 2016 Jan 16; cited 2017 Mar 1]. Available from: http://www.hse.ie/eng/health/immunisation/pubinfo/schoolprog/hpv/
7. Block SL, Nolan T, Sattler C, et al. Comparison of the immunogenicity and reactogenicity of a prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in male and female adolescents and young adult women. Paediatrics 2006; 118(5): 2135-45
8. Centers for Disease Control and Prevention. Human Papillomavirus Vaccination: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2014: 63(RR05): 1-30
9. Health Protection Surveillance Centre. HPV Immunisation Uptake Statistics [Internet]. Dublin: HPSC; 2017 [cited 2017 Mar 1]. Available from: http://www.hpsc.ie/A-Z/VaccinePreventable/Vaccination/ImmunisationUptakeStatistics/HPVImmunisationUptakeStatistics/File,16039,en.pdf
10. World Health Organization (WHO). Global Advisory Committee on Vaccine Safety, 2-3 December 2015. Weekly Epidemiological Record 2016; 91: 21-31
11. European Medicines Agency. HPV vaccines: EMA confirms evidence does not support that they cause CRPS or POTS [Internet] 2015 [cited 2017 Mar 1]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2015/11/news_detail_002436.jsp&mid=WC0b01ac058004d5c1
12. Centers for Disease Control and Prevention. Frequently Asked Questions about HPV Vaccine Safety [Internet]. Atlanta GA: CDC; 2015 [updated 2017 Jan 23; cited 2017 Mar 1]. Available from: https://www.cdc.gov/vaccinesafety/vaccines/hpv/hpv-safety-faqs.html#A6c
13. Crowe E, Pandeya N, Brotherton JM, et al. Effectiveness of quadrivalent human papillomavirus vaccine for the prevention cervical abnormalities: case-control study nested within a population based screening programme in Australia. BMJ 2014; 348: g1458
14. Gertig DM, Brotherton JM, Budd AC, et al. Impact of a population-based HPV vaccination program on cervical abnormalities: a data linkage study. BMC Med 2013; 11: 227
15. Pollock KG, Kavanagh K, Potts A, et al. Reduction of low- and high-grade cervical abnormalities associated with high uptake of the HPV bivalent vaccine in Scotland. Br J Cancer 2014; 111(9): 1824-30
16. Baldur-Felskov B, Dehlendorff C, Munk C, et al. Early impact of human papillomavirus vaccination on cervical neoplasia – nationwide follow-up of young Danish women. J Natl Cancer Inst 2014; 106(3): djt460
17. Baldur-Felskov B, Dehlendorff C, Junge J, et al. Incidence of cervical lesions in Danish women before and implementation of a national HPV vaccination program. Cancer Causes Control 2014; 25(7): 915-22
18. Herweijer E, Sundstrom K, Ploner A, et al. Quadrivalent HPV vaccine effectiveness against high-grade cervical lesions by age at vaccination: a population-based study. Int J Cancer 2016; 138(12): 2867-74
19. Science Alert. 10 years on, HPV vaccine halves cervical cancer rates [Internet]. 2016 [cited 2017 Mar 1]. Available from: http://www.sciencealert.com/the-hpv-vaccine-has-halved-cervical-cancer-rates-in-the-past-10-years
20. Ali H, Donovan B, Wand H, et al. Genital warts in young Australians five years into national human papillomavirus vaccination programme: national surveillance data. BMJ 2013; 346: f2032