Prophylactic HPV vaccination for women over 18 years of age

Vaccine 27 (2009) 3391–3394

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Prophylactic HPV vaccination for women over 18 years of age M. Adams a,∗ , B. Jasani b , A. Fiander b a b

Velindre Cancer Centre, Whitchurch, Cardiff, Wales CF14 2TL, UK School of Medicine, Cardiff University, Wales CF14 4XN, UK

a r t i c l e

i n f o

Article history: Available online 5 February 2009 Keyword: Vaccination over 18 years

a b s t r a c t Cervical screening has resulted in a major reduction in the incidence and mortality of cervical cancer in the UK and other developed countries. Nevertheless approximately 2700 women present with cervical cancer in the UK each year with mortality in excess of 1000 cases. Prophylactic HPV vaccination against HPV 16 and 18 has been shown to be highly effective in preventing HPV related malignancy in clinical trials. Newly introduced HPV vaccination programmes in the UK and elsewhere are ultimately likely to result in a further significant reduction in the incidence and mortality of cervical cancer. These vaccination programmes will be most effective in early adolescence when prevalence of HPV infection is low. Consequently, vaccination programmes in the UK have been initially targeted at 12 to 13-year olds. In Australia favourable estimates of cost effectiveness have supported funding of a ‘catch-up’ programme to 26 years. In the UK the catch up programme has for the present been restricted to 18 years for cost effectiveness reasons. In addition the value of HPV vaccination beyond 26 years has not yet been fully clarified. Nevertheless women up to 45 years of age have been shown to exhibit strong immune responses to the bivalent HPV vaccine which might be expected to reduce the risk of HPV re-infection and address the second peak of HPV related malignancy in later life, evident over 45 years of age. Early data from randomised trials testing the quadrivalent HPV vaccine in women over 25 years has suggested high vaccine efficacy comparable to younger women. This paper will explore the evidence supporting HPV vaccination in HPV naïve and HPV exposed sexually active women up to 26 years and beyond this age group. © 2009 Elsevier Ltd. All rights reserved.

1. Introduction Cervical screening has resulted in a major reduction in the incidence and mortality of cervical cancer in the UK and other developed countries [1]. Nevertheless approximately 2700 women continue to present with cervical cancer in the UK each year with mortality in excess of 1000 cases. The recognition of the causative link between high-risk HPV and cervical cancer worldwide [2] has led to the development of two highly effective licensed vaccines capable of preventing HPV infection. In developed countries it is expected that HPV vaccination will compliment cervical screening and further reduce the morbidity and mortality of cervical cancer. The currently licensed vaccines (Cervarix and Gardasil) are both composed of virus like particles prepared from the LI capsid protein of HPV 16 and 18 viruses, which are immunologically similar to the true viruses and induce powerful antibody responses [3,4].

∗ Corresponding author at: Velindre Hospital, Whitchurch Cardiff, Cardiff CF14 2TL, Wales, UK. Tel.: +44 2920 316944; fax: +44 2920 316901. E-mail address: [email protected] (M. Adams). 0264-410X/$ – see front matter © 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2009.01.067

HPV16 and 18 has been shown to cause over 70% of cervical cancers with HPV types 31, 33, 35, 45, 52 and 58 being responsible for a further 20% with significant variation in HPV type specific distribution worldwide [5]. Gardasil also contains VLPs, which prevent HPV 6 and 11 infection responsible for 90% of genital warts. Both vaccines prevent HPV infection by neutralising the virus in body fluids by inducing a neutralising antibody response. Cervarix has an innovative adjuvant that has been demonstrated to enhance immune responses. Enhanced immunogenicity is evidenced by higher HPV type specific antibody titres and B cell memory response as compared to the conventional alum adjuvant [6]. These licensed HPV vaccines appear to be strictly prophylactic in effect. They have been shown not to increase clearance of prevalent HPV infections and have no demonstrable therapeutic effect against existing HPV infection [7]. Consequently, HPV vaccine efficacy will be greatest in women naive to the viruses. They are best targeted at adolescents prior to sexual debut and exposure to HPV. However ‘catch-up’ vaccination of older age groups could shorten the otherwise long period before the beneficial effects on HPV malignancy start to be realised. In the UK, a school based vaccination programme has been approved, initially targeted at 12 to 13 year olds with a catch-up

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Table 1 Efficacy, safety and immunogenicity of bivalent and quadrivalent vaccines in HPV naïve subjects in Phase II/III trials. Reference

Harper et al. [11,16]

Villa and co-workers [10,17]

Vaccine Population size

Bivalent HPV 16/18 Updated analysis 1113 vaccinees and controls

Age trial subjects Duration of follow up

15–25 years Up to 6.4 years

Quadrivalent 16/18/6/11 Updated composite analysis 20,887 women from phase 2 and 3 trials 16–23 years Up to 5 years

Efficacy (% CI intervals) ITT (a) Persistent HPV infection (b) Cytological abnormalities (c) HPV 16/18 pre-malignancy Serious adverse events reported

94% 97% 100% Nil

– – 100% Nil

Immune response (a) Seroconversion (b) Antibody titres

98% 50–80 times natural infection

98% 10–20 times natural infection

programme for women up to 18 years deemed to be cost effective [8]. In some developed countries such as Australia, HPV vaccination has been extended for women up to 26 years of age [9]. In the UK a public vaccination programme for women beyond 18 years is not considered cost effective at present and therefore has not been approved. It will be the subject to further consideration at some time in the future by the JCVI. For women beyond age 26 years the benefits of HPV vaccination have not yet been fully clarified. 2. How much HPV16/18 protection in HPV naïve women (HPV serologically and DNA HPV 16/18 type negative)—evidence from trials? The large phase 2 and 3 trials testing the two licensed prophylactic vaccines (Cervarix and Gardasil) have provided considerable information on efficacy and HPV prevalence in almost 50,000 women aged 15–26 years. HPV status on trial entry has been determined by HPV type serology and DNA presence in genital samples. The results of these trials have allowed comparison of the efficacy of HPV vaccination to prevent HPV infection and HPV related disease in women proven to be HPV naïve or previously exposed to HPV at trial entry (see Tables 1 and 2) [10–14]. An updated analysis including 20,887 women from randomised phase 2 and 3 trials of the quadrivalent vaccine has revealed efficacy rates of between 97% and 100% for prevention of HPV 6, 11, 16 and 18 related HPV cervical vaginal and vulvar malignancy together with genital warts (see Table 1) [15]. The investigators reported sustained protection for up to 5 years. Similarly an updated analysis for 1113 HPV naïve women randomised to the bivalent vaccine or placebo revealed efficacy of 100% against 12-month persistent HPV 16/18 infection and HPV 16/18 related CIN2+ with follow up to 6.4 years (see Table 1) [16]. The quadrivalent phase 3 trial (FUTURE II) [12] vaccine efficacy against HPV 16/18 CIN2/3 of 99% (95% CI 93–100) in the 17, 129/20, 583 women who were HPV naïve at trial entry. The women recruited into this trial had an HPV prevalence of 27% (serology or DNA) at baseline prior to randomisation and included sexually active women with up to 4–5 lifetime partners. The quadrivalent vaccine was also found to be effective in prevention of high grade Table 2 Efficacy of bivalent and quadrivalent vaccines against HPV16/18 CIN2/3 in HPV naïve women phase 3 trials. Trial (reference)

Vaccine

Age group

Trial numbers

PATRICIA [14] FUTURE II [12]

16/18 6/11/16/18

16–25 16–26

18,644 20,583

a

Efficacy in women HPV naïve on entry to trial 90%a 100%

Further causality analysis found the vaccine had an estimated 100% (97.9% CI 74.2–100) prophylactic efficacy against HPV 16/18.

HPV 16/18 associated vulval and vaginal pre-malignancy in the HPV naïve population [13]. The PATRICIA phase 3 trial randomised 18,644 women aged 16–25 years to either the bivalent HPV16/18 vaccine or hepatitis A vaccine. Women entering the trial could be sexually active with up to 6 lifetime partners. Naivety for HPV 16 and 18 infection was evident (serology and DNA) in 81% and 87%, respectively. A preliminary modified intention to treat analysis was performed on the 7778 HPV vaccinated women and 7838 controls found to be HPV naïve. Vaccine efficacy was found to be 90% for prevention of HPV 16/18 related HPV CIN2+. However further analysis to determine the causality for HPV type related CIN2+ was found not to be straight forward as a high proportion of lesions (61%) contained multiple HPV types. Careful analysis of HPV type specific persistent infection prior to development of the CIN2+ lesion was suggested as a way to define causality. With this causality analysis the bivalent vaccine was estimated to be 100% effective in the prevention of CIN2 caused by HPV 16/18 [14]. Seroconversion following vaccination has been seen in 98% of subjects for both vaccine studies with neutralising antibody titres 10–80 times higher than those observed in natural infection. Comparison of antibody titres induced by both vaccines is difficult because different methodologies have been employed for measuring the levels of neutralising antibodies. An accurate comparison awaits an ongoing head to head randomised trial of immunogenicity, which is expected to be reported within the next year. To date the bivalent vaccine has the longest follow up. Immunogenicity as assessed by GMTs was maintained at levels 11-fold higher than natural infection for both HPV types 16 and 18 for up to 6.4 years. Immunogenicity age bridging studies have revealed 98.5% seroconversion with antibody titres greater than 25 times natural immunity in women age 25–55 years and there has to date been no falling off of immunity [17] suggesting the vaccine should offer effective protection at any age for HPV 16 and 18 in HPV naïve women over 25 years of age. Both vaccines appear be safe with no proven serious adverse events and offering 100% prevention aged women 15–26 years and potentially beyond 26 years. The majority women in the large phase 3 trials proved to be HPV negative serologically and HPV DNA negative in genital samples and could therefore anticipate 100% protection from HPV vaccination. 3. What is the efficacy of 16/18 HPV vaccination in women previously exposed to HPV 16/18 (sero −ve DNA +ve, sero +ve DNA +ve, sero +ve DNA −ve)—evidence from trials? The majority of sexually active women in the large phase 3 trials are either HPV naïve for both HPV16/18 types or only harbour one of the HPV types. HPV vaccination should therefore potentially offer

M. Adams et al. / Vaccine 27 (2009) 3391–3394 Table 3 Efficacy in subjects with evidence current or prior infection (FUTURE II) [12] and Olsson [18]. Population status at randomisation

Efficacy at 3 years

Sero/DNA negative HPV16/18 [10] Including HPV16/18 sero/DNA positive Including HPV 16/18 seropositive DNA negative [18]

99% (86–100) 44% (26–58) 100% (28.7–100)

100% vaccine efficacy for protection from one or more of the vaccine types. Whilst infection with more than one HPV type is common infection with both HPV 16 and 18 is rare and occurs in less than 1%. Olsson [18] has also reviewed the efficacy of quadrivalent vaccination in women 16–26 years who have evidence of HPV16/18 exposure at trial enrolment. This population came from 18,150 women enrolled in three large clinical studies with an HPV prevalence of 27% with up to four lifetime sexual partners. At the time of vaccination 15% had evidence of a previously cleared HPV infection (sero +ve, DNA −ve) for one or more vaccine types. In this group vaccine efficacy was 100% [cervical 95% (CI 28.7–100); external anogenital lesions 95% (CI 39.5–100). These data suggest women who have previously cleared HPV infection have produced an antibody response, which is not fully protective over time. Consequently women previously exposed may benefit from additional protection as a consequence of a vaccine induced antibody response. Simon [19] expanded the previously reported analysis of the PATRICIA bivalent phase 3 trial to include women with evidence of cleared HPV16/18 infection (sero +ve DNA −ve) at trial entry and reported comparable high efficacy to those of HPV naïve women. Overall seropositivity was approximately 15% but only 0.2% was DNA positive for both HPV 16 and 18, and therefore could not expect any benefit from vaccination. An early intention to treat analysis for overall vaccine efficacy performed in the quadrivalent FUTURE 2 trial [12] suggested prematurely poor efficacy for overall vaccine efficacy when HPV 16/18 naïve and HPV exposed women were grouped together in the same analysis. Vaccine efficacy at that time point was only 44% (95% CI 31–55) (see Table 3). This cohort included HPV naïve, HPV cleared and HPV DNA positive women on entry into the trial. In all but one, HPV 16/18 CIN2/3 cases observed in the vaccinated group were found to have been infected with HPV 16 or HPV 18 prior to vaccination. Mean follow up for this study was only 3 years at the time of publication and the CIN2/3 end point may take several years to develop after HPV infection. This explains why the cumulative number of CIN 2/3 cases associated with vaccine targeted HPV types began to plateau after 18 months in the vaccine group but continued to increase in the placebo group [13]. It is likely that the overall benefit of vaccination in this group will continue to rise. The final true overall type specific efficacy will reflect the proportion of women who are HPV naïve or HPV cleared, and will therefore benefit from HPV vaccination and the proportion that are HPV DNA positive and will therefore not benefit. Since only 0.2% was DNA positive for both HPV 16 and 18 types, the vast majority of patients will benefit from HPV16/18 vaccination [19]. The Australian cost effectiveness analysis supported a public funded programme of vaccination of women aged 18–26 years [9]. Further consideration should be given in developed countries to a funded programme for this age group in the light of the emerging evidence supporting both full and partial protection in sexually active women in this age group. An uptake rate of 50% for primary care based HPV vaccination in this age group supports the feasibility of a programme in this group of women who are less accessible to vaccination programmes than adolescent girls [21].

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Preliminary data from a phase 3 quadrivalent vaccine study (FUTURE III) evaluating vaccine efficacy in women age 24–45 years has recently been presented [19]. This group were found to be 100% sexually active with 58% having 0–2 lifetime partners, 19% 2–4 partners and 23% >4 partners with 15% seropositive for HPV 16 or 18 and only 0.2% DNA positive for HPV 16 and 18. Vaccine efficacy in this group was found to be 90% against HPV 16/18 CIN2/3 and vaccine efficacy was felt to be similar to the 15–25 years age group [19,21,22]. Since less than 1% of women who are sexually active are DNA positive for both HPV 16 and 18 types, the vast majority of women are likely to benefit from HPV vaccination whether they are under 25 years or over 25 years with either full or partial prevention of HPV 16 and 18 type infection. 4. What is the overall efficacy for HPV vaccination when patients with all types are included? HPV types 31, 33, 35, 45, 52 and 58 are responsible for approximately 20–25% of HPV related cervical malignancy [5]. It was initially anticipated that current HPV 16/18 vaccines would only protect against HPV 16/18 related malignancy. However extended follow up in the bivalent vaccine phase 2 studies have shown some cross protection against non-vaccine types in addition to HPV16/18. Whilst VLP vaccines would be expected to be type specific it has been shown that the bivalent vaccine offers a significant degree of cross protection [11,14,23] against infection with non-vaccine HPV types and potentially cyto-histological outcomes beyond that anticipated for an HPV16/18 vaccine. In the MITT cohort of the PATRICIA trial the bivalent vaccine had an efficacy against 6-month persistent infection of 59.9% (97.9% CI: 2.6–85.2) for HPV45, 36% (97.9% CI: 0.5–59.5) for HPV 31 and 32% (97.9% CI 3.5–51.9) for HPV 52. The results obtained using the HPV- type specific end points of incident and persistent infection suggest long term (5.5 years) protection against new infection with HPV- 45 and 31 in addition to sustained protection against HPV 16 and 18 infections [23]. Cross protection against HPV related disease has been presented for the quadrivalent vaccine with efficacy for clinical disease associated with 10 non-vaccine HPV types responsible for CIN/AIS particularly HPV 31. Overall cross protection was 33%, which included 70% protection against HPV 31 [24]. This may be the result of overlapping epitopes for HPV genotypes 16, 31, 18 and 45, which have similar sequencing. Consequently overall coverage of high-risk HPV types could be higher than initially expected with both HPV16/18 vaccines. In addition studies have shown a higher than expected prevalence of HPV16/18 in cervical cancers which could unexpectedly increase the protection of these vaccines against cervical cancer. HPV prevalence studies from Wales and Scotland have revealed up to 82% of cervical cancers were related to HPV 16/18 [25,26]. 5. Summary and conclusions The efficacy for both HPV vaccines has proven to be very high for populations of sexually active women found to be HPV naïve or HPV exposed. Vaccine efficacy approaches 100% in HPV naïve women who constituted the majority of 15–26 years old women recruited into the large trials including 50,000 women. There appears at present to be no obvious difference in efficacy for women HPV naïve and women who have been previously HPV exposed and who have successfully cleared the infection. HPV vaccination has no therapeutic efficacy against HPV infection. However the number of women who will have no benefit from HPV vaccination, namely those women both HPV DNA 16 and 18 positive is likely to be very small as this group has been found to constitute less than 1% in clinical trials. In most sexually active women HPV vaccination would provide either partial or full HPV16/18 protection.

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In the light of the Australian evidence which supports a cost effectiveness programme for vaccination of women age 18–26 years in primary care further consideration should be given a the funded programme for this age group. The preliminary report of this programme based on primary care based HPV vaccination in this age group supports its feasibility [20]. Preliminary reports from randomised trials in women over 25 years, who were 100% sexually active suggest similar levels of HPV protection can be provided to women over 25 years as for younger women aged 16–25 years. For these women there may be significant individual benefit from HPV vaccination even if a public vaccination programme proves not sufficiently cost effective to be funded. For all women vaccination should be considered as complementary to cervical screening which remains essential for optimal protection from cervical cancer. Large population studies will need to monitor the efficacy of HPV vaccination for many years, monitor the effects on cervical screening and changes in natural history which may require changes in cervical cancer prevention strategies in the years to come. References [1] International Agency for Research on Cancer (IARC). Handbooks of cancer prevention: cervix cancer screening, vol. 10. Lyon, France: IARC; 2005. [2] Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189:12–9. [3] EMEA (2006). European Medicines Agency; 20 September 2006 [http://www.emea.europa.eu/humandocs/PDFs/EPAR/gardisil/070306en.pdf]. [4] EMEA (2007). European Medicines Agency; 20 September 2007 [http:// www.emea.europa.eu/humandocs/Humans/EPAR/cervarix/cervarix.htm]. [5] Clifford GM, Gallus S, Herrero R, Munoz N, Snidjders PJ, Vaccarella S, et al. Worldwide distribution of human papillomavirus types in cytologically normal women in the International Agency for Research on Cancer HPV prevalence surveys: a pooled analysis. Lancet 2005;366(9440):991–8. [6] Giannini SL, Hanon E, Moris P, Van Mechelen M, Morel S, Dessy F, et al. Enhanced humoral and memory B cellular immunity using HPV16/18 L1 VLP vaccine formulated with the MPL/aluminium salt combination (AS04) compared to aluminium salt only. Vaccine, 2006; 24(August (33–34)):5937–49 [Epub 2006 Jun 19]. [7] Hildesheim A, Herrero R, Wacholder S, Rodriguez AC, Solomon D, Bratti MC, et al., Costa Rican HPV Vaccine Trial Group. Effect of human papillomavirus 16/18 L1 virus like particle vaccine among young women with pre-existing infection: a randomized trial. JAMA 2007;298(August (7)):743–53. [8] JCVI statement on human papillomavirus vaccines to protect against cervical cancer. http://www.advisorybodies.doh.gov.uk/jcvi/HPVJCVI [report1807 2008.pdf]. [9] Australian Government, Department of Health and Aging. The National HPV vaccination programme; 2007. Available at: http://www.health. gov.au/cervical cancer. [10] Villa LL, Costa RL, Petta CA, Andrade RP, Ault KA, Guiliano AR, et al. Prophylactic quadrivalent human papillomavirus (types 6,11,16 and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase 11 efficacy trial. Lancet Oncol 2005;6(5):271–8. [11] Harper DM, Franco EL, Wheeler CM, Mosicki AB, Romanowski B, Rotelli-Martins CM, et al. 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 2006;367:1247.

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