The ability to generate human papillomavirus (HPV) virus like particles (VLPs) by the synthesis and selfassembly in vitro of the major virus capsid protein L1 has transformed our prospects for preventing benign and malignant disease caused by HPV particularly the most prevalent HPV caused malignancy - cervical cancer in women. HPV L1 VLPs are structures geometrically and antigenically almost identical to the native virion but lack DNA and are therefore non-infectious. Three HPV L1 VLP prophylactic vaccines have been developed and are commercially available (figure 1); Cervarix, a bivalent HPV16/18 product (2vHPV) from GlaxoSmithKline Biologicals Rixensart Belgium, and Gardasil also known as Silgard, a quadrivalent HPV16/18/6/11 product (4vHPV) from MSD Merck, Whitehouse Station, New Jersey USA have been licensed since 2006/7 in the USA and Europe, Gardasil9 HPV 6, 11, 16, 18, 31, 33, 45, 52, 58 a nonavalent product (9vHPV) licensed in 2014/15 in the USA and Europe.

In the randomised control trials (RCTs) that led to licensure of the current vaccines a classic prime, prime boost dosage regimen designed to generate high affinity, high avidity antibodies and a large B memory pool was used. This conservative approach was driven by the available knowledge (or lack of it) in the 1990’s when these studies were being designed. There was not then, nor indeed is there now, an immune correlate of protection to guide clinical development and, since the vaccine would need to provide long term protection, the optimal immune response was desired if the developers were to maximise the likelihood of success.¹1. Inglis S, Shaw A, Koenig S. Chapter 11: HPV vaccines: commercial research & development. Vaccine. 2006;24(Suppl 3):S3/99-105. https://doi.org/10.1016/j.vaccine.2006.05.119
https://doi.org/10.1016/j.vaccine.2006.0... Based on these considerations and the success of Hepatitis B immunisation (another sub unit particulate protein vaccine) the efficacy proof of principle studies carried out in 15-25 year old females for HPV vaccines used a 3 dose schedule of 0, 1, 6 months (Cervarix) or 0, 2, 6 months (Gardasil, Gardasil9).

The 2vHPV and 4vHPV HPV vaccines licensed first in 2006/2007 have been in some National Immunisation Programmes (NIPs) for 10 years. Their impact and effectiveness has been shown in high income countries that initially implemented a three-dose female-only vaccination program with >70% coverage (the threshold for optimal cost effectiveness) in 12-14 year-old girls with or without catch up programs of varying extent. Disease reductions have been reported for high grade cervical intra epithelial neoplasia (CIN, the surrogate endpoint for cervical cancer) and anogenital warts²2. Garland SM, Kjaer SK, Munoz N, Block SL, Brown DR, DiNubile MJ, et al. Impact and Effectiveness Of the Quadrivalent Human Papillomavirus Vaccine: A Systematic Review of Ten Years of Real-World Experience. Clin Infect Dis. 2016;63(4):519-27. https://doi.org/10.1093/cid/ciw354
https://doi.org/10.1093/cid/ciw354... ^,33. Pollock KG, Kavanagh K, Potts A, Love J, Cuschieri K, Cubie H, 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. https://doi.org/10.1038/bjc.2014.479
https://doi.org/10.1038/bjc.2014.479... together with dramatic falls in vaccine HPV-type prevalence in the vaccinated groups⁴4. Kavanagh K, Pollock KG, Cuschieri K, Palmer T, Cameron RL, Watt C, et al. Changes in the prevalence of human papillomavirus following a national bivalent human papillomavirus vaccination programme in Scotland: a 7-year cross-sectional study. Lancet Infect Dis. 2017; 17(12):1293-302. https://doi.org/10.1016/S1473-3099(17)30468-1
https://doi.org/10.1016/S1473-3099(17)30... and herd effects in unvaccinated men and women.⁵5. Ali H, Donovan B, Wand H, Read TR, Regan DG, Grulich AE, et al. Genital warts in young Australians five years into national human papillomavirus vaccination programme: national surveillance data. BMJ. 2013;346:f2032. https://doi.org/10.1136/bmj.f2032
https://doi.org/10.1136/bmj.f2032... ^,66. Drolet M, Benard E, Boily MC, Ali H, Baandrup L, Bauer H, et al. Population- level impact and herd effects following human papillomavirus vaccination programmes: a systematic review and meta-analysis. Lancet Infect Dis. 2015;15(5):565-80. https://doi.org/10.1016/S1473-3099(14)71073-4
https://doi.org/10.1016/S1473-3099(14)71... The impact and effectiveness of these vaccines is no longer in doubt but despite introduction in 71 NIPs⁷7. World Health Organization. Human papillomavirus vaccines: WHO position paper, May 2017. Wkly Epidemiol Rec. 2017;92(19):241-68. current estimates are that less than 4% of eligible women have been vaccinated gobally.⁸8. Bruni L, Diaz M, Barrionuevo-Rosas L, Herrero R, Bray F, Bosch FX, et al. Global estimates of human papillomavirus vaccination coverage by region and income level: a pooled analysis. Lancet Glob Health. 2016;4(7):e453-63. https://doi.org/10.1016/S2214-109X(16)30099-7
https://doi.org/10.1016/S2214-109X(16)30... Furthermore most of these women come from highincome countries but the populations with the highest incidence and mortality of cervical cancer are in middle and low income countries (MIC,LIC) and they remain unprotected.⁹9. Brotherton JML, Bloem PN. Population-based HPV vaccination programmes are safe and effective: 2017 update and the impetus for achieving better global coverage. Best Pract Res Clin Obstet Gynaecol. 2017;47:42- 58. https://doi.org/10.1016/j.bpobgyn.2017.08.010
https://doi.org/10.1016/j.bpobgyn.2017.0...

HPV vaccines face many hurdles for implementation but recurring themes are cost and the operational challenges of delivering a multi dose vaccine to adolescents since in most countries there is no infrastructure outside the routine infant and early childhood schedules. Even in developed countries, with notable exceptions where school programmes have been implemented,¹⁰10. Garland SM, Skinner SR, Brotherton JM. Adolescent and young adult HPV vaccination in Australia: achievements and challenges. Prev Med. 2011;53(Suppl 1):S29-35. https://doi.org/10.1016/j.ypmed.2011.08.015
https://doi.org/10.1016/j.ypmed.2011.08.... immunisation programmes do not deliver successfully the complete regimen and vaccination coverage varies hugely.¹¹11. Bloem P, Ogbuanu I. Vaccination to prevent human papillomavirus infections: From promise to practice. PLoS medicine. 2017;14(6):e1002325. https://doi.org/10.1371/journal.pmed.1002325
https://doi.org/10.1371/journal.pmed.100... HPV vaccines are expensive to buy and expensive and complex to deliver. The realities for implementation faced by many health authorities are that rigid adherence to the dosage schedules is impractical and unaffordable. Flexibility in the dosing schedules is important for national vaccination policies particularly for low and middle income countries if the key objective of reaching enough vaccine coverage (>80%) for population impact is achieved in the target cohorts.

In 2008 the government of Quebec Province Canada on recommendation from the Quebec Immunisation Committee introduced an extended 3 dose school based schedule of 0, 6 60 months in 9-10 year old girls in the routine immunization programme. This step wise approach was based both on operational - better compliance in this age group, experience from the existing school based Hepatitis B programme- and immunological criteria.¹²12. Gilca V, Salmeron-Castro J, Sauvageau C, Ogilvie G, Landry M, Naus M, et al. Early use of the HPV 2-dose vaccination schedule: Leveraging evidence to support policy for accelerated impact. Vaccine. 2018;36(32 PtA):4800-5. https://doi.org/10.1016/j.vaccine.2018.02.004
https://doi.org/10.1016/j.vaccine.2018.0... Evidence from the immunobridging trials undertaken in 10-15 year olds showed that GMTs in these cohorts were twice those achieved in the 16-23 year old women in whom efficacy had beendemonstrated in the RCTs.¹³13. Block SL, Nolan T, Sattler C, Barr E, Giacoletti KE, Marchant CD, 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. Pediatrics. 2006;118:2135-45. https://doi.org/10.1542/peds.2006-0461
https://doi.org/10.1542/peds.2006-0461... Furthermore in these trials the seroconversion rates one month post a second dose given at 2 months in 10-15 year-old girls were similar to those reported one month post-third dose in 16-23 year-old women. After introduction of the 0-6-60-month extended schedule in Quebec, in 2008 a similar 0-6- 60 schedule for girls under 14 years was initiated in Mexico, following recommendations by a group of experts coordinated by the National Institute of Public Health of Mexico (INSP). Universal HPV vaccination for girls between 10 and 11 years of age was introduced in Mexico in 2012 using an extended alternative vaccine schedule (0-6-60 months) as recommended by the INSP and based on the strength of the immune response to the VLP vaccines in 9-11 year-old girls. This strategy was implemented in Mexico as a vaccination policy to increase coverage at a time of financial constraint but also anticipating that scientific evidence would soon be available to give guidance as to the need for the 3rd dose booster.¹⁴14. Lazcano-Ponce E, Salmeron-Castro J, Garcia-Carranca A, Aranda-Flores C, Madrid-Marina V, Gomez-Altamirano CM, et al. Recomendaciones para la definición de la política de vacunación contra el virus del papiloma en México. Salud Publica Mex. 2009;51(4):336-41. https://doi.org/10.1590/S0036-36342009000400011
https://doi.org/10.1590/S0036-3634200900... In both Quebec and Mexico programmes were put in place for the monitoring and evaluation of new scientific data to inform the decision of the need for the third dose of vaccine at 60 months. An INSP-implemented clinical trial in Mexico to evaluate the immunogenicity and non-inferiority of alternative HPV vaccination schedules found antibody titres generated by both the 2v and 4v vaccines were significantly higher after administration of two doses in 9-10-year-old girls than after three doses in 18-24-year-old women. Based on the available evidence both Quebec and Mexico in 2013/2014 adopted an alternative two-dose 0-6 vaccination schedule without intention for a third dose, a schedule that was proven to be not inferior to the traditional schedule in terms of immunogenicity.¹⁵15. Gilca V, Sauvageau C, Boulianne N, De Serres G, Crajden M, Ouakki M, et al. The effect of a booster dose of quadrivalent or bivalent HPV vaccine when administered to girls previously vaccinated with two doses of quadrivalent HPV vaccine. Hum Vaccin Immunother. 2015;11(3):732-8. https://doi.org/10.1080/21645515.2015.1011570
https://doi.org/10.1080/21645515.2015.10... ^.1616. Lazcano-Ponce E, Stanley M, Munoz N, Torres L, Cruz-Valdez A, Salmeron J, et al. Overcoming barriers to HPV vaccination: non-inferiority of antibody response to human papillomavirus 16/18 vaccine in adolescents vaccinated with a two-dose vs. a three-dose schedule at 21 months. Vaccine . 2014;32(6):725-32. https://doi.org/10.1016/j.vaccine.2013.11.059
https://doi.org/10.1016/j.vaccine.2013.1... ^,1717. Hernandez-Avila M, Torres-Ibarra L, Stanley M, Salmeron J, Cruz-Valdez A, Munoz N, et al. Evaluation of the immunogenicity of the quadrivalent HPV vaccine using 2 versus 3 doses at month 21: An epidemiological surveillance mechanism for alternate vaccination schemes. Hum Vaccin Immunother. 2016;12(1):30-8. https://doi.org/10.1080/21645515.2015.1058458
https://doi.org/10.1080/21645515.2015.10... In parallel with the off license programmes in young adolescents in Canada and Mexico the feasibility of changing from the 3 dose ‘prime, prime, boost’ to a 2 dose ‘prime, boost’ at 0 and 6 months only in the young adolescent cohort was being assessed in RCTs.¹⁸18. Romanowski B, Schwarz TF, Ferguson LM, Peters K, Dionne M, Schulze K, et al. Immunogenicity and safety of the HPV-16/18 AS04- adjuvanted vaccine administered as a 2-dose schedule compared with the licensed 3-dose schedule: results from a randomized study. Hum Vaccin. 2011;7(12):1374-86. https://doi.org/10.4161/hv.7.12.18322
https://doi.org/10.4161/hv.7.12.18322... ^,1919. Dobson SR, McNeil S, Dionne M, Dawar M, Ogilvie G, Krajden M, et al. Immunogenicity of 2 doses of HPV vaccine in younger adolescents vs 3 doses in young women: a randomized clinical trial. JAMA. 2013;309(17):1793-802. https://doi.org/10.1001/jama.2013.1625
https://doi.org/10.1001/jama.2013.1625... These studies showed that in 9-14 year old girls (and boys) given 2 doses at 0 and 6 months, antibody responses (titres and avidity) are non-inferior to those achieved after 3 doses in 16- 26 year old women, the group in whom efficacy has been shown. After reviewing the evidence in 2014 the Strategic Advisory Group of Experts (SAGE) of WHO 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. The recommended minimal interval between the 2 doses is 6 months. This interval may be extended to 12 months if this facilitates administration. A 3-dose schedule (i.e. at 0, 1-2, and 6 months) remains recommended for immunocompromised individuals, including those known to be HIV-infected”.²⁰20. World Health Organization. Meeting of the Strategic Advisory Group of Experts on immunization, April 2014 - conclusions and recommendations. Wkly Epidemiol Rec. 2014;89(21):221-36.

However even with a 2 dose schedule, the effective delivery of these vaccines to the populations that most need them in MIC and LIC still faces programmatic and cost hurdles but what if the regimen could be reduced to 1 dose? This is a radical policy proposal but the reduction in programme costs achieved by implementing a one-dose schedule in terms of delivery costs and vaccine price would make it a very attractive option to public health authorities and governments. So is there data to support this? There is no data for immunogenicity and efficacy for 1 versus 2 or 3 doses from RCTs these trials are in progress. However immunogenicity and efficacy data from two studies, a post hoc analysis of the Guanacaste trial using the 2HPV vaccine²¹21. Kreimer AR, Herrero R, Sampson JN, Porras C, Lowy DR, Schiller JT, et al. Evidence for single-dose protection by the bivalent HPV vaccine-Review of the Costa Rica HPV vaccine trial and future research studies. Vaccine . 2018;36(32 Pt A):4774-82. https://doi.org/10.1016/j.vaccine.2017.12.078
https://doi.org/10.1016/j.vaccine.2017.1... ^,2222. Safaeian M, Sampson JN, Pan Y, Porras C, Kemp TJ, Herrero R, et al. Durability of protection afforded by fewer doses of the HPV16/18Vaccine : The CVT Trial. J Natl Cancer Inst. 2018;110(2). https://doi.org/10.1093/jnci/djx158
https://doi.org/10.1093/jnci/djx158... and an observational cohort study sponsored by IARC/WHO in India²³23. Sankaranarayanan R, Prabhu PR, Pawlita M, Gheit T, Bhatla N, Muwonge R, et al. Immunogenicity and HPV infection after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a multicentre prospective cohort study. Lancet Oncol. 2016;17(1):67-77. https://doi.org/10.1016/S1470-2045(15)00414-3
https://doi.org/10.1016/S1470-2045(15)00... ^,2424. Sankaranarayanan R, Joshi S, Muwonge R, Esmy PO, Basu P, Prabhu P, et al. Can a single dose of human papillomavirus (HPV) vaccine prevent cervical cancer? Early findings from an Indian study. Vaccine . 2018;36(32 PtA):4783-91. https://doi.org/10.1016/j.vaccine.2018.02.087
https://doi.org/10.1016/j.vaccine.2018.0... using the 4vHPV vaccine show that 1 dose is as protective as 2 or 3 doses of vaccine against persistent infection with HPV 16 and 18 (a pre-requisite for the development of high grade CIN) up to 10 years after vaccination of girls and women aged 15-25 years (2VHPV) or 7 years for those 10-18 years (4vHPV).

A central issue for the 1 dose scenario is duration of protection. Protection will have to be maintained in women who are immunised at 12/13years of age for the following 2-4 decades. However there is no immune correlate of protection, no antibody threshold or other immune measurement has been defined that correlates with protection and even in individuals who apparently become seronegative post vaccination, protection against vaccine type HPV infection and disease is maintained. In all studies reported to date GMTs after 2 doses 0,6 or 0,12 months are non-inferior to the standard 3 dose schedule and the expectation is that, in view of this, protection will be equivalent to the standard 3 dose schedule. However GMTs after 1 dose in these studies are inferior to 2 or 3 doses but seroconversion rates do not differ between 1, 2 or 3 doses and the antibody kinetics are the same with antibody persisting above natural infection levels over time.²²22. Safaeian M, Sampson JN, Pan Y, Porras C, Kemp TJ, Herrero R, et al. Durability of protection afforded by fewer doses of the HPV16/18Vaccine : The CVT Trial. J Natl Cancer Inst. 2018;110(2). https://doi.org/10.1093/jnci/djx158
https://doi.org/10.1093/jnci/djx158... ^,2424. Sankaranarayanan R, Joshi S, Muwonge R, Esmy PO, Basu P, Prabhu P, et al. Can a single dose of human papillomavirus (HPV) vaccine prevent cervical cancer? Early findings from an Indian study. Vaccine . 2018;36(32 PtA):4783-91. https://doi.org/10.1016/j.vaccine.2018.02.087
https://doi.org/10.1016/j.vaccine.2018.0... Importantly in the IARC/WHO Indian trial all the geometric mean avidity indices after fewer than three doses in any group were noninferior to those after three doses of vaccine suggesting that antibody quality was as good as that achieved after 2 or 3 doses.²³23. Sankaranarayanan R, Prabhu PR, Pawlita M, Gheit T, Bhatla N, Muwonge R, et al. Immunogenicity and HPV infection after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a multicentre prospective cohort study. Lancet Oncol. 2016;17(1):67-77. https://doi.org/10.1016/S1470-2045(15)00414-3
https://doi.org/10.1016/S1470-2045(15)00... Could the stepwise extended schedule approach be applied to the one dose scenario with a single priming dose followed by a second dose if necessary and if so how long could the interval be between the first and second dose? A single dose of the 4HPV vaccine elicits high titres of somatically mutated, class switched neutralising antibody and potent B memory cells.²⁵25. Scherer EM, Smith RA, Carter JJ, Wipf GC, Gallego DF, Stern M, et al. Analysis of memory B cell responses reveals suboptimal dosing schedule of a licensed vaccine. J Infect Dis. 2018;217(4):572-580. https://doi.org/10.1093/infdis/jix566
https://doi.org/10.1093/infdis/jix566... In a recent study from Fiji²⁶26. Toh ZQ, Russell FM, Reyburn R, Fong J, Tuivaga E, Ratu T, et al. Sustained antibody responses 6 years following 1, 2, or 3 doses of quadrivalent Human Papillomavirus (HPV) vaccine in adolescent Fijian girls, and subsequent responses to a single dose of bivalent HPV vaccine: A prospectivecohort study. Clin Infect Dis. 2017;64(7):852-9 a single dose of 4v vaccine elicited antibodies that persisted for 6 years and induced immune memory that was boosted by a single dose of 2v vaccine with neutralising antibody titres that did not differ from those generated after 2 or 3doses. This is a small study and should not be over interpreted but it does support an extended interval of years between doses should a flexible schedule be implemented.

The adoption of an alternative 1 dose or 1+1 regimen as opposed to standard dosage regimens in the absence of data from RCTs is a risk and the question then arises how much and how significant is the risk, what is the risk benefit balance? So far the evidence indicates sustained efficacy of 1 dose for 10 years but what if there is a loss of efficacy over time? How do we balance a possible loss in efficacy with the potential for a big increase in coverage and a herd effect? Public health authorities will address these questions in the context of their own disease burden, economic and social priorities. They will make risk assessments based on the evidence and devise risk management strategies for worst case scenarios. However it should be remembered that the worst case scenario in communities with a high burden of cervical cancer, ineffective screening and low or no vaccine coverage is the status quo.

References

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