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Monitoring the HPV vaccination program in The Netherlands

Donken, R.

2018

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Donken, R. (2018). Monitoring the HPV vaccination program in The Netherlands: Effects, changing schedule and future perspective.

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CHAPTER 4

Inconclusive evidence for

non-inferior immunogenicity of

two- compared with three-dose

HPV immunization schedules

in pre-adolescent girls:

a systematic review and

meta-analysis

Robine Donken Mirjam J. Knol Johannes A. Bogaards Fiona R.M. van der Klis

Chris J.L.M. Meijer Hester E. de Melker

4

ABSTRACT

Background

The European Medicines Agency (EMA) recently approved two-dose immunization schedules for bivalent (HPV16/18) and quadrivalent (HPV6/11/16/18) human papillomavirus (HPV) vaccines in nine to fourteen and thirteen year-old-girls, respectively. Registration was based on trials comparing immunogenicity of two-dose schedules in girls 9-14 years to three-two-dose schedules in young women 15-26 years. We evaluate comparability of antibody levels between and within age groups and discuss potential implications for monitoring the effectiveness of HPV vaccination.

Methods

A systematic literature search was performed for studies comparing immunogenicity of two- to three-dose schedules of HPV vaccination. We compared geometric mean concentrations (GMCs) of vaccine type antibodies between different dosing schedules across different age groups. Meta-analysis was used to estimate pooled GMC ratios (bivalent vaccine) of two- compared with three-dose schedules within girls.

Findings

For both vaccines, two-dose immunization of girls yielded non-inferior GMCs relative to a three-dose schedule in young women up to respectively 36 and 48 months follow-up. Pooled GMC ratios for the bivalent vaccine within girls showed the two-dose schedule becoming inferior to the three-dose schedule in girls for HPV16 at approximately two years after the first dose. For the quadrivalent vaccine, antibody responses for HPV18 became inferior from 18 months follow-up onwards when comparing the two-dose schedule with the three-dose schedule within in girls.

Implications

INTRODUCTION

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Benefits for two-dose schedules are the lower costs of the vaccination program and a smaller risk of adverse events.[12] Lower costs of the vaccination program might be particularly beneficial for low-income countries, where the wide-scale use of HPV vaccines has been impeded by high dose prices. In addition, simplification of vaccination schedules might lead to improved adherence to the full schedule and increased vaccination coverage. On the other hand, a third-dose might be necessary to afford optimal efficacy, depending on the duration of protection of the two-dose schedule and on the antibody waning process, assuming that the antibody level is a correlate of protection. In European countries HPV vaccination starts from the age of ten years.[13] As the peak of infection for HPV is around twenty years of age, protection against infection provided by a two-dose vaccination strategy among young girls should last for at least ten years.[8] Therefore a long duration of protection is needed. A comparison of antibody levels between girls and adult women does not take the need for differences in duration of protection into account. This could be better noticed in a direct comparison of the two-dose schedule with the three-dose schedule in girls of the same age group, which showed inconclusive results in a World Health Organization (WHO) report, and inferior antibodies in an observational cohort study evaluating alternate dosing schedules for HPV vaccination.[11, 14]

The aim of this study was to systematically review and compare the antibody levels against HPV16 and 18 of two- and three-dose schedules for HPV vaccination, not only between women and girls, but also within girls of the same age group, and to discuss potential implications for monitoring the introduction of a two-dose schedule.

METHODS

Literature search and study selection

vaccinated women as outcome. Exclusion criteria were clinical, virological or safety endpoints. The selection was performed on title first, second on abstract and finally on the full-text article. Additionally we checked whether all studies submitted for EMA approval were included. If a study was not yet published in a scientific journal, this study was also included.

Data extraction

Two reviewers (MK and RD) extracted data from selected full-text articles by the use of a standardized data extraction form. Data included general characteristics of the study and characteristics specific to the research question, for example treatment arms, timing of the schedules and GMC ratio.

Definitions

Unless otherwise mentioned, girls are defined as preadolescent girls from nine up to fourteen years of age. Young women are adolescent and adult females between 15 and 26 years of age. Non-inferiority is concluded if the upper boundary of the 95% CI does not exceed the predefined NI margin. GMC ratios for two- compared to three-dose schedules were recalculated from the GMCs reported in the papers. Even if a GMC ratio was already reported, the recalculated GMCs were used in the analysis. GMC ratio and corresponding 95% CI were calculated based on formulas given by Altman et al.[15] Three-dose schedules are vaccinations given at 0, 1 or 2 and 6 months, a two-dose schedule is here considered as vaccinations at 0 and 6 months. Licensure of the two-dose schedule by the EMA was done for a schedule where vaccination is given at 0 and 6 months. In the studies also other timing schedules were examined. In this review we included only results of the two-dose schedule given at 0 and 6 months in the analysis.

Analysis

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Figure 1. Selection process after systematic search.

* After removal of duplicates

therefore the GMC ratio used for meta-analysis was based on the GMC ratio in the included studies, namely 2·0. We also indicated a possible alternative NI margin at 1·5. Heterogeneity in GMC ratio between studies was examined by χ 2_{, which} examines homogeneity and by I2 _{, which gives an indication of the percentage of} variation across studies.[18] Due to the low number of studies a random effects approach was used.

Meta-analyses were performed in Review Manager (RevMan, Cochrane Collaboration, version 5.2.8) and meta-regression with the package BRugs in R (The R project, version 3·1) and Open Bugs (Open Bugs version 3.2.3). Data visualization was performed using R.

RESULTS

In total 552 articles were retrieved by the systematic search.(Figure 1) After the selection on predefined criteria, four full-text articles on the bivalent and one on the quadrivalent vaccine were found.[12, 19-22] We added an additional study, which was mentioned in the EMA report used for approval of the bivalent vaccine but not published yet, to the selection. Consequently, six study reports were included in this systematic review. Table 1 summarizes general characteristics of the included studies and how immunogenicity was evaluated. Appendix 3 shows assessment for risk of bias. Most included studies compared immunogenicity (assessed in serum ) between a schedule given at 0, 1 and 6 months (bivalent) or at 0, 2 and 6 months (quadrivalent) among young women and a two-dose schedule at 0 and 6 months in girls after vaccination with the currently licensed dose. [5, 12, 19-22]

Geometric Mean Concentrations

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Two-doses (girls) compared to three-doses (young women)

Comparing a two-dose schedule in girls to a three-dose schedule in young women showed that the upper boundary of the 95% CI of the GMC ratio (three-doses/ two-doses) for HPV16 and 18 did not exceed the NI margin of 2·0, supporting the conclusion of non-inferiority.(Figure 2) Meta-regression showed that the GMC ratio for HPV18 increased over time for the bivalent vaccine (p<0.01), indicating a change in antibody kinetics. We did not observe this for HPV18 for the quadrivalent vaccine (p=0.16) and for both vaccines for HPV16 (respectively p=0.31 and p=0.18 for the bi- and quadrivalent vaccine.

Two- compared with three -doses (within the same age group)

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Figure 2. GMC ratios for both bi- and quadrivalent vaccine. GMC after a three-dose (0,1/2, 6 months) schedule in young adults(15-25 years) divided by a two-dose schedule (0,6 months) in preadolescents (9-15 years) in the according to protocol population (principle of immuno-bridging).

Mentioned initial is the first letter of last name of the author (D=Dobson, R=Romanowski, LP=Lazcano-Ponce, G=GSK study HPV-070), number is the amount of months after the first dose.

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Figure 4. Pooled estimates for the GMC ratio for a three-dose (0,1,6 months) divided by a two-dose (0,6 months) schedule of the bivalent vaccine in girls.

Two studies were included for this meta-analysis, Romanowski et al 2011 and Lazcano-Ponce et al. 2014. [12, 22] In grey the GMC ratios where the pooled estimates are based on, in bold are the pooled estimates.

DISCUSSION

and showed that non-inferiority, when comparing the antibody levels of the two- with three-dose schedules within girls, is not proven for both the bivalent and quadrivalent vaccine. For the quadrivalent vaccine antibody levels of the two-dose schedule were not non-inferior to the three-dose schedule for HPV18 from 18 months onwards. Meta-analysis of antibody level estimates of the bivalent vaccine within girls showed non-inferior estimates up to two years vaccination for HPV18, but no longer non-inferior for HPV16 two years after the first dose.

EMA market authorization for the two-dose schedule among pre-adolescents is based on the immuno-bridging principle and a NI margin of 2·0.[5, 6] In doing so, it is assumed that vaccine efficacy of a two-dose schedule in girls might be comparable to the efficacy demonstrated for a three-dose schedule in young adults if the antibody levels among these girls are comparable to the antibody levels among young adults. Decision-making on the basis of such immunological correlates is complicated because the correlate of protection is unknown. Therefore, it is uncertain how to value antibody titers or concentrations and at what level they can be considered protective. In a study evaluating the correlation between antibody responses and efficacy of the quadrivalent vaccine in a three-dose schedule, researchers found that 40% of vaccine recipients were seronegative for HPV18 after a mean follow-up of 44 months, while the efficacy against HPV18 related endpoints at that time was still high.[23] Moreover, because of the long incubation period between infection and onset of cervical cancer, efficacy estimates regarding cancer are based on surrogate endpoints, such as persistent infection or precancerous lesions.[24]

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persistent infections in women (18-25 years) receiving different doses. The vaccine efficacy (95% CI) was 80·9% (71·7%-87·7%), 84·1% (50·2%-96·3%) and 100% (66·5%-100%), for women receiving a three-, two- (0,1 months) or one-dose schedule respectively.[26] However this study was not randomized and results could be confounded by for example sexual behavior. A long term efficacy study evaluating possible differences between three- and two-dose schedules is currently ongoing.[10, 27]

Because of an unknown correlate of protection, absence of explicit guidelines on NI margins for vaccine studies[17], absence of clinical efficacy data and the need for long term protection in girls, the choice of the NI margin and age groups used for comparison is debatable. One could argue that a more conservative NI margin, for example 1·5, would have taken into account the uncertainties in a more appropriate way and would have declared less comparisons as non-inferior, or equally immunogenic. The registration authorities decided to compare the different dosing schedules between different age groups (two-dose in girls with three-doses in young women). Duration of protection, especially when vaccinating girls, is important because otherwise a booster dose at later age might be necessary. Jit et al. estimated the differences in cervical cancers prevented between a two- and three-dose schedule assuming different durations of protection and vaccination coverage. If protection lasts for twenty years additional benefits from a third dose are small. If protection of a two-dose schedule only lasts for ten years, the number of prevented cervical cancer cases almost doubles with a three-dose schedule.[8] Given the long time between eligibility for vaccination, from ten years of age, and the peak incidence of HPV infection, around twenty years of age, the protection for young girls needed might be longer than ten years. Moreover we think that the higher antibody responses in young girls as demonstrated after a three-dose schedule compared to those in adult women[28, 29] ask for comparison of antibody titers in girls within the same age group to guarantee long term protection in a more certain way. This might also give a better indication of possible consequences for public health.

long-term antibody kinetics up to 9.4 years are known, in contrast to the long-long-term antibody kinetics for the two-dose schedule.[30] For two-doses of the bivalent vaccine good antibody stability, among women 18-25 years, between 24 to 48 months after the first dose was shown.[21] For the quadrivalent vaccine a waning response for HPV6 and 18 was shown.[19] Close monitoring of antibody levels in girls vaccinated with the two-dose schedule is needed to assure that antibody levels are still high when exposure to HPV infection is highest, i.e. around the age of twenty years.

Besides importance of the level, duration and kinetics of antibodies, also quality of antibodies and other immune responses influence the success of different HPV vaccination schedules.[31] Neutralizing potential of antibodies against HPV16 was observed independent of the number of received doses.[21] For HPV31 (cross-protection) neutralization increased with the number of doses received. T memory cell formation is influenced by the number of doses, as T memory cell responses to a two-dose schedule were less strong than for a three-dose schedule, which might affect long term protection.[32] Antibody avidity comparing a two- to three-dose schedule was nonetheless comparable at 7, 24 and 48 months after vaccination.[33] Alongside introduction of a two-dose schedule it is important to further study the kinetics, duration and quality of generated antibody responses to indicate the long-term protection of the two-dose schedule.

Eventually, the effectiveness of the different dosing schedules against clinical outcomes should be established by closely monitoring cohorts of vaccinated girls. [34] Cohort studies monitoring the effects of HPV vaccination in countries with low completion rates might be able to give insight on the long term effects of level, duration and quality of antibodies, surrogate and clinical endpoints. However these studies might have confounded comparisons due to differences between completers and non-completers. Additionally, starting new cohort studies and comparing these to former studies might give insight on effects of the two-dose schedule and result in less confounded estimates. Population-based serological evaluation studies might indicate differences between antibody levels of cohorts vaccinated with different doses.[35, 36]

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rates of adverse events between cohorts receiving different dosing schedules might indicate the effects on safety when implementing a two-dose schedule for HPV vaccination. In general, fewer vaccinations might improve adherence, resulting in higher vaccination coverage, and are likely to result in less adverse events. Romanowski et al. showed no significant differences in the reported adverse events per dose after a three- or two-dose schedule.[12] Lazcano-Ponce et al. found lower percentages of reported pain, redness and headaches per dose in a two-dose schedule compared to a three-dose schedule. For paresthesia, the percentage of reported symptoms per dose was higher in the two-dose schedule.[22] However, an overall lower number of symptoms was reported as compared to the three-dose schedule, as less vaccination moments result in a lower number of instances in which reactions can occur.

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APPENDICES

Appendix 1. Terms to search Medline for indexed papers Database: MEDLINE 1950 to present

Search Strategy:

---1 exp Papillomavirus Vaccines/ad [Administration & Dosage] (1279) 2 exp Papillomavirus Vaccines/im [Immunology] (899)

3 (dose or doses or dosing$ or dosage$).ti,ab. (1040869) 4 exp *Papillomavirus Vaccines/ (3099)

5 (dose or doses or dosing$ or dosage$).ti. and 4 (33) 6 exp Immunization Schedule/ (8513)

7 (1 or 2) and (3 or 6) (343) 8 7 or 5 (349)

9 exp *Papillomavirus Vaccines/ad and (dose or doses or dosing$ or dosage$).ti. (19) 10 exp *Papillomavirus Vaccines/im and (dose or doses or dosing$ or dosage$).ti. (7) 11 9 or 10 (24)

12 limit 11 to humans (22)

13 (exp *Papillomavirus Vaccines/ad or exp *Papillomavirus Vaccines/im) and 6 (66) 14 (“1” or one or first).ti,ab. (5879987) 15 (“2” or two or second).ti,ab. (5699154) 16 (“3” or three or third).ti,ab. (4023519) 17 (“4” or four or fourth).ti,ab. (2703146) 18 14 and (15 or 16 or 17) (4342367) 19 15 and (16 or 17) (3062006) 20 16 and 17 (1383429) 21 18 or 19 or 20 (5438905) 22 8 and 21 (203) 23 13 and (14 or 15 or 16 or 17) (45) 24 12 or 22 or 23 (216) 25 limit 24 to humans (207)

Appendix 2. Terms to search Medline for unindexed and in-process papers Database: MEDLINE In-Process & Other Non-Indexed Citations Search Strategy: ---1 papillomavirus$.ti. (911) 2 vaccin$.ti. (6809) 3 hpv.ti. (642) 4 (3 or 1) and 2 (360)

5 (dose$ or dosag$ or dosi$).ti. (7335) 6 4 and 5 (7)