Efficacy, effectiveness and immunogenicity of reduced HPV vaccination schedules

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Published by: The Public Health Agency of Canada
Issue: CCDR Volume 50–6, June 2024: Cancer Vaccines
Date published: June 2024
ISSN: 1481-8531

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Volume 50-6, June 2024: Cancer Vaccines

Table of contents

Overview

Efficacy, effectiveness and immunogenicity of reduced HPV vaccination schedules: A review of available evidence

Joshua Montroy¹, Marina I Salvadori¹, Nicole Forbes¹, Vinita Dubey², Sarah Almasri¹, Anna Jirovec¹, Cathy Yan¹, Katarina Gusic¹, Adrienne Stevens¹, Kelsey Young¹, Matthew Tunis¹

Affiliations

¹ Centre for Immunization Programs, Public Health Agency of Canada, Ottawa, ON

² Toronto Public Health and University of Toronto Dalla Lana School of Public Health, Toronto, ON

Correspondence

joshua.montroy@phac-aspc.gc.ca

Suggested citation

Montroy J, Salvadori MI, Forbes N, Dubey V, Almasri S, Jirovec A, Yan C, Gusic K, Stevens A, Young K, Tunis M. Efficacy, effectiveness and immunogenicity of reduced HPV vaccination schedules: A review of available evidence. Can Commun Dis Rep 2024;50(6):166–78. https://doi.org/10.14745/ccdr.v50i06a01

Keywords: HPV, vaccination, dose-reduction, dosing schedule, effectiveness, cancer, evidence review

Abstract

Background: Current National Advisory Committee on Immunization (NACI) guidance recommends human papillomavirus (HPV) vaccines be administered as a two or three-dose schedule. Recently, several large clinical trials have reported the clinical benefit of a single HPV vaccine dose. As a result, the World Health Organization released updated guidance on HPV vaccines in 2022, recommending a two-dose schedule for individuals aged 9–20 years, and acknowledging the use of an alternative off-label single dose schedule.

Objective: The objective of this overview is to provide a detailed account of the available evidence comparing HPV vaccination schedules, which was considered by NACI when updating recommendations on HPV vaccines.

Methods: To identify relevant evidence, existing systematic reviews were leveraged where possible. Individual studies were critically appraised, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence.

Results: Available evidence suggests that a one, two, or three-dose HPV vaccine schedule may provide similar protection from HPV infection. While antibody levels against HPV vaccine types were statistically significantly lower with a single dose schedule compared to two or three doses, titres were sustained for up to 16 years. The clinical significance of lower antibody titres is unknown, as there is no established immunologic correlate of protection.

Conclusion: While the available evidence on single-dose HPV vaccination schedules shows a one-dose schedule is highly effective, continued follow-up of single-dose cohorts will be critical to understanding the relative duration of protection for reduced dose schedules and informing future NACI guidance on HPV vaccines.

Introduction

Human papillomavirus (HPV) infections are the causative agent of several cancers, including virtually all cervical cancers, other anogenital cancers, as well as head and neck cancers and anogenital warts (AGW) ^{Footnote 1}^{Footnote 2}. HPV vaccines were first authorized in 2006 and have been shown to be highly effective ^{Footnote 3}^{Footnote 4}. In Canada, a two or three-dose schedule is recommended for healthy individuals aged 9–14 years, and a three-dose schedule is recommended for healthy individuals aged 15 years and over, and for immunocompromised individuals ^{Footnote 5}. Recently, the World Health Organization (WHO) released an updated position paper on HPV vaccination schedules, detailing that while a two-dose schedule is recommended for those over 9 years of age, an alternative off-label, single-dose schedule can be used in those aged 9–20 years ^{Footnote 6}. Several other jurisdictions, such as the United Kingdom, have since updated their HPV vaccination recommendations to include a single-dose schedule ^{Footnote 7}^{Footnote 8}^{Footnote 9}. This updated guidance was based on several factors, including emerging evidence indicating that a single dose of HPV vaccine provides similar levels of protection from HPV infection as multi-dose schedules ^{Footnote 10}.

Canadian provinces and territories have asked that the National Advisory Committee on Immunization (NACI) review the currently available evidence and potentially provide updated guidance on reduced HPV immunization schedules. The Public Health Agency of Canada (PHAC) has prepared this overview to review the available clinical evidence on reduced HPV vaccination schedules (with a focus on single-dose schedules), with an objective to help inform NACI evidence-informed recommendations and decision-making for vaccine programs in Canada.

Methods

Table 1 outlines eligibility criteria for studies included in this analysis. To identify relevant studies, an update of a 2022 systematic review ^{Footnote 10} performed by Cochrane Response in collaboration with the Strategic Advisory Group of Experts on Immunization (SAGE) (which itself was a modified update of a previous Cochrane Response review ^{Footnote 11}) was performed. The updated literature search allowed for identification of any additional studies published since 2022 or any available updated data from included studies (e.g., both recent publications and proceedings from international conferences).

Table 1: Study eligibility criteria
Criteria	Eligibility (one vs. two/three doses)	Eligibility (two vs. three doses)
Population	Individuals ≥9 years of age
Intervention	One dose of GARDASIL^®9 or CERVARIX^®. Considering limitations to evidence (e.g., limited follow-up time) on GARDASIL^®9, indirect evidence from studies using GARDASIL^®4 was also considered.	Two doses of GARDASIL^®9 or CERVARIX^®. Considering limitations to evidence (e.g., limited follow-up time) on GARDASIL^®9, indirect evidence from studies using GARDASIL^®4 was also considered.
Comparator	Two or three doses of GARDASIL^®9 or CERVARIX^®(with the interval between the first and last dose in the series being at least six months). Considering limitations to evidence (e.g., limited follow-up time) on GARDASIL^®9, indirect evidence from studies using GARDASIL^®4 was also considered. Note: While not directly comparing the clinical benefit of HPV vaccines by the number of doses, studies evaluating the immunogenicity or vaccine efficacy/effectiveness of a one-dose HPV vaccine schedule compared to no HPV vaccine were also included.	Three doses of GARDASIL^®9 or CERVARIX^®. Considering limitations to evidence (e.g., limited follow-up time) on GARDASIL^®9, indirect evidence from studies using GARDASIL^®4 was also considered.
Outcomes	Outcomes rated as critical for decision-making (deemed equally critical): HPV-associated cancers CIN2+ Histological and/or cytological abnormalities (including CIN1) Infection with vaccine-associated serotypes HPV vaccine type antibody titres Outcomes rated as important for decision-making (deemed equally important): Anogenital warts Juvenile onset recurrent respiratory papillomatosis (JORPP)
Study design	Randomized controlled trials, non-randomized trials, and observational studies. Observational studies assessed to be at a serious or critical risk of bias were excluded.
Abbreviations Abbreviations: CIN, cervical intraepithelial neoplasia; HPV, human papilloma virus

For analyses comparing a single dose to zero, two, or three doses, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology ^{Footnote 12} was used to assess available evidence considered by NACI during guidance development. Following critical appraisal of individual studies, summary tables with ratings of the certainty of evidence using the GRADE methodology were prepared. For analyses comparing a two-dose to a three-dose HPV vaccine schedule, a methodology informed by A MeaSurement Tool to Assess systematic Reviews (AMSTAR 2) ^{Footnote 13} was used to assess available evidence considered by NACI during guidance development. Detailed information regarding the methodology used in the update of this review can be found elsewhere.

Results

Efficacy/effectiveness against HPV infection

A GRADE assessment of the available randomized controlled trial (RCT) evidence concluded that a one-dose HPV vaccine schedule resulted in a large reduction in persistent infection compared to no vaccine (high certainty of evidence; Table 2). Currently, the KENya Single-dose HPV-vaccine Efficacy (KEN SHE) trial represents the sole RCT evidence demonstrating the efficacy of a single-dose schedule ^{Footnote 14}. This trial randomized women aged 15–20 years (n=2,275) to one dose of either GARDASIL^®9, CERVARIX^®, or meningococcal vaccine. After three years of follow-up, vaccine effectiveness (VE) against persistent HPV16/18 infection was 97.5% (95% CI: 90.0%–99.4%) and 98.8% (95% CI: 91.3%–99.8%) for GARDASIL^®9 and CERVARIX^®, respectively. Similar results were seen in the non-RCT evidence, with a single dose probably resulting in reductions in persistent ^{Footnote 15}^{Footnote 16}, incident ^{Footnote 16}^{Footnote 17}, and prevalent ^{Footnote 17}^{Footnote 18} HPV infections compared to no vaccination (moderate certainty of evidence; Table 2, Figure 1).

Table 2: Summary of findings comparing one dose to no doses of HPV vaccine
Number of studies	Study design	Number of events/number of participants		Effect		Certainty of evidence	Comments
Number of studies	Study design	Zero doses	One dose	Relative effect (95% CI)	Absolute effect (95% CI)	Certainty of evidence	Comments
Persistent HPV infection with vaccine types (follow-up ranging from 3–10 years)
1 ^{Footnote 14}	RCT^{Table 2 footnote a}	72/757 (9.5%)	3/1,518 (0.2%)	RR 0.02 (0.01–0.07)	94 fewer per 1,000 (94 fewer to 88 fewer)	High	A single dose of HPV vaccine results in a large reduction in persistent HPV infections compared to no vaccine
2 ^{Footnote 15}^{Footnote 16}	Post-hoc RCT analysis	A small number of events in the intervention groups across studies (n=292–2,135); high VE was estimated in each study^{Table 2 footnote b}				Moderate^{Table 2 footnote c}	A single dose of HPV vaccine probably results in a large reduction in persistent HPV infections compared to no vaccine
Prevalent HPV infection with vaccine types (follow-up ranging from 6–11 years)
2 ^{Footnote 17}^{Footnote 18}	1 post-hoc RCT analysis, 1 observational study	A small number of events in the intervention groups across studies (n=87–221); large reductions in infection prevalence associated with a single dose in each study^{Table 2 footnote d}				Moderate^{Table 2 footnote c}	A single dose of HPV vaccine probably results in reduction in prevalent HPV infections compared to no vaccine
Incident HPV infection with vaccine types (follow-up ranging from 10–11 years)
2 ^{Footnote 16}^{Footnote 17}	Post-hoc RCT analysis	Number of events dissimilar between studies (n=112–2,858); however, similar reductions in risk compared to unvaccinated were observed^{Table 2 footnote e}				Moderate^{Table 2 footnote c}	A single dose of HPV vaccine probably results in reduction in incident HPV infections compared to no vaccine
Antibody titres (follow-up ranging from 4–10 years)
3 ^{Footnote 18}^{Footnote 19}^{Footnote 20}	Observational	Varying number of participants in each study (n=30–324), with differing lengths of follow-up and magnitudes of effect across studies; however, the direction of effect was consistent across studies^{Table 2 footnote f}				High	A single dose of HPV vaccine results in an increased immune response compared to no vaccine
Anogenital warts (follow-up of approximately 2.5 years)
1 ^{Footnote 21}	Observational	523/52,779 (1.0%)	69/9,898 (0.7%)	aHR^{Table 2 footnote g} 0.32 (0.20–0.52)	7 fewer per 1,000 (8 fewer to 5 fewer)	Moderate^{Table 2 footnote h}	A single dose of HPV vaccine probably reduces the risk of anogenital warts compared to no vaccine
Juvenile-onset recurrent respiratory papillomatosis (JoRPP)
N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A
Table 2 footnotes and abbreviations Table 2 Abbreviations Abbreviations: aHR, adjusted hazard ratio; aVE, adjusted vaccine effectiveness; CI, confidence interval; HPV, human papilloma virus; N/A, not applicable; RCT, randomized controlled trial; RR, relative risk; VE, vaccine effectiveness Table 2 footnote a The groups receiving a single dose of GARDASIL^®9 and CERVARIX^®were collapsed into a single group for the purpose of the analysis Return to Table 2 footnote a referrer Table 2 footnote b Consistent results were observed across studies, with both included studies estimating single-dose VE to be similarly high. One study estimated VE at 95.1% (95% CI: 73.2%–99.8%) and the other estimated aVE (adjusted for disease-risk score) at 93.4% (95% CI: 81.1%–99.1%). The definition of persistent infection was similar across studies Return to Table 2 footnote b referrer Table 2 footnote c Downgraded by one level due to some concerns with bias due to confounding and selection of the reported result Return to Table 2 footnote c referrer Table 2 footnote d Consistent results were observed across studies. A post-hoc analysis of an RCT estimated single-dose VE at 82.1% (95% CI: 40.2%–97.0%). A retrospective observational study did not provide an estimate of VE; however, the adjusted prevalence ratio of HPV infections (adjusted for employment status and income) was 0.08 (95% CI: 0.01%–0.56%) compared to unvaccinated individuals. The definition of prevalent infection was consistent across studies Return to Table 2 footnote d referrer Table 2 footnote e Although the risk of incident infection with a single dose was dissimilar between the two included studies (1.8% vs. 5.4%), consistent reductions in risk were observed when compared to unvaccinated individuals. Both included studies estimated similar VE, with one study estimating VE at 53.9% (95% CI: −57.1%–92.4%) and the other estimating aVE (adjusted for disease-risk score) at 54.1% (95% CI: 41.8%–64.1%). The definition of incident infection was consistent across studies Return to Table 2 footnote e referrer Table 2 footnote f Magnitude of effect differs across studies; however, this is potentially explained by the differences in study populations and differing lengths of follow-up. In addition, the direction of effect is consistent across studies Return to Table 2 footnote f referrer Table 2 footnote g Hazard ratio was adjusted for race/ethnicity, health plan (site), age at enrollment in the health plan, age at beginning of study period, age at first evidence of probable sexual activity (as defined by Healthcare Effectiveness Data and Information Set criteria), age at first dose of HPV vaccine (or proxy date), months enrolled in the health plan, Medicaid enrollment, oral contraceptive use, or history of tests for pregnancy, chlamydia or gonorrhea Return to Table 2 footnote g referrer Table 2 footnote h Downgraded by one level due to some concerns with bias, including due to confounding, selection of participants into the study and selection of the reported result Return to Table 2 footnote h referrer

Figure 1: Risk ratios and 95% CI for persistent, prevalent, and incident HPV vaccine-type infections, one dose compared to no doses^{Figure 1 footnote a}^{Figure 1 footnote b}^{Figure 1 footnote c}^{Figure 1 footnote d}^{Figure 1 footnote e}^{Figure 1 footnote f}^{Figure 1 footnote g}^{Figure 1 footnote h}^{Figure 1 footnote i}^{Figure 1 footnote j}

Fgure 1
Study name	Events/total 1 dose	Events/total 0 doses	Risk ratio	Lower limit	Upper limit
Persistent infections, RCT evidence
Barnabas et al.^{Figure 1 footnote a}^{Figure 1 footnote b}	3/1,518	72/757	0.02	0.01	0.07
Persistent infections, non-RCT evidence
Basu et al.^{Figure 1 footnote c}^{Figure 1 footnote d}	2/2,135	35/1,265	0.03	0.01	0.14
Kreimer et al.^{Figure 1 footnote e}^{Figure 1 footnote f}	1/292	17 249	0.05	0.01	0.37
Incident infections, non-RCT evidence
Kreimer et al.^{Figure 1 footnote g}	2/112	69/1,783	0.46	0.11	1.86
Basu et al.^{Figure 1 footnote h}	154/2,858	192/1,479	0.42	0.34	0.51
Prevalent infections, non-RCT evidence
Kreimer et al.^{Figure 1 footnote i}	2/112	178/1,783	0.18	0.04	0.71
Batmunkh et al.^{Figure 1 footnote j}	1/87	41/266	0.07	0.01	0.53

A GRADE assessment of the available evidence concluded that, compared to two or three doses, there may be little to no difference in persistent, incident, or prevalent HPV infection risk with a one-dose HPV vaccine schedule (low certainty of evidence, Table 3 and Table 4, Figure 2 and Figure 3). Two RCTs evaluating the effectiveness of a two and/or three-dose HPV vaccine schedule have conducted post-hoc analyses to also estimate the VE of a one-dose schedule, with both studies reporting similar VE across all dosing schedules, up to 10 ^{Footnote 16} or 11 years ^{Footnote 17} (low certainty of evidence; Table 3 and Table 4, Figure 2 and Figure 3).

Table 3: Summary of findings comparing one dose to two doses of HPV vaccine
Number of studies	Study design	Number of events/number of participants		Effect		Certainty of evidence	Comments
Number of studies	Study design	Two doses	One dose	Relative effect (95% CI)	Absolute effect (95% CI)	Certainty of evidence	Comments
Persistent HPV infection with vaccine types (follow-up ranging from 4–10 years)
2 ^{Footnote 15}^{Footnote 16}	Post-hoc RCT analysis	A small number of events in both the intervention (n=292–2,135) and control arms (n=611–1,452) across studies; high VE estimated for both arms in each study^{Table 3 footnote a}				Low^{Table 3 footnote b}^{Table 3 footnote c}	A single dose of HPV vaccine may result in little to no difference in persistent HPV infections compared to two doses
Prevalent HPV infection with vaccine types (follow-up of 11 years)
1 ^{Footnote 17}	Post-hoc RCT analysis	1/62 (1.6%)	2/112 (1.8%)	RR 1.11 (0.10–11.97)	2 more per 1,000 (15 fewer to 177 more)	Low^{Table 3 footnote d}^{Table 3 footnote e}	A single dose of HPV vaccine may result in little to no difference in prevalent HPV infections compared to two doses
Incident HPV infection with vaccine types (follow-up ranging from 10–11 years)
2 ^{Footnote 16}^{Footnote 17}	Post-hoc RCT analysis	Number of events dissimilar between studies (n [one dose]=112–2,858; n [two doses]=62–2,166), as the baseline risk of events varies across studies; however, VE estimates for each group are similar across studies^{Table 3 footnote f}				Low^{Table 3 footnote d}^{Table 3 footnote e}	A single dose of HPV vaccine may result in little to no difference in incident HPV infections compared to two doses
Antibody titres (follow-up ranging from 2–16 years)
1 ^{Footnote 22}	RCT	310	310	Ratio of GMTs ranging from 0.11 (0.09–0.14) to 0.21 (0.16–0.26)	N/A	High	A single dose of HPV vaccine results in a decreased immune response compared to two doses
2 ^{Footnote 21}^{Footnote 23}	Post-hoc RCT analysis	Dissimilar number of participants between intervention and control arms, across all studies; however, consistent magnitude and direction of effect across studies				High	A single dose of HPV vaccine results in a decreased immune response compared to two doses
Histological and cytological abnormalities (follow-up of 10 years)
1 ^{Footnote 16}	Post-hoc RCT analysis	1/1,128 (0.9%)	4/1,511 (2.6%)	RR 2.99 (0.33–26.80)	2 more per 1,000 (1 fewer to 23 more)	Low^{Table 3 footnote b}^{Table 3 footnote e}	A single dose of HPV vaccine may result in little to no difference in cervical abnormalities compared to two doses
CIN2+ (follow-up of 10 years)
1 ^{Footnote 16}	Post-hoc RCT analysis	0/1,128 (0%)	0/1,511 (0%)	Not estimable	Not estimable	Low^{Table 3 footnote b}^{Table 3 footnote g}	A single dose of HPV vaccine may result in little to no difference in CIN2+ compared to two doses
HPV-associated cancer (follow-up of 10 years)
1 ^{Footnote 16}	Post-hoc RCT analysis	0/1,128 (0%)	0/1,511 (0%)	Not estimable	Not estimable	Very low^{Table 3 footnote b}^{Table 3 footnote h}^{Table 3 footnote i}	Data insufficient to determine association
Anogenital warts (follow-up of approximately 2.5 years)
1 ^{Footnote 21}	Observational	42/8,046 (0.5%)	69/9,898 (0.7%)	aHR^{Table 3 footnote j} 0.74 (0.35–1.60)	2 more per 1,000 (5 fewer to 4 more)	Low^{Table 3 footnote e}^{Table 3 footnote k}	A single dose of HPV vaccine may result in little to no difference in the risk of anogenital warts compared to two doses
Juvenile-onset recurrent respiratory papillomatosis (JoRPP)
N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A
Table 3 footnotes Abbreviations Abbreviations: aHR, adjusted hazard ratio; CI, confidence interval; CIN, cervical intraepithelial neoplasia; GMT, geometric mean titre; HPV, human papilloma virus; N/A, not applicable; RCT, randomized controlled trial; RR, relative risk; VE, vaccine effectiveness Table 3 footnote a Consistent results observed across studies, with both included studies estimating one and two-dose VE to be similarly high. One study estimated VE at 93.4% (95% CI: 81.1%–99.1%) and 93.7% (95% CI: 78.9%–99.8%) and the other estimated VE at 95.1% (95% CI: 73.2%–99.8%) and 89.6% (95% CI: 68.9%–97.5%) for one and two-dose groups, respectively. The definition of persistent infection was similar across studies Return to Table 3 footnote a referrer Table 3 footnote b Downgraded one level due to some concerns with bias due to confounding and selection of the reported result Return to Table 3 footnote b referrer Table 3 footnote c Downgraded one level due to imprecision, few events and a 95% CI that encompasses a potential benefit, no effect, and a potential harm Return to Table 3 footnote c referrer Table 3 footnote d Downgraded one level due to some concerns with bias due to confounding Return to Table 3 footnote d referrer Table 3 footnote e Downgraded one level due to imprecision and a 95% CI that encompasses a potential benefit, no effect, and a potential harm Return to Table 3 footnote e referrer Table 3 footnote f The baseline risk of incident infection for both one and two doses was dissimilar across the two included studies. However, VE estimated for both the one and two-dose arms of the trials was similar across studies, with one study reporting VE of 54.1% (95% CI: 41.8%–64.1%) and 59% (95% CI: 46.9%–69.1%) and the other reporting VE of 53.9% (95% CI: −57.1%–92.4%) and 58.4% (95% CI: −110.9%–97.9%) for one and two-dose groups, respectively Return to Table 3 footnote f referrer Table 3 footnote g Downgraded by one level due to imprecision, as the optimal information size was not met Return to Table 3 footnote g referrer Table 3 footnote h Downgraded by two levels due serious concerns over indirectness, due to a small number of events, owing to the follow-up period. A 10-year follow-up is insufficient to determine the effect on cancer incidence Return to Table 3 footnote h referrer Table 3 footnote i Downgraded by one level due to some concerns over imprecision. There are no events and the optimal information size was not met Return to Table 3 footnote i referrer Table 3 footnote j Hazard ratio was adjusted for race/ethnicity, health plan (site), age at enrollment in the health plan, age at beginning of study period, age at first evidence of probable sexual activity (as defined by Healthcare Effectiveness Data and Information Set criteria), age at first dose of HPV vaccine (or proxy date), months enrolled in the health plan, Medicaid enrollment, oral contraceptive use, or history of tests for pregnancy, chlamydia, or gonorrhea Return to Table 3 footnote j referrer Table 3 footnote k Downgraded by one level due to some concerns with bias, including due to confounding, selection of participants into the study and selection of the reported result Return to Table 3 footnote k referrer

Table 4: Summary of findings comparing one dose to three doses of HPV vaccine
Number of studies	Study design	Number of events/number of participants		Effect		Certainty of evidence	Comments
Number of studies	Study design	Three doses	One dose	Relative effect (95% CI)	Absolute effect (95% CI)	Certainty of evidence	Comments
Persistent HPV infection with vaccine types (follow-up ranging from 4–10 years)
2 ^{Footnote 15}^{Footnote 16}	Post-hoc RCT analysis	A small number of events in both the intervention (n=292–2,135) and control (n=1,460–11,104) arms across studies; high VE estimated for both arms in each study^{Table 4 footnote a}				Low^{Table 4 footnote b}^{Table 4 footnote c}	A single dose of HPV vaccine may result in little to no difference in persistent HPV infections compared to three doses
Prevalent HPV infection with vaccine types (follow-up of 11 years)
1 ^{Footnote 17}	Post-hoc RCT analysis	27/1,365 (2.0%)	2/112 (1.8%)	RR 0.90 (0.22–3.75)	2 fewer per 1,000 (15 fewer to 54 more)	Low^{Table 4 footnote d}^{Table 4 footnote e}	A single dose of HPV vaccine may result in little to no difference in prevalent HPV infections compared to three doses
Incident HPV infection with vaccine types (follow-up ranging from 10–11 years)
2 ^{Footnote 16}^{Footnote 17}	Post-hoc RCT analysis	Number of events dissimilar between studies (n [one dose]=112–2,858; n [two doses]=1,365–2,019), as the baseline risk of events varies across studies^{Table 4 footnote f}				Low^{Table 4 footnote d}^{Table 4 footnote e}	A single dose of HPV vaccine may result in little to no difference in incident HPV infections compared to three doses
Antibody titres (follow-up ranging from 2–16 years)
1 ^{Footnote 22}	RCT	310	310	Ratio of GMTs ranging from 0.06 (0.05–0.07) to 0.19 (0.15–0.24)	N/A	High	A single dose of HPV vaccine results in a decreased immune response compared to three doses
2 ^{Footnote 21}^{Footnote 23}	Post-hoc RCT analyses	Dissimilar number of participants between intervention and control arms, across all studies; however, consistent magnitude and direction of effect across studies				High	A single dose of HPV vaccine results in a decreased immune response compared to three doses
Histological and cytological abnormalities (follow-up of 10 years)
1 ^{Footnote 16}	Post-hoc RCT analysis	1/1,037 (0.9%)	4/1,511 (2.6%)	RR 2.75 (0.31–24.53)	2 more per 1,000 (1 fewer to 23 more)	Low^{Table 4 footnote b}^{Table 4 footnote e}	A single dose of HPV vaccine may result in little to no difference in cervical abnormalities compared to three doses
CIN2+ (follow-up of 10 years)
1 ^{Footnote 16}	Post-hoc RCT analysis	0/1,037 (0%)	0/1,511 (0%)	Not estimable	Not estimable	Low^{Table 4 footnote b}^{Table 4 footnote g}	A single dose of HPV vaccine may result in little to no difference in CIN2+ compared to three doses
HPV-associated cancer (follow-up of 10 years)
1 ^{Footnote 16}	Post-hoc RCT analysis	0/1,037 (0%)	0/1,511 (0%)	Not estimable	Not estimable	Very low^{Table 4 footnote b}^{Table 4 footnote h}^{Table 4 footnote i}	Data insufficient to determine association
Anogenital warts (follow-up of approximately 2.5 years)
1 ^{Footnote 21}	Observational	91/57,287 (0.2%)	69/9,898 (0.7%)	aHR^{Table 4 footnote j} 0.63 (0.37–1.09)	3 more per 1,000 (1 fewer to 4 more)	Low^{Table 4 footnote e}^{Table 4 footnote k}	A single dose of HPV vaccine may result in little to no difference in the risk of anogenital warts compared to three doses
Juvenile-onset recurrent respiratory papillomatosis (JoRPP)
N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A
Table 4 footnotes Abbreviations Abbreviations: aHR, adjusted hazard ratio; CI, confidence interval; CIN, cervical intraepithelial neoplasia; GMT, geometric mean titre; HPV, human papilloma virus; N/A, not applicable; RCT, randomized controlled trial; RR, relative risk; VE, vaccine effectiveness Table 4 footnote a Consistent results observed across studies, with both included studies estimating one and three-dose VE to be similarly high. One study estimated VE at 93.4% (95% CI: 81.1%–99.1%) and 90.3% (95% CI: 71.9%–98.5%) and the other estimated VE at 95.1% (95% CI: 73.2%–99.8%) and 87.0% (95% CI: 83.7%–89.7%) for one- and three-dose groups, respectively. The definition of persistent infection was similar across studies Return to Table 4 footnote a referrer Table 4 footnote b Downgraded one level due to some concerns with bias due to confounding and selection of the reported result Return to Table 4 footnote b referrer Table 4 footnote c Downgraded one level due to imprecision, few events and a 95% CI that encompasses a potential benefit, no effect, and a potential harm Return to Table 4 footnote c referrer Table 4 footnote d Downgraded one level due to some concerns with bias due to confounding Return to Table 4 footnote d referrer Table 4 footnote e Downgraded one level due to imprecision and a 95% CI that encompasses a potential benefit, no effect, and a potential harm Return to Table 4 footnote e referrer Table 4 footnote f The baseline risk of incident infection for both one and three doses was dissimilar across the two included studies, as was the estimated VE for one of the included studies. The VE estimated for the one and two-dose arms of the trials was 54.1% (95% CI: 41.8%–64.1%) and 54.7% (95% CI: 40.9%–65.0%) in one study and 53.9% (95% CI: −57.1%–92.4%) and 84.9% (95% CI: 69.8%–93.2%) in the other, for one and two-dose groups, respectively. The difference in VE reported can be at least partially explained by the small number of events and participants in the one-dose group Return to Table 4 footnote f referrer Table 4 footnote g Downgraded by one level due to imprecision, as the optimal information size was not met Return to Table 4 footnote g referrer Table 4 footnote h Downgraded by two levels due serious concerns over indirectness, due to a small number of events, owing to the follow-up period. A 10-year follow-up is insufficient to determine the effect on cancer incidence Return to Table 4 footnote h referrer Table 4 footnote i Downgraded by one level due to some concerns over imprecision. There are no events, and the optimal information size was not met Return to Table 4 footnote i referrer Table 4 footnote j Hazard ratio was adjusted for race/ethnicity, health plan (site), age at enrollment in the health plan, age at beginning of study period, age at first evidence of probable sexual activity (as defined by Healthcare Effectiveness Data and Information Set criteria), age at first dose of HPV vaccine (or proxy date), months enrolled in the health plan, Medicaid enrollment, oral contraceptive use, or history of tests for pregnancy, chlamydia or gonorrhea Return to Table 4 footnote j referrer Table 4 footnote k Downgraded by one level due to some concerns with bias, including due to confounding, selection of participants into the study and selection of the reported result Return to Table 4 footnote k referrer

Figure 2: Risk ratios and 95% CI for persistent, prevalent and incident HPV vaccine-type infections, one dose compared to either two or three doses^{Figure 2 footnote a}^{Figure 2 footnote b}^{Figure 2 footnote c}^{Figure 2 footnote d}^{Figure 2 footnote e}

Fgure 2
Study name	Events/total 1 dose	Events/total 2 or 3 doses	Risk ratio	Lower limit	Upper limit
Persistent infections, 1 vs. 2 doses
Basu et al.^{Figure 2 footnote a}^{Figure 2 footnote b}	2/2,135	1/1,452	1.36	0.12	14.99
Kreimer et al.^{Figure 2 footnote c}^{Figure 2 footnote d}	1/292	3/611	0.70	0.07	6.68
Persistent infections, 1 vs. 3 doses
Basu et al.^{Figure 2 footnote a}^{Figure 2 footnote b}	2/2,135	1/1,460	1.37	0.12	15.07
Kreimer et al.^{Figure 2 footnote c}^{Figure 2 footnote d}	1/292	84/11,104	0.45	0.06	3.24
Incident infections, 1 vs. 2 doses
Kreimer et al.^{Figure 2 footnote e}	2/112	1/62	1.11	0.10	11.97
Basu et al.^{Figure 2 footnote b}	154/2,858	107/2,166	1.09	0.86	1.39
Incident infections, 1 vs. 3 doses
Kreimer et al.^{Figure 2 footnote e}	2/112	8/1,365	3.05	0.65	14.18
Basu et al.^{Figure 2 footnote b}	154/2,858	110/2,019	0.99	0.78	1.25
Prevalent infections, 1 vs. 2 doses
Kreimer et al.^{Figure 2 footnote e}	2/112	1/62	1.11	0.10	11.97
Prevalent infections, 1 vs. 3 doses
Kreimer et al.^{Figure 2 footnote e}	2/112	27/1,365	0.90	0.22	3.75

Figure 3: Risk ratios and 95% CI for persistent, prevalent and incident HPV infections, two doses compared to three doses^{Figure 3 footnote a}^{Figure 3 footnote b}^{Figure 3 footnote c}^{Figure 3 footnote d}^{Figure 3 footnote e}

Fgure 3
Study name	Events/total 2 doses	Events/total 3 doses	Risk ratio	Lower limit	Upper limit
Persistent infections
Basu et al.^{Figure 3 footnote a}^{Figure 3 footnote b}	1/1,452	1/1,460	1.01	0.06	16.06
Kreimer et al.^{Figure 3 footnote c}^{Figure 3 footnote d}	3/611	84/11,104	0.65	0.21	2.05
Incident infections
Basu et al.^{Figure 3 footnote b}	107/2,166	110/2,019	0.91	0.70	1.17
Kreimer et al.^{Figure 3 footnote e}	1/62	8/1,365	2.75	0.35	21.66
Prevalent infections
Kreimer et al.^{Figure 3 footnote e}	1/62	27/1,365	0.82	0.11	5.90

The Costa Rica Vaccine Trial (CVT) was originally designed to test the efficacy of a three-dose schedule of CERVARIX^®in females aged 18–25 years (compared to control hepatitis A vaccine); however, approximately 20% of participants did not complete their three-dose schedule, primarily due to pregnancy or colposcopy referral, thus creating cohorts who received a one or two-dose schedule. After 11 years of follow-up, VE against prevalent HPV16/18 infection was similar among recipients of either one-dose (82.1%; 95% CI: 40.2%–97.0%), two-dose (83.8%; 95% CI: 19.5%–99.2%) or three-dose (80.2%; 95% CI: 70.7%–87.0%) schedules ^{Footnote 17}.

Similar results were also seen in the International Agency for Research on Cancer (IARC) study from India, which was originally designed to compare two and three doses of GARDASIL^®in females aged 10–18 years. However, numerous participants did not complete their full vaccine schedule, as recruitment of girls into HPV trials was suspended by the Indian government in 2010. Vaccine effectiveness against persistent HPV16/18 infection was similar among women who received one (95.4%; 95% CI: 85%–99.1%), two (93.1%; 95% CI: 77.3%–99.8%) or three (93.3%; 95% CI: 77.5%–99.7%) doses after 10 years of follow-up ^{Footnote 16}.

Efficacy/effectiveness against cervical precancerous lesions

Among included studies, only the IARC trial ^{Footnote 16} reported data on the effect of different HPV vaccine schedules on cervical precancers and HPV-related cancers. After 10 years of follow-up, 16/4,626 (0.3%) of unvaccinated women reported cervical intraepithelial neoplasia (CIN) grade 1, compared to 4/1,511 (0.3%), 1/1,128 (0.1%) and 1/1,037 (0.1%) in the one, two and three-dose groups, respectively. There were no cases of CIN2 or greater in any of the vaccine groups, regardless of the number of doses received, while 5/4,626 women (0.1%) in the unvaccinated group experienced CIN2 or greater. Additionally, there were no cases of HPV-related cancers in any of the groups.

A GRADE assessment of the available evidence concluded that there may be little to no difference in the risks of cervical abnormalities or CIN2+ between one and either two or three-dose schedules (low certainty of evidence; Table 3 and Table 4).

Efficacy/effectiveness against anogenital warts

There is currently no clinical trial evidence comparing the effect of a single dose to either two or three doses on the risk of AGW. However, an observational study from the United States (n=64,517) compared the risk of AGW in female participants who received one dose to those who received no, two, or three doses of GARDASIL^®^{Footnote 21}. Propensity score-weighted incidence rates were 761.9 (95% CI: 685.5–849.1), 256.6 (95% CI: 161.8–432.3), 194.2 (95% CI: 108.0–386.4), and 161.8 (95% CI: 124.4–214.6) per 100,000 person-years in the unvaccinated, one, two and three-dose groups, respectively. Propensity score-weighted hazard ratios (HRs) demonstrated no statistically significant difference between the groups, with HRs of 0.74 (95% CI: 0.35–1.60) and 0.63 (95% CI: 0.37–1.09) for two and three doses (compared to one), respectively (no direct comparison of the two and three-dose groups).

A GRADE assessment of the available evidence concluded that a single dose of HPV vaccine probably reduces the risk of AGW compared to no vaccine (moderate certainty of evidence; Table 2), and that there may be little to no difference in risk, compared to a two or three-dose schedule (low certainty of evidence; Table 3 and Table 4).

Antibody titres

A GRADE assessment of the available evidence concluded that a single dose of HPV vaccine results in an increased immune response compared to no vaccine ^{Footnote 18}^{Footnote 19}^{Footnote 20} (high certainty of evidence; Table 2, Figure 4), and a decreased immune response compared to two or three doses (high certainty of evidence; Table 3 and Table 4, Figure 5).

**Figure 4: Ratio of geometric mean titres and 95% CI comparing one dose to zero doses^{Figure 4 footnote a}**

Fgure 4
Study name	HPV type	Time point (years)^{Figure 4 footnote a}	Ratio of GMTs	Lower limit	Upper limit
Safaeian et al.	16	4	9.36	6.40	13.68
Safaeian et al.	18	4	4.79	3.37	6.80
Batmunkh et al.	16	6	5.73	3.03	10.84
Batmunkh et al.	18	6	2.28	1.51	3.44
Joshi et al.	16	10	2.05	1.34	3.15
Joshi et al.	18	10	3.49	2.80	4.35

**Figure 5: Ratio of geometric mean titres and 95% CI comparing one dose to either two or three doses^{Figure 5 footnote a}**

Fgure 5
Study name	Vaccine	HPV type	Time point (years)^{Figure 5 footnote a}	Ratio of GMTs	Lower limit	Upper limit
1 vs. 2 doses, RCT evidence
Watson-Jones et al.	Cervarix	16	2	0.14	0.12	0.17
Watson-Jones et al.	Gardasil9	16	2	0.11	0.09	0.14
Watson-Jones et al.	Cervarix	18	2	0.20	0.17	0.24
Watson-Jones et al.	Gardasil9	18	2	0.21	0.16	0.26
1 vs. 3 doses, RCT evidence
Watson-Jones et al.	Cervarix	16	2	0.06	0.05	0.07
Watson-Jones et al.	Gardasil9	16	2	0.12	0.10	0.15
Watson-Jones et al.	Cervarix	18	2	0.09	0.08	0.11
Watson-Jones et al.	Gardasil9	18	2	0.19	0.15	0.24
1 vs. 2 doses, non-RCT evidence
Joshi et al.	Gardasil	16	10	0.29	0.24	0.34
Joshi et al.	Gardasil	18	10	0.39	0.31	0.48
Romero et al.	Cervarix	16	16	0.54	0.42	0.71
Romero et al.	Cervarix	18	16	0.57	0.43	0.75
1 vs. 3 doses, RCT evidence
Joshi et al.	Gardasil	16	10	0.28	0.23	0.34
Joshi et al.	Gardasil	18	10	0.32	0.25	0.40
Romero et al.	Cervarix	16	16	0.36	0.29	0.44
Romero et al.	Cervarix	18	16	0.50	0.41	0.62

The Dose Reduction Immunobridging and Safety study (DoRIS) from Tanzania randomized females aged 9–14 years (n=930) to receive one, two, or three doses of CERVARIX^®or GARDASIL^®9 ^{Footnote 22}. Antibody titres were statistically significantly lower for one-dose recipients compared to two or three-dose recipients for both vaccines (Figure 5). However, while lower titres were observed for the one-dose schedule, the antibody response was sustained through year two (end of study). In individuals who received two doses of GARDASIL^®9, antibody titres were non-inferior compared to those who received three doses; however, they were significantly lower (and non-inferiority was not met) for those receiving two doses of CERVARIX^®(Figure 6).

**Figure 6: Ratio of geometric mean titres and 95% CI comparing two doses to three doses^{Figure 6 footnote a}^{Figure 6 footnote b}^{Figure 6 footnote c}^{Figure 6 footnote d}^{Figure 6 footnote e}**

Fgure 6
Study name	Vaccine	HPV type	Time point (years)^{Figure 6 footnote a}	Ratio of GMTs	Lower limit	Upper limit
RCTs
Watson-Jones et al.	Gardasil9	16	2	1.06	0.85	1.32
Watson-Jones et al.	Gardasil9	18	2	0.91	0.71	1.16
Watson-Jones et al.	Cervarix	16	2	0.40	0.32	0.48
Watson-Jones et al.	Cervarix	18	2	0.47	0.37	0.59
Bornstein et al.^{Figure 6 footnote b}	Gardasil9	16	3	0.75	0.61	0.91
Bornstein et al.^{Figure 6 footnote b}	Gardasil9	18	3	0.69	0.58	0.81
Bornstein et al.^{Figure 6 footnote c}	Gardasil9	16	3	0.85	0.69	1.04
Bornstein et al.^{Figure 6 footnote c}	Gardasil9	18	3	0.77	0.65	0.91
Bornstein et al.^{Figure 6 footnote d}	Gardasil9	16	3	1.83	1.42	2.35
Bornstein et al.^{Figure 6 footnote d}	Gardasil9	18	3	1.24	1.00	1.52
Bornstein et al.^{Figure 6 footnote e}	Gardasil9	16	3	2.05	1.59	2.64
Bornstein et al.^{Figure 6 footnote e}	Gardasil9	18	3	1.46	1.18	1.80
Leung et al.	Gardasil	16	3	0.80	0.68	0.95
Leung et al.	Gardasil	18	3	0.60	0.49	0.73
Romanowski et al.	Cervarix	16	5	0.53	0.42	0.65
Romanowski et al.	Cervarix	18	5	0.75	0.59	0.95
Ogilvie et al.	Gardasil	16	10	1.21	0.75	1.95
Ogilvie et al.	Gardasil	18	10	0.72	0.37	1.39
Post-hoc RCT analyses
Joshi et al.	Gardasil	16	10	0.98	0.80	1.20
Joshi et al.	Gardasil	18	10	0.82	0.63	1.05
Romero et al.	Cervarix	16	16	0.61	0.48	0.77
Romero et al.	Cervarix	18	16	0.89	0.70	1.13

Two post-hoc analyses of the CVT and IARC trials (data up to 16 ^{Footnote 23} and 10 ^{Footnote 21}, respectively) have produced similar results to the DoRIS study, with a single-dose schedule producing inferior but sustained antibody titres (high certainty of evidence; Table 3 and Table 4, Figure 5).

Several RCTs provide data comparing the antibody titres of a two-dose versus three-dose schedule (Figure 6). The long-term follow-up of a Canadian RCT in girls aged 9–13 years receiving GARDASIL^®demonstrated a non-inferior antibody response with two doses for HPV6, HPV11 and HPV16, ten years following vaccination (non-inferiority not met for HPV18) ^{Footnote 24}. Another RCT of girls aged 9–14 years receiving GARDASIL^®demonstrated a non-inferior immune response for HPV16 and HPV18, three years following vaccination ^{Footnote 25}. In a multinational RCT using GARDASIL^®9, girls aged 9–14 years were randomized to receive two (six or 12 months apart) or three doses (six months apart), while boys aged 9–14 years were randomized to receive two doses six or 12 months apart. While the individuals receiving two doses six months apart had generally lower/similar antibody levels compared to those receiving three doses, those receiving two doses 12 months apart generally had higher/similar antibody levels compared to those given three doses within six months, three years after vaccination ^{Footnote 26}, suggesting the interval between doses may be more important than the number of doses. Lastly, in an RCT of females aged 9–25 years receiving CERVARIX^®, HPV16 and HPV18 antibody titres appeared slightly higher after a three-dose schedule compared to a two-dose schedule, regardless of age strata (9–14 and 15–25 years), five years following vaccination. However, no test of non-inferiority was performed ^{Footnote 27}.

Discussion

The effectiveness/efficacy and immunogenicity of various HPV vaccine schedules were reviewed. Available evidence suggests that single-dose VE against HPV infection may be similar to that of two or three doses. Antibody titres, however, indicate a lower immune response with a single dose compared to two or three doses. Currently, there is no established correlate of protection for HPV, and therefore the clinical relevance of this decreased immune response is unknown. The interpretation of results from other clinical outcomes, such as the risks of CIN and abnormal cytology, remain challenging due to limitations of the included studies. In addition to the currently available evidence outlined above, which includes follow-up for up to 16 years post-immunization depending on the study and clinical protection outcome, longer follow-up data are expected in the coming years from multiple key studies. As trials continue to accrue data, follow-up will remain important as trial participants reach the age of increased baseline risk of cervical abnormalities and associated cancers, as data for these outcomes is currently limited. Two additional RCTs from Costa Rica are underway and are expected to produce estimates of single dose VE in females 12–16 years and 18–30 years of age by 2025 and 2026, respectively ^{Footnote 28}^{Footnote 29}.

Limitations

There are several limitations to the current data. Data are predominately limited to female adolescents and young women, with a primary focus on cervical HPV infection and cervical cancer precursors. However, several additional cancers are attributable to HPV infections (i.e., other anogenital, and head/neck cancers) ^{Footnote 2}, for which there are currently no data. While there is no clinical trial data on VE of a single vaccine dose in males, several retrospective observational studies include both biological sexes. However, only two studies report results stratified by sex, with neither study reporting a difference in HPV infection risk between dosing schedules in males ^{Footnote 30}^{Footnote 31}. Neither study was eligible for inclusion, however, as both were considered at serious risk of bias. It is possible that different antibody levels or immunologic factors are required for protection in the female versus male genital tract, and for protection against warts and head/neck/anal cancer. Future research on the effect of single dose HPV vaccination and other HPV-related cancers, including trials where clinical outcomes are assessed among male populations, will be important for public health decision-making. Data are also currently lacking on the effect of a one-dose schedule in immunocompromised individuals. Only one observational study that provided data for this group was identified, with no difference in the incidence of abnormal cervical cytology observed between dosing schedules in HIV-positive females. This study was, however, considered at serious risk of bias and therefore not eligible for inclusion ^{Footnote 32}.

Conclusion

Current clinical data on reduced HPV dosing schedules are promising. Longer-term follow-up of clinical trial participants, as well as monitoring real-world outcomes in countries where the change to single-dose schedules have already taken place, can help better understand the duration of protection against HPV infection conferred from reduced dosing schedules. In addition, when considering population-level programmatic changes, several additional factors will likely require consideration, including impacts of a program change on acceptability and uptake of the HPV vaccine, as well as on health inequities and access to the vaccine.

Authors' statement

JM — Conceptualization, methodology, formal analysis, data curation, writing–original draft
NF — Conceptualization, methodology, formal analysis, data curation, writing–review & editing
MS — Conceptualization, methodology, data curation, writing–review & editing, supervision
VD — Conceptualization, methodology, writing–review & editing, supervision
SA — Conceptualization, methodology, formal analysis, data curation, writing–review & editing
AJ — Conceptualization, methodology, formal analysis, data curation, writing–review & editing
CY — Conceptualization, data curation, writing–review & editing
KG — Conceptualization, data curation, writing–review & editing
KY — Conceptualization, methodology, writing–review & editing, supervision
MT — Conceptualization, methodology, writing–review & editing, supervision

Competing interests

None.

Acknowledgements

We would like to acknowledge the contributions of the Public Health Agency of Canada Library Services and the NACI HPV Working Group.

Funding

This work was supported by the Public Health Agency of Canada.

References

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Kreimer AR, Struyf F, Del Rosario-Raymundo MR, Hildesheim A, Skinner SR, Wacholder S, Garland SM, Herrero R, David MP, Wheeler CM, González P, Jiménez S, Lowy DR, Pinto LA, Porras C, Rodriguez AC, Safaeian M, Schiffman M, Schiller JT, Schussler J, Sherman ME, Bosch FX, Castellsague X, Chatterjee A, Chow SN, Descamps D, Diaz-Mitoma F, Dubin G, Germar MJ, Harper DM, Lewis DJ, Limson G, Naud P, Peters K, Poppe WA, Ramjattan B, Romanowski B, Salmeron J, Schwarz TF, Teixeira JC, Tjalma WA; Costa Rica Vaccine Trial Study Group Authors; PATRICIA Study Group Authors; HPV PATRICIA Principal Investigators/Co-Principal Investigator Collaborators; GSK Vaccines Clinical Study Support Group. Efficacy of fewer than three doses of an HPV-16/18 AS04-adjuvanted vaccine: combined analysis of data from the Costa Rica Vaccine and PATRICIA Trials. Lancet Oncol 2015;16(7):775–86. https://doi.org/10.1016/S1470-2045(15)00047-9

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Basu P, Malvi SG, Joshi S, Bhatla N, Muwonge R, Lucas E, Verma Y, Esmy PO, Poli UR, Shah A, Zomawia E, Pimple S, Jayant K, Hingmire S, Chiwate A, Divate U, Vashist S, Mishra G, Jadhav R, Siddiqi M, Sankaran S, Prabhu PR, Kannan TP, Varghese R, Shastri SS, Anantharaman D, Gheit T, Tommasino M, Sauvaget C, Pillai MR, Sankaranarayanan R. Vaccine efficacy against persistent human papillomavirus (HPV) 16/18 infection at 10 years after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a multicentre, prospective, cohort study. Lancet Oncol 2021;22(11):1518–29. https://doi.org/10.1016/S1470-2045(21)00453-8

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Kreimer AR, Sampson JN, Porras C, Schiller JT, Kemp T, Herrero R, Wagner S, Boland J, Schussler J, Lowy DR, Chanock S, Roberson D, Sierra MS, Tsang SH, Schiffman M, Rodriguez AC, Cortes B, Gail MH, Hildesheim A, Gonzalez P, Pinto LA; Costa Rica HPV Vaccine Trial (CVT) Group. Evaluation of durability of a single dose of the bivalent HPV vaccine: the CVT trial. J Natl Cancer Inst 2020;112(10):1038–46. https://doi.org/10.1093/jnci/djaa011

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Batmunkh T, Dalmau MT, Munkhsaikhan ME, Khorolsuren T, Namjil N, Surenjav U, Toh ZQ, Licciardi PV, Russell FM, Garland SM, Mulholland K, von Mollendorf C. A single dose of quadrivalent human papillomavirus (HPV) vaccine is immunogenic and reduces HPV detection rates in young women in Mongolia, six years after vaccination. Vaccine 2020;38(27):4316–24. https://doi.org/10.1016/j.vaccine.2020.04.041

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Safaeian M, Porras C, Pan Y, Kreimer A, Schiller JT, Gonzalez P, Lowy DR, Wacholder S, Schiffman M, Rodriguez AC, Herrero R, Kemp T, Shelton G, Quint W, van Doorn LJ, Hildesheim A, Pinto LA; CVT Group. 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 (Phila) 2013;6(11):1242–50. https://doi.org/10.1158/1940-6207.CAPR-13-0203

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Joshi S, Anantharaman D, Muwonge R, Bhatla N, Panicker G, Butt J, Rani Reddy Poli U, Malvi SG, Esmy PO, Lucas E, Verma Y, Shah A, Zomawia E, Pimple S, Jayant K, Hingmire S, Chiwate A, Divate U, Vashist S, Mishra G, Jadhav R, Siddiqi M, Sankaran S, Pillai Rameshwari Ammal Kannan T, Kartha P, Shastri SS, Sauvaget C, Radhakrishna Pillai M, Waterboer T, Müller M, Sehr P, Unger ER, Sankaranarayanan R, Basu P. Evaluation of immune response to single dose of quadrivalent HPV vaccine at 10-year post-vaccination. Vaccine 2023;41(1):236–45. https://doi.org/10.1016/j.vaccine.2022.11.044

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Watson-Jones D, Changalucha J, Whitworth H, Pinto L, Mutani P, Indangasi J, Kemp T, Hashim R, Kamala B, Wiggins R, Songoro T, Connor N, Mbwanji G, Pavon MA, Lowe B, Mmbando D, Kapiga S, Mayaud P, de SanJosé S, Dillner J, Hayes RJ, Lacey CJ, Baisley K. Immunogenicity and safety of one-dose human papillomavirus vaccine compared with two or three doses in Tanzanian girls (DoRIS): an open-label, randomised, non-inferiority trial. Lancet Glob Health 2022;10(10):e1473–84. https://doi.org/10.1016/S2214-109X(22)00309-6

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Romero B, Herrero R, Porras C. Durability of HPV-16/18 antibodies 16 years after a single dose of the bivalent HPV vaccine: The Costa Rica HPV vaccine trial. 35th International Papillomavirus Conference. 2023.

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Donken R, Dobson SR, Marty KD, Cook D, Sauvageau C, Gilca V, Dionne M, McNeil S, Krajden M, Money D, Kellner J, Scheifele DW, Kollmann T, Bettinger JA, Liu S, Singer J, Naus M, Sadarangani M, Ogilvie GS. Immunogenicity of 2 and 3 doses of the quadrivalent human papillomavirus vaccine up to 120 months postvaccination: follow-up of a randomized clinical trial. Clin Infect Dis 2020;71(4):1022–9. https://doi.org/10.1093/cid/ciz887

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Footnote 25

Leung TF, Liu AP, Lim FS, Thollot F, Oh HM, Lee BW, Rombo L, Tan NC, Rouzier R, De Simoni S, Suryakiran P, Hezareh M, Thomas F, Folschweiller N, Struyf F. Comparative immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine and 4vHPV vaccine administered according to two- or three-dose schedules in girls aged 9-14 years: results to month 36 from a randomized trial. Vaccine 2018;36(1):98–106. https://doi.org/10.1016/j.vaccine.2017.11.034

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Footnote 26

Bornstein J, Roux S, Kjeld Petersen L, Huang LM, Dobson SR, Pitisuttithum P, Diez-Domingo J, Schilling A, Ariffin H, Tytus R, Rupp R, Senders S, Engel E, Ferris D, Kim YJ, Tae Kim Y, Kurugol Z, Bautista O, Nolan KM, Sankaranarayanan S, Saah A, Luxembourg A. Three-Year Follow-up of 2-Dose Versus 3-Dose HPV Vaccine. Pediatrics 2021;147(1):e20194035. https://doi.org/10.1542/peds.2019-4035

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Footnote 27

Romanowski B, Schwarz TF, Ferguson L, Peters K, Dionne M, Behre U, Schulze K, Hillemanns P, Suryakiran P, Thomas F, Struyf F. Sustained immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine administered as a two-dose schedule in adolescent girls: five-year clinical data and modeling predictions from a randomized study. Hum Vaccin Immunother 2016;12(1):20–9. https://doi.org/10.1080/21645515.2015.1065363

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Footnote 28

National Cancer Institute. Single-dose HPV vaccination for the prevention of cervical cancer in young adult women in Costa Rica, the PRISMA ESCUDDO trial (PRISMA). 2023. https://clinicaltrials.gov/study/NCT05237947

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Footnote 29

Porras C, Sampson JN, Herrero R, Gail MH, Cortés B, Hildesheim A, Cyr J, Romero B, Schiller JT, Montero C, Pinto LA, Schussler J, Coronado K, Sierra MS, Kim JJ, Torres CM, Carvajal L, Wagner S, Campos NG, Ocampo R, Kemp TJ, Zuniga M, Lowy DR, Avila C, Chanock S, Castrillo A, Estrada Y, Barrientos G, Monge C, Oconitrillo MY, Kreimer AR. Rationale and design of a double-blind randomized non-inferiority clinical trial to evaluate one or two doses of vaccine against human papillomavirus including an epidemiologic survey to estimate vaccine efficacy: the Costa Rica ESCUDDO trial. Vaccine 2022;40(1):76–88. https://doi.org/10.1016/j.vaccine.2021.11.041

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Footnote 30

Chandler E, Ding L, Gorbach P, Franco EL, Brown DA, Widdice LE, Bernstein DI, Kahn JA. Epidemiology of any and vaccine-type anogenital human papillomavirus among 13-26-year-old young men after HPV vaccine introduction. J Adolesc Health 2018;63(1):43–9. https://doi.org/10.1016/j.jadohealth.2018.01.005

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Footnote 31

Widdice LE, Bernstein DI, Franco EL, Ding L, Brown DR, Ermel AC, Higgins L, Kahn JA. Decline in vaccine-type human papillomavirus prevalence in young men from a Midwest metropolitan area of the United States over the six years after vaccine introduction. Vaccine 2019;37(45):6832–41. https://doi.org/10.1016/j.vaccine.2019.08.052

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Footnote 32

Moscicki AB, Karalius B, Tassiopoulos K, Yao TJ, Jacobson DL, Patel K, Purswani M, Seage GR; Pediatric HIV/AIDS Cohort Study. Human papillomavirus antibody levels and quadrivalent vaccine clinical effectiveness in perinatally human immunodeficiency virus-infected and exposed, uninfected youth. Clin Infect Dis 2019;69(7):1183–91. https://doi.org/10.1093/cid/ciy1040

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