Comparative efficacy of human papillomavirus vaccines: systematic review and network meta-analysis

Figures & data

Figure 1. Flow diagram for selection of studies.

Table 1. Characteristics of the 11 randomized controlled trials.

Study	9vHPV/4vHPV		FUTURE I/II (Gardasil)		China Trial (Cecolin)	China Trial (Cervarix)	CVT (Cervarix)
ClinicalTrials.gov Identifier	NCT00543543		NCT00092521/NCT00092534		NCT01735006	NCT00779766	NCT00128661
Publications included	Huh et al. (2017) [24] and Joura et al. (2015) [25]		Darron R et al. (2009) [27], Muñoz et al. (2010) [26], and Talía Malagón et al. (2012) [15]		Fang-Hui Zhao et al. (2022) [28] and You-Lin Qiao et al. (2020) [29]	Feng-Cai Zhu et al. (2014) [30] (2017) [31] and (2019) [32]	Allan et al. (2014) [33] and Rolando et al. (2011) [34]
HPV subgroup included	Per protocol		RMITT2		Per protocol	Per protocol	Per protocol
Number of participants	11,741		11,364		6,612	5,782	5,312
Study regions	Austria, Brazil, Canada, Chile, Colombia, Denmark, Germany, Hong Kong, Japan, South Korea, Mexico, New Zealand, Norway, Peru, Sweden, Taiwan, Thailand, and the U.S.A. (including Puerto Rico)		Australia, Austria, Brazil, Canada, Colombia, Czech Republic, Denmark, Finland, Germany, Hong Kong, Iceland, Italy, Mexico, New Zealand, Norway, Peru, Poland, Puerto Rico, Russia, Singapore, Sweden, Thailand, the UK, and the USA		China	China	Costa Rica
Fun ding	Merck		Merck		Xiamen Innovax Biotech	GlaxoSmithKline	GlaxoSmithKline
Characteristics of the population	Age: 16–26 years Lifetime sexual partners: ≤4		Age: 16–26 years Lifetime sexual partners: ≤4		Age: 18–45 years Lifetime sexual partners: ≤4	Age: 18–25 years	Age: 18–25 years
Intervention group	Nine-valent vaccine (Gardasil 9)		Quadrivalent vaccine (Gardasil)		Bivalent vaccine (Cecolin)	Bivalent vaccine (Cervarix)	Bivalent vaccine (Cervarix)
Control group	Quadrivalent vaccine (Gardasil)		Placebo		Hepatitis E vaccine	Placebo	Hepatitis A vaccine
Cytological status	Normal at screening; not reported at baseline		Normal at baseline		Normal at screening; not reported at baseline	Normal at screening; not reported at baseline	NA
Serological status	Serologically negative forcorresponding HPV type at screening; not reported at baseline		Serologically negative for HPV 6, 11, 16, and 18 at baseline		Serologically negative for corresponding HPV type at screening; not reported at baseline	Serologically negative for corresponding HPV type at screening; not reported at baseline	NA
HPV DNA status	DNA negative for corresponding HPV type at baseline		DNA negative for 14 oncogenic HPV types at baseline		DNA negative for corresponding HPV type at baseline	DNA negative for corresponding HPV type at baseline	DNA negative for corresponding HPV type at baseline
Mean age at enrollment, [years (SD)]	21.9 (2.5)		19.8 (2.1)		30 (7.4)	20 (1.73)	21.1 (2.3)
Received three doses (%)	100% in the per protocol group		97.2% of enrolled participants		100% in the per protocol group	100% in the per protocol group	100% in the per protocol group
Start case recording	After the third vaccination		After the first vaccination		After the third vaccination	After the third vaccination	After the third vaccination
Duration of follow-up	Up to 6 years		Mean 3.6 years (up to 4.9 years)		Up to 5.5 years	Up to 6 years	Median follow-up 53.8 months
Study		HPV-007 (Cervarix)		Japan Trial 1 (Cervarix)	Japan Trial 2 (Cervarix)	PATRICIA (Cervarix)	VIVIANE (Cervarix)
ClinicalTrials.gov Identifier		NCT00120848		NCT00316693	NCT00316693/NCT00929526	NCT00122681	NCT00294047
Publications included		Harper et al. (2006) [35],GlaxoSmithKline (2009) [36], and Talía Malagón et al. (2012) [15]		Ryo Konno et al. (2010) [37]	Ryo Konno et al. (2014) [38]	Wheeler et al. (2012) [39], Lehtinen et al. (2012) [41], and Apter et al. (2015) [40]	Skinner et al. (2014) [42] and Cosette et al. (2016) [43]
HPV subgroup included		Per protocol		Per protocol	Per protocol	TVC naive	Per protocol
Number of participants		919		1,002	997	11,644	4,505
Study regions		Brazil, Canada, and the USA		Japan	Japan	Australia, Belgium, Brazil, Canada, Finland, Germany, Italy, Mexico, Philippines, Spain, Taiwan, Thailand, the UK, and the USA	Australia, Canada, Mexico, Netherlands, Peru, Philippines, Portugal, Russia, Singapore, Thailand, the UK, and the USA
Fun ding		GlaxoSmithKline		GlaxoSmithKline	GlaxoSmithKline	GlaxoSmithKline	GlaxoSmithKline
Characteristics of the population		Age: 15–25 years Lifetime sexual partners: ≤6		Age: 20–25 years	Age: 20–25 years	Age: 15–25 years Lifetime sexual partners: ≤6	Age: ≥25 years
Intervention group		Bivalent vaccine (Cervarix)		Bivalent vaccine (Cervarix)	Bivalent vaccine (Cervarix)	Bivalent vaccine (Cervarix)	Bivalent vaccine (Cervarix)
Control group		Placebo		Hepatitis A vaccine	Hepatitis A vaccine	Hepatitis A vaccine	Placebo
Cytological status		Normal at screening; not reported at baseline		Normal at baseline	Normal at baseline	Normal at baseline	Normal at screening; not reported at baseline
Serological status		Serologically negative for HPV 16 and HPV 18 at screening; not reported at baseline		Serologically negative for corresponding HPV type at baseline	Serologically negative for corresponding HPV type at baseline	Serologically negative for HPV 16 and HPV 18 at baseline	Unspecified
HPV DNA status		DNA negative for 14 oncogenic HPV types at screening; not reported at baseline		DNA negative for corresponding HPV type at baseline	DNA negative for corresponding HPV type at baseline	DNA negative for 14 oncogenic HPV types at baseline	DNA negative for corresponding HPV type at baseline
Mean age at enrollment, [years (SD)]		20 (3)		NA	NA	19.9 (3.1)	37 (7.2)
Received three doses (%)		100% in the per protocol group		100% in the per protocol group	100% in the per protocol group	92% of enrolled participants	100% in the per protocol group
Start case recording		After the third vaccination		After the third vaccination	After the third vaccination	After the first vaccination	After the third vaccination
Duration of follow-up		Up to 6.4 years		Mean 13.6 months (SD 3.7)	Approximately 48 months	Mean 3.7 years (up to 4 years)	Up to 7 years

FUTURE I/II: combined report of two Gardasil randomized controlled trials; HPV: human papillomavirus; RMITT2: restricted modified intention to treat 2 (no oncogenic HPV infection at baseline); TVC naive: subgroups without oncogenic HPV infection at baseline.

Figure 2. Network plots. Network plots for persistent infection with HPV 16 (a), Persistent infection with HPV 18 (b), Cervical intraepithelial neoplasia grade 2 or worse associated with HPV 16 (c), Cervical intraepithelial neoplasia grade 2 or worse associated with HPV 18 (d), Persistent infection with HPV 31 (e), Persistent infection with HPV 33 (f), Persistent infection with HPV 45 (g), Persistent infection with HPV 52 (h), and persistent infection with HPV 58 (i). The area of the circle represents the number of participants. The width of the line represents the number of trials of the two treatments. vHPV, valent human papillomavirus.

Figure 3. Network meta-analysis. Network meta-analysis for persistent infection with HPV 16 (a), Persistent infection with HPV 18 (b), Cervical intraepithelial neoplasia grade 2 or worse associated with HPV 16 (c), Cervical intraepithelial neoplasia grade 2 or worse associated with HPV 18 (d), Persistent infection with HPV 31 (e), Persistent infection with HPV 33 (f), Persistent infection with HPV 45 (g), Persistent infection with HPV 52 (h), and persistent infection with HPV 58 (i). Results are column-defined RRs in treatment compared with row-defined RRs in treatment. RR, risk ratio; vHPV, valent human papillomavirus.

Figure 4. Probability of efficacy rankings for each vaccine. Probability of vaccines’ efficacy for persistent infection with HPV 16 (a), Persistent infection with HPV 18 (b), Cervical intraepithelial neoplasia grade 2 or worse associated with HPV 16 (c), Cervical intraepithelial neoplasia grade 2 or worse associated with HPV 18 (d), Persistent infection with HPV 31 (e), Persistent infection with HPV 33 (f), Persistent infection with HPV 45 (g), Persistent infection with HPV 52 (h), and persistent infection with HPV 58 (i). The ranking for each vaccine is shown on a cumulative probability plot, with the area under the curve representing the magnitude of the probability. Higher rankings indicate greater efficacy. vHPV, valent human papillomavirus.

Huh WK, Joura EA, Giuliano AR, et al. Final efficacy, immunogenicity, and safety analyses of a nine-valent human papillomavirus vaccine in women aged 16-26 years: a randomised, double-blind trial. Lancet. 2017 Nov 11;390(10108):2143–2159. doi: 10.1016/S0140-6736(17)31821-4

 PubMed Web of Science ®Google Scholar

Joura EA, Giuliano AR, Iversen OE, et al. A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. N Engl J Med. 2015 Feb 19;372(8):711–723. doi: 10.1056/NEJMoa1405044

 PubMed Web of Science ®Google Scholar

Brown DR, Kjaer SK, Sigurdsson K, et al. The impact of quadrivalent human papillomavirus (HPV; types 6, 11, 16, and 18) L1 virus-like particle vaccine on infection and disease due to oncogenic nonvaccine HPV types in generally HPV-naive women aged 16-26 years. J Infect Dis. 2009 Apr 1;199(7):926–935. doi: 10.1086/597307

 PubMed Web of Science ®Google Scholar

Muñoz N, Kjaer SK, Sigurdsson K, et al. Impact of human papillomavirus (HPV)-6/11/16/18 vaccine on all HPV-associated genital diseases in young women. J Natl Cancer Inst. 2010 Mar 3;102(5):325–339. doi:10.1093/jnci/djp534

 PubMed Web of Science ®Google Scholar

Malagón T, Drolet M, Boily MC, et al. Cross-protective efficacy of two human papillomavirus vaccines: a systematic review and meta-analysis. Lancet Infect Dis. 2012 Oct;12(10):781–789. doi: 10.1016/S1473-3099(12)70187-1

 PubMed Web of Science ®Google Scholar

Zhao FH, Wu T, Hu YM, et al. Efficacy, safety, and immunogenicity of an Escherichia coli-produced human papillomavirus (16 and 18) L1 virus-like-particle vaccine: end-of-study analysis of a phase 3, double-blind, randomised, controlled trial. Lancet Infect Dis. 2022 Dec;22(12):1756–1768. doi: 10.1016/S1473-3099(22)00435-2

 PubMed Web of Science ®Google Scholar

Qiao YL, Wu T, Li RC, et al. Efficacy, safety, and immunogenicity of an Escherichia coli-produced Bivalent human papillomavirus vaccine: an interim analysis of a randomized clinical trial. J Natl Cancer Inst. 2020 Feb 1;112(2):145–153. doi: 10.1093/jnci/djz074

 PubMedGoogle Scholar

Zhu FC, Chen W, Hu YM, et al. Efficacy, immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine in healthy Chinese women aged 18-25 years: results from a randomized controlled trial. Int J Cancer. 2014 Dec 1;135(11):2612–2622. doi: 10.1002/ijc.28897

 PubMed Web of Science ®Google Scholar

Zhu FC, Hu SY, Hong Y, et al. Efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine in Chinese women aged 18-25 years: event-triggered analysis of a randomized controlled trial. Cancer Med. 2017 Jan;6(1):12–25. doi: 10.1002/cam4.869

 PubMed Web of Science ®Google Scholar

Zhu FC, Hu SY, Hong Y, et al. Efficacy, immunogenicity and safety of the AS04-HPV-16/18 vaccine in Chinese women aged 18-25 years: end-of-study results from a phase II/III, randomised, controlled trial. Cancer Med. 2019 Oct;8(14):6195–6211. doi: 10.1002/cam4.2399

 PubMed Web of Science ®Google Scholar

Hildesheim A, Wacholder S, Catteau G, et al. Efficacy of the HPV-16/18 vaccine: final according to protocol results from the blinded phase of the randomized Costa Rica HPV-16/18 vaccine trial. Vaccine. 2014 Sep 3;32(39):5087–5097. doi: 10.1016/j.vaccine.2014.06.038

 PubMed Web of Science ®Google Scholar

Herrero R, Wacholder S, Rodríguez AC, et al. Prevention of persistent human papillomavirus infection by an HPV16/18 vaccine: a community-based randomized clinical trial in Guanacaste, Costa Rica. Cancer Discov. 2011 Oct;1(5):408–419. doi: 10.1158/2159-8290.CD-11-0131

 PubMed Web of Science ®Google Scholar

Harper DM, Franco EL, Wheeler CM, et al. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet. 2006 Apr 15;367(9518):1247–1255. doi: 10.1016/S0140-6736(06)68439-0

 PubMed Web of Science ®Google Scholar

Romanowski B, de Borba PC, Naud PS, et al. Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebo-controlled trial up to 6.4 years. Lancet. 2009 Dec 12;374(9706):1975–1985. doi: 10.1016/S0140-6736(09)61567-1

 PubMed Web of Science ®Google Scholar

Konno R, Tamura S, Dobbelaere K, et al. Efficacy of human papillomavirus 16/18 AS04-adjuvanted vaccine in Japanese women aged 20 to 25 years: interim analysis of a phase 2 double-blind, randomized, controlled trial. Int J Gynecol Cancer. 2010 Apr;20(3):404–410. doi: 10.1111/IGC.0b013e3181d373a5

 PubMed Web of Science ®Google Scholar

Konno R, Yoshikawa H, Okutani M, et al. Efficacy of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical intraepithelial neoplasia and cervical infection in young Japanese women. Hum Vaccin Immunother. 2014;10(7):1781–1794. doi: 10.4161/hv.28712

 PubMed Web of Science ®Google Scholar

Wheeler CM, Castellsagué X, Garland SM, et al. Cross-protective efficacy of HPV-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by non-vaccine oncogenic HPV types: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial. Lancet Oncol. 2012 Jan;13(1):100–110. doi: 10.1016/S1470-2045(11)70287-X

 PubMed Web of Science ®Google Scholar

Lehtinen M, Paavonen J, Wheeler CM, et al. Overall efficacy of HPV-16/18 AS04-adjuvanted vaccine against grade 3 or greater cervical intraepithelial neoplasia: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial. Lancet Oncol. 2012 Jan;13(1):89–99. doi: 10.1016/S1470-2045(11)70286-8

 PubMed Web of Science ®Google Scholar

Apter D, Wheeler CM, Paavonen J, et al. Efficacy of human papillomavirus 16 and 18 (HPV-16/18) AS04-adjuvanted vaccine against cervical infection and precancer in young women: final event-driven analysis of the randomized, double-blind PATRICIA trial. Clin Vaccine Immunol. 2015 Apr;22(4):361–373. doi: 10.1128/CVI.00591-14

 PubMed Web of Science ®Google Scholar

Skinner SR, Szarewski A, Romanowski B, et al. Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 4-year interim follow-up of the phase 3, double-blind, randomised controlled VIVIANE study. Lancet. 2014 Dec 20;384(9961):2213–2227. doi: 10.1016/S0140-6736(14)60920-X

 PubMed Web of Science ®Google Scholar

Wheeler CM, Skinner SR, Del Rosario-Raymundo MR, et al. Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 7-year follow-up of the phase 3, double-blind, randomised controlled VIVIANE study. Lancet Infect Dis. 2016 Oct;16(10):1154–1168. doi: 10.1016/S1473-3099(16)30120-7

 PubMed Web of Science ®Google Scholar