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Randomized Controlled Trial
. 2017 Jun 1;215(11):1711-1719.
doi: 10.1093/infdis/jix154.

Sustained Immunogenicity of 2-dose Human Papillomavirus 16/18 AS04-adjuvanted Vaccine Schedules in Girls Aged 9-14 Years: A Randomized Trial

Li-Min Huang  1 , Thanyawee Puthanakit  2 , Chiu Cheng-Hsun  3 , Tang Ren-Bin  4 , Tino Schwarz  5 , Angelo Pellegrino  6 , Susanna Esposito  7 , Louise Frenette  8 , Shelly McNeil  9 , Paolo Durando  10 , Paul Rheault  11 , Carlo Giaquinto  12 , Michael Horn  13 , Karl Ulrich Petry  14 , Klaus Peters  15 , Toma Azhar  16 , Peter Hillemanns  17 , Stephanie De Simoni  18 , Damien Friel  18 , Suryakiran Pemmaraju  19 , Marjan Hezareh  20 , Florence Thomas  18 , Dominique Descamps  18 , Nicolas Folschweiller  18 , Frank Struyf  18
Affiliations
Randomized Controlled Trial

Sustained Immunogenicity of 2-dose Human Papillomavirus 16/18 AS04-adjuvanted Vaccine Schedules in Girls Aged 9-14 Years: A Randomized Trial

Li-Min Huang et al. J Infect Dis. .

Abstract

Background: We previously reported the noninferiority 1 month after the last dose of 2-dose human papillomavirus 16/18 AS04-adjuvanted (AS04-HPV-16/18) vaccine schedules at months 0 and 6 (2D_M0,6) and months 0 and 12 (2D_M0,12) in girls aged 9-14 years compared with a 3-dose schedule at months 0, 1, and 6 (3D_M0,1,6) in women aged 15-25 years. Here, we report the results at study end (month 36 [M36]).

Methods: Girls were randomized 1:1 and received 2 vaccine doses either 6 months (2D_M0,6) or 12 months apart (2D_M0,12); women received 3 doses at months 0, 1, and 6 (3D_M0,1,6). Endpoints included noninferiority of HPV-16/18 antibodies for 2D_M0,6 versus 3D_M0,1,6; 2D_M0,12 versus 3D_M0,1,6; and 2D_M0,12 versus 2D_M0,6; and assessment of neutralizing antibodies, T cells, B cells, and safety.

Results: At M36, the 2D_M0,6 and 2D_M0,12 schedules remained noninferior to the 3D_M0,1,6 schedule in terms of seroconversion rates and 3D/2D geometric mean titers for anti-HPV-16 and anti-HPV-18. All schedules elicited sustained immune responses up to M36.

Conclusions: Both 2-dose schedules in young girls remained noninferior to the 3-dose schedule in women up to study conclusion at M36. The AS04-HPV-16/18 vaccine administered as a 2-dose schedule was immunogenic and well tolerated in young girls.

Keywords: 2-dose schedule; Cervarix; cervical cancer; human papillomavirus (HPV).

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Figures

Figure 1.
Figure 1.
Flow of participants. Abbreviations: 2D_M0,6, 2-dose schedule administered at months 0 and 6; 2D_M0,12, 2-dose schedule administered at months 0 and 12; 3D_M0,1,6, 3-dose schedule administered at months 0, 1, and 6; ATP-I, according-to-protocol cohort for immunogenicity; M, month; SAE, serious adverse event; TVC, total vaccinated cohort.
Figure 2.
Figure 2.
Anti–human papillomavirus (HPV) 16 (A) and anti–HPV-18 (B) antibody levels in initially seronegative participants at month 36 (according-to-protocol cohort for immunogenicity). Natural infection: Geometric mean titers in women aged 15–25 years who had cleared a natural infection in a previous trial (NCT00122681). Geometric mean titers were 29.8 and 22.7 enzyme-linked immunosorbent assay units (EU)/mL for HPV-16 and HPV-18 antibodies, respectively [34]. Plateau: Geometric mean titers at the plateau level (month 45–50 timepoint) in women aged 15–25 years who received 3 doses of the HPV-16/18 AS04–adjuvanted vaccine at months 0, 1, and 6 in a previous trial (NCT00120848). Geometric mean titers were 397.8 and 297.3 EU/mL for HPV-16 and HPV-18 antibodies, respectively [22]. The error bars represent 95% confidence intervals. Abbreviations: 2D_M0,6, 2-dose schedule administered at months 0 and 6 (n = 339); 2D_M0,12, 2-dose schedule administered at months 0 and 12 (n = 330); 3D_M0,1,6, 3-dose schedule administered at months 0, 1, and 6 (n = 455); EU, enzyme-linked immunosorbent assay units; GMTs, geometric mean titers.
Figure 3.
Figure 3.
Anti–human papillomavirus (HPV) 16 (A) and anti–HPV-18 (B) neutralizing antibody levels in initially seronegative participants at month 36 (according-to-protocol cohort for immunogenicity). Pseudovirion-based neutralization assay (PBNA) cutoff: 40 ED50. Natural infection: Geometric mean titers corresponding to natural infection in a previous study. Geometric mean titers measured by PBNA were 180.1 ED50 for HPV-16 and 137.3 ED50 for HPV-18 [35]. The error bars represent 95% confidence intervals. Abbreviations: 2D_M0,6, 2-dose schedule administered at months 0 and 6 (n = 88); 2D_M0,12, 2-dose schedule administered at months 0 and 12 (n = 85); 3D_M0,1,6, 3-dose schedule administered at months 0, 1, and 6 (n = 95); ED50, estimated dose: serum dilution giving a 50% reduction of the signal compared to a control without serum; GMT, geometric mean titer; PBNA, pseudovirion-based neutralization assay.
Figure 4.
Figure 4.
Human papillomavirus (HPV) 16–specific (A) and HPV-18–specific (B) CD4+ T-cell responses at month 36 (according-to-protocol cohort for immunogenicity). Boxplots show median, lower quartile, and upper quartile frequency of cells. Abbreviations: 2D_M0,6, 2-dose schedule administered at months 0 and 6 (n = 75 [A] and 72 [B]); 2D_M0,12, 2-dose schedule administered at months 0 and 12 (n = 70 [A] and 75 [B]); 3D_M0,1,6, 3-dose schedule administered at months 0, 1, and 6 (n = 57 [A] and 56 [B]); HPV, human papillomavirus.
Figure 5.
Figure 5.
Human papillomavirus (HPV) 16–specific (A) and HPV-18–specific (B) B-cell responses at month 36 (according-to-protocol cohort for immunogenicity). Boxplots show median, lower quartile, and upper quartile frequency of cells. Abbreviations: 2D_M0,6, 2-dose schedule administered at months 0 and 6 (n = 70 [A] and 67 [B]); 2D_M0,12, 2-dose schedule administered at months 0 and 12 (n = 67 [A] and 72 [B]); 3D_M0,1,6, 3-dose schedule administered at months 0, 1 and 6 (n = 53 [A] and 54 [B]); HPV, human papillomavirus.
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