Background

The AS04-adjuvanted HPV-16/18 (AS04-HPV-16/18) vaccine provides excellent protection against targeted HPV types and a variable degree of cross-protection against others, including types 6/11/31/33/45. High efficacy against any cervical intraepithelial neoplasia grade 3 or greater (CIN3+; >90%) suggests lower levels of protection may exist for a wide-range of oncogenic HPV types, which is difficult to quantify in individual trials. Pooling individual-level data from two randomized controlled trials (RCTs), we aimed to evaluate AS04-HPV-16/18 vaccine efficacy against incident HPV infections and cervical abnormalities.

Methods

Data were available from the Costa Rica Vaccine Trial (CVT; NCT00128661) and PATRICIA trial (NCT00122681) – two large-scale, double-blind RCTs of the AS04-HPV-16/18 vaccine. Primary analyses focused on disease-free women with no detectable cervicovaginal HPV at baseline.

Results

12,550 women were included in our primary analyses (HPV arm=6,271; control arm=6,279). Incidence of six month persistent oncogenic/non-oncogenic infections, excluding known/accepted protected types 6/11/16/18/31/33/45 (focusing on 34/35/39/40/42/43/44/51/52/53/54/56/58/59/66/68/73/70/74), was statistically significantly lower in the HPV arm than in the control arm (efficacy=9.9%, 95% Confidence Interval [CI] 1.7%-17.4%). Statistically significant efficacy (p < 0.05) was observed for individual oncogenic types 16/18/31/33/45/52 and non-oncogenic types 6/11/53/74. Efficacy against cervical abnormalities (all types) increased with severity, ranging from 27.7% (95% CI 21.7%-33.3%) to 58.7% (95% CI 34.1%-74.7%) for cytologic outcomes (low-grade squamous intraepithelial neoplasia lesion or greater, and high-grade squamous intraepithelial neoplasia lesion or greater, respectively) and 66.0% (95% CI 54.4%-74.9%) to 87.8% (95% CI 71.1%-95.7%) for histologic outcomes (CIN2+ and CIN3+, respectively). Comparing CVT and PATRICIA results, there was no evidence of heterogeneity, except for type 51 (efficacy=-28.6% and 20.7%, respectively; two-sided p = 0.03).

Conclusions

The AS04-HPV-16/18 vaccine provides some additional cross-protection beyond established protected types, which partially explains the high efficacy against CIN3+.

中文翻译：

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AS04 佐剂 HPV16/18 疫苗的功效：哥斯达黎加疫苗和 PATRICIA 随机对照试验的汇总分析。

 背景

AS04 佐剂 HPV-16/18 (AS04-HPV-16/18) 疫苗可针对目标 HPV 类型提供出色的保护，并针对其他类型（包括 6/11/31/33/45 型）提供不同程度的交叉保护。对任何 3 级或以上宫颈上皮内瘤变（CIN3+；>90%）的高效作用表明，对于多种致癌 HPV 类型可能存在较低水平的保护，这在个别试验中很难量化。我们汇集了两项随机对照试验 (RCT) 的个体水平数据，旨在评估 AS04-HPV-16/18 疫苗针对偶发 HPV 感染和宫颈异常的功效。

 方法

数据来自哥斯达黎加疫苗试验（CVT；NCT00128661）和 PATRICIA 试验（NCT00122681）——两项针对 AS04-HPV-16/18 疫苗的大规模双盲随机对照试验。主要分析集中于基线时未检测到宫颈阴道 HPV 的无病女性。

 结果

我们的主要分析纳入了 12,550 名女性（HPV 组=6,271；对照组=6,279）。六个月持续致癌/非致癌感染的发生率，不包括已知/接受的保护类型 6/11/16/18/31/33/45（重点关注 34/35/39/40/42/43/44/51/ 52/53/54/56/58/59/66/68/73/70/74），HPV 组在统计学上显着低于对照组（功效 = 9.9%，95% 置信区间 [CI] 1.7 %-17.4%）。对于个体致癌类型 16/18/31/33/45/52 和非致癌类型 6/11/53/74 观察到统计学上显着的疗效 (p < 0.05)。针对宫颈异常（所有类型）的疗效随着严重程度的增加而增加，细胞学结果（低度鳞状上皮内瘤变病变）的有效率为 27.7%（95% CI 21.7%-33.3%）至 58.7%（95% CI 34.1%-74.7%）组织学结果（CIN2+ 和 CIN3+，分别）。比较 CVT 和 PATRICIA 结果，除 51 型外，没有异质性证据（功效分别=-28.6% 和 20.7%；两侧 p = 0.03）。

 结论

AS04-HPV-16/18 疫苗在已建立的保护类型之外提供了一些额外的交叉保护，这部分解释了针对 CIN3+ 的高效性。