Cortés Bernal, Ocampo Rebeca, Porras Carolina, Liu Danping, Gail Mitchell H, Sierra Monica S, Herrero Rolando, Lowy Douglas R, Carvajal Loretto J, Kemp Troy J, Fantin Romain, Schussler John, Hildesheim Allan, Sampson Joshua N, Pinto Ligia A, Schiller John T, Kreimer Aimée R
Agencia Costarricense de Investigaciones Biomédicas (ACIB-FUNIN), San José, Costa Rica.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
Lancet Infect Dis. 2025 Jul 16. doi: 10.1016/S1473-3099(25)00284-1.
In 2022, WHO recommended single-dose human papillomavirus (HPV) vaccination as an alternative schedule to multidose regimens. To provide evidence to support approval of a single-dose indication for the AS04-adjuvanted bivalent HPV vaccine (Cervarix, GlaxoSmithKline), we investigated whether the immune response to a single dose of the bivalent vaccine in girls aged 9-14 years was non-inferior to the immune response to three doses of the quadrivalent HPV vaccine (Gardasil-4, Merck) in women aged 18-25 years, a dose and population combination with demonstrated efficacy.
This non-randomised, open-label, immunobridging trial enrolled girls aged 9-14 years and women aged 18-25 years in Guanacaste Province, Costa Rica. Healthy girls aged 9-14 years received one dose of bivalent HPV vaccine, whereas healthy women aged 18-25 years received three doses of quadrivalent HPV vaccine at 0, 2, and 6 months. The primary endpoint was geometric mean concentrations (GMCs) of HPV-specific serum antibodies measured by a validated virus-like-particle-based ELISA assay at 36 months. The per-protocol cohort included participants who received the correct number of doses within the predefined vaccination windows, had blood collected at the 36-month study visit for the final analysis, were seronegative at baseline for the specified HPV type, and did not receive additional HPV vaccine doses outside the study. Non-inferiority was declared when the lower bound of the 96% CI for the GMC ratio was greater than or equal to 0·67 for HPV-16 and HPV-18. Seropositivity was a secondary objective. Safety was analysed in the total vaccinated population. This trial is registered with ClinicalTrials.gov, NCT03728881, and is complete.
Between April 1 and Aug 16, 2019, 620 girls and 620 women were enrolled and received their first HPV vaccination. After exclusions, 539 girls and 366 women were HPV-16 seronegative at enrolment and were included in the HPV-16 per-protocol cohort; 523 girls and 373 women were HPV-18 seronegative at enrolment and were included in the HPV-18 per-protocol cohort. At 36 months, the HPV-16 GMC was 21·4 international units (IU)/mL (95% CI 19·7-23·3) in girls in the single-dose bivalent vaccine group and 42·9 IU/mL (95% CI 38·9-47·3) in women in the three-dose quadrivalent vaccine group, resulting in a GMC ratio of 0·50 (96% CI 0·44-0·57); the HPV-18 GMC was 8·0 IU/mL (95% CI 7·4-8·8) in girls in the single-dose bivalent vaccine group and 7·2 IU/mL (95% CI 6·4-8·1) in women in the three-dose quadrivalent vaccine group, resulting in a GMC ratio of 1·11 (96% CI 0·95-1·29). At 36 months, 538 (99·8%, 95% CI 99·1-100) of 539 girls in the single-dose bivalent vaccine group were seropositive for HPV-16 compared with 366 (100%, 99·2-100) of 366 women in the three-dose quadrivalent vaccine group (p=1·00). The proportion of participants who were seropositive for HPV-18 was higher in the single-dose bivalent vaccine group (517 [98·9%, 95% CI 97·6-99·5] of 523 girls) than in the three-dose quadrivalent vaccine group (358 [96·0%, 93·6-97·6] of 373 women; p=0·0065). Two serious adverse events were reported in 620 girls and 13 serious adverse events were reported in 620 women; all serious adverse events were deemed to be unrelated to HPV vaccination.
Non-inferior antibody responses for the single-dose bivalent HPV vaccine were seen for HPV-18 but not HPV-16, which would be insufficient evidence to motivate regulatory change, even though seropositivity approached 100% in the follow-up phase and the observed antibody concentrations were similar to protective levels seen in previous trials. Trials that directly evaluate protection afforded by single-dose HPV vaccination against persistent HPV infection will definitively address the level of protection afforded by single-dose HPV vaccination.
National Cancer Institute, Cancer Research UK, and the Gates Foundation.
For the Spanish translation of the abstract see Supplementary Materials section.
2022年，世界卫生组织推荐单剂量人乳头瘤病毒（HPV）疫苗接种作为多剂量方案的替代接种程序。为提供证据支持批准佐剂为AS04的二价HPV疫苗（希瑞适，葛兰素史克公司）的单剂量适应证，我们研究了9至14岁女孩单剂量接种二价疫苗后的免疫反应是否不劣于18至25岁女性接种三剂四价HPV疫苗（佳达修4，默克公司）后的免疫反应，后者是一种已证实有效的剂量和人群组合。
这项非随机、开放标签的免疫桥接试验在哥斯达黎加瓜纳卡斯特省招募了9至14岁的女孩和18至25岁的女性。9至14岁的健康女孩接种一剂二价HPV疫苗，而18至25岁的健康女性在0、2和6个月时接种三剂四价HPV疫苗。主要终点是在36个月时通过基于病毒样颗粒的经验证的酶联免疫吸附测定法测量的HPV特异性血清抗体的几何平均浓度（GMC）。符合方案队列包括在预定接种窗口内接种正确剂数、在36个月研究访视时采血进行最终分析、在基线时针对特定HPV型别血清学阴性且在研究外未接种额外HPV疫苗剂量的参与者。当HPV-16和HPV-18的GMC比值的96%置信区间下限大于或等于0.67时，宣布非劣效性。血清阳性是次要目标。在所有接种疫苗的人群中分析安全性。本试验已在ClinicalTrials.gov注册，注册号为NCT03728881，且已完成。
2019年4月1日至8月16日，620名女孩和620名女性入组并接受了首次HPV疫苗接种。排除后，539名女孩和366名女性在入组时HPV-16血清学阴性，被纳入HPV-16符合方案队列；523名女孩和373名女性在入组时HPV-18血清学阴性，被纳入HPV-18符合方案队列。在36个月时，单剂量二价疫苗组女孩的HPV-16 GMC为21.4国际单位（IU）/mL（95%置信区间19.7 - 23.3），三剂四价疫苗组女性的为42.9 IU/mL（95%置信区间38.9 - 47.3），GMC比值为0.50（96%置信区间0.44 - 0.57）；单剂量二价疫苗组女孩的HPV-18 GMC为8.0 IU/mL（95%置信区间7.4 - 8.8），三剂四价疫苗组女性的为7.2 IU/mL（95%置信区间6.4 - 8.1），GMC比值为1.11（96%置信区间0.95 - 1.29）。在36个月时，单剂量二价疫苗组539名女孩中有538名（99.8%，95%置信区间99.1 - 100）HPV-16血清阳性，而三剂四价疫苗组366名女性中有366名（100%，99.2 - 100）（p = 1.00）。单剂量二价疫苗组HPV-18血清阳性的参与者比例高于三剂四价疫苗组（523名女孩中有517名[98.9%，95%置信区间97.6 - 99.5]）（373名女性中有358名[96.0%，93.6 - 97.6]；p = 0.0065）。620名女孩中报告了2例严重不良事件，620名女性中报告了13例严重不良事件；所有严重不良事件均被认为与HPV疫苗接种无关。
单剂量二价HPV疫苗在HPV-18方面显示出非劣效抗体反应，但在HPV-16方面未显示，这不足以作为推动监管变更的证据，尽管在随访阶段血清阳性率接近100%且观察到的抗体浓度与先前试验中所见的保护水平相似。直接评估单剂量HPV疫苗接种对持续性HPV感染的保护作用的试验将明确解决单剂量HPV疫苗接种所提供的保护水平问题。
美国国立癌症研究所、英国癌症研究中心和盖茨基金会。
摘要的西班牙语译文见补充材料部分。
