Immunogenicity and safety of the human papillomavirus vaccine in young survivors of cancer in the USA: a single-arm, open-label, phase 2, non-inferiority trial.
Immunogenicity and safety of the human papillomavirus vaccine in young survivors of cancer in the USA: a single-arm, open-label, phase 2, non-inferiority trial.
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DOI：
10.1016/s2352-4642(21)00278-9
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发表时间：
2022-01
影响因子：
36.4
通讯作者：
Klosky, James L.
中科院分区：
文献类型：
--
作者：
Landier, Wendy;Bhatia, Smita;Wong, F. Lennie;York, Jocelyn M.;Flynn, Jessica S.;Henneberg, Harrison M.;Singh, Purnima;Adams, Kandice;Wasilewski-Masker, Karen;Cherven, Brooke;Jasty-Rao, Rama;Leonard, Marcia;Connelly, James A.;Armenian, Saro H.;Robison, Leslie L.;Giuliano, Anna R.;Hudson, Melissa M.;Klosky, James L.
年轻的癌症幸存者患与人乳头瘤病毒 (HPV) 相关的癌症的风险增加，主要由致癌 HPV 16 和 18 型引起。我们的目的是检查三剂量系列 HPV 疫苗在年轻癌症幸存者中的免疫原性和安全性。我们在美国国家癌症研究所指定的五个综合癌症中心进行了一项由研究者发起的、2 期、单组、开放标签、非劣效性试验。符合资格的参与者是未接种过 HPV 疫苗、年龄在 9 至 26 岁、处于缓解期、并在 1 至 5 年前完成癌症治疗的癌症幸存者。参与者在 6 个月内（第 1 天、第 2 个月和第 6 个月）接受了三剂四价 HPV 疫苗（HPV4；2016 年 3 月 1 日或之前登记）或非价 HPV 疫苗（HPV9；2016 年 3 月 1 日之后登记）肌肉注射。我们还从已发表的临床试验中获得了数据，该试验评估了 9-26 岁普通人群中 HPV4 和 HPV9 的安全性和免疫原性，作为比较组。主要终点是第 7 个月时符合方案人群针对 HPV 16 和 18 型的抗体反应。如果癌症幸存者与普通人群中抗 HPV-16 和抗 HPV-18 几何平均滴度 (GMT) 比率的多重调整 95% CI 下限大于 0·5，则认为反应不较差。按年龄组（即 9-15 岁和 16-26 岁）分别检查男性和女性参与者的反应。对所有接受至少一剂疫苗且可获得安全数据的参与者进行安全性评估。本研究已在 ClinicalTrials.gov 注册，NCT01492582。该试验现已完成。 2013年2月18日至2018年6月22日期间，我们招募了453名癌症幸存者，其中436人接受了一剂或多剂疫苗：203名（47%）参与者死于白血病，185名（42%）是女性，280名（64%）是非西班牙裔白人。首次给药的平均年龄为 15·6 岁 (SD 4·6)。 453 名参与者中的 378 名（83%）拥有可评估的免疫原性数据；排除在符合方案分析之外的主要原因是失访、患者原因和医疗原因。数据还从 26 486 个一般人群对照中获得。在两个疫苗队列中，癌症幸存者中所有亚组（即年龄 9-15 岁、16-26 岁、男性和女性组）的癌症幸存者中抗 HPV 16 型和 18 型的平均 GMT 比率均大于 1（接受 HPV9 的 9-15 岁女性参与者中抗 HPV 16 型的范围为 1·64 [95% CI 1·12–2·18]，在接受 HPV4 的 16-26 岁男性参与者中，抗 HPV 18 型为 4·77 [2·48–7·18]。除 16-26 岁女性参与者接受 HPV9 的 HPV 18 型外（4·30 [0·00–9·05]），每个年龄和性别亚组均满足非劣效标准。 435 名参与者中有 237 名 (54%) 报告了不良事件；注射部位疼痛最常见（174 名 [40%] 参与者）。一种严重不良事件（即结节性红斑）可能与疫苗（HPV9；16-26 岁女性队列）有关。癌症幸存者中 HPV 疫苗三剂系列的免疫原性和安全性与一般人群相似，为在这一临床易感人群中使用提供了证据。美国国家癌症研究所、Merck、Sharp & Dohme 和美国黎巴嫩叙利亚相关慈善机构。
Young survivors of cancer are at increased risk for cancers that are related to human papillomavirus (HPV), primarily caused by oncogenic HPV types 16 and 18. We aimed to examine the immunogenicity and safety of the three-dose series of HPV vaccine in young survivors of cancer. We conducted an investigator-initiated, phase 2, single-arm, open-label, non-inferiority trial at five National Cancer Institute-designated comprehensive cancer centres in the USA. Eligible participants were survivors of cancer who were HPV vaccine-naive, were aged 9–26 years, in remission, and had completed cancer therapy between 1 and 5 years previously. Participants received three intramuscular doses of either quadrivalent HPV vaccine (HPV4; enrolments on or before March 1, 2016) or nonavalent HPV vaccine (HPV9; enrolments after March 1, 2016) over 6 months (on day 1, at month 2, and at month 6). We also obtained data from published clinical trials assessing safety and immunogenicity of HPV4 and HPV9 in 9–26-year-olds from the general population, as a comparator group. The primary endpoint was antibody response against HPV types 16 and 18 at month 7 in the per-protocol population. A response was deemed non-inferior if the lower bound of the multiplicity-adjusted 95% CI was greater than 0·5 for the ratio of anti-HPV-16 and anti-HPV-18 geometric mean titres (GMTs) in survivors of cancer versus the general population. Responses were examined separately in male and female participants by age group (ie, 9–15 years and 16–26 years). Safety was assessed in all participants who received at least one vaccine dose and for whom safety data were available. This study is registered with ClinicalTrials.gov, NCT01492582. This trial is now completed. Between Feb 18, 2013, and June 22, 2018, we enrolled 453 survivors of cancer, of whom 436 received one or more vaccine doses: 203 (47%) participants had survived leukaemia, 185 (42%) were female, and 280 (64%) were non-Hispanic white. Mean age at first dose was 15·6 years (SD 4·6). 378 (83%) of 453 participants had evaluable immunogenicity data; main reasons for exclusion from per-protocol analysis were to loss to follow-up, patient reasons, and medical reasons. Data were also obtained from 26 486 general population controls. The ratio of mean GMT for anti-HPV types 16 and 18 in survivors of cancer versus the general population was more than 1 for all subgroups (ie, aged 9–15 years, aged 16–26 years, male, and female groups) in both vaccine cohorts (ranging from 1·64 [95% CI 1·12–2·18] for anti-HPV type 16 in female participants aged 9–15 years who received HPV9, to 4·77 [2·48–7·18] for anti-HPV type 18 in male participants aged 16–26 years who received HPV4). Non-inferiority criteria were met within each age and sex subgroup, except against HPV type 18 in female participants aged 16–26 years receiving HPV9 (4·30 [0·00–9·05]). Adverse events were reported by 237 (54%) of 435 participants; injection site pain was most common (174 [40%] participants). One serious adverse event (ie, erythema nodosum) was possibly related to vaccine (HPV9; 16–26 year female cohort). Immunogenicity and safety of HPV vaccine three-dose series in survivors of cancer is similar to that in the general population, providing evidence for use in this clinically vulnerable population. US National Cancer Institute, Merck, Sharp & Dohme, and American Lebanese Syrian Associated Charities.