背景:为了满足全球消除宫颈癌的努力,我们需要更广泛的负担得起的人乳头瘤病毒(HPV)疫苗.我们的目的是评估四价HPV疫苗(针对HPV6、11、16和18型)的免疫原性和安全性。由印度血清研究所(SIIPL)开发和制造。在这里,我们报告了9-14年队列的结果。
方法:这是随机的,主动控制,2/3期试验在印度12家三级医院进行.没有HPV疫苗接种史的9-14岁或15-26岁的健康参与者符合招募条件。女性参与者被随机分配(1:1)使用交互式网络响应系统,通过使用中央计算机生成的时间表和块随机化(块大小为2、4、6和8),接受SIIPL四价HPV疫苗(Cervavac;SIIPL,浦那,印度)或比较四价HPV疫苗(Gardasil;MerckSharp&Dohme,Harleem,荷兰)。参与者,调查员,实验室技术人员,和赞助者对女性参与者的治疗分配进行了掩盖.男性参与者以开放标签的方式给予SIIPL四价HPV疫苗。在9-14岁的队列中,以两剂方案(第0天和第6个月)肌内注射研究疫苗,并且在15-26岁的队列中使用三剂量方案(在第0天,第2个月和第6个月)。在最后一次给药后30天通过使用多重ELISA评估免疫原性。主要结果是,就SIIPL四价HPV疫苗在女孩和男孩(9-14岁)中产生的针对HPV6、11、16和18型抗体的几何平均滴度(GMT)而言,免疫反应的非劣效性与在改良的按方案人群中第7个月时在15-26岁的女性中比较四价HPV疫苗产生的GMT(即,每个指定治疗组接受所有剂量研究疫苗的所有参与者,并在方案定义的窗口期后的最后一次给药后第0天和第1个月进行免疫原性测量,无主要方案偏差).如果GMT比率的98·75%CI的下限为0·67或更高,则可以确定非劣效性。在所有入选并接受至少一剂研究疫苗的参与者中评估征求的不良事件(在每次剂量的7天内)和非征求的不良事件(最后一次剂量后长达30天)的发生的共同主要结果。该试验已在印度临床试验注册中心注册(CTRI/2018/06/014601),长期随访正在进行中。
结果:在2018年9月20日至2021年2月9日之间,筛选了2341名个体,其中2307名符合条件的个体被纳入并接种疫苗:9-14岁队列中的1107人(738名女孩和369名男孩)和15-26岁队列中的1200人(819名女性和381名男性).没有收集种族或民族数据。SIIPL四价HPV疫苗组中的350名女孩和349名男孩以及比较疫苗组中的338名妇女被纳入修改的符合方案人群,用于主要终点分析。SIIPL四价HPV疫苗组中,女孩的中位随访时间为221天(IQR215-231),男孩为222天(217-230)。比较疫苗组中的女孩为223天(216-232),和222天(216-230)的妇女在比较疫苗组。与接受比较疫苗的女性相比,接受SIIPL四价HPV疫苗的女孩和男孩的GMT比率不低于:HPV6型女孩的GMT比率为1·97(98·75%CI1·67-2·32),HPV11型为1·63(1·38-1·91),HPV16型为1·90(1·60-2·25),HPV61型为2·16(1·79-对于男孩,HPV6型的GMT比率为1·86(1·57-2·21),HPV11型为1·46(1·23-1·73),HPV16型为1·62(1·36-1·94),HPV18型为1·80(1·48-2·18)。安全性人群包括所有1107名参与者(SIIPL四价HPV疫苗组的369名女孩和369名男孩,和369名女孩在比较组)。SIIPL疫苗组中369名女孩中有176名(48%),369名男孩中有124名(34%),比较疫苗组中369名女孩中有179名(49%)。在每个剂量的7天内没有发生3-4级请求的不良事件。在SIIPL疫苗组中,143名(39%)女孩和147名(40%)男孩发生了不请自来的不良事件,和143(39%)女孩在比较疫苗组。最常见的3级未经请求的不良事件是登革热,SIIPL疫苗组的一名(<1%)女孩和对照组的三名(1%)女孩。没有发生4级或5级不良事件。SIIPL疫苗组中3名(1%)女孩和3名(1%)男孩发生严重不良事件,比较疫苗组中有5名(1%)女孩。未报告疫苗相关的严重不良事件。没有治疗相关的死亡。
结论:我们观察到SIIPL四价HPV疫苗在9-14岁的女孩和男孩中的免疫反应不差,与比较疫苗相比,安全性可接受。这些发现支持在年轻人群中从比较疫苗到SIIPL四价HPV疫苗的效力外推。SIIPL四价HPV疫苗的可用性可以帮助满足全球对HPV疫苗的需求。并提高全球女孩和男孩的覆盖率。
背景:生物技术产业研究援助委员会,生物技术系(DBT),印度政府,和印度血清研究所。
To meet global cervical cancer elimination efforts, a wider range of affordable and accessible vaccines against human papillomavirus (HPV) are needed. We aimed to evaluate the immunogenicity and safety of a quadrivalent HPV vaccine (targeting HPV types 6, 11, 16, and 18), developed and manufactured by the Serum Institute of India (SIIPL). Here we report outcomes in the 9-14 years cohort.
This randomised, active-controlled, phase 2/3 trial was conducted at 12 tertiary care hospitals across India. Healthy participants aged 9-14 years or 15-26 years with no history of HPV vaccination were eligible for enrolment. Female participants were randomly assigned (1:1) with an interactive web response system, by use of a central computer-generated schedule and block randomisation (block sizes of 2, 4, 6, and 8), to receive the SIIPL quadrivalent HPV vaccine (Cervavac; SIIPL, Pune, India) or the comparator quadrivalent HPV vaccine (Gardasil; Merck Sharp & Dohme, Harleem, the Netherlands). Participants, investigators, laboratory technicians, and sponsors were masked to treatment allocation of female participants. Male participants were given the SIIPL quadrivalent HPV vaccine in an open-label manner. Study vaccines were administered intramuscularly with a two-dose schedule (at day 0 and 6 months) in the cohort aged 9-14 years, and with a three-dose schedule (at day 0, month 2, and month 6) in the cohort aged 15-26-years. Immunogenicity was assessed 30 days after the last dose by use of multiplexed ELISA. The primary outcome was the non-inferiority of immune response in terms of the geometric mean titre (GMT) of antibodies against HPV types 6, 11, 16, and 18 generated by the SIIPL quadrivalent HPV vaccine in girls and boys (aged 9-14 years) compared with the GMT generated by the comparator quadrivalent HPV vaccine in women aged 15-26 years at month 7 in the modified per-protocol population (ie, all participants who received all doses of study vaccines per assigned treatment group and had both day 0 and 1-month immunogenicity measurements after the last dose following protocol-defined window periods with no major protocol deviations). Non-inferiority was established if the lower bound of the 98·75% CI of the GMT ratio was 0·67 or higher. The co-primary outcome of occurrence of solicited adverse events (within 7 days of each dose) and unsolicited adverse events (up to 30 days after the last dose) was assessed in all participants who were enrolled and received at least one dose of study vaccine. The trial is registered with the Clinical Trials Registry - India (CTRI/2018/06/014601), and long-term follow-up is ongoing.
Between Sept 20, 2018, and Feb 9, 2021, 2341 individuals were screened, of whom 2307 eligible individuals were enrolled and vaccinated: 1107 (738 girls and 369 boys) in the cohort aged 9-14 years and 1200 (819 women and 381 men) in the cohort aged 15-26 years. No race or ethnicity data were collected. 350 girls and 349 boys in the SIIPL quadrivalent HPV vaccine group and 338 women in the comparator vaccine group were included in the modified per-protocol population for the primary endpoint analysis. The median follow-up for the analyses was 221 days (IQR 215-231) for girls and 222 days (217-230) for boys in the SIIPL quadrivalent HPV vaccine group, 223 days (216-232) for girls in the comparator vaccine group, and 222 days (216-230) for women in the comparator vaccine group. GMT ratios were non-inferior in girls and boys receiving the SIIPL quadrivalent HPV vaccine compared with women receiving the comparator vaccine: GMT ratios for girls were 1·97 (98·75% CI 1·67-2·32) for HPV type 6, 1·63 (1·38-1·91) for HPV type 11, 1·90 (1·60-2·25) for HPV type 16, and 2·16 (1·79-2·61) for HPV type 18. For boys the GMT ratios were 1·86 (1·57-2·21) for HPV type 6, 1·46 (1·23-1·73) for HPV type 11, 1·62 (1·36-1·94) for HPV type 16, and 1·80 (1·48-2·18) for HPV type 18. The safety population comprised all 1107 participants (369 girls and 369 boys in the SIIPL quadrivalent HPV vaccine group, and 369 girls in the comparator group). Solicited adverse events occurred in 176 (48%) of 369 girls and 124 (34%) of 369 boys in the SIIPL vaccine group and 179 (49%) of 369 girls in the comparator vaccine group. No grade 3-4 solicited adverse events occurred within 7 days of each dose. Unsolicited adverse events occurred in 143 (39%) girls and 147 (40%) boys in the SIIPL vaccine group, and 143 (39%) girls in the comparator vaccine group. The most common grade 3 unsolicited adverse event was dengue fever, in one (<1%) girl in the SIIPL vaccine group and three (1%) girls in the comparator group. There were no grade 4 or 5 adverse events. Serious adverse events occurred in three (1%) girls and three (1%) boys in the SIIPL vaccine group, and five (1%) girls in the comparator vaccine group. No vaccine-related serious adverse events were reported. There were no treatment-related deaths.
We observed a non-inferior immune response with the SIIPL quadrivalent HPV vaccine in girls and boys aged 9-14 years and an acceptable safety profile compared with the comparator vaccine. These findings support extrapolation of efficacy from the comparator vaccine to the SIIPL quadrivalent HPV vaccine in the younger population. The availability of the SIIPL quadrivalent HPV vaccine could help meet the global demand for HPV vaccines, and boost coverage for both girls and boys globally.
Biotechnology Industry Research Assistance Council, Department of Biotechnology (DBT), Government of India, and Serum Institute of India.