Background

A pneumococcal conjugate vaccine (PCV) specifically focused on serotypes associated with adult residual disease burden is urgently needed. We aimed to assess V116, an investigational 21-valent PCV, that contains pneumococcal polysaccharides (PnPs), which account for 74–94% of invasive pneumococcal disease in adults aged 65 years or older.

Methods

We did a phase 1/2, randomised, double-blind, active comparator-controlled, multicentre, non-inferiority and superiority trial. The phase 1 study was done at two clinical sites in the USA, and the phase 2 study was done in 18 clinical sites in the USA. Eligible participants were healthy adults with or without chronic medical conditions assessed as stable, aged 18–49 years in the phase 1 trial and aged 50 years or older in the phase 2 trial. Participants were excluded if they had a history of invasive pneumococcal disease or other culture-positive pneumococcal disease within the past 3 years, known hypersensitivity to a vaccine component, known or suspected impairment of immunological function, were pregnant or were breastfeeding, or had previously received any pneumococcal vaccine. Participants had to abstain from sexual activity or use protocol approved contraception. All participants were centrally randomly assigned to a vaccine group using an interactive response technology system. Participants and investigators were masked to group assignment. In phase 1, participants were randomly assigned (1:1:1) to receive a single dose of V116-1 (2 μg per pneumococcal polysaccharide [PnP] per 0·5 mL) or V116-2 (4 μg per PnP per 1·0 mL) or the 23-valent unconjugated PnP vaccine, PPSV23 (25 μg per PnP per 0·5 mL). In phase 2, participants were randomly assigned (1:1) to receive one dose of V116 (4 μg per PnP per 1·0 mL) or PPSV23 (25 μg per PnP per 0·5 mL), stratified by age. Safety analyses included all randomly assigned participants who received study vaccine; immunogenicity analyses were per protocol. For both phases, the primary safety outcome was the proportion of participants with solicited injection-site adverse events and solicited systemic adverse events up to day 5 after vaccination and the proportion of participants with vaccine-related serious adverse events to 6 months after vaccination. In phase 2, primary immunogenicity outcomes were to test non-inferiority of V116 compared with PPSV23 as measured by serotype-specific opsonophagocytic antibody geometric mean titres (OPA-GMT) ratios for the serotypes common to the two vaccines at 30 days after vaccination (using a 0·33 margin) and to test superiority of V116 compared with PPSV23 as measured by serotype-specific OPA-GMT ratios for the serotypes unique to V116 at 30 days after vaccination (using a 1·0 margin). This trial is registered with Clinicaltrials.gov, NCT04168190.

Findings

Between Dec 6 and 26, 2019, 92 volunteers were screened and 90 (98%) enrolled for phase 1 (59 [66%] women; 31 [34%] men); 30 participants were assigned to each group and received study vaccine. 30 (100%) participants in the V116-1 group, 29 (97%) in the V116-2 group, and 30 (100%) participants in the PPSV23 group were included in the per-protocol immunogenicity evaluation. From Sept 23, 2020, to Jan 12, 2021, 527 volunteers were screened, and 510 (97%) participants were enrolled in the phase 2 trial. 508 participants (>99%; 254 [100%] of 254 participants randomly assigned to the V116 group and 254 [99%] of 256 randomly assigned to PPSV23 group) received study vaccine (281 [55%] women; 227 [45%] men). 252 (99%) of 254 of participants in the V116 group and 254 (99%) of 256 participants in the PPSV23 group were included in the primary immunogenicity analyses. There were no vaccine-related serious adverse events or vaccine-related deaths in either study phase. In both phases, the most common solicited injection site adverse event was injection site pain (phase 1 22 [73%] participants in V116-1 group, 23 [77%] participants in V116-2 group, and 17 [57%] participants in the PPSV23 group; phase 2 118 [46%] of 254 participants in the V116 group and 96 [38%] of 254 in the PPSV23 group]. The most common solicited systemic adverse events in phase 1 was fatigue (eight [27%] participants in the V116-1 group, eight [27%] participants in the V116-2 group, and five [17%] participants in PPSV23 group) and myalgia (eight [27%] participants in the V116-1 group, nine (30%) participants in the V116-2 group, and four (13%) participants in the PPSV23 group]. In phase 2, the most frequently reported solicited systemic adverse event was fatigue (49 [19%] participants in V116 group, and 31 [12%] participants in PPSV23 group). In both phases, most of the solicited adverse events in all vaccine groups were mild and of short duration (≤3 days). V116 met non-inferiority criteria compared with PPSV23 for the 12 shared serotypes and met superiority criteria compared to PPSV23 for the nine unique serotypes.

Interpretation

V116 was well tolerated with a safety profile generally similar to PPSV23; consistent with licensed pneumococcal conjugate vaccines. Functional OPA antibodies were induced to all V116 vaccine serotypes. The vaccine was non-inferior to PPSV23 for the 12 serotypes common to both vaccines and superior to PPSV23 for the nine unique serotypes in V116. Our findings support the development of V116 for prevention of pneumococcal disease in adults.

Funding

Merck Sharp & Dohme, subsidiary of Merck & Co, Rahway, NJ, USA.

中文翻译：

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21 价肺炎球菌结合疫苗 V116 在健康成人中的安全性、耐受性和免疫原性：1/2 期、随机、双盲、主动对照、多中心、美国试验

背景

迫切需要一种专门针对与成人残留疾病负担相关的血清型的肺炎球菌结合疫苗 (PCV)。我们旨在评估 V116，这是一种研究性 21 价 PCV，它含有肺炎球菌多糖 (PnP)，占 65 岁或以上成年人侵袭性肺炎球菌疾病的 74-94%。

方法

我们进行了一项 1/2 期、随机、双盲、主动比较器对照、多中心、非劣效性和优效性试验。第一阶段研究在美国的两个临床地点进行，第二阶段研究在美国的 18 个临床地点进行。符合条件的参与者是有或没有慢性疾病的健康成年人，在 1 期试验中评估为稳定，年龄在 18-49 岁，在 2 期试验中年龄在 50 岁或以上。如果参与者在过去 3 年内有侵袭性肺炎球菌病史或其他培养阳性肺炎球菌病史、已知对疫苗成分过敏、已知或疑似免疫功能受损、怀孕或正在哺乳，或之前接受过疫苗接种，则被排除在外任何肺炎球菌疫苗。参与者必须避免性活动或使用协议批准的避孕措施。使用交互式响应技术系统，所有参与者都被集中随机分配到疫苗组。参与者和调查人员对分组分配设盲。在第 1 阶段，参与者被随机分配 (1:1:1) 接受单剂量 V116-1（每 0·5 mL 每肺炎球菌多糖 [PnP] 2 微克）或 V116-2（每 PnP 4 微克每 1 ·0 mL) 或 23 价未结合的 PnP 疫苗 PPSV23（每 0·5 mL 每 PnP 25 μg）。在第 2 阶段，参与者被随机分配 (1:1) 接受一剂 V116（每 PnP 每 1·0 mL 4 μg）或 PPSV23（每 PnP 每 0·5 mL 25 μg），按年龄分层。安全性分析包括所有随机分配的接受研究疫苗的参与者；免疫原性分析按照方案进行。对于两个阶段，主要安全性结果是疫苗接种后第 5 天发生注射部位不良事件和全身不良事件的参与者比例，以及疫苗接种后 6 个月内发生疫苗相关严重不良事件的参与者比例。在第 2 阶段，主要免疫原性结果是测试 V116 与 PPSV23 相比的非劣效性，这是通过疫苗接种后 30 天两种疫苗共有的血清型的血清型特异性调理吞噬抗体几何平均滴度 (OPA-GMT) 比率来衡量的（使用0·33 边缘）并测试 V116 与 PPSV23 相比的优势，这是通过疫苗接种后 30 天 V116 特有血清型的血清型特异性 OPA-GMT 比率来衡量的（使用 1·0 边缘）。该试验已在 Clinicaltrials.gov 注册，NCT04168190。

发现

2019 年 12 月 6 日至 26 日期间，对 92 名志愿者进行了筛选，90 名 (98%) 登记参加了第一阶段（59 名 [66%] 女性；31 名 [34%] 男性）；每组分配 30 名参与者并接种研究疫苗。V116-1 组的 30 名 (100%) 参与者、V116-2 组的 29 名 (97%) 参与者和 PPSV23 组的 30 名 (100%) 参与者被纳入符合方案的免疫原性评估。从 2020 年 9 月 23 日到 2021 年 1 月 12 日，筛选了 527 名志愿者，510 名 (97%) 参与者参加了 2 期试验。508 名参与者（>99%；随机分配到 V116 组的 254 名参与者中的 254 名 [100%] 和随机分配到 PPSV23 组的 256 名参与者中的 254 名 [99%]）接受了研究疫苗（281 名 [55%] 女性；227 名 [45%] ] 男人）。V116 组 254 名参与者中的 252 名 (99%) 和 PPSV23 组 256 名参与者中的 254 名 (99%) 被纳入主要免疫原性分析。在两个研究阶段均未发生与疫苗相关的严重不良事件或与疫苗相关的死亡。在这两个阶段，最常见的注射部位不良事件是注射部位疼痛（第 1 阶段 V116-1 组有 22 [73%] 名参与者，V116-2 组有 23 [77%] 名参与者，V116-2 组有 17 [57%] 名参与者在 PPSV23 组；第 2 阶段 V116 组 254 名参与者中的 118 名 [46%] 和 PPSV23 组 254 名参与者中的 96 名 [38%]]。第 1 阶段最常见的系统性不良事件是疲劳（8 [27%] ] V116-1 组参与者，V116-2 组八名 [27%] 参与者，PPSV23 组五名 [17%] 参与者）和肌痛（V116-1 组八名 [27%] 参与者，V116-2 组有 9 名 (30%) 参与者，PPSV23 组有 4 名 (13%) 参与者]。在第 2 阶段，最常报告的系统性不良事件是疲劳（V116 组有 49 名 [19%] 名参与者，PPSV23 组有 31 名 [12%] 名参与者）。在这两个阶段，所有疫苗组中的大多数不良事件都是轻微的且持续时间短（≤3 天）。对于 12 种共有血清型，V116 与 PPSV23 相比达到了非劣效性标准，而对于 9 种独特血清型，V116 达到了与 PPSV23 相比的优效性标准。在所有疫苗组中，大多数征求的不良事件都是轻微的且持续时间短（≤3 天）。对于 12 种共有血清型，V116 与 PPSV23 相比达到了非劣效性标准，而对于 9 种独特血清型，V116 达到了与 PPSV23 相比的优效性标准。在所有疫苗组中，大多数征求的不良事件都是轻微的且持续时间短（≤3 天）。对于 12 种共有血清型，V116 与 PPSV23 相比达到了非劣效性标准，而对于 9 种独特血清型，V116 达到了与 PPSV23 相比的优效性标准。

解释

V116 耐受性良好，安全性与 PPSV23 基本相似；与获得许可的肺炎球菌结合疫苗一致。对所有 V116 疫苗血清型都诱导了功能性 OPA 抗体。该疫苗在两种疫苗共有的 12 种血清型方面不劣于 PPSV23，在 V116 中的九种独特血清型方面优于 PPSV23。我们的研究结果支持开发用于预防成人肺炎球菌疾病的 V116。

资金

Merck Sharp & Dohme，默克公司的子公司，位于美国新泽西州拉威。