Malawi Liverpool Wellcome Research Programme, Blantyre, Malawi.
Department of Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK; Critical Care Department, Liverpool University Hospitals NHS Foundation Trust, Liverpool, UK.
Lancet Microbe. 2023 Sep;4(9):e683-e691. doi: 10.1016/S2666-5247(23)00178-7.
The effect of childhood pneumococcal conjugate vaccine implementation in Malawi is threatened by absence of herd effect. There is persistent vaccine-type pneumococcal carriage in both vaccinated children and the wider community. We aimed to use a human infection study to measure 13-valent pneumococcal conjugate vaccine (PCV13) efficacy against pneumococcal carriage.
We did a double-blind, parallel-arm, randomised controlled trial investigating the efficacy of PCV13 or placebo against experimental pneumococcal carriage of Streptococcus pneumoniae serotype 6B (strain BHN418) among healthy adults (aged 18-40 years) from Blantyre, Malawi. We randomly assigned participants (1:1) to receive PCV13 or placebo. PCV13 and placebo doses were prepared by an unmasked pharmacist to maintain research team and participant masking with identification only by a randomisation identification number and barcode. 4 weeks after receiving either PCV13 or placebo, participants were challenged with 20 000 colony forming units (CFUs) per naris, 80 000 CFUs per naris, or 160 000 CFUs per naris by intranasal inoculation. The primary endpoint was experimental pneumococcal carriage, established by culture of nasal wash at 2, 7, and 14 days. Vaccine efficacy was estimated per protocol by means of a log-binomial model adjusting for inoculation dose. The trial is registered with the Pan African Clinical Trials Registry, PACTR202008503507113, and is now closed.
Recruitment commenced on April 27, 2021 and the final visit was completed on Sept 12, 2022. 204 participants completed the study protocol (98 PCV13, 106 placebo). There were lower carriage rates in the vaccine group at all three inoculation doses (0 of 21 vs two [11%] of 19 at 20 000 CFUs per naris; six [18%] of 33 vs 12 [29%] of 41 at 80 000 CFUs per naris, and four [9%] of 44 vs 16 [35%] of 46 at 160 000 CFUs per naris). The overall carriage rate was lower in the vaccine group compared with the placebo group (ten [10%] of 98 vs 30 [28%] of 106; Fisher's p value=0·0013) and the vaccine efficacy against carriage was estimated at 62·4% (95% CI 27·7-80·4). There were no severe adverse events related to vaccination or inoculation of pneumococci.
This is, to our knowledge, the first human challenge study to test the efficacy of a pneumococcal vaccine against pneumococcal carriage in Africa, which can now be used to establish vaccine-induced correlates of protection and compare alternative strategies to prevent pneumococcal carriage. This powerful tool could lead to new means to enhance reduction in pneumococcal carriage after vaccination.
Wellcome Trust.
在马拉维，儿童型肺炎球菌结合疫苗的实施效果受到群体效应缺失的威胁。已接种疫苗的儿童和更广泛的社区中仍持续存在疫苗型肺炎球菌携带。我们旨在使用人体感染研究来衡量 13 价肺炎球菌结合疫苗（PCV13）对肺炎球菌携带的效果。
我们进行了一项双盲、平行臂、随机对照试验，研究了 PCV13 或安慰剂对来自马拉维布兰太尔的健康成年人（18-40 岁）中血清型 6B（菌株 BHN418）肺炎链球菌的实验性肺炎球菌携带的疗效。我们将参与者（1:1）随机分配接受 PCV13 或安慰剂。PCV13 和安慰剂剂量由一名未蒙面的药剂师制备，以保持研究团队和参与者的蒙眼状态，仅通过随机化识别号码和条形码进行识别。在接受 PCV13 或安慰剂后 4 周，通过鼻内接种将 20000 个菌落形成单位（CFU）/每侧鼻腔、80000 CFU/每侧鼻腔或 160000 CFU/每侧鼻腔的量对参与者进行挑战。主要终点是通过 2、7 和 14 天鼻冲洗培养确定的实验性肺炎球菌携带。通过对数二项式模型调整接种剂量来估计疫苗效力。该试验在泛非临床试验注册处（PACTR202008503507113）注册，现已关闭。
招募于 2021 年 4 月 27 日开始，最后一次随访于 2022 年 9 月 12 日完成。204 名参与者完成了研究方案（PCV13 组 98 名，安慰剂组 106 名）。在所有三种接种剂量下，疫苗组的携带率均较低（20000 CFU/每侧鼻腔接种时，21 人中无携带，19 人中有 2 人[11%]；80000 CFU/每侧鼻腔接种时，33 人中 6 人[18%]，41 人中有 12 人[29%]，160000 CFU/每侧鼻腔接种时，44 人中 4 人[9%]，46 人中有 16 人[35%]）。与安慰剂组相比，疫苗组的总体携带率较低（98 人中 10 人[10%]，106 人中 30 人[28%]；Fisher's p 值=0·0013），疫苗效力估计为 62.4%（95%CI 27.7-80.4）。没有与疫苗接种或肺炎球菌接种相关的严重不良事件。
这是我们所知的首个在非洲测试肺炎球菌疫苗对肺炎球菌携带的人体挑战研究，现在可以用于建立疫苗诱导的保护相关性，并比较预防肺炎球菌携带的替代策略。这种强大的工具可能会带来新的方法来增强接种疫苗后肺炎球菌携带的减少。
惠康信托基金会。
