Will the ongoing use of a two-dose, rather than three-dose schedule of pneumococcal conjugate vaccine, have similar impact in rural Gambia?

许多国家推出了肺炎球菌结合疫苗(PCV)，使用三到四个剂量程序，大大减少了侵袭性肺炎球菌病(IPD)和肺炎的发生。在接种疫苗的儿童中，群体保护效果预防的病例多于直接影响。许多非洲和亚洲国家现已在婴儿早期采用三剂标准计划(3+0计划)采用PCV。来自南非和肯尼亚的数据表明，PCV的直接和牛群保护作用是巨大的。在冈比亚，我们观察到，在引入PCV后，由于疫苗血清型(VT)，IPD减少了90%。然而，肺炎球菌病的全球控制受到PCV费用的阻碍。低收入国家通过全球疫苗和免疫联盟获得补贴疫苗。然而，当各国的人均收入超过世界银行的“低收入”门槛时，它们就会从全球疫苗和免疫联盟的资助和共同支付中“毕业”。未来5年，全球疫苗和免疫联盟将在PCV上花费28亿美元，约占其疫苗预算的一半。成本使大多数中等收入国家无法引入PCV，为了有效，两剂PCV必须在婴儿期提供充分的直接保护，并保持VT肺炎球菌在社区中的低传播，这对维持羊群保护至关重要。事实上，随着免疫接种计划的成熟，羊群保护的作用变得比直接保护更重要。因此，我们建议测试一个包括9个月龄加强剂量的疫苗计划，与没有加强剂量的计划相比，这与1-4岁时更高的抗体水平和1-2岁时对肺炎球菌携带的更好保护有关。我们假设，新时间表中的第一剂疫苗(在6周龄时)将在我们的环境中提供预防2-9个月龄VT疾病的低风险。我们假设，与3+0计划相比，9个月龄的加强剂量将在1-3岁提供更好的直接和羊群保护效果。这项试验将比较根据政府免疫诊所提供的两剂和三剂PCV计划，这些诊所服务于离散地理地区的亚群。我们计划在4年内向居住在试验区的婴儿提供两剂(6周和9个月，1+1)或三剂(6，10，14周，3+0)的计划。免疫接种计划将在68个免疫诊所接种疫苗，服务于不同的集水区人群(群组)。免疫诊所的受试者将随机分为试验组(1+1或3+0)。在整个试验期间，将通过监测1-59个月龄组的IPD、肺炎和死亡率来进行安全监测。在为两个时间表的潜在不同影响留出时间后，研究终点将在试验的第四年进行测量。主要终点将是1-59个月大的临床肺炎儿童鼻咽携带VT肺炎球菌。次要终点将是6-12周婴儿出现第一剂PCV时VT携带者。分析将测试两组之间的VT携带量差异是否小于预先设定的阈值。数学建模将探索加强剂量和引入羊群保护所需的覆盖率的作用。模型输入将包括试验数据和社区肺炎球菌携带率和人际接触模式调查的数据。我们将对1+1和3+0时间表进行成本效益分析。最后，我们将与世卫组织合作，对影响实施1+1时间表的因素进行多国调查。

Many countries have introduced pneumococcal conjugate vaccines (PCV) using three or four dose schedules with substantial reductions of invasive pneumococcal disease (IPD) and pneumonia. Herd protection effects have prevented more cases than the direct effects in vaccinated children. Many African and Asian countries have now introduced PCV using the standard schedule of three doses in early infancy (3+0 schedule). Data from South Africa and Kenya suggest that direct and herd protection effects of PCV are substantial. In The Gambia, we have observed a 90% reduction in IPD due to vaccine serotypes (VT) following the introduction of PCV. Global control of pneumococcal disease however, is hampered by the cost of PCV. Low-income countries receive subsidised vaccine through the GAVI Alliance. However, when countries' per capita income exceeds the World Bank 'low-income' threshold, they 'graduate' from GAVI support and co-payments increase substantially. GAVI will spend 2.8 billion USD on PCV in the next 5 years, which represents approximately half of its vaccine budget. Cost has prevented most middle-income countries from introducing PCV.To be effective, a two-dose schedule of PCV must provide adequate direct protection in infancy and maintain the low transmission of VT pneumococci in the community that is critical to sustain herd protection. In fact, as immunisation programmes mature the role of herd protection becomes predominant over that of direct protection. Thus, we propose to test a vaccine schedule that includes a booster dose at 9 months of age, which when compared to schedules without a booster dose, has been associated with greater antibody levels at ages 1-4 years and greater protection against pneumococcal carriage at ages 1-2 years. We hypothesise that the first dose in the new schedule (at age 6 weeks) will provide protection against a low risk of VT disease from 2-9 months of age in our setting. We hypothesise that the booster dose at age 9 months will provide superior direct and herd protection effects from 1-3 years of age compared to the 3+0 schedule.This trial will compare two- versus three-dose schedules of PCV delivered according to government immunisation clinics which serve subpopulations in discrete geographic areas. We plan to deliver two-dose (doses at age 6 weeks and 9 months, '1+1') or three-dose (doses at age 6, 10, 14 weeks, '3+0') schedules to infants resident in the trial area over a period of 4 years. The immunisation programme will administer vaccines at 68 immunisation clinics serving separate catchment populations (clusters). The immunisation clinic catchment population will be randomised to either trial group (1+1 or 3+0). Safety monitoring by surveillance for IPD, pneumonia and mortality in the 1-59 month age group will be conducted throughout the trial. After allowing time for the potentially different effects of the two schedules to develop, the study endpoints will be measured during the 4th year of the trial. The primary endpoint will be nasopharyngeal carriage of VT pneumococci in children aged 1-59 months with clinical pneumonia. The secondary endpoint will be VT carriage in infants aged 6-12 weeks presenting for their 1st dose of PCV. The analysis will test whether the difference in VT carriage between the two groups is less than a pre-set threshold.Mathematical modelling will explore the role of the booster dose and the coverage needed to induce herd protection. Modelling inputs will include trial data and data from surveys of pneumococcal carriage and interpersonal contact patterns in the community. We will conduct a cost-effectiveness analysis of the 1+1 versus 3+0 schedule. Finally, working with WHO we will conduct a multi-country investigation of factors that will influence the implementation of 1+1 schedule.