Duration of protection and density of colonisation following pneumococcal conjugate vaccination with a booster dose

在许多国家，肺炎球菌结合疫苗(PCV)的使用已经有效地控制了疫苗中包括的肺炎球菌血清型引起的肺炎球菌疾病。PCV计划一般使用三到四剂。在婴儿早期注射PCV可以预防疾病，并启动免疫系统，以便在以后的生活中做出反应。较晚的剂量，在9到18个月龄之间，会导致显著更强的免疫反应，被称为增强反应。尽管提供了PCV，但肺炎球菌疾病的全球控制受到成本的阻碍。全球疫苗和免疫联盟为低收入国家提供补贴疫苗。未来5年，全球疫苗和免疫联盟将在PCV上花费28亿美元，各国对全球疫苗和免疫联盟的共同支付数额很大。随着各国国民总收入的增加，它们的共同支付也在增加，在某个门槛上，它们就没有资格获得补贴疫苗。预计将有20多个国家在未来5年内“过渡”对全球疫苗和免疫联盟的支持。继续实施PCV方案将要求各国大幅增加其在PCV方面的支出。成本也阻碍了大多数中等收入国家引入PCV。因此，全世界约有一半的儿童无法获得PCV。减少PCV计划的剂量和成本将增加全球PCV的覆盖面和可持续性。冈比亚在2009年采用了常规的三剂计划，没有加强剂量(即‘3 0’计划)，从而大大减少了由于疫苗类型肺炎球菌和严重肺炎引起的侵袭性肺炎。现在VT IPD已得到控制，2019年在冈比亚农村地区开始了一项大型流行病学研究，以比较正在使用的30剂计划和两剂计划的使用情况，其中包括9个月龄时的加强剂量(即1 1计划)。理论上，11时间表将在社区中刺激更多的羊群保护，因为它可能对防止鼻部感染肺炎球菌有更大的效果。英国联合全球健康试验计划和盖茨基金会为这项研究提供资金。这项流行病学研究衡量了这两个时间表对18个月龄以下肺炎球菌携带者的影响以及免疫措施。这项拟议的研究将确定以下方面的关键未知因素：a)加强剂量对减少肺炎球菌携带的影响的持续时间，b)加强剂量对鼻部肺炎球菌定植密度的影响，以及c)免疫学测量是否与PCV预防获得肺炎球菌定植有关。这些知识将有助于解释大规模流行病学研究的结果，提供对其结果原因的理解。这项拟议的研究将把对784名接受这两种方案的儿童的随访从18个月延长到28个月。我们将在23至28个月龄期间每月采集鼻咽样本，并测量不同组之间肺炎球菌获得率的差异。在给予加强剂量一个月后，我们将测量不同组之间肺炎球菌定植密度的差异，因为密度可能与人与人之间的传播有关。最后，我们将在10个月和18个月龄时对抗肺炎球菌免疫球蛋白G进行额外的功能测试，并确定免疫球蛋白G浓度或功能与以后肺炎球菌获得率之间的最佳相关性。这些数据将对国际和国家审查PCV时间表的建议至关重要。

In many countries, the use of pneumococcal conjugate vaccine (PCV) has effectively controlled pneumococcal disease caused by the pneumococcal serotypes included in the vaccines. PCV schedules generally use three or four doses. PCV given in early infancy provides protection from disease and priming of the immune system for response later in life. Later doses, between 9 and 18 months of age, result in a substantially greater immune response, termed a 'booster' response. Despite the availability of PCV, global control of pneumococcal disease is hampered by cost. The GAVI Alliance provides subsidised vaccines for low-income countries. GAVI will spend 2.8 billion USD on PCV in the next 5 years and country co-payments to GAVI are substantial. As countries' Gross National Income increases so do their co-payments and at a threshold they become ineligible for subsidised vaccine. More than 20 countries are projected to 'transition' from GAVI support in the next 5 years. Continuation of PCV programmes will require countries to substantially increase their expenditure on PCV. Cost has also prevented most middle-income countries from introducing PCV. As a result, approximately half of children worldwide have no access to PCV. Reducing the doses and cost of PCV schedules will increase global PCV coverage and sustainability.The Gambia introduced PCV in 2009 using a routine three-dose schedule without a booster dose (i.e., a '3+0' schedule), with resulting large reductions in invasive pneumococcal disease (IPD) due to vaccine-type (VT) pneumococci and severe pneumonia. Now that VT IPD is controlled, a large epidemiological study began in 2019 in rural Gambia to compare the ongoing use of the 3+0 schedule to a two-dose schedule that includes a booster dose at 9 months of age (i.e., a '1+1' schedule). Theoretically, the 1+1 schedule will stimulate greater herd protection in the community given its likely greater effect to prevent acquisition of pneumococcal bacteria in the nose. The UK Joint Global Health Trials scheme and the Gates Foundation are funding the study. This epidemiological study measures the effect of the two schedules on acquisition of pneumococcal carriage to 18 months of age as well as immunological measures. The proposed study will determine key unknown factors regarding, a) the duration of the effect of the booster dose to reduce acquisition of pneumococcal carriage, b) the effect of the booster dose on the density of pneumococcal colonisation in the nose, and c) whether immunological measurements are associated with PCV protection against acquisition of pneumococcal colonisation. This knowledge will assist the interpretation of the results of the large epidemiological study, providing understanding of the reasons for its outcome. The proposed study will extend follow-up of 784 children receiving the two schedules from 18 to 28 months of age. We will take nasopharyngeal specimens each month between 23 and 28 months of age and measure the difference in rate of pneumococcal acquistion between groups. One month after administration of the booster dose we will measure the difference in density of pneumococcal colonisation between groups, as density is likely related to transmission from person to person. Finally, we will perform additional functional tests of anti-pneumococcal immunoglobulin G at 10 and 18 months of age and determine whether immunoglobulin G concentration or function best correlate with later rates of pneumococcal acquisition. These data will be critical to international and national review of recommendations for PCV scheduling.