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）的使用有效地控制了由疫苗中包含的肺炎球菌血清型引起的肺炎球菌疾病。PCV方案通常使用三个或四个剂量。在婴儿早期给予PCV可以保护免疫系统免受疾病的侵害，并为以后的免疫反应提供启动。后来的剂量，在9至18个月大之间，导致更大的免疫反应，称为“助推器”反应。尽管PCV可用，但全球肺炎球菌疾病的控制受到成本的阻碍。GAVI联盟为低收入国家提供补贴疫苗。全球疫苗和免疫联盟将在未来5年内花费28亿美元用于PCV，各国对全球疫苗和免疫联盟的共同支付数额巨大。随着各国国民总收入的增加，它们的共同支付额也在增加，在一个门槛上，它们就没有资格获得补贴疫苗。预计未来5年将有20多个国家从免疫联盟的支持“过渡”。要继续开展多氯联苯方案，就需要各国大幅度增加多氯联苯方面的支出。成本也使大多数中等收入国家无法采用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覆盖率和可持续性。冈比亚于2009年采用常规三剂计划引入PCV，没有加强剂量（即，"3+0“方案），从而大大减少了由疫苗型（VT）肺炎球菌和严重肺炎引起的侵袭性肺炎球菌疾病（IPD）。现在VT IPD得到了控制，2019年在冈比亚农村开始了一项大型流行病学研究，将3+0方案的持续使用与包括9个月大时加强剂量的两剂方案进行比较（即，“1+1”时间表）。从理论上讲，1+1计划将刺激社区中更大的群体保护，因为它可能会更有效地防止鼻子中的肺炎球菌感染。英国联合全球健康试验计划和盖茨基金会正在资助这项研究。这项流行病学研究测量了两种时间表对18个月龄肺炎球菌携带的影响以及免疫措施。拟定的研究将确定关键未知因素，包括：a）加强剂量减少肺炎球菌携带的作用持续时间，B）加强剂量对鼻内肺炎球菌定植密度的影响，以及c）免疫学测量是否与PCV预防肺炎球菌定植相关。这些知识将有助于解释大型流行病学研究的结果，了解其结果的原因。这项拟议的研究将对784名接受这两种时间表的儿童进行随访，从18个月延长到28个月。我们将在23至28个月龄之间每月采集鼻咽标本，并测量各组之间肺炎球菌获得率的差异。加强剂量给药后一个月，我们将测量各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个月大时进行抗肺炎球菌免疫球蛋白G的额外功能测试，并确定免疫球蛋白G浓度或功能是否与以后的肺炎球菌获得率最相关。这些数据对于国际和国家审查PCV调度建议至关重要。

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.