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

在许多国家，使用肺炎球菌结合疫苗（PCV）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计划通常使用三到四剂。在婴儿早期接种PCV可以预防疾病，并为以后的免疫系统反应提供准备。在9至18个月大之间的较晚剂量会导致更大的免疫反应，称为“增强”反应。尽管可获得PCV，但全球控制肺炎球菌疾病受到成本的阻碍。全球疫苗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上投入28亿美元，各国对全球疫苗和免疫联盟的共同支付额相当可观。随着国家国民总收入的增加，他们的共同支付额也在增加，达到一定限度后，他们就没有资格获得补贴疫苗了。预计20多个国家将在今后5年内从免疫联盟的支持“过渡”。继续开展PCV规划将要求各国大幅增加PCV支出。成本也阻碍了大多数中等收入国家引进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年引入PCV，采用常规的三剂计划，不加加强剂（即“3+0”计划），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，将正在使用的3+0计划与两剂计划进行比较，其中包括9个月大时的加强剂量（即“1+1”计划）。理论上，“1+1”计划对预防鼻腔感染肺炎球菌可能有更大的效果，因此会加强社区对畜群的保护。英国联合全球健康试验计划和盖茨基金会资助了这项研究。本流行病学研究测量了两个时间表对18个月大的肺炎球菌携带的影响，以及免疫措施。建议的研究将确定以下几个关键的未知因素：a)加强剂量减少肺炎球菌携带的效果持续多久；b)加强剂量对鼻内肺炎球菌定植密度的影响；以及c)免疫测量是否与预防PCV获得肺炎球菌定植有关。这些知识将有助于解释大型流行病学研究的结果，为其结果的原因提供理解。拟议的研究将延长784名接受两种计划的儿童的随访时间，从18个月到28个月。我们将每月采集23至28个月大的婴儿的鼻咽标本，并测量各组之间肺炎球菌感染率的差异。在给予加强剂量一个月后，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浓度或功能是否与后来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.