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

持续使用两剂而非三剂肺炎球菌结合疫苗是否会对冈比亚农村地区产生类似的影响？

• 批准号: MC_EX_MR/R006121/1
• 负责人: Grant Mackenzie
• 金额: $ 345.18万
• 依托单位: MRC Unit the Gambia
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MC_EX_MR%2FR006121%2F1
• 关键词: Will; ongoing; use; two; dose

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.

许多国家采用了三种或四种剂量表的肺炎球菌结合疫苗（PCV），大大减少了侵袭性肺炎球菌病（IPD）和肺炎。在接种疫苗的儿童中，群体保护效果比直接效果预防的病例更多。许多非洲和亚洲国家现已采用婴儿早期三剂的标准接种方案（3+0接种方案）引入PCV。来自南非和肯尼亚的数据表明，PCV的直接和群体保护效果是巨大的。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，肺炎球菌疾病的全球控制受到PCV成本的阻碍。低收入国家通过全球疫苗免疫联盟获得补贴疫苗。然而，当国家的人均收入超过世界银行的“低收入”门槛时，它们就从全球疫苗和免疫联盟的支持中“毕业”，共同支付额就会大幅增加。未来5年，全球疫苗免疫联盟将在PCV上投入28亿美元，约占其疫苗预算的一半。成本问题阻碍了大多数中等收入国家引进PCV。为了有效，两剂PCV计划必须在婴儿期提供足够的直接保护，并保持VT肺炎球菌在社区的低传播，这对维持群体保护至关重要。事实上，随着免疫规划的成熟，群体保护的作用超过了直接保护的作用。因此，我们建议测试在9个月大时接种加强剂的疫苗计划，与不接种加强剂的疫苗计划相比，1-4岁儿童的抗体水平更高，1-2岁儿童对肺炎球菌携带的保护更强。我们假设，在我们的环境中，新方案中的第一剂（6周大时）将提供对2-9个月大的VT疾病低风险的保护。我们假设，与3+0疫苗相比，9月龄加强剂量将在1-3岁时提供更好的直接和群体保护效果。该试验将比较根据政府免疫诊所提供的两剂和三剂PCV时间表，这些诊所为离散地理区域的亚人群提供服务。我们计划在4年的时间里为试验区内的婴儿提供两剂（6周和9个月的剂量，“1+1”）或三剂（6、10、14周的剂量，“3+0”）方案。免疫方案将在68个免疫诊所接种疫苗，为不同的集水区人口（群）提供服务。免疫诊所集水区人口将随机分配到任一试验组（1+1或3+0）。在整个试验期间，将对1-59个月年龄组的IPD、肺炎和死亡率进行安全监测。在允许两种方案的潜在不同影响发展的时间之后，研究终点将在试验的第四年进行测量。主要终点将是1-59个月临床肺炎患儿的VT肺炎球菌的鼻咽部携带。次要终点是第一次接种PCV时6-12周婴儿的VT携带情况。该分析将测试两组之间的VT传导差异是否小于预先设定的阈值。数学模型将探讨加强剂量的作用和诱导群体保护所需的覆盖范围。模型输入将包括试验数据和来自社区肺炎球菌携带和人际接触模式调查的数据。我们将对1+1与3+0计划进行成本效益分析。最后，我们将与世卫组织合作，对影响1+1计划实施的因素进行多国调查。

项目成果

Quantifying excess mortality during the COVID-19 pandemic in 2020 in The Gambia: a time-series analysis of three health and demographic surveillance systems.

• DOI: 10.1016/j.ijid.2022.12.017
• 发表时间: 2023-03
• 期刊: INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES
• 影响因子: 8.4
• 作者: Mohammed, Nuredin I.;Mackenzie, Grant;Ezeani, Esu;Sidibeh, Mamadi;Jammeh, Lamin;Sarwar, Golam;Saine, Aji Kumba Folawiyo;Sonko, Bakary;Gomez, Pierre;Dondeh, Bai Lamin;Hossain, M. Jahangir;Jasseh, Momodou;Usuf, Effua;Prentice, Andrew M.;Jeffries, David;Dalessandro, Umberto;Roca, Anna
• 通讯作者: Roca, Anna

Pneumococcal conjugate vaccination schedules in infants-acquisition, immunogenicity, and pneumococcal conjugate and yellow fever vaccine co-administration study.

肺炎球菌偶联疫苗接种时间表在婴儿辅助，免疫原性和肺炎球菌缀合物和黄热病疫苗共同给药研究中。

• DOI: 10.1186/s13063-021-05949-4
• 发表时间: 2022-01-15
• 期刊: Trials
• 影响因子: 2.5
• 作者: Mackenzie GA;Osei I;Salaudeen R;Secka O;D'Alessandro U;Clarke E;Schmidt-Chanasit J;Licciardi PV;Nguyen C;Greenwood B;Mulholland K
• 通讯作者: Mulholland K

A Cluster-randomised, Non-inferiority Trial of the Impact of a Two-dose Compared to Three-dose Schedule of Pneumococcal Conjugate Vaccination in Rural Gambia: the PVS Trial

冈比亚农村地区肺炎球菌结合疫苗接种两剂与三剂相比效果的整群随机、非劣效性试验：PVS 试验

• DOI: 10.21203/rs.3.rs-917454/v1
• 发表时间: 2021
• 作者: Mackenzie G

Verbal autopsy analysis of childhood deaths in rural Gambia.

• DOI: 10.1371/journal.pone.0277377
• 发表时间: 2023
• 期刊: PloS one
• 影响因子: 3.7

Pneumococcal Vaccine Schedules (PVS) study: a cluster-randomised, non-inferiority trial of an alternative versus standard schedule for pneumococcal conjugate vaccination: Statistical Analysis Plan

肺炎球菌疫苗接种计划 (PVS) 研究：肺炎球菌结合疫苗接种替代计划与标准计划的整群随机、非劣效性试验：统计分析计划

• DOI: 10.21203/rs.3.rs-1646100/v1
• 发表时间: 2022
• 作者: Mackenzie G