MRC/FAPESP - bilateral agreement: Multiple-epitope vaccine to confer serotype-independent protection against pneumonia

MRC/FAPESP - 双边协议：多表位疫苗可提供独立于血清型的肺炎保护

• 批准号: MR/K01188X/1
• 负责人: Stephen Gordon
• 金额: $ 29.7万
• 依托单位: Liverpool School of Tropical Medicine
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK01188X%2F1
• 关键词: MRC; FAPESP; bilateral; agreement; Multiple

Pneumococcal infections account for 11% of all deaths in children under 5 years of age and in older adults, Streptococcus pneumoniae is the leading cause of community-acquired pneumonia. Pneumococcal infections in both children and adults are potentially preventable by vaccination but current vaccines do not offer the level of protection needed. Furthermore, the use of polysaccharide conjugate vaccine is associated with disease caused by non-vaccine types, a phenomenon known as serotype replacement. The existence of >90 different pneumococcal types implies that serotype replacement will be a persistent problem for anti-capsular vaccines. The development of a vaccine based on pneumococcal proteins common to all strains offers the potential for serotype-independent protection and the complete eradication of carriage. Pneumococcal surface proteins A (PspA) and Pneumococcal surface protein C (PspC) among the most promising candidates for a protein-based vaccine. Although these proteins are variable among different clinical isolates, we have found some variants that are able to induce antibodies with broad reactivity, recognizing different PspA and PspC variants. We have also shown that fusion of PspA protein fragments is an efficient strategy to extend protection provided by a protein, but the ideal epitopes (parts of the protein) to be included in the vaccine has yet to be defined. The selection of epitopes capable of inducing antibodies with broad cross-reactivity (able to recognize all variants of PspA and PspC) is of clinical importance to the successful development of a vaccine using this approach. We will use peptide array techniques to describe the entire range of cross-reactive epitopes target by sera that are known to be cross-reactive (murine immunized and human sera) and determine the optimal epitopes to be included in the vaccine. The approach of using peptide arrays has been successful used to identify immunogenic epitopes of candidates for Plasmodium and Leptospira vaccine but not yet for S. pneumoniae. Our group at LSTM has successful established an Experimental Human Pneumococcal Carriage (EHPC) model and has established pneumonia patient cohorts. We will use a unique set of pre- and post-pneumococcal intranasal inoculation samples to dissect responses to PspA and PspC epitopes to a known carriage event. We will use samples from pneumonia patients to compare healthy and susceptible antibody function. Results obtained in a previous experimental human carriage study showed that presence of serum antibodies against PspA correlated with failure to establish carriage. We have observed increased antibody responses to PspA and PspC in serum, nasal wash and bronchoalveolar lavage following carriage. Immunoglobulin reponses to exposure, carriage and disease are different and show compartmentalization. There is an urgent need for a pneumonia vaccine that is effective in childhood and in old age. We propose that an optimal vaccine will protect both age groups against pneumonia caused by all serotypes of pneumococci. We will achieve this by identifying epitopes of PspA and PspC to produce a multiple-epitope vaccine, test this vaccine in murine models of invasive disease and confirm cross-reactivity of antibodies using a wide panel of pneumococcal clinical isolates. Further we will use the effective acquired immunity that protects healthy adults against carriage and the deficient response of pneumonia patients to determine the effective levels and function of antibodies to this vaccine candidate. Finally, we will confirm induction of cellular responses elicited by immunisation in mice and the presence of multiple-epitope antigen specific CD4 T cells in healthy adults and pneumonia patients.

肺炎球菌感染占5岁以下儿童和老年人所有死亡的11%，肺炎链球菌是社区获得性肺炎的主要原因。儿童和成人的肺炎球菌感染可以通过接种疫苗来预防，但目前的疫苗不能提供所需的保护水平。此外，多糖结合疫苗的使用与由非疫苗类型引起的疾病有关，这是一种称为血清型替代的现象。>90种不同肺炎球菌类型的存在意味着血清型替换将是抗荚膜疫苗的持续问题。基于所有菌株共有的肺炎球菌蛋白的疫苗的开发提供了不依赖于细菌型的保护和完全根除携带的潜力。肺炎球菌表面蛋白A（PspA）和肺炎球菌表面蛋白C（PspC）是基于蛋白质的疫苗的最有希望的候选者。虽然这些蛋白在不同的临床分离株中是可变的，但我们已经发现了一些能够诱导具有广泛反应性的抗体的变体，识别不同的PspA和PspC变体。我们还表明PspA蛋白片段的融合是延长蛋白质提供的保护的有效策略，但是要包括在疫苗中的理想表位（蛋白质的部分）尚未被定义。选择能够诱导具有广泛交叉反应性（能够识别PspA和PspC的所有变体）的抗体的表位对于使用该方法成功开发疫苗具有临床重要性。我们将使用肽阵列技术来描述已知具有交叉反应性的血清（鼠免疫血清和人血清）靶向的交叉反应性表位的整个范围，并确定疫苗中包含的最佳表位。利用肽阵列的方法已成功地用于鉴定疟原虫和钩端螺旋体疫苗候选物的免疫原性表位，但尚未用于鉴定S。肺炎。我们在LSTM的团队已经成功建立了实验性人类肺炎球菌携带（EHPC）模型，并建立了肺炎患者队列。我们将使用一组独特的前和后肺炎球菌鼻内接种样品来解剖对PspA和PspC表位的响应，以已知的携带事件。我们将使用来自肺炎患者的样本来比较健康和易感抗体功能。在先前的实验性人类携带研究中获得的结果表明，抗PspA的血清抗体的存在与未能建立携带相关。我们已经观察到携带后血清、鼻洗液和支气管肺泡灌洗液中对PspA和PspC的抗体应答增加。免疫球蛋白对暴露、携带和疾病的反应不同，呈区室化。迫切需要一种对儿童和老年有效的肺炎疫苗。我们建议，最佳的疫苗将保护这两个年龄组对肺炎引起的所有血清型的肺炎球菌。我们将通过鉴定PspA和PspC的表位以产生多表位疫苗来实现这一点，在侵袭性疾病的小鼠模型中测试该疫苗，并使用广泛的肺炎球菌临床分离株确认抗体的交叉反应性。此外，我们将使用保护健康成人免受携带和肺炎患者的应答不足的有效获得性免疫来确定针对该候选疫苗的抗体的有效水平和功能。最后，我们将确认小鼠中免疫诱导的细胞应答的诱导以及健康成人和肺炎患者中多表位抗原特异性CD4 T细胞的存在。

项目成果

The influence of pneumococcal conjugate vaccine-13 on nasal colonisation in a controlled human infection model of pneumococcal carriage in Malawi: a double-blinded randomised controlled trial protocol

肺炎球菌结合疫苗 13 对马拉维肺炎球菌携带受控人类感染模型中鼻定植的影响：双盲随机对照试验方案

• DOI: 10.12688/wellcomeopenres.17172.1
• 发表时间: 2021
• 期刊: Wellcome Open Research
• 作者: Morton B

"At first, I was very afraid"-a qualitative description of participants' views and experiences in the first Human Infection Study in Malawi

“一开始，我非常害怕”——马拉维首次人类感染研究参与者的观点和经历的定性描述

• DOI: 10.12688/wellcomeopenres.16587.1
• 发表时间: 2021
• 期刊: Wellcome Open Research
• 作者: Mtunthama Toto N

"At first, I was very afraid"-a qualitative description of participants' views and experiences in the first Human Infection Study in Malawi.

• DOI: 10.12688/wellcomeopenres.16587.2
• 发表时间: 2021
• 期刊: Wellcome open research
• 作者: Mtunthama Toto N;Gooding K;Kapumba BM;Jambo K;Rylance J;Burr S;Morton B;Gordon SB;Manda-Taylor L
• 通讯作者: Manda-Taylor L

Anti-protein immunoglobulin M responses to pneumococcus are not associated with aging.

• DOI: 10.1186/s41479-018-0048-3
• 发表时间: 2018
• 期刊: Pneumonia (Nathan Qld.)
• 作者: German EL;Al-Hakim B;Mitsi E;Pennington SH;Gritzfeld JF;Hyder-Wright AD;Banyard A;Gordon SB;Collins AM;Ferreira DM
• 通讯作者: Ferreira DM

Clinical trials: The mathematics of falling vaccine efficacy with rising disease incidence.

• DOI: 10.1016/j.vaccine.2016.04.065
• 发表时间: 2016-06-08
• 期刊: Vaccine
• 影响因子: 5.5
• 作者: Gomes MGM;Gordon SB;Lalloo DG
• 通讯作者: Lalloo DG