Development of a Live Attenuated Vaccine Against Salmonella Paratyphi (VASP)

肠热病是一种每年影响2000多万人的疾病，对幼儿来说是一个特别的问题。伤寒和副伤寒是两种沙门氏菌引起的疾病，虽然有伤寒疫苗可用，但还没有副伤寒疫苗。副伤寒每年影响500多万人，占英国回国旅行者肠热病病例的50%。随着新一代伤寒疫苗在未来几年的推出，副伤寒预计将成为肠道热的主要原因。还有一种担心是，副伤寒在抗生素耐药性方面很重要，可能会取代伤寒，变得更加常见，但无法预防，而且由于抗生素耐药性，治疗选择减少。目前还没有获得许可的副伤寒疫苗，但我们最近在n MRC研究项目中表明，实验感染副伤寒的个体可以对再次感染产生抵抗力。因此，我们建议测试一种不会导致疾病的副伤寒弱毒株，作为口服活疫苗。该疫苗已经接种给志愿者，并被证明是安全的，并产生了免疫反应。在本申请中，我们建议在严格的条件下生产这种减毒活疫苗(CVD1902)，并与志愿者一起进行测试，看看它是否可以预防感染。我们将要求志愿者在饮料中口服疫苗，然后在一个月后，试图通过让他们饮用碳酸氢盐溶液中的细菌来感染副伤寒。如果疫苗有效，它将阻止志愿者出现副伤寒的早期症状(在我们治疗他们之前)。我们还将研究免疫反应，以了解疫苗是如何保护我们的志愿者的。我们将确定CVD1902是否能够提供保护，如果能够，我们将开发用于控制这种疾病的疫苗。

Enteric fever is a disease affecting more than 20 million people every year and is a particular problem for young children. Two types of Salmonella cause the diseases, typhoid and paratyphoid, and while there is a vaccine available for typhoid, there is no vaccine for paratyphoid. Paratyphoid affects more than 5 million people annually, and accounts for 50% of cases of enteric fever in returning travellers in the UK. Paratyphoid is expected to become the main cause of enteric fever following the roll out of new generation of typhoid vaccines in the next few years. There is also a fear that paratyphoid is important in antibiotic resistance and could take over the place of typhoid and become more common but not preventable and with reduced options for treatment as a result of antibiotic resistance. There are no licensed paratyphoid vaccines but we have recently shown in n MRC research project that individuals experimentally infected with paratyphoid can become resistant to reinfection. We have therefore proposed testing a weakened strain of paratyphoid, which cannot cause disease, as a live vaccine to be taken by mouth. The vaccine has already been given to volunteers and shown to be safe and make an immune response. In this application we propose to manufacture this live attenuated vaccine (CVD 1902) under strict conditions and test it with volunteers to see if it can prevent infection. We will ask volunteers to take the vaccine by mouth in a drink and then, one month later, try and infect them with paratyphoid by getting them to drink the bacteria in a bicarbonate solution. If the vaccine works it will stop the volunteers developing early signs of paratyphoid (before we treat them). We will also study the immune responses to understand how the vaccine works to protect our volunteers. We will define whether CVD 1902 can provide protection and, if it does so, develop the vaccine for use to control this disease.