A phase I clinical trial of a Chikungunya vaccine using a single dose and no adjuvant

这项提议的目的是将一种新的基孔肯雅疫苗推进到I期临床试验。基孔肯雅病毒(CHIKV)感染的特点是在急性期出现严重的关节疼痛和发烧，在慢性期出现持久的衰弱关节痛。传播CHIKV的媒介伊蚊经历了戏剧性的扩张，使CHIKV成为一种全球威胁，导致地方性国家的长期经济影响。开发有效的CHIKV疫苗是一个可以实现的目标，部分原因是该病毒的抗原性变异性很低。理想的疫苗应该是安全、廉价、高免疫原性、无佐剂、能够在单剂接种后诱导持久免疫。目前还没有预防CHIKV感染的疫苗。在大约23种实验性疫苗中，目前只有2种正在进行临床试验。一种疫苗由一种类似病毒的颗粒组成，它以类似于病毒的阵列呈现抗原，但没有复制，比非颗粒蛋白更好地刺激免疫反应。然而，这种方法需要多次注射才能诱导血清转换并达到高抗体滴度，这增加了成本，使后勤更加复杂，并限制了低收入国家的使用。另一种方法是利用表达CHIKV表面抗原的重组减毒麻疹病毒(MV)。该疫苗已被证明对人类具有免疫原性和安全性，但它还需要两剂才能诱导良好的免疫反应。Jenner研究所设计了一种新的疫苗平台，该平台由黑猩猩腺病毒载体ChAdOx2组成，该载体已经被生产成GMP，并将在2016年底之前进入临床试验。黑猩猩腺病毒基因稳定，可以在常温下进行热稳定储存，适合在所有年龄的种群中使用。表达埃博拉抗原的类似猿腺病毒载体ChAd3被证明能诱导与复制能力VSV载体埃博拉疫苗相同的高滴度中和抗体滴度，后者在III期试验中表现出100%的疗效。我们建议进行一项I期临床试验，以评估表达基孔肯雅结构抗原：衣壳和包膜糖蛋白的单剂ChAdOx2疫苗的安全性和免疫原性。CHIKV结构抗原已被证明能刺激保护性抗体的诱导。我们的初步结果表明，我们的CHIKV病毒载体疫苗在临床前模型中具有高度的免疫原性，并且能够在单剂后激发高滴度的中和抗体，类似于在感染者中诱导的滴度。

The aim of this proposal is to progress a novel Chikungunya vaccine to a phase I clinical trial. Chikungunya virus (CHIKV) infections are characterised by severe joint pain and fever during the acute phase and long-lasting debilitating arthralgia during the chronic phase. Aedes mosquitoes, the vectors transmitting CHIKV have undergone a dramatic expansion, causing CHIKV to become a global threat leading to long-term economic impacts in endemic countries. Development of an efficacious CHIKV vaccine is an achievable goal partly due to the low antigenic variability of the virus. An ideal vaccine should be safe, cheap, highly immunogenic, adjuvant-free and able to induce long-lasting immunity after a single dose. No vaccine is yet available for the prevention of CHIKV infection. Of approximately 23 experimental vaccines, only 2 are currently being tested in clinical trials. One vaccine consists of a virus-like particle that presents antigens in a similar array to those of a virus but without replicating, stimulating immune responses better than a non-particulate protein. However, this approach requires multiple injections to induce seroconversion and reach high antibody titres, increasing the costs, making logistics more complex and limiting use in low-income countries. Another approach consists on a recombinant live attenuated measles virus (MV) expressing surface CHIKV antigens. The vaccine has been shown to be immunogenic and safe in humans but it also requires two doses to induce good immune responses. The Jenner Institute has designed a new vaccine platform consisting on a chimpanzee adenoviral vector, ChAdOx2, which has already been manufactured to GMP and will enter clinical trials before the end of 2016. Chimpanzee adenoviruses are genetically stable, can be thermostabilised for ambient temperature storage and are suitable for use in all ages of the population. A similar simian adenoviral vector, ChAd3 expressing ebola antigens was shown to induce high titre neutralising antibody titres equivalent to those induced by the replication competent VSV-vectored Ebola vaccine that demonstrated 100% efficacy in a phase III trial. We are proposing to perform a phase I clinical trial to assess safety and immunogenicity of a single dose of a ChAdOx2 vaccine expressing chikungunya structural antigens: capsid and envelope glycoproteins. CHIKV structural antigens have been shown to stimulate the induction of protective antibodies. Our preliminaty results indicate that our CHIKV viral vectored vaccine is highly immunogenic in pre-clinical models and is able to stimulate high titres of neutralising antibodies after a single dose, similar to titres induced in infected people.