Clinical Stage multivalent vaccines against viral haemorrhagic fevers

自2013-2016年埃博拉病毒（扎伊尔埃博拉病毒/EBOZ）暴发以来，已经发生了一些其他有记录的由丝状病毒和沙粒病毒引起的致命出血热暴发。人们普遍认为，要么需要一种单价疫苗的混合物，要么最好是一种多价疫苗，以获得对病毒性出血热的保护性免疫。开发针对丝状病毒和沙病毒（拉沙病毒）的单独疫苗的成本将高得令人望而却步，而且有可能找不到开发单独疫苗的资金，从而使低收入和中等收入国家的人口处于危险之中。我们选择的疫苗生产方式是黑猩猩腺病毒载体（ChAdOx1）。在临床试验中，已对8个疾病领域的6500多名疫苗接种者接种了ChAds，在成人、儿童和婴儿中具有良好的安全性。单剂量方案是高度免疫原性的，产生体液和细胞免疫。重要的是，这些疫苗可以通过一个简单的过程进行热稳定，从而消除了冷链储存的需要，并大大降低了运输成本。值得注意的是，对埃博拉的紧急应对导致了病毒载体的大规模生产，现在已经积累了大规模生产病毒载体疫苗的经验。为了降低成本并增加针对新出现病原体的疫苗的效用，我们在第一批资金中采取了逐步和迭代的方法，设计和测试针对主要爆发病原体的多价疫苗；丝状病毒（EBOZ， SUDV， MARV）和LASV。到我们的规划结束时，我们已经开发、测试和生产了可扩展的、免疫原性的和保护性的多价病毒载体疫苗，用于部署对抗丝状病毒和拉沙热。我们现在的目标是迅速将这些有希望的临床前疫苗转化为临床试验。这得益于与内部生物制造设施（CBF）的密切联系，该设施是临床疫苗学和热带医学中心（CCVTM）经验丰富的人员团队，擅长推进首次人体临床试验，并在非洲进行现场合作，以便在相关环境中临床评估候选疫苗。我们寻求在这一经验的基础上，将我们早期的临床前工作推进到临床开发，并在首次人体I期临床试验中测试多价病毒载体疫苗。

Since the 2013-2016 Ebola virus (Zaire Ebolavirus/EBOZ) outbreak, there have been a number of other documented outbreaks of lethal haemorrhagic fever caused by filoviruses and arenaviruses. It is generally accepted that either a mixture of monovalent vaccines or, preferably, a multivalent vaccine, will be required to confer protective immunity against viral haemorrhagic fever. The costs of developing individual vaccines against filoviruses and an arenavirus (Lassa virus (LASV)) will be prohibitively high, and there is a risk that funding will not be found to develop individual vaccines, leaving the populations in low and middle income countries at risk. Our vaccine modality of choice, for vaccine manufacture, is a chimpanzee adenoviral vector (ChAdOx1). ChAds have been administered in clinical trials to over 6,500 vaccinees, across eight disease areas, with an excellent safety profile in adults, children and babies. Single dose regimens are highly immunogenic, generating humoral and cellular immunity. Importantly, these vaccines can be thermostabilised by a simple process, removing the need for a cold chain storage and greatly reducing delivery costs. Of note, the emergency response to Ebola led to large-scale manufacture of viral vectors and there is now an accumulated manufacturing experience for viral vectored vaccines at scale. To reduce the costs and increase the utility of vaccines against emerging pathogens, we took a stepwise and iterative approach, in our stream I funding, toward the design and testing of multivalent vaccines against key outbreak pathogens; filoviruses (EBOZ, SUDV, MARV) and LASV. By the end of our programme we had developed, tested and produced scalable, immunogenic, and protective multivalent viral vectored vaccines for deployment against Filoviruses and Lassa fever. We now aim to rapidly translate these promising preclinical vaccines into clinical trials. This is facilitated by the close ties to an in-house bio-manufacturing facility (CBF), an experienced team of personnel at the Centre for Clinical Vaccinology and Tropical Medicine (CCVTM), adept at progressing first-in-human clinical trials and collaborations in-situ in Africa to clinically assess candidate vaccines in relevant settings. We seek to build on this experience and progress our early pre-clinical work to clinical development and to test a multivalent viral vectored vaccine in a first-in-human Phase I clinical trial.