HFVac4: A Quadrivalent Viral Haemorrhagic Fever Vaccine for Africa

我们开发了一种临床前三价出血热候选疫苗，能够对抗三种重要的非洲出血热病毒：拉沙热病毒（LASV）、埃博拉病毒（EBOV）和马尔堡病毒（MARV）。另外，我们的合作者Miles Carroll开发了第四种针对克里米亚-刚果出血热（CCHF）的单价候选疫苗，即将开始1期试验。这些高致病性RNA病毒经常引起流行病，在低收入和中等收入国家，疫情爆发会造成大量发病率和死亡率，对人类健康产生重大影响（Heeney，内科医学杂志，2006年）。拉沙热是西非的地方病，估计感染人数在30万至100万之间，每年有5000人死亡。它与埃博拉病毒（EBOV）等丝状病毒引起的其他病毒性出血热（vhf）重叠的地理分布使2014/2015年西非疫情中埃博拉病毒病的早期临床诊断复杂化。在西非和中非研制一种能预防四种主要出血热的甚高频联合疫苗将大有裨益。目前尚无针对这些感染的许可疫苗。非常需要一种单一疫苗，以防止所有这些具有区域重要性的甚高频病毒，这种疫苗经济、易于生产、易于部署，并且在没有连续冷链储存的情况下温度稳定。改良安卡拉牛痘（MVA）疫苗平台是一种非复制的第三代天花疫苗载体，也是人类临床试验中最安全、最先进的大抗原有效载荷重组痘疫苗载体之一（Cottingham & Carroll, vaccine, 2013）。MVA是一个强大的载体系统，能够共表达多个转基因，促进有效的启动子和稳定的插入位点（Orubu等人，PLOSone, 2012）。通过设计一种MVA载体策略，将这3种病原体的抗原与MVA中的CCHF结合起来，我们的目标是利用MVA疫苗载体提供的对猴痘的固有保护，覆盖非洲vhf的所有4个主要重叠原因。为了开发一种覆盖甚高频4种主要病因的泛病毒性出血热疫苗，该VHFvac4项目将来自CCHF-MVA项目（Carroll、Innovate UK与HFVac3项目）的协同新平台技术结合在一起。使用DIOS合成免疫优化疫苗插入物，提供尽可能广泛的疫苗保护，我们的三价疫苗在Tri-LEMvac联盟中证明了强大的概念证明（PoC）。我们现在采取下一步大胆措施，将其扩展到第四大甚高频，即刚果出血热，作为非洲的一种全合一多价泛甚高频疫苗。

We have developed a pre-clinical trivalent Haemorrhagic Fever Vaccine (HFV) candidate able to combat three important African haemorrhagic fever viruses: Lassa Fever virus (LASV), Ebola (EBOV) and Marburg (MARV) viruses. Separately, a fourth vaccine monovalent candidate against Crimean-Congo Haemorrhagic Fever (CCHF) has been developed by our collaborator Miles Carroll is about to start Phase 1 trials. These highly pathogenic RNA viruses cause regular epidemics, and outbreaks cause significant morbidity and mortality with significant impact on human health in low- and middle-income countries (Heeney, J Internal Med, 2006). Lassa fever is endemic to Western Africa with estimates ranging between 300,000 to a million infections, with 5,000 deaths per year. Its overlapping geographic distribution with other Viral Haemorrhagic Fevers (VHFs) caused by Filoviruses such as Ebola virus (EBOV) complicated the early clinical diagnosis of Ebola virus disease in the 2014/2015 West African outbreak.A combined VHF vaccine eliciting protection against the four major haemorrhagic fevers in West and Central Africa would be of great benefit. Currently there are no licensed vaccines for these infections. A single vaccine to protect against all these regionally important VHFs that is economic, easy to produce, readily deployable and temperature stable in the absence of continuous cold chain storage is highly desirable. The Modified Vaccinia Ankara (MVA) vaccine platform is a non-replicating, third generation smallpox vaccine vector and one of the safest, most advanced large antigen payload recombinant pox-based vaccine vectors in human clinical trials (Cottingham & Carroll, Vaccine, 2013). MVA is a robust vector system capable of co-expressing multiple transgenes facilitating potent promoters and stable insertion sites (Orubu et al, PLOSone, 2012). By designing an MVA vector strategy to combining antigens from these 3 pathogens together with CCHF in MVA we aim to cover all 4 major overlapping causes of VHFs in Africa with the inherent protection against Monkeypox afforded by the MVA vaccine vector.To develop a pan-Viral Haemorrhagic Fever vaccine covering the 4 major causes of VHF, this VHFvac4 project brings the synergistic new platform technologies together from the CCHF-MVA project (Carroll, Innovate UK with the HFVac3 projects). Using the DIOS synthetic immune optimised vaccine inserts which provide the broadest possible vaccine protection, our trivalent vaccine demonstrated robust proof of concept (PoC) in the Tri-LEMvac consortium. We now take the next bold step to expand this to the 4th major VHF, CCHF as an all in one multivalent pan VHF vaccine for Africa.