HFVac4: A Quadrivalent Viral Haemorrhagic Fever Vaccine for Africa

我们开发了一种临床前三价出血热疫苗（HFV）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卡罗尔已经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，即将开始第一阶段试验。这些高致病性RNA病毒引起常规流行病，并且爆发引起显著的发病率和死亡率，对低收入和中等收入国家的人类健康具有显著影响（Heeney，J Internal Med，2006）。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5,000人死亡。在2014/2015年西非爆发的埃博拉病毒病中，其与其他由丝状病毒（如埃博拉病毒（EBOV））引起的病毒性出血热（VHF）的地理分布重叠，使早期临床诊断复杂化。目前还没有针对这些感染的许可疫苗。非常需要一种经济、易于生产、易于部署且在不存在连续冷链储存的情况下温度稳定的单一疫苗来保护免受所有这些区域性重要VHF的侵害。改良的安卡拉牛痘（MVA）疫苗平台是非复制型第三代天花疫苗载体，并且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基疫苗载体之一（Cottingham &卡罗尔，Vaccine，2013）。MVA是能够共表达促进有效启动子和稳定插入位点的多个转基因的稳健载体系统（Orubu等，PLOSOne，2012）。通过设计MVA载体策略，将来自这3种病原体的抗原与MVA中的CCHF结合在一起，我们的目标是覆盖非洲VHF的所有4个主要重叠原因，并通过MVA疫苗载体提供对猴痘的固有保护。该VHFvac 4项目将来自CCHF-MVA项目（卡罗尔，Innovate UK with the HFVac3 projects）的协同新平台技术结合在一起。使用DIOS合成免疫优化的疫苗插入物，提供最广泛的疫苗保护，我们的三价疫苗在Tri-LEMvac联盟中证明了强大的概念验证（proof of concept，简称proof）。我们现在采取下一个大胆的步骤，将其扩展到第四大VHF，CCHF作为非洲的多价泛VHF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.