The human immune response to viral vectored vaccine regimens against Ebola virus and Sudan virus in clinical trials

Thesis

Ebola disease (EBOD), caused by viruses of the Orthoebolavirus genus, poses a significant public health threat, with the majority of outbreaks caused by the Ebola and Sudan virus species. EBOD is a viral haemorrhagic fever characterised by symptoms including fever, fatigue, internal and external bleeding, and a high case fatality rate of 48.5%. Effective control of Ebola virus and Sudan virus requires a combination of robust public health measures, effective therapeutics and efficacious vaccines. The 2014-2016 Ebola virus epidemic accelerated vaccine efforts towards Ebola virus, ultimately leading to the licensure of two WHO-approved vaccines, rVSV-ZEBOV and Ad26.ZEBOV/MVA-BN-Filo, which were then deployed for use in future outbreaks. However, at the time of writing no vaccines have been approved for use against Sudan virus. This thesis aims to address longstanding questions in the development of vaccines against orthoebolaviruses. First, it evaluates the durability of several key vaccine candidates targeting Ebola virus: the approved Ad26.ZEBOV/MVA-BN-Filo regimen, as well as the experimental candidates cAd3/MVA-BN-Filo and cAd3-EBOZ/Ad26.ZEBOV in UK volunteers and cAd3/MVA-EBO Z in both UK and Senegalese volunteers. Evaluating the durability of Ebola virus vaccines is essential when considering immunisation strategies to incorporate prophylactic immunisation of at-risk individuals such as healthcare or laboratory workers. Durability was assessed between 43 and 62 months, depending on the vaccine, with good durability observed in antigen-specific IgG as well as T cell responses. At the time of writing, this represents the longest term follow-up of any Ebola virus vaccine. In some volunteers, a third ebolavirus vaccine dose in the form of an Ad26.ZEBOV boost was administered between 43 to 48 months after the original prime-boost vaccines. Ad26.ZEBOV induced a strong anamnestic response and boosted T cells and IgG titres to levels above those enumerated at baseline. In a previous study, the immunogenicity of the cAd3-EBOZ/MVA-EBO Z vaccine differed between a UK and Senegalese cohort but data from this thesis indicate these differences were no longer observed following the Ad26.ZEBOV boost. Secondly, this thesis measured the immune response to the glycoproteins from both Ebola virus and Sudan virus induced by vaccination with the novel bivalent vaccine, biEBOV, in a first in-human dose escalation trial. biEBOV was found to be immunogenic towards the glycoprotein from both species, although it did not induce a neutralising antibody response against pseudotyped lentiviruses expressing the Sudan virus glycoprotein. Together, these findings provide new insight into the durability of potential prophylactic ebolavirus vaccines, and on the development of biEBOV, a key candidate multivalent Sudan and Ebola virus vaccine.

Authors: Makinson, R

• DOI: 10.5287/ora-7rpreokva
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: MVA-BN-Filo; Sudan virus; ChAdOx1 biEBOV; durability; Ebola virus
• Subjects: Immunology; Clinical trials