Elucidating the Immunogenicity and Protective Immune Response of a Trivalent Vaccine for Sudan Ebola, Marburg, and Lassa Fever Viruses

Sudan Ebola (SUDV), Marburg (MARV), and Lassa fever (LASV) viruses cause acute, severe haemorrhagic fevers resulting in high morbidity and mortality in overlapping regions of Africa. Despite millions of individuals in Africa being at risk of contracting an infection from one of these viruses, preventative measures are limited. Considering the challenges associated with production costs and delivery, particularly to populations with restricted access to healthcare, the development of a multivalent vaccine candidate with the aim of eliciting protection against all three viruses presents a preferred approach. However, administering multiple antigens simultaneously may lead to antigenic competition, potentially diminishing the immunogenicity of individual antigens. In this project the pre-clinical immunogenicity and efficacy of a trivalent DNA and modified vaccinia Ankara (MVA)-based vaccine candidate expressing an optimised SUDV glycoprotein (GP), MARV GP, and LASV nucleoprotein (NP) were investigated. I assessed the impact of combining all three antigens in a single vector and the effect of a homologous versus a heterologous prime-boost immunisation schedule on the induction of both humoral and cellular immune responses. To do so, I first developed a highly sensitive, multiplex assay for the simultaneous detection of antigen-specific antibodies against several targets of interest, optimising the use of scarce samples from small animal models. I then assessed the immunogenicity of the trivalent and monovalent vaccine candidates expressing the same antigens in female BALB/c mice. While combining all three antigens in a single vector led to antigenic competition, the trivalent vaccine candidates still elicited robust antibody responses against all three antigens and a significant LASV NP-specific T cell response. To investigate the efficacy of the trivalent vaccine candidates, we collaborated with researchers from the National Microbiology Laboratory, Canada to challenge male, immunised guinea pigs with guinea pig-adapted strains of SUDV, MARV, and LASV. Following three immunisations, animals demonstrated significant levels of binding antibodies against all three antigens, as well as neutralising antibodies targeting several circulating filovirus strains. While a homologous prime-boost immunisation schedule was superior in BALB/c mice, the vaccine-induced immune response in guinea pigs benefitted from a heterologous prime-boost regimen. Importantly, all immunised animals (n=5) survived the challenge with SUDV, MARV and LASV, while all control animals succumbed to the disease. Taken together, these findings demonstrate that this multivalent vaccine candidate elicits robust immune responses and protection against three different haemorrhagic fever viruses and is a promising candidate for advancement to clinical trials.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2024

Author dc:creator

• Krause, Nina

Advisors dc:contributor.advisor

• Heeney, Jonathan Luke
• Blacklaws, Barbara

• MVA
• EBOV
• SUDV
• MARV
• LASV
• Correlates of protection
• multivalent vaccine
• Modified Vaccinia Ankara
• Sudan ebolavirus
• Lassa fever virus
• immunogenicity
• protective immunity
• challenge study
• Marburgvirus
• vaccine

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/8ea6e79a-7a96-43ff-aac4-6310ed2ec92b/download
• http://purl.org/NET/rdflicense/allrightsreserved

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.115744

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/379774