LassaVacc

This project will generate and test a vaccine for Lassa Fever (LF), for which there is currently none available. LF is a haemorrhagic fever common in West Africa, caused by Lassa virus (LASV). In addition to causing approximately half a million cases with over 5000 deaths a year, LF is regularly imported into Europe, often into the UK. The proposed vaccine will be a live virus based on the widely used orthopox Modified Vaccinia Ankara (MVA), which does not grow in humans. MVA will be genetically modified to express the capsid and surface glycoproteins from LASV. This will result in the induction of an appropriate and protective immune response. In this work the immune response will be examined in ‘humanised’ mice which possess a human immune system. LASV is naturally reservoired in rodents and normal laboratory mice remain resistant to LF. In consequence, past research has been limited to the use of guinea pigs which complicate mechanistic studies on immunity. Following the assesment of the induced immune response in humanised mice we will conduct a vaccintion - challenge study with wild type LASV. Research Objectives 1) Create an MVA Lassa virus capsid - glycoprotein construct (MVA-LassaVacc). 2) Develop a challenge model in humanised mice to test the efficacy of Lassa virus vaccines. 3) Determine the immune response of the MVA-Lassa construct in humanised mice. 4) Test the MVA-Lassa construct for protection in the humanised mice challenge model. PHE-Porton is a WHO Collaborating Centre for the most dangerous virus pathogens such as LASV. As such it has access to a wide range of laboratory strains and active links to colleagues in the field who can provide circulating strains. MVA with full freedom to operate is also available at PHE-Porton. Indeed PHE-Porton has a successful background of work on vaccine candidates based on MVA for other pathogens such as Crimean-Congo Haemorrhagic fever virus. Significantly PHE-Porton has a track record in producing attenuated orthopoxvirus vaccine candidates – including vaccinia Lister which has been manipulated in the past to construct an efficacious Lassa vaccine candidate. The vaccinia Lister approach is limited however, because it cannot be used with immunocompromised idividuals such as those in many parts of Africa who have HIV. Nevertheless, we can now build on this experience by adopting the highly attenuated MVA platform which has a proven safety history, including in immunocompromised patients, since its use in over 100,000 doses in humans during the smallpox eradication campaign of the 1970s. It is also amenable to large scale GMP manufacture, does not require a cold chain and is thus suited to use in low resource settings.