Chimeric YFV-17D Lassa Vaccine for Thermostable Single-Dose Immunity
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Solution Overview
Problem
Current Lassa virus vaccines face challenges such as high dose requirements, genetic instability, cold chain dependency, and safety concerns, making them impractical for use in rural areas where Lassa virus is endemic, and existing vaccine candidates have shown low efficacy or stability issues.
Innovation Solution
A live-attenuated vaccine using a modified yellow fever virus vector (YFV-17D) expressing Lassa virus glycoprotein with specific mutations and additional transmembrane domains, allowing for a single-dose, thermostable vaccine that induces immunity against both Lassa and yellow fever.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If multiple high doses are delivered via dermal electroporation to achieve full protection, then immune response is enhanced, but implementation becomes very challenging in rural areas
Solution Approach 1:
The vaccine is segmented into a live-attenuated yellow fever virus vector component and a Lassa virus glycoprotein antigen component, allowing the immune system to process them separately while achieving comprehensive protection through a single administration
Solution Approach 2:
The vaccine combines two viral components (yellow fever virus vector and Lassa virus glycoprotein) into a single chimeric construct that provides dual functionality: replication capability from the yellow fever vector and antigenic stimulation from the Lassa glycoprotein, achieving full protection in one dose
2Reliability
If VSV-based vaccine is used to express Lassa virus glycoprotein, then vaccine candidate is replication-competent, but cold chain preservation is required which involves high cost
Solution Approach 1:
The vaccine uses yellow fever virus (YFV-17D) as the vector backbone instead of VSV, changing the thermal stability parameter of the vaccine. YFV-17D possesses inherent thermostability that allows the vaccine to maintain replication competence without requiring cold chain preservation, thereby reducing costs and improving feasibility in resource-limited settings
3Ease of manufacture
If YF17D vector is used to express Lassa glycoprotein, then vaccine construct is created, but genetic instability prevents scaling up production
Solution Approach 1:
The Lassa virus glycoprotein gene was pre-optimized with codon usage adapted to mammalian cells before insertion into the YFV-17D vector. This preliminary codon optimization ensures efficient and stable expression during vaccine production, preventing genetic instability and enabling scalable manufacturing while maintaining the integrity of the vaccine construct
4Ease of manufacture
If Lassa virus glycoprotein is inserted between YF-E/NS1 with fusion sequences, then vaccine construct is created, but the approach requires transfection in cells and shows safety concerns
Solution Approach 1:
The vaccine design extracts only the essential Lassa virus glycoprotein antigenic determinants and inserts them into the YFV-17D vector between the E and NS1 genes, eliminating the need for complex transfection procedures. The resulting vaccine can be produced through standard cell culture methods, improving manufacturing ease while reducing safety concerns associated with transfection-based approaches
Data Source
AI summary
The present invention relates to polynucleotides comprising a sequence of a live, infectious, attenuated Flavivirus wherein a nucleotide sequence encoding at least a part of a arenavirus glycoprotein protein is located at the intergenic region between the E and NS1 gene of said Flavivirus, such that a chimeric virus is expressed, characterised in that the encoded sequence C terminally of the E protein of said Flavivirus and N terminally of the signal peptide of the NS1 protein of said Flavivirus comprises in the following order: —a further signal peptide of a Flavivirus NS1 protein, —an arenavirus Glycoprotein protein lacking the N terminal signal sequence and the GP2 transmembrane domain, —a TM1 and TM2 domain of a flaviviral E protein.