Preparedness for Future Pandemics Using a Highly Effective Recombinant Vesicular Stomatitis Virus-Based Vaccine Platform Technology: Strategies for Developing Superior Vaccines

We have developed highly effective, avirulent vesicular stomatitis virus (VSV) vectors to create potent recombinant viral vector-based vaccines. These vaccines induce both humoral and cellular immune responses. For developing a safe and effective viral vector vaccine, we chose VSV because of its broad host range and efficient replication. To enhance the safety of the rVSV vector, we introduced mutations in the M gene to attenuate it, since the VSV M protein is responsible for VSV-induced pathogenesis. The combined mutations G21E, M51R, and L111F (GML) in the M protein of the Indiana serotype of VSV (VSV_Ind-GML), along with mutations G22E, M48R, and M51R (GMM), and G22E, M48R, M51R, and L110F (GMML) in the M protein of VSV New Jersey serotype (VSV_NJ), were used to generate VSV_NJ-GMM and VSV_NJ-GMML, respectively. The rVSV_Ind-GML, rVSV_NJ-GMM, and rVSV_NJ-GMML exhibited reduced cytopathic effects in vitro and across various animal species. Animals injected with up to 5 billion live M gene mutant VSV showed no significant adverse effects, whereas only 1,000 wild-type VSV were enough to kill mice within four days.

All future pandemics are likely caused by airborne enveloped RNA viruses that feature surface glycoproteins on their virions. An effective signal peptide at the N-terminus of all glycoproteins is crucial for efficient synthesis, proper processing, glycosylation, intracellular transport, and secretion. Therefore, we replaced the natural signal peptides of viral glycoproteins with a highly efficient signal peptide from honeybee melittin, known for its effectiveness in glycoprotein biosynthesis and intracellular transport. Additionally, we attached the transmembrane domain and cytoplasmic tail of VSV G protein (Gtc) to the C-terminus of the target glycoprotein to enhance its incorporation into pseudotype virions. To prevent vector immunity in booster immunization, we utilised two different serotypes of VSV, along with pseudotype virions carrying the VSV G protein and the glycoproteins of the target virus. These pseudovirions will bind to the VSV receptor, low-density lipoprotein (LDL) receptor, and the receptors of the target surface glycoprotein to initiate infection.

The M gene mutants of VSV_Ind and VSV_NJ vectors, which carry surface glycoprotein genes from target viruses, stimulate strong humoral and cellular immune responses and protect animals from challenges with wild-type viruses. These M gene mutant vectors are ideal for developing vaccines to fight future pandemics.

This article explains how to develop an effective vaccine for future pandemics caused by enveloped RNA viruses.