RNA virus attenuation by alteration of mutational robustness and sequence space

Summary

RNA viruses pose serious threats to human health. Their success relies on their capacity to generate genetic variability and, consequently, on their adaptive potential. We describe a strategy to attenuate RNA viruses by altering their evolutionary potential. As an example, we rationally altered the genome of influenza A virus to redirect its evolutionary trajectories towards detrimental regions in sequence space. Specifically, viral genomes were engineered to harbour more serine and leucine codons with nonsense mutation targets: codons that could generate Stop mutations after a single nucleotide substitution. Indeed, these viruses generated more Stop mutations in vivo, accompanied by significant losses in viral fitness. The virus were attenuated, generated high levels of neutralizing antibodies and protected against lethal challenge. The higher the number of replication cycles, the higher the chance to have Stop codons being generated, leading to a small viremia, that is sufficient for inducing an immune response but that is not sufficient for inducing the disease.

Unmet need

Demonstration has been done with Influenza virus. Influenza is a worldwide public health concern. The WHO estimates that flu kills between 250,000 and 500,000 people around the world every year. Current influenza vaccines have moderate efficacy, good safety, and acceptable tolerability; however, they have unsatisfactory efficacy in older adults, are dependent on egg supply for production, and are time-consuming to manufacture. In the northern hemisphere, annual influenza epidemics typically occur during the autumn and winter months. The global attack rate is estimated to be 5-10% in adults and 20-30% in children. However, complications and hospitalizations are more frequent among individuals aged ≥ 65 years, children aged < 2 years, and those with underlying medical conditions that confer higher risk for influenza-related complications. Vaccination is the primary strategy used to prevent and control influenza.

Current Development Status

Immunogenicity studies done
Full protection in challenged mice with lethal dose

Applications

Prophylactic vaccine against Flu

Advantages

Mimics a subclinical infection resulting in induction of a complete immune response, including IgG and IgA antibodies, CD4+ and CD8+ T lymphocytes and memory cells.
Dosage administered is small leading to low cost of preparation and limited allergic response
Theoretically, only one dose is necessary, although often more doses are recommended
Can be extended to all RNA viruses (Enteroviruses, Flaviviruses, coronaviruses, Ebola, etc)

Publications