Genome-wide identification of interferon-sensitive mutations enables influenza vaccine design

Science. 2018 Jan 19;359(6373):290-296. doi: 10.1126/science.aan8806.

Abstract

In conventional attenuated viral vaccines, immunogenicity is often suboptimal. Here we present a systematic approach for vaccine development that eliminates interferon (IFN)-modulating functions genome-wide while maintaining virus replication fitness. We applied a quantitative high-throughput genomics system to influenza A virus that simultaneously measured the replication fitness and IFN sensitivity of mutations across the entire genome. By incorporating eight IFN-sensitive mutations, we generated a hyper-interferon-sensitive (HIS) virus as a vaccine candidate. HIS virus is highly attenuated in IFN-competent hosts but able to induce transient IFN responses, elicits robust humoral and cellular immune responses, and provides protection against homologous and heterologous viral challenges. Our approach, which attenuates the virus and promotes immune responses concurrently, is broadly applicable for vaccine development against other pathogens.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ferrets
  • Genetic Fitness
  • Genome, Viral
  • Genome-Wide Association Study
  • Humans
  • Immunity, Cellular
  • Immunogenicity, Vaccine / genetics*
  • Influenza A virus / drug effects
  • Influenza A virus / genetics*
  • Influenza A virus / immunology*
  • Influenza Vaccines / genetics*
  • Influenza Vaccines / immunology*
  • Influenza, Human / prevention & control*
  • Interferons / immunology*
  • Interferons / pharmacology
  • Mice
  • Mutation
  • Orthomyxoviridae Infections / prevention & control
  • Virus Replication / genetics

Substances

  • Influenza Vaccines
  • Interferons