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

19 January 2018  Vol 359, Issue 6373

Research Articles
Genome-wide identification of interferon-sensitive mutations enables influenza vaccine design
By Yushen Du, Li Xin, Yuan Shi, Tian-Hao Zhang, Nicholas C. Wu, Lei Dai, Danyang Gong, Gurpreet Brar, Sara Shu, Jiadi Luo, William Reiley, Yen-Wen Tseng, Hongyan Bai, Ting-Ting Wu, Jieru Wang, Yuelong Shu, Ren Sun
Science19 Jan 2018 : 290-296 Restricted Access
Avoiding interferon avoidance
Interferon (IFN) expression is a mammal’s first response to viral infection. Many viruses have thus evolved mechanisms to evade IFN. Du et al. developed a method to systematically ablate IFN evasion genes from live, attenuated influenza virus (see the Perspective by Teijaro and Burton). A combination of mutants was assembled to construct a virus that triggered transient IFN responses in mice but that was unable to replicate effectively. The transient IFN responses led to robust antibody and memory responses that protected against subsequent challenge with different influenza viruses. This approach could be adapted to improve other RNA virus vaccines.
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.