@article{94816277da32490a9223276556589dbd,
title = "Genome-wide identification of interferon-sensitive mutations enables influenza vaccine design",
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.",
author = "Yushen Du and Li Xin and Yuan Shi and Zhang, {Tian Hao} and Wu, {Nicholas C.} and Lei Dai and Danyang Gong and Gurpreet Brar and Sara Shu and Jiadi Luo and William Reiley and Tseng, {Yen Wen} and Hongyan Bai and Wu, {Ting Ting} and Jieru Wang and Yuelong Shu and Ren Sun",
note = "Funding Information: We greatly appreciate the communication with A. te Velthuis and E. Fodor, who found that the same and similar mutations in PB2 produce mini viral RNAs (mvRNAs), which bind to RIG-I and induce IFN production. Using their method, we were able to detect these mvRNAs produced by our PB2 mutants. We thank Q. Zhou, A. York, and S. Bensinger for THP1 cells with specific gene knockouts and for discussions. We thank S. Park and S. Dubinett for the immortalized HSAECs and HBECs. Support was provided by the Whitcome Fellowship, the Burroughs Wellcome Fund, and the NIH (grants CA177322 and DE023591) to Y.D. and R.S.; the NIH (grant HL113655) to J.W.; the National Science Fund for Distinguished Young Scholars (grant 81525017) to Y. Shu; and National Science and Technology Major Project (grant 2015ZX09101044) to L.X. The sequencing data are deposited in the NIH Sequence Read Archive with accession numbers PRJNA383938, PRJNA254185, PRJNA318707, and PRJNA285135.",
year = "2018",
month = jan,
day = "19",
doi = "10.1126/science.aan8806",
language = "English (US)",
volume = "359",
pages = "290--296",
journal = "Science",
issn = "0036-8075",
publisher = "American Association for the Advancement of Science",
number = "6373",
}