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. Science, this issue p. 290; see also p. 277 High-throughput genomics can be used to retune attenuated viruses to optimize vaccine development. 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.

中文翻译：

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干扰素敏感突变的全基因组鉴定使流感疫苗设计成为可能

避免干扰素回避 干扰素 (IFN) 表达是哺乳动物对病毒感染的第一反应。许多病毒因此进化出逃避干扰素的机制。杜等人。开发了一种从活的减毒流感病毒中系统地消除 IFN 逃避基因的方法（参见 Teijaro 和 Burton 的观点）。突变体的组合被组装以构建一种病毒，该病毒在小鼠中引发瞬时干扰素反应，但无法有效复制。短暂的 IFN 反应导致强大的抗体和记忆反应，可防止随后受到不同流感病毒的攻击。这种方法可用于改进其他 RNA 病毒疫苗。科学，这个问题 p。290; 另见第。277 高通量基因组学可用于重新调整减毒病毒以优化疫苗开发。在传统的减毒病毒疫苗中，免疫原性通常不理想。在这里，我们提出了一种疫苗开发的系统方法，该方法可以消除全基因组范围内的干扰素 (IFN) 调节功能，同时保持病毒复制适应性。我们将定量高通量基因组学系统应用于甲型流感病毒，该系统同时测量整个基因组中突变的复制适应性和 IFN 敏感性。通过结合八种干扰素敏感突变，我们生成了一种超干扰素敏感 (HIS) 病毒作为候选疫苗。HIS 病毒在具有 IFN 能力的宿主中高度减毒，但能够诱导短暂的 IFN 反应，引发强大的体液和细胞免疫反应，并提供针对同源和异源病毒攻击的保护。我们的方法，