Conventional attenuated viral vaccines usually lead to suboptimal immunogenicity. The authors developed a systematic approach for developing vaccines that eliminates interferon (IFN)-modulating functions genome-wide but whilst maintaining viral replication fitness. They used a quantitative high-throughput genomics system on influenza A virus that could simultaneously measure the replication fitness and IFN sensitivity of mutations across the entire genome. Eight IFN-sensitive mutations were then incorporated to generate a hyper-interferon-sensitive (HIS) virus as a vaccine candidate. This HIS virus was found to be highly attenuated in IFN-competent hosts but still able to induce transient IFN responses, elicit robust humoral and cellular immune responses and protect against homologous and heterologous viral challenges. Therefore this novel approach both attenuates the virus and promotes immune responses concurrently and is broadly applicable for developing vaccines against other pathogens.
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