Advanced mRNA vaccines play vital roles against SARS-CoV-2. However, most current mRNA delivery platforms need to be stored at −20 °C or −70 °C due to their poor stability, which severely restricts their availability. Herein, we develop a lyophilization technique to prepare SARS-CoV-2 mRNA-lipid nanoparticle vaccines with long-term thermostability. The physiochemical properties and bioactivities of lyophilized vaccines showed no change at 25 °C over 6 months, and the lyophilized SARS-CoV-2 mRNA vaccines could elicit potent humoral and cellular immunity whether in mice, rabbits, or rhesus macaques. Furthermore, in the human trial, administration of lyophilized Omicron mRNA vaccine as a booster shot also engendered strong immunity without severe adverse events, where the titers of neutralizing antibodies against Omicron BA.1/BA.2/BA.4 were increased by at least 253-fold after a booster shot following two doses of the commercial inactivated vaccine, CoronaVac. This lyophilization platform overcomes the instability of mRNA vaccines without affecting their bioactivity and significantly improves their accessibility, particularly in remote regions.

先进的 mRNA 疫苗在对抗 SARS-CoV-2 方面发挥着至关重要的作用。然而，目前大多数 mRNA 递送平台由于稳定性差，需要在-20 °C 或-70 °C 下储存，这严重限制了它们的可用性。在此，我们开发了一种冻干技术来制备具有长期热稳定性的 SARS-CoV-2 mRNA-脂质纳米颗粒疫苗。冻干疫苗的理化特性和生物活性在 25°C 下 6 个月内没有变化，冻干 SARS-CoV-2 mRNA 疫苗无论是在小鼠、兔子还是恒河猴中都可以引发有效的体液和细胞免疫。此外，在人体试验中，冻干的 Omicron mRNA 疫苗作为加强针注射也产生了强大的免疫力，没有严重的不良事件，其中针对 Omicron BA.1/BA.2/BA 的中和抗体的滴度。在两剂商业灭活疫苗 CoronaVac 后加强注射后，4 增加了至少 253 倍。这种冻干平台在不影响其生物活性的情况下克服了 mRNA 疫苗的不稳定性，并显着提高了它们的可及性，特别是在偏远地区。