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Adjuvantation of a SARS-CoV-2 Mrna Vaccine with Controlled Tissue-Specific Expression of an Mrna Encoding IL-12p70

Byron Brook, Valerie Duval,Soumik Barman,Lauren Speciner,Cali Sweitzer, Asad Khanmohammed,Manisha Menon, Kimberly Foster, Pallab Ghosh, Kimia Abedi, Jacob Koster,Etsuro Nanishi,Lindsey R. Baden,Ofer Levy, Thomas Vancott, Romain Micol,David J. Dowling

Science translational medicine(2024)SCI 1区

Boston Childrens Hosp

Cited 3|Views7
Abstract
Messenger RNA (mRNA) vaccines were pivotal in reducing severe acute respiratory syndrome 2 (SARS-CoV-2) infection burden, yet they have not demonstrated robust durability, especially in older adults. Here, we describe a molecular adjuvant comprising a lipid nanoparticle (LNP)–encapsulated mRNA encoding interleukin-12p70 (IL-12p70). The bioactive adjuvant was engineered with a multiorgan protection (MOP) sequence to restrict transcript expression to the intramuscular injection site. Admixing IL-12–MOP (CTX-1796) with the BNT162b2 SARS-CoV-2 vaccine increased spike protein–specific immune responses in mice. Specifically, the benefits of IL-12–MOP adjuvantation included amplified humoral and cellular immunity and increased immune durability for 1 year after vaccination in mice. An additional benefit included the restoration of immunity in aged mice to amounts comparable to those achieved in young adult animals, alongside amplification with a single immunization. Associated enhanced dendritic cell and germinal center responses were observed. Together, these data demonstrate that an LNP-encapsulated IL-12–MOP mRNA-encoded adjuvant can amplify immunogenicity independent of age, demonstrating translational potential to benefit vulnerable populations.
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要点】:本研究提出了一种通过脂质纳米颗粒封装的mRNA编码IL-12p70作为分子佐剂,增强了SARS-CoV-2 mRNA疫苗的免疫原性,且对老年小鼠同样有效,具有应用于易感人群的潜力。

方法】:研究利用分子工程方法,在mRNA编码IL-12p70中嵌入了一个多器官保护(MOP)序列,以限制其在肌肉注射部位的转录表达。

实验】:通过在小鼠中混合IL-12-MOP(CTX-1796)与BNT162b2 SARS-CoV-2疫苗,实验结果显示增强了针对刺突蛋白的免疫反应,提升了免疫持久性可达1年,并在老年小鼠中恢复了与年轻小鼠相当的免疫水平。使用的数据集未明确提及。