A safe and effective vaccine against RSV remains an important unmet public health need. Intranasally (IN) delivered live-attenuated vaccines represent the most extensively studied approach for immunization of RSV-naïve infants and children, however, achieving an effective balance of attenuation and immunogenicity has proven challenging. Here we report pre-clinical immunogenicity and efficacy data utilizing a live-attenuated vaccine candidate, RGΔM2-2, which was obtained by deleting the M2-2 open reading frame from the genome of the MSA1 clinical isolate. Intramuscular (IM) administration of RGΔM2-2 in cotton rats induced immunity and protective efficacy that was comparable to that induced by intranasal (IN) immunization. In contrast, the protective efficacy of RGΔM2-2 delivered by the IM route to African green monkeys was substantially reduced as compared to the efficacy following IN administration, despite comparable levels of serum neutralizing antibodies. This result suggests that mucosal immunity may play an important role in RSV protection. The RGΔM2-2 vaccine also demonstrated different attenuation profiles when tested in cotton rats, non-human primates, and a human airway epithelial (HAE) cell model. The data suggest RGΔM2-2 is less attenuated than a similarly designed vaccine candidate constructed on the A2 genetic background. These findings have important implications with regard to both the design and the preclinical safety testing of live-attenuated vaccines.

安全有效的针对RSV的疫苗仍然是重要的未满足的公共卫生需求。经鼻内（IN）递送的减毒活疫苗代表了初次接种RSV的婴儿和儿童的免疫研究最广泛的方法，但是，在减毒和免疫原性之间取得有效平衡已被证明具有挑战性。在这里，我们报告了使用减毒活疫苗RGΔM2-2的临床前免疫原性和功效数据，该数据是通过从MSA1临床分离株的基因组中删除M2-2开放阅读框而获得的。肌内（IM）给予棉鼠RGΔM2-2所产生的免疫力和保护功效与鼻内（IN）免疫所产生的相当。相比之下，与IN给药后的功效相比，IM途径递送的RGΔM2-2的保护功效与IN给药后的功效相比大大降低，尽管血清中和抗体的水平相当。该结果表明粘膜免疫可能在RSV保护中起重要作用。当在棉鼠，非人类灵长类动物和人类气道上皮（HAE）细胞模型中进行测试时，RGΔM2-2疫苗还显示出不同的减毒曲线。数据表明，与在A2遗传背景上构建的类似设计的候选疫苗相比，RGΔM2-2的衰减程度较小。这些发现对于减毒活疫苗的设计和临床前安全性测试都具有重要意义。尽管血清中和抗体水平相当。该结果表明粘膜免疫可能在RSV保护中起重要作用。当在棉鼠，非人类灵长类动物和人类气道上皮（HAE）细胞模型中进行测试时，RGΔM2-2疫苗还显示出不同的减毒曲线。数据表明，与在A2遗传背景上构建的类似设计的候选疫苗相比，RGΔM2-2的衰减程度较小。这些发现对于减毒活疫苗的设计和临床前安全性测试都具有重要意义。尽管血清中和抗体水平相当。该结果表明粘膜免疫可能在RSV保护中起重要作用。当在棉鼠，非人类灵长类动物和人类气道上皮（HAE）细胞模型中进行测试时，RGΔM2-2疫苗还显示出不同的减毒曲线。数据表明，与在A2遗传背景上构建的类似设计的候选疫苗相比，RGΔM2-2的衰减程度较小。这些发现对于减毒活疫苗的设计和临床前安全性测试都具有重要意义。数据表明，与在A2遗传背景上构建的类似设计的候选疫苗相比，RGΔM2-2的衰减程度较小。这些发现对于减毒活疫苗的设计和临床前安全性测试都具有重要意义。数据表明，与在A2遗传背景上构建的类似设计的候选疫苗相比，RGΔM2-2的衰减程度较小。这些发现对于减毒活疫苗的设计和临床前安全性测试都具有重要意义。