Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, IA 52242.
Center for Veterinary Health Sciences, Oklahoma State University, Stillwater, OK 74078.
J Immunol. 2019 Jun 1;202(11):3234-3245. doi: 10.4049/jimmunol.1900050. Epub 2019 Apr 19.
Respiratory syncytial virus (RSV) is the leading cause of severe respiratory tract infection in infants and young children, but no vaccine is currently available. Live-attenuated vaccines represent an attractive immunization approach; however, balancing attenuation while retaining sufficient immunogenicity and efficacy has prevented the successful development of such a vaccine. Recently, a recombinant RSV strain lacking the gene that encodes the matrix (M) protein (RSV M-null) was developed. The M protein is required for virion assembly following infection of a host cell but is not necessary for either genome replication or gene expression. Therefore, infection with RSV M-null produces all viral proteins except M but does not generate infectious virus progeny, resulting in a single-cycle infection. We evaluated RSV M-null as a potential vaccine candidate by determining its pathogenicity, immunogenicity, and protective capacity in BALB/c mice compared with its recombinant wild-type control virus (RSV recWT). RSV M-null-infected mice exhibited significantly reduced lung viral titers, weight loss, and pulmonary dysfunction compared with mice infected with RSV recWT. Despite its attenuation, RSV M-null infection induced robust immune responses of similar magnitude to that elicited by RSV recWT. Additionally, RSV M-null infection generated serum Ab and memory T cell responses that were similar to those induced by RSV recWT. Importantly, RSV M-null immunization provided protection against secondary viral challenge by reducing lung viral titers as efficiently as immunization with RSV recWT. Overall, our results indicate that RSV M-null combines attenuation with high immunogenicity and efficacy and represents a promising novel live-attenuated RSV vaccine candidate.
呼吸道合胞病毒（RSV）是导致婴儿和幼儿严重呼吸道感染的主要原因，但目前尚无可用的疫苗。减毒活疫苗是一种有吸引力的免疫接种方法；然而，为了在保持足够的免疫原性和疗效的同时实现减毒，这种疫苗的成功开发一直受到阻碍。最近，开发了一种缺乏编码基质（M）蛋白基因的重组 RSV 株（RSV M-null）。M 蛋白是病毒粒子在感染宿主细胞后组装所必需的，但对于基因组复制或基因表达都不是必需的。因此，感染 RSV M-null 会产生除 M 蛋白之外的所有病毒蛋白，但不会产生传染性病毒后代，从而导致单周期感染。我们通过确定 RSV M-null 在 BALB/c 小鼠中的致病性、免疫原性和保护能力，并与重组野生型对照病毒（RSV recWT）进行比较，评估了 RSV M-null 作为潜在疫苗候选物的潜力。与感染 RSV recWT 的小鼠相比，感染 RSV M-null 的小鼠肺部病毒滴度、体重减轻和肺功能障碍显著降低。尽管 RSV M-null 具有衰减性，但它诱导的免疫反应与 RSV recWT 相当强烈。此外，RSV M-null 感染诱导的血清 Ab 和记忆 T 细胞反应与 RSV recWT 诱导的反应相似。重要的是，RSV M-null 免疫接种通过降低肺部病毒滴度，与 RSV recWT 免疫接种一样有效地提供针对二次病毒攻击的保护。总体而言，我们的结果表明，RSV M-null 结合了衰减性、高免疫原性和疗效，是一种有前途的新型 RSV 减毒活疫苗候选物。
