A live RSV vaccine with engineered thermostability is immunogenic in cotton rats despite high attenuation.

A live RSV vaccine with engineered thermostability is immunogenic in cotton rats despite high attenuation.

Nature communications (2016-12-22)

Christopher C Stobart, Christina A Rostad, Zunlong Ke, Rebecca S Dillard, Cheri M Hampton, Joshua D Strauss, Hong Yi, Anne L Hotard, Jia Meng, Raymond J Pickles, Kaori Sakamoto, Sujin Lee, Michael G Currier, Syed M Moin, Barney S Graham, Marina S Boukhvalova, Brian E Gilbert, Jorge C G Blanco, Pedro A Piedra, Elizabeth R Wright, Martin L Moore

PMID28000669

ABSTRACT

Respiratory syncytial virus (RSV) is a leading cause of infant hospitalization and there remains no pediatric vaccine. RSV live-attenuated vaccines (LAVs) have a history of safe testing in infants; however, achieving an effective balance of attenuation and immunogenicity has proven challenging. Here we seek to engineer an RSV LAV with enhanced immunogenicity. Genetic mapping identifies strain line 19 fusion (F) protein residues that correlate with pre-fusion antigen maintenance by ELISA and thermal stability of infectivity in live RSV. We generate a LAV candidate named OE4 which expresses line 19F and is attenuated by codon-deoptimization of non-structural (NS1 and NS2) genes, deletion of the small hydrophobic (SH) gene, codon-deoptimization of the attachment (G) gene and ablation of the secreted form of G. OE4 (RSV-A2-dNS1-dNS2-ΔSH-dGm-Gsnull-line19F) exhibits elevated pre-fusion antigen levels, thermal stability, immunogenicity, and efficacy despite heavy attenuation in the upper and lower airways of cotton rats.

MATERIALS

Product Number

Brand

Product Description

MAB858-2-5

Sigma-Aldrich

Anti-RSV Antibody, glycoprotein, all type A, B strains, clone 131-2G, clone 131-2G, Chemicon^®, from mouse