Protection of calves by a prefusion-stabilized bovine RSV F vaccine

Baoshan Zhang,Davide Corti,Michael Joyce ,Wing Pui Kong ,Efrain Guzman,Chiara Silacci,Lei Chen,Yaroslav Tsybovsky,Yen‐Ting Lai ,Michelle Thom,John R Mascola,Geraldine Taylor,Guillaume Stewart‐Jones ,Ulrich Baxa,Tongqing Zhou,Yongping Yang,Antonio Lanzavecchia,Aliaksandr Druz,Jeffrey C Boyington,Peter D Kwong

doi:10.1038/s41541-017-0005-9

Abstract

Bovine respiratory syncytial virus, a major cause of respiratory disease in calves, is closely related to human RSV, a leading cause of respiratory disease in infants. Recently, promising human RSV-vaccine candidates have been engineered that stabilize the metastable fusion (F) glycoprotein in its prefusion state; however, the absence of a relevant animal model for human RSV has complicated assessment of these vaccine candidates. Here, we use a combination of structure-based design, antigenic characterization, and X-ray crystallography to translate human RSV F stabilization into the bovine context. A “DS2” version of bovine respiratory syncytial virus F with subunits covalently fused, fusion peptide removed, and pre-fusion conformation stabilized by cavity-filling mutations and intra- and inter-protomer disulfides was recognized by pre-fusion-specific antibodies, AM14, D25, and MPE8, and elicited bovine respiratory syncytial virus-neutralizing titers in calves >100-fold higher than those elicited by post-fusion F. When challenged with a heterologous bovine respiratory syncytial virus, virus was not detected in nasal secretions nor in respiratory tract samples of DS2-immunized calves; by contrast bovine respiratory syncytial virus was detected in all post-fusion- and placebo-immunized calves. Our results demonstrate proof-of-concept that DS2-stabilized RSV F immunogens can induce highly protective immunity from RSV in a native host with implications for the efficacy of prefusion-stabilized F vaccines in humans and for the prevention of bovine respiratory syncytial virus in calves.

Highlights

Bovine respiratory syncytial virus is a member of the Paramyxoviridae family that is responsible for the majority of respiratory disease in cattle annually, resulting in considerable morbidity and losses approaching $1 billion per year.[1,2,3] bRSV is genetically and antigenically related to human RSV,[2] which is responsible for over 3 million hospitalizations for severe respiratory illness in young children and the elderly each year[4,5,6] and for which no licensed vaccine is available
Design and initial characterization of bRSV F immunogens The RSV F glycoprotein is conserved between bRSV and human RSV (hRSV), with sequence identities of ~80% (Fig. 1b, d, Supplementary Fig. 1 and Supplementary Table 1), and multiple F-directed antibodies can neutralize both hRSV and bRSV.[21,22,23,24]
Upon expression in Expi293F cells only three of the seven bDSCav1s expressed at greater than 0.5 mg/l of culture (Supplementary Table 2). All three of these bDS-cavity-filling mutations S190F and V207L (Cav1) were recognized by pre-Fspecific monoclonal antibodies (mAbs) D25 and MPE8 as well as by mAb motavizumab (Mz)[25] (Supplementary Table 2)

Summary

Introduction

Bovine respiratory syncytial virus (bRSV) is a member of the Paramyxoviridae family that is responsible for the majority of respiratory disease in cattle annually, resulting in considerable morbidity and losses approaching $1 billion per year.[1,2,3] bRSV is genetically and antigenically related to human RSV (hRSV),[2] which is responsible for over 3 million hospitalizations for severe respiratory illness in young children and the elderly each year[4,5,6] and for which no licensed vaccine is available. Young calves are vulnerable to bRSV, even in the presence of moderate levels of maternal antibodies,[8] with prevalence rates of up to 70% in the first year of life.[3] several licensed vaccines are available for bRSV, none are fully effective: low levels of maternal antibodies against bRSV can mitigate vaccine response in calves;[8, 9] inactivated bRSV vaccines may enhance disease;[10, 11] and live vaccines have the potential to exacerbate bRSV disease if administered intramuscularly in the presence of a concurrent bRSV infection.[12] By contrast, recombinant subunit-based vaccines do not pose risks associated with live viruses, but do provide an opportunity to generate highly effective and targeted immune responses. They have potential advantages in terms of ease and speed of manufacturing, quality control of purity, and long term stability

Methods

Results

Conclusion