Effects of Formalin-Inactivated Respiratory Syncytial Virus (FI-RSV) in the Perinatal Lamb Model of RSV

Rachel J Derscheid,Albert Van Geelen,Cory J Knudson,Jack M Gallup,Mark R Ackermann,Drew D Grosz,Shannon J Hostetter,Steven M Varga,Stephania Ann Cormier

doi:10.1371/journal.pone.0081472

Rachel J Derscheid, Albert Van Geelen + Show 7 more

Open Access

https://doi.org/10.1371/journal.pone.0081472

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Journal: PloS one	Publication Date: Dec 6, 2013
Citations: 37	License type: CC BY 3.0

Affiliation: Iowa State University, University of Iowa

Abstract

Respiratory syncytial virus (RSV) is the most frequent cause of bronchiolitis in infants and children worldwide. There are currently no licensed vaccines or effective antivirals. The lack of a vaccine is partly due to increased caution following the aftermath of a failed clinical trial of a formalin-inactivated RSV vaccine (FI-RSV) conducted in the 1960’s that led to enhanced disease, necessitating hospitalization of 80% of vaccine recipients and resulting in two fatalities. Perinatal lamb lungs are similar in size, structure and physiology to those of human infants and are susceptible to human strains of RSV that induce similar lesions as those observed in infected human infants. We sought to determine if perinatal lambs immunized with FI-RSV would develop key features of vaccine-enhanced disease. This was tested in colostrum-deprived lambs immunized at 3–5 days of age with FI-RSV followed two weeks later by RSV infection. The FI-RSV-vaccinated lambs exhibited several key features of RSV vaccine-enhanced disease, including reduced RSV titers in bronchoalveolar lavage fluid and lung, and increased infiltration of peribronchiolar and perivascular lymphocytes compared to lambs either undergoing an acute RSV infection or naïve controls; all features of RSV vaccine-enhanced disease. These results represent a first step proof-of-principle demonstration that the lamb can develop altered responses to RSV following FI-RSV vaccination. The lamb model may be useful for future mechanistic studies as well as the assessment of RSV vaccines designed for infants.

Highlights

Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory infection and is the leading cause of infantile bronchiolitis worldwide [1,2]
It was our hypothesis that perinatal lambs vaccinated with formalin-inactivated alum-precipitated RSV vaccine (FI-RSV) would develop key features of the vaccine-enhanced disease previously observed in human infants
Consistent with FI-RSV vaccination providing modest protection in mice, immunized lambs infected with RSV had significantly reduced (P,0.05) viral titers in the bronchoalveolar lavage fluid (BALF) (Fig. 2) compared to lambs that received mock vaccine

Summary

Introduction

Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory infection and is the leading cause of infantile bronchiolitis worldwide [1,2]. RSV vaccine development has been hampered since the 1960s when a clinical trial of a formalin-inactivated alum-precipitated RSV vaccine (FI-RSV) resulted in enhanced disease, two deaths, and hospitalization of 80% of the FI-RSV-vaccinated subjects [3,4,5]. Caution stemming from this incident has led to the development of animal models that mimic the FI-RSV vaccine-induced immunologic and pulmonary responses that follow RSV infection. Much has been learned from these models with regard to the mechanistic basis underlying this enhanced host response, and the growing number of animal models that can mimic this condition suggests that the mechanism(s) may be universal across species

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