Vaccine-Induced Immunopathology during Bovine Respiratory Syncytial Virus Infection: Exploring the Parameters of Pathogenesis

Abstract

The bovine and human respiratory syncytial viruses cause severe lower respiratory tract infections. Effective vaccines against the respiratory syncytial viruses have been lacking since vaccine failures in the 1960s and 1970s. In this report, we describe a bovine respiratory syncytial virus (bRSV) challenge model in which both classical bRSV respiratory infection and vaccine-enhanced immune pathology were reproduced. The classical, formalin-inactivated (FI) bRSV vaccine that has been associated with vaccine failure was efficient in inducing high antibody titers and reducing viral loads but also primed calves for a far more serious enhanced respiratory disease after a bRSV challenge, thereby mimicking the enhanced clinical situation in FI human RSV (hRSV)-immunized and hRSV-infected infants in the 1960s. We show that immunization with FI-bRSV mainly primes a Th2-like inflammatory response that is characterized by a significant eosinophilic influx in the bronchial alveolar lung fluid and lung tissues and high levels of immunoglobulin E serum antibodies. The current model may be useful in the evaluation of new bRSV candidate vaccines for potency and safety.

Kinetics of antiviral CD8 T cell responses during primary and post-vaccination secondary bovine respiratory syncytial virus infection

“…Vaccination and challenge experiments have been described in detail previously [1]. Briefly, bRSV was cultured on embryonic bovine trachea (EBTr) cells.…”

“…This phenomenon was first observed in a human vaccine trial in the 1960s [4] and was later found to also occur in cattle immunized with formalin-or beta-propriolactone-inactivated bRSV [5,6]. Enhanced disease resulting from immunization with Fl-virus has an immunopathological basis and has now been modeled in hRSV-infected mice [2,[7][8][9] and monkeys [10] and in bRSV-infected cattle [1,[11][12][13]. In mice, immunization with inactivated virus evokes a Th-2 biased CD4 T cell response, which is associated with eosinophilia and clinical symptoms upon challenge [2].…”

“…Both with respect to epidemiology and pathogenesis, bRSV infection in calves closely resembles hRSV infection in infants and bRSV therefore, provides a valuable animal model for hRSV [1]. Vaccine development has been hampered by the fact that immunization with formalin-inactivated (FI) virus primes for a much more severe, and sometimes even lethal, form of respiratory disease [2][3][4][5][6].…”

“…In mice, immunization with inactivated virus evokes a Th-2 biased CD4 T cell response, which is associated with eosinophilia and clinical symptoms upon challenge [2]. In cattle, enhanced clinical symptoms post-immunization were associated with pulmonary eosinophilia and increased IgE titers [1].…”

“…Thus, these specific virus-host relationships provide an argument to study natural host-pathogen interactions, in parallel to the murine hRSV model. The bRSV challenge model in calves is promising because FI-bRSV associated enhanced pathogenesis can be experimentally reproduced in bRSV-infected animals [1,13]: after challenge, FIbRSV immunized calves presented with severe symptoms, eosinophilia and high IgE titers, with specificity for the F protein (Antonis et al, unpublished observations).…”