Degree Type

Dissertation

Date of Award

2017

Degree Name

Doctor of Philosophy

Department

Veterinary Pathology

Major

Veterinary Pathology

First Advisor

Mark R. Ackermann

Second Advisor

Michael J. Yaeger

Abstract

Respiratory Syncytial Virus (RSV) is an enveloped single stranded RNA pneumovirus in the paramyxoviridae family that causes bronchiolitis and pneumonia in preterm and term newborns and elderly adults resulting in 75,000 to 125,000 hospitalizations of children below 1 year of age in the US each year.

Currently, there are no approved vaccines or effective therapeutic drugs for RSV infection, with treatment being solely limited to supportive care. One of the hurdles for developing vaccines or effective therapeutic drugs for RSV infection is a clinically relevant animal model. Animal models developed to study RSV infection include mice, cotton rats, ferrets, non-human primates, cattle, and lambs. Lambs have several biological features that closely mimic RSV infection in human infants such as: similarities to human infants in lung development, lung structure and airway branching, cellular composition and immune responses, and susceptibility to various strains of RSV including human strains (Long, A2, and Memphis Strain 37) for example.

To utilize the neonatal lamb model for therapeutic and vaccine studies, we characterized the viral kinetics of human M37 RSV strain to follow the progressive development of clinical signs, lung pathology and inflammatory/immune responses over time that closely resembled those of human infants. Once the viral kinetics of M37 were established, ALX-0171, a trivalent nanobody targeting the RSV F-protein was evaluated for its therapeutic potential, safety, and dose levels in newborn lambs infected with RSV M37. ALX-0171 was well-tolerated in RSV infected newborn lambs and exerted a positive effect on RSV-induced lung lesions while reduceing symptoms of illness.

To determine the clinical response(s) of the therapeutic drugs being tested, the use of video recording and surveillance was implemented to better define and correlate clinical signs and sickness behavior of RSV to severity of disease in the neonatal lamb model.

Copyright Owner

Alejandro Larios

Language

en

File Format

application/pdf

File Size

136 pages

Included in

Pathology Commons

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