Single Immunization of a Vaccine Vectored by a Novel Recombinant Vaccinia Virus Affords Effective Protection Against Respiratory Syncytial Virus Infection in Cotton Rats

Marsha S Russell; Sathya N Thulasi Raman; Caroline Gravel; Wanyue Zhang; Annabelle Pfeifle; Wangxue Chen; Gary Van Domselaar; David Safronetz; Michael Johnston; Simon Sauve; Lisheng Wang; Michael Rosu-Myles; Jingxin Cao; Xuguang Li

doi:10.3389/fimmu.2021.747866

Single Immunization of a Vaccine Vectored by a Novel Recombinant Vaccinia Virus Affords Effective Protection Against Respiratory Syncytial Virus Infection in Cotton Rats

Front Immunol. 2021 Sep 17:12:747866. doi: 10.3389/fimmu.2021.747866. eCollection 2021.

Authors

Marsha S Russell¹, Sathya N Thulasi Raman¹, Caroline Gravel¹, Wanyue Zhang^{1

2}, Annabelle Pfeifle^{1

2}, Wangxue Chen³, Gary Van Domselaar⁴, David Safronetz⁴, Michael Johnston^{1

5}, Simon Sauve¹, Lisheng Wang², Michael Rosu-Myles^{1

2}, Jingxin Cao⁴, Xuguang Li^{1

2}

Affiliations

¹ Centre for Biologics Evaluation, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch (HPFB), Health Canada and WHO Collaborating Center for Standardization and Evaluation of Biologicals, Ottawa, ON, Canada.
² Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
³ National Research Council of Canada, Human Health Therapeutics, Ottawa, ON, Canada.
⁴ National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada.
⁵ Department of Chemistry, Carleton University, Ottawa, ON, Canada.

Abstract

Respiratory syncytial virus (RSV) is a leading cause of respiratory infections worldwide and disease management measures are hampered by the lack of a safe and effective vaccine against the infection. We constructed a novel recombinant RSV vaccine candidate based on a deletion mutant vaccinia virus platform, in that the host range genes E3L and K3L were deleted (designated as VACVΔE3LΔK3L) and a poxvirus K3L ortholog gene was used as a marker for the rapid and efficient selection of recombinant viruses. The safety of the modified vaccinia virus was investigated by intranasal administration of BALB/c mice with the modified vaccinia vector using a dose known to be lethal in the wild-type Western Reserve. Only a minor loss of body weight by less than 5% and mild pulmonary inflammation were observed, both of which were transient in nature following nasal administration of the high-dose modified vaccinia virus. In addition, the viruses were cleared from the lung in 2 days with no viral invasions of the brain and other vital organs. These results suggest that the virulence of the virus has been essentially abolished. We then investigated the efficiency of the vector for the delivery of vaccines against RSV through comparison with another RSV vaccine delivered by the widely used Modified Vaccinia virus Ankara (MVA) backbone. In the cotton rats, we found a single intramuscular administration of VACVΔE3LΔK3L-vectored vaccine elicited immune responses and protection at a level comparable to the MVA-vectored vaccine against RSV infection. The distinct features of this novel VACV vector, such as an E3L deletion for attenuation and a K3L ortholog for positive selection and high efficiency for vaccine delivery, could provide unique advantages to the application of VACV as a platform for vaccine development.

Keywords: antibodies; respiratory syncytial virus; vaccine; vaccinia; vector; virus.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Female
Genetic Vectors
Mice
Mice, Inbred BALB C
Respiratory Syncytial Virus Infections / prevention & control*
Respiratory Syncytial Virus Vaccines / immunology*
Respiratory Syncytial Viruses
Sigmodontinae
Vaccine Development
Vaccines, Synthetic / immunology*
Viral Fusion Proteins / immunology

Substances

Respiratory Syncytial Virus Vaccines
Vaccines, Synthetic
Viral Fusion Proteins