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Journal of Virology, December 2007, p. 13710-13722, Vol. 81, No. 24
0022-538X/07/$08.00+0     doi:10.1128/JVI.01351-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Venezuelan Equine Encephalitis Virus Replicon Particles Encoding Respiratory Syncytial Virus Surface Glycoproteins Induce Protective Mucosal Responses in Mice and Cotton Rats{triangledown}

Hoyin Mok,1,5 Sujin Lee,1,5,{dagger} Thomas J. Utley,2 Bryan E. Shepherd,3 Vasiliy V. Polosukhin,4 Martha L. Collier,6 Nancy L. Davis,6 Robert E. Johnston,6 and James E. Crowe Jr.1,2,5*

Departments of Pediatrics,1 Microbiology and Immunology,2 Biostatistics,3 Medicine, Division of Allergy, Pulmonary and Critical Care Medicine,4 The Program for Vaccine Sciences, Vanderbilt University Medical Center, Vanderbilt University, Nashville, Tennessee 37232,5 Carolina Vaccine Institute and Department of Microbiology and Immunology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina 275996

Received 20 June 2007/ Accepted 28 September 2007

Respiratory syncytial virus (RSV) is an important viral pathogen that causes severe lower respiratory tract infection in infants, the elderly, and immunocompromised individuals. There are no licensed RSV vaccines to date. To prevent RSV infection, immune responses in both the upper and lower respiratory tracts are required. Previously, immunization with Venezuelan equine encephalitis virus replicon particles (VRPs) demonstrated effectiveness in inducing mucosal protection against various pathogens. In this study, we developed VRPs encoding RSV fusion (F) or attachment (G) glycoproteins and evaluated the immunogenicity and efficacy of these vaccine candidates in mice and cotton rats. VRPs, when administered intranasally, induced surface glycoprotein-specific virus neutralizing antibodies in serum and immunoglobulin A (IgA) antibodies in secretions at the respiratory mucosa. In addition, fusion protein-encoding VRPs induced gamma interferon (IFN-{gamma})-secreting T cells in the lungs and spleen, as measured by reaction with an H-2Kd-restricted CD8+ T-cell epitope. In animals vaccinated with F protein VRPs, challenge virus replication was reduced below the level of detection in both the upper and lower respiratory tracts following intranasal RSV challenge, while in those vaccinated with G protein VRPs, challenge virus was detected in the upper but not the lower respiratory tract. Close examination of histopathology of the lungs of vaccinated animals following RSV challenge revealed no enhanced inflammation. Immunization with VRPs induced balanced Th1/Th2 immune responses, as measured by the cytokine profile in the lungs and antibody isotype of the humoral immune response. These results represent an important first step toward the use of VRPs encoding RSV proteins as a prophylactic vaccine for RSV.

* Corresponding author. Mailing address: T-2220 Medical Center North, 1161 21st Avenue South, Nashville, TN 37232-2905. Phone: (615) 343-8064. Fax: (615) 343-4456. E-mail: james.crowe{at}vanderbilt.edu

{triangledown} Published ahead of print on 10 October 2007.

{dagger} Present address: Immunology Program, H. Lee Moffitt Cancer Center & Research Institute, University of South Florida, 12902 Magnolia Drive SRB-2, Tampa, FL 33612.

Journal of Virology, December 2007, p. 13710-13722, Vol. 81, No. 24
0022-538X/07/$08.00+0     doi:10.1128/JVI.01351-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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  • Mok, H., Tollefson, S. J., Podsiad, A. B., Shepherd, B. E., Polosukhin, V. V., Johnston, R. E., Williams, J. V., Crowe, J. E. Jr (2008). An Alphavirus Replicon-Based Human Metapneumovirus Vaccine Is Immunogenic and Protective in Mice and Cotton Rats. J. Virol. 82: 11410-11418 [Abstract] [Full Text]  


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