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Journal of Virology, October 2001, p. 9229-9238, Vol. 75, No. 19
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.19.9229-9238.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Protective Immunity and Antibody-Secreting Cell Responses Elicited by Combined Oral Attenuated Wa Human Rotavirus and Intranasal Wa 2/6-VLPs with Mutant Escherichia coli Heat-Labile Toxin in Gnotobiotic Pigs

Lijuan Yuan,dagger Cristiana Iosef, Marli S. P. Azevedo, Yunjeong Kim, Yuan Qian,Dagger Annelise Geyer,§ Trang Van Nguyen, Kyeong-Ok Chang, and Linda J. Saif*

Food Animal Health Research Program, Department of Veterinary Preventive Medicine, Ohio Agricultural Research and Development Center, Ohio State University, Wooster, Ohio 44691-4096

Received 27 April 2001/Accepted 22 June 2001

Two combined rotavirus vaccination regimens were evaluated in a gnotobiotic pig model of rotavirus infection and disease and were compared to previously tested rotavirus vaccination regimens. The first (AttHRV/VLP2×) involved oral inoculation with one dose of attenuated (Att) Wa human rotavirus (HRV), followed by two intranasal (i.n.) doses of a rotavirus-like particle (2/6-VLPs) vaccine derived from Wa (VP6) and bovine RF (VP2) rotavirus strains. The 2/6-VLPs were coadministered with a mutant Escherichia coli heat-labile toxin, LT-R192G (mLT) adjuvant. For the second regimen (VLP2×/AttHRV), two i.n. doses of 2/6-VLPs+mLT were given, followed by one oral dose of attenuated Wa HRV. To compare the protective efficacy and immune responses induced by the combined vaccine regimens with individual rotavirus vaccine regimens, we included in the experiments the following vaccine groups: one oral dose of attenuated Wa HRV (AttHRV1× and Mock2×/AttHRV, respectively), three oral doses of attenuated Wa HRV (AttHRV3×), three i.n. doses of 2/6-VLPs plus mLT (VLP3×), three i.n. doses of purified double-layered inactivated Wa HRV plus mLT (InactHRV3×), mLT alone, and mock-inoculated pigs. The isotype, magnitude, and tissue distribution of antibody-secreting cells (ASCs) in the intestinal and systemic lymphoid tissues were evaluated using an enzyme-linked immunospot assay. The AttHRV/VLP2× regimen stimulated the highest mean numbers of intestinal immunoglobulin A (IgA) ASCs prechallenge among all vaccine groups. This regimen induced partial protection against virus shedding (58%) and diarrhea (44%) upon challenge of pigs with virulent Wa HRV. The reverse VLP2×/AttHRV regimen was less efficacious than the AttHRV/VLP2× regimen in inducing IgA ASC responses and protection against diarrhea (25% protection rate) but was more efficacious than VLP3× or InactHRV3× (no protection). In conclusion, the AttHRV/VLP2× vaccination regimen stimulated the strongest B-cell responses in the intestinal mucosal immune system at challenge and conferred a moderately high protection rate against rotavirus disease, indicating that priming of the mucosal inductive site at the portal of natural infection with a replicating vaccine, followed by boosting with a nonreplicating vaccine at a second mucosal inductive site, may be a highly effective approach to stimulate the mucosal immune system and induce protective immunity against various mucosal pathogens.

* Corresponding author. Mailing address: Food Animal Health Research Program, Department of Veterinary Preventive Medicine, Ohio Agricultural Research and Development Center, Ohio State University, Wooster, OH 44691-4096. Phone: (330) 263-3744. Fax: (330) 263-3677. E-mail: saif.2{at}osu.edu.

dagger Present address: Epidemiology Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-0720.

Dagger Present address: Laboratory of Virology, Capital Institute of Pediatrics, Beijing 100080, People's Republic of China.

§ Present address: MRC/MEDUNSA Diarrhoeal Pathogens Research Unit, Medical University of Southern Africa, Medunsa 0204, South Africa.

Journal of Virology, October 2001, p. 9229-9238, Vol. 75, No. 19
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.19.9229-9238.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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