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Journal of Virology, October 1998, p. 8220-8229, Vol. 72, No. 10
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Nasal Immunization of Mice with Human Papillomavirus Type 16 Virus-Like Particles Elicits Neutralizing Antibodies in Mucosal Secretions

Carole Balmelli,1 Richard Roden,2 Alexandra Potts,1 John Schiller,2 Pierre De Grandi,1 and Denise Nardelli-Haefliger1,*

Department of Gynecology, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland,1 and Laboratory of Cellular Oncology, National Cancer Institute, Bethesda, Maryland 20892-40402

Received 22 April 1998/Accepted 24 June 1998

To specifically induce a mucosal antibody response to purified human papillomavirus type 16 (HPV16) virus-like particles (VLP), we immunized female BALB/c mice orally, intranasally, and/or parenterally and evaluated cholera toxin (CT) as a mucosal adjuvant. Anti-HPV16 VLP immunoglobulin G (IgG) and IgA titers in serum, saliva, and genital secretions were measured by enzyme-linked immunosorbent assay (ELISA). Systemic immunizations alone induced HPV16 VLP-specific IgG in serum and, to a lesser extent, in genital secretions but no secretory IgA. Oral immunization, even in the presence of CT, was inefficient. However, three nasal immunizations with 5 µg of VLP given at weekly intervals to anesthetized mice induced high (>104) and long-lasting (>15 weeks) titers of anti-HPV16 VLP antibodies in all samples, including IgA and IgG in saliva and genital secretions. CT enhanced the VLP-specific antibody response 10-fold in serum and to a lesser extent in saliva and genital secretions. Nasal immunization of conscious mice compared to anesthetized mice was inefficient and correlated with the absence of uptake of a marker into the lung. However, a 1-µg VLP systemic priming followed by two 5-µg VLP intranasal boosts in conscious mice induced both HPV16 VLP-specific IgG and IgA in secretions, although the titers were lower than in anesthetized mice given three intranasal immunizations. Antibodies in serum, saliva, and genital secretions of immunized mice were strongly neutralizing in vitro (50% neutralization with ELISA titers of 65 to 125). The mucosal and systemic/mucosal HPV16 VLP immunization protocols that induced significant titers of neutralizing IgG and secretory IgA in mucosal secretions in mice may be relevant to genital HPV VLP-based human vaccine trials.

* Corresponding author. Mailing address: Département de Gynécologie, c/o Institut de Microbiologie, Bugnon 44, 1011 Lausanne, Switzerland. Phone: 021/314 40 81. Fax: 021/314 40 95. E-mail: DNARDELL{at}ulrec1.unil.ch.

Journal of Virology, October 1998, p. 8220-8229, Vol. 72, No. 10
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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