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(1) Intranasal immunization of mice with HPV16 virus-like particles elicits neutralizing antibodies in mucosal secretions.

(2) Trachea lung and tracheo-bronchial lymph nodes are the major inductive sites after nasal vaccination of mice with HPV16 virus-like particle (VLP).

(3) In vitro presentation of HPV16 virus-like particle by professionnal antigen-presenting cells (APC).

The human papillomaviruses, mainly type 16 (HPV16), are the primary etiologic agents of cervical cancer, which is the second cause of cancer death in women worldwide. Thus HPV-associated malignancies might be prevented by vaccine inducing virus-specific immune responses. 

The papillomavirus capsid protein L1, when expressed in various expression systems, spontaneously assembles into virus-like particle (VLP) that are devoid of the oncogenic viral genome. Parenteral injection of these VLPs elicits high titers of serum neutralizing antibodies and protection from experimental challenge with infectious virus in several animal papillomavirus models. However the efficiency of a prophylactic vaccine against genital HPV infection relies on its ability to induce specific neutralizing antibodies in the genital tract of women. 

During this thesis, we have tested musosal or parenteral routes of immunization for their ability to induce neutralizing antibodies in genital secretions of mice. We have demonstrated that the most effective route to induce high and long-lasting antibody titers in the genital tract throughout the estrous cycle was when the antigen was inhaled after nasal vaccination. To localize the major immune inductive sites responsible for the induction of this mucosal antibody response, we constructed a L1-specific CD4+ T-cell hybridoma (HD9L1). 

We observed that HPV16 VLP were rapidly taken up by dendritic cells (DC) cells and B cells in the trachea and the lung. Sustained HPV16 L1 presentation was then observed in the tracheo-bronchial lymph nodes (TBLN). Altogether, these results suggest that approaches of vaccination to induce specific immunity in the genital tract of women should target the lower respiratory tract.

Effective prophylactic vaccines most often require a strategy that targets antigen to professional antigen-presenting cells (APC) and/or allows efficient MHC cl.II presentation of the antigen. Our data show that in vitro the HPV16 VLP is efficiently taken up and processed by APC. This offers an explanation for the ability of HPV16 VLP to induce high immune responses even in the absence of adjuvant.