The available virus-like particle (VLP)-based prophylactic vaccines against specific human papillomavirus (HPV) types afford close to 100% protection against the type-associated lesions and disease. Based on papillomavirus animal models, it is likely that protection against genital lesions in humans is mediated by HPV type-restricted neutralizing antibodies that transudate or exudate at the sites of genital infection. However, a correlate of protection was not established in the clinical trials because few disease cases occurred, and true incident infection could not be reliably distinguished from the emergence or reactivation of prevalent infection. In addition, the current assays for measuring vaccine-induced antibodies, even the gold standard HPV pseudovirion (PsV) in vitro neutralization assay, may not be sensitive enough to measure the minimum level of antibodies needed for protection. Here, we characterize the recently developed model of genital challenge with HPV PsV and determine the minimal amounts of VLP-induced neutralizing antibodies that can afford protection from genital infection in vivo after transfer into recipient mice. Our data show that serum antibody levels >100-fold lower than those detectable by in vitro PsV neutralization assays are sufficient to confer protection against an HPV PsV genital infection in this model. The results clearly demonstrate that, remarkably, the in vivo assay is substantially more sensitive than in vitro PsV neutralization and thus may be better suited for studies to establish correlates of protection.Cervical cancer, the second most common cause of cancer death in women worldwide, is associated with high-risk types of human papillomavirus (HPV) infections (27). HPV vaccines based on L1 virus-like particles (VLPs) have been shown to be safe and efficient at preventing infections and precancerous lesions caused by HPV vaccine-related types (26, 33) and now have been commercialized, specifically the HPV6/11/16/18 VLP Gardasil and the HPV16/18 VLP Cervarix vaccines. Neutralizing antibodies (Ab) are thought to be the primary immune mechanism of protection by HPV vaccination, primarily based on preclinical papillomavirus (PV) animal models showing that the passive transfer of immunized sera is protective in naïve rabbits and dogs against skin and oral mucosal challenge, respectively (3, 31). In addition, clinical trials showed that vaccinated individuals developed robust anti-VLP antibody titers in serum (15, 32) and in cervicovaginal secretions (21, 23), and that antibody-mediated cross-type neutralization in in vitro assays largely parallels the cross-type protection in the trials. However, these trials did not allow the establishment of antibody concentrations or thresholds that could be correlated to protection, mainly because too few disease cases occurred (26, 33) and because breakthrough infections could not be unambiguously distinguished from the emergence or reactivation of prevalent infection. In addition, the serological assays that were used in the trials (pr...
Human papillomaviruses (HPV)-related cervical cancer is the second leading cause of cancer death in women worldwide. Despite active development, HPV E6/E7 oncogene-specific therapeutic-vaccines have had limited clinical efficacy to date. Here we report that intravaginal instillation of CpG-ODN (TLR9-agonist) or poly-(I:C) (TLR3-agonist) after subcutaneous E7 vaccination increased approximately 5-fold the number of vaccine-specific IFN-γ-secreting CD8 T-cells in the genital mucosa (GM) of mice, without affecting the E7-specific systemic response. The intravaginal treatment locally increased both E7-specific and total CD8 T-cells, but not CD4 T-cells. This previously unreported selective recruitment of CD8 T-cells from the periphery by intravaginal CpG-ODN or poly-(I:C) was mediated by TLR9 and TLR3/Mda5 signaling-pathways, respectively. For CpG, this recruitment was associated with a higher proportion of GM-localized CD8 T-cells expressing both CCR5 and CXCR3 chemokine receptors and E-selectin ligands. Most interestingly, intravaginal CpG-ODN following vaccination led to complete regression of large genital HPV-tumors in 75% of mice, instead of 20% with vaccination alone. These findings suggest that mucosal application of immunostimulatory molecules might substantially increase the effectiveness of parenterally administered vaccines.
Human papillomavirus (HPV) vaccines based on L1 virus-like particles (VLPs) can prevent HPV-induced genital neoplasias, the precursors of cervical cancer. However, most cervical cancers occur in developing countries, where the implementation of expensive vaccines requiring multiple injections will be difficult. A live Salmonella-based vaccine could be a lower-cost alternative. We previously demonstrated that high HPV type 16 (HPV16)-neutralizing titers are induced after a single oral immunization of mice with attenuated Salmonella enterica serovar Typhimurium strains expressing a codon-optimized version of HPV16 L1 (L1S). To allow the testing of this type of vaccine in women, we constructed a new L1-expressing plasmid, kanL1S, and tested kanL1S recombinants of three Salmonella enterica serovar Typhi vaccine strains shown to be safe in humans, i.e., Ty21a, the actual licensed typhoid vaccine, and two highly immunogenic typhoid vaccine candidates, Ty800 and CVD908-htrA. In an intranasal mouse model of Salmonella serovar Typhi infection, Ty21a kanL1S was unique in inducing HPV16-neutralizing antibodies in serum and genital secretions, while anti-Salmonella responses were similar to those against the parental Ty21a vaccine. Electron microscopy examination of Ty21a kanL1S lysates showed that L1 assembled in capsomers and capsomer aggregates but not well-ordered VLPs. Comparison to the neutralizing antibody response induced by purified HPV16 L1 VLP immunizations in mice suggests that Ty21a kanL1S may be an effective prophylactic HPV vaccine. Ty21a has been widely used against typhoid fever in humans with a remarkable safety record. These finds encourage clinical testing of Ty21a kanL1S as a combined typhoid fever/cervical cancer vaccine with the potential for worldwide application.
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