It is interesting to speculate why the efficacy of this vaccine has proven to be so high, while that of other STI vaccines have not. First, the vaccine is based on the production of neutralizing antibodies, not T cell effector responses, and antibody-mediated protection is a well-established principle on which to base a prophylactic viral vaccine. Second, strong neutralizing antibody responses are induced in greater than 99% of vaccinees. The mammalian immune system has clearly evolved to induce exceptionally strong antibody responses against the highly ordered and repetitive epitopes characteristically displayed on the surface of a VLP, presumably because virion neutralizing antibodies are so critical for defense against most viral infections. Third, papillomaviruses have a unique lifecycle that involves limited exposure of the virions to the systemic immune system. Therefore, there has been limited pressure on the virus to evolve mechanisms to escape systemic antibody responses induced by intramuscular vaccination. The fact that papillomaviruses have DNA genomes and therefore evolve very slowly also makes it unlikely that the viruses will rapidly generate escape variants under the selective pressure of vaccine-induced antibodies. Fourth, the site and mechanism of the mucosal infection appear to make the virus exceptionally susceptible to neutralization by systemic antibodies. Fortunately, IgG, presumably transudated from serum, comprises a large proportion of the antibody in cervical mucus, in contrast to most mucosal surfaces. The levels of VLP-specific IgG in the cervical mucus of parenterally vaccinated women are approximately 10% the levels in their sera . In addition, we have determined in animal models that HPV infection of the female genital tract requires trauma or permeabilization sufficient to expose the epithelial basement membrane to virus binding . This requirement would expose the virus to direct exudation of serum antibodies at the site of trauma. The virtually complete protection against genital warts, many of which are on genital skin that is not bathed by mucus, argues that the latter mechanism is sufficient to prevent infection. Further, papillomavirus infection is a remarkably slow process , and the virus is susceptible to antibody-mediated neutralization for several hours, even after attachment to cell surfaces . Therefore, there is an exceptionally long window of opportunity for neutralizing antibodies to act. Taken together these factors may explain the truly remarkable finding that the HPV vaccines appear to induce sterilizing immunity in most women, in that the viral DNA is never detected at the cervix, despite the use of sensitive PCR-based assays.
Some of the principles established with the HPV vaccines, e.g. the high intrinsic immunogenicity of VLPs, might be applicable to vaccines targeting other local mucosal STIs. However one is left with the impression that several of the unusual characteristics of papillomavirus infection make them exceptionally susceptible to a prophylactic vaccine. We consider ourselves lucky to have been involved in developing a vaccine against a virus that, in retrospect, turned out to be a easy target. However, in the beginning not even the most optimistic of vaccinologists would have predicted the remarkable level of efficacy achieved by these vaccines. In 1990, the prospects of developing HPV vaccines seemed no better than the prospects are today for developing effective HIV or malaria vaccines. Hopefully, the story of the development of the HPV VLP vaccines will encourage continued investment in the development of vaccines against other challenging targets.
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