V
accine StrategiesThere are currently no vaccines for HPV. Given the worldwide prevalence of HPV and its diversity of symptoms, designing vaccines for prophylaxis and immunotherapy is required for reducing HPV transmission and virulence. One major limitation to vaccine development has been the inability to grow HPV in cell cultures. Recent breakthroughs that have improved the scope of design possibilities include genetically engineered virus-like particles (VLPs) from yeast or vaccinia virus expressed in eukaryotic cells and the establishment of animal models. Natural infection with HPV at the anogenital-mucosal surface appears to be poorly immunogenic. Several vaccine strategies have been designed in order to illicit a heightened immune response that use HPV type-specific epitopes (components of viral surface antigens) involved in viral replication and transformation.
There are several clinical goals for HPV vaccines:
P
rophylactic VaccinesPoints of consideration have been made for prophylactic vaccine design. HPV doesn’t, for the most part, have a systemic phase before colonizing the epithelium. The goal of the prophylactic vaccine would be to create an immunological barrier at the portal of entry. LI and L2 capsid proteins or the cellular component of the viral binding or uptake mechanisms could be the antigens administered via a route that would favor mucosal IgA secretion. HPVs can attach and penetrate various cell membrane tissue types. This epitheliotropism of HPV suggests that there may be a genetically conserved cell surface receptor that is unidentified. Thus, strategies to prevent infection are directed to the virus rather than the receptor. Antibodies can prevent HPV infection by the inhibition of cell surface receptor binding and also the uncharacterized subsequent step in the cell invasive pathway.
There have been isolated reports of HPV DNA in peripheral blood mononuclear cells and studies have identified circulating HPV neutralizing antibodies after parenteral immunization. However, the effectiveness of these antibodies is dependent on their availability at the genitomucosal surface. Recent evidence indicates that parenterally illicited-circulating IgA is not a good indicator of the functional effectiveness of secretory IgA.
Protection against infection directed towards mucosal surfaces is best achieved by immunization that targets mucosal associated lymphoid tissue (MALT) so that a Th-1 CTL response may be activated. MALT, associated cytokine environment is comprised of IL-4, and TGF-beta which promotes isotype switching to IgA, and IL-5, IL-6, and IL-10 which are responsible for promoting IgA secreting B cell maturation. Antigen presentation occurs predominantly in this environment.
Vaccine models:
HPV L1 capsid proteins from types 6, 11,16, and 45 have been shown in animal models to self-assemble into virus-like particles (VLPs) that are antigenically similar to real PV particles but are non-infectious. Studies show that VLPs may be a promising delivery system in prophylactic vaccine against warts or cervical dysplasia. VLPs could be genetically engineered to contain to CTL-stimulating HPV epitopes from different HPV strains (White et al 1998). Hybrid bovine papillomavirus (BPV) VLPs with L1 capsid proteins have been shown to be effective carriers of target epitopes that can stimulate a MHC class 1 or MHC class II response in SCID mice (Shiwen et al 1998). Other studies have demonstrated that sera from HPV infected individuals often contains antibodies against a different HPV genotype(s) than the strain present, indicating cross-reactive antibodies may block HPV infection. In vitro and SCID mice studies showed that antibodies raised against VLP LI from HPV-33 can block a challenge with HPV-16 L1 VLPs (White et al 1998). So far only two cross-reactive HPV genotype pairs have been identified: HPV type 16 with 33, and type 6 with 11 (Touze et al 1998). The possibilities of a recombinant DNA and whole killed virus-based vaccines are proceeding in animal trials (Tindle et al 1998).
Studies indicate that the preferred route of choice for immunization would be through the gut. Oral immunization appears to be preferable for selective stimulation of a secretory IgA-mediated anti-HPV virion response in genital mucosa since antigenic exposure at one mucosal surface site can illicit an immune response at a distant site. Vaginal immunization efficacy is not supported by many studies. A dilemma facing prophylactic vaccine design is that IgA cervical secretions would be effective in neutralizing infecting viral particles but would not control already existing infections.
Tindle et al. (1998) suggests that important considerations for prophylactic HPV vaccine include:
Thus, several questions are raised. Who should be immunized and when as well as the universal efficacy and cost of a prophylaxis vaccine are potential problems.
Strategies to eliminate preexisting infection:
Vaccine designs for asymmptomatic infected individuals would target HPV replication once it has entered epithelial cells. Specifically, such vaccines would target E1 and E2, proteins involved with viral replication by stimulating a CTL response. E1 and E2 are the preferred targets compared to other E proteins since they are produced early in the viral cycle in the replicating basal stem cells that are the primary reservoirs for new virus. One problem for targeting E proteins is that they are expressed in proximal epithelial layers often below the threshold required to illicit a CTL response.