The ultimate expression of medical success is prevention of a disease, and subsequently, its total eradication. It was not until the last case of endemic smallpox occurred in Somalia in 1977, with eradication of the disease declared shortly thereafter that vaccination was recognized as the means to eliminate diseases from the planet. The first mass vaccination strategy to prevent a cancer was the hepatitis B vaccine. Although, it has taken 20 years to demonstrate impact on hepatoma rates, the success of this preventive vaccine is now clear. Because the etiology of cervical cancer is infectious in nature, interfering with HPV infection with a prophylactic vaccine should theoretically prevent development of the disease and potentially achieve total eradication of cervical cancer and other HPV-related cancers. However, prophylaxis does not benefit those with preexisting disease. This is a significant issue because of the considerable burden of HPV infection worldwide. Furthermore, purely prophylactic vaccines will not impact cervical cancer rates for approx 10-20 years from the introduction of a mass vaccination program because of the existing infections and the slow process of carcinogenesis.
As the target population of a preventative HPV vaccine will most likely be healthy adolescents who are not yet sexually active, the primary concern of prophylactic vaccine development is safety. The use of a live attenuated virus vaccine has been shown to be safe and effective in the prevention of diseases, such as influenza, measles, mumps, and rubella. Yet, the difficulty of propagating large amounts of HPV combined with necessity of viral oncoproteins in the HPV replication process, has made this strategy impractical. Although, vaccines targeting the early viral antigens could prevent establishment of infection, current strategies for safe and effective prophylactic vaccination have focussed on inducing neutralizing antibodies against the major and/or minor capsid proteins.
When the major capsid protein L1 is overexpressed in various cell types, it spontaneously assembles into virus-like particles (VLPs) (62-64). Although, the viral genome and the minor capsid protein L2 are absent, L1 VLPs possess similar morphology and antigenicity to natural virions. Parenteral vaccination with papillomavirus L1 VLPs has been shown to induce high titers of serum neutralizing antibodies in animal models. Importantly, intramuscular vaccination with HPV L1 VLPs in women has been shown to be both immunogenic and safe in early phase clinical trials.
HPV is transmitted through sexual intercourse, and animal models of papillomavirus infection do not mimic sexual transmission. Therefore, there has been great concern that animal models with cutaneous or oral papillomaviruses would not be useful in vaccine development for genital HPVs, and that successful vaccine preclinical studies might not be predictive in patients. Because HPV infection is limited to the epithelium and local and therefore does not produce viremia, another significant concern in the field has been that an effective prophylactic HPV vaccine might require the local generation of virus-specific immune responses. Although, human studies confirm that high titers of specific antibodies are present in cervical secretions of women receiving intramuscular HPV16 L1 VLP immunization (65,66). In this case, transfer of serum IgG to the genital tract occurs through the process of transudation or exudation at the site of microtrauma rather than local synthesis of specific antibody. Transudation results in a diffusion gradient and thus significantly lowers titers of antibodies as compared with the serum concentration. Furthermore, the efficiency of transudation and therefore titers of antibody at the mucosal surface varies across the menstrual cycle, raising the possibility of protection during only certain phases.
Despite these concerns, a landmark clinical trial of 2392 women demonstrated that HPV-16 L1 VLPs are capable of protecting women from HPV infection and HPV-associated CIN (11). In this study, the incidence of persistent HPV-16 infection was 3.8 per 100 woman-years at risk in the placebo group and 0 per 100 woman-years at risk in the vaccine group. In short, the L1 VLP vaccine was 100% effective (confidence interval = 90-100%) at preventing persistent HPV-16 infection in the population of females tested and during this relatively short period of approximately one and a half years. This protection has been most recently extended to three and a half years (67).
Prevention of cervical cancer is not a reasonable efficacy end point for these preventive vaccine studies. Rather, as the precursor of cervical cancer, protection against incident HPV-related CIN is an appropriate measure of vaccine efficacy. Importantly, new HPV16-related CIN only occurred among the placebo recipients, although the numbers were small in this study (11). This study suggests that VLP vaccination can protect throughout the menstrual cycle against HPV infection. It should be noted that a contribution of L1-specific cellular immunity to protection has not been ruled out. The longevity of protection is currently under investigation and is likely to be influenced by the adjuvants used with the VLPs. More clinical trials of VLP vaccines are currently under way (summarized in Table 4), including a large, randomized, double-blind, placebo-controlled trial of HPV16 and HPV18 L1 VLPs in 21,000 Costa Rican women (68) to investigate the long-term protective efficacy of the VLP vaccination. Although human and nonhuman primate studies suggest that these antibodies are quite durable (33,69), tracking the level of the antibodies in vaccines and breakthrough in infections in the long-term is an important area of ongoing study. In particular, it will be important to define the threshold protective titer of neutralizing antibodies to allow monitoring of successful vaccination, and decisions on the timing for booster vaccinations.
The results from the VLP clinical trials are promising, but further work is required. For example, Koutsky and colleagues recently reported that vaccination of uninfected women with VLPs comprising HPV16 L1 was 100% effective in preventing acquisition of HPV16 infection and HPV16-related CIN (11). The incidence of other HPV-related cervical neoplasia was equal in placebo and vaccine groups (Table 3). This suggests that HPV L1 VLP vaccines may only provide protection against infection by the homologous papillomavirus type and this is consistent with the type-restricted specificity of the neutralizing antibodies that mediate protection. However, recent reports from GSK's VLP vaccine trials suggest the possibility of partial protection against very closely related types, for example, HPV18 and HPV45 (70). Interestingly, this is consistent with earlier in vitro neutralization studies, further supporting the importance of neutralizing antibodies in protection and the validity of this approach to monitor immunization (71). However, if immunity is very type-restricted, then this renders comprehensive vaccination against cervical cancer with L1 VLPs extremely difficult and increases the cost and complexity of vaccine development. For example, a completely effective and type-specific HPV prophylactic vaccine would require 11 distinct types of VLPs to prevent 95% of cervical cancer (Fig. 5) (72). Current formulations of both L1 VLP vaccines in phase III clinical trials run by Merck and GSK contain only two oncogenic HPV genotypes, HPV16 and HPV18, which together account for only 70% of cervical cancers (73,74). Merck has also chosen to include HPV6 and HPV11 L1 VLPs in their vaccine "Uardasil," but these will only protect against benign genital warts (74). The current formulation of HPV VLP vaccine protects against the most prevelant, but not all oncogenic HPV types, and this will have important implications for screening programs. The Pap screening program in the US costs in excess of 6 billion USD per year, but cessation of this program would likely require a vaccine that protects against most if not all oncogenic HPV types (Fig. 5).
Although, major capsid protein L1 is the immunodominant antigen in the generation of neutralizing antibodies in vivo (75), minor capsid protein L2 has also arisen as a possible target for vaccine development (Table 4). Preclinical studies suggest that L1 VLP-based vaccines elicit a stronger immunogenic response than L2-based vaccines, but unlike L1 VLP-based vaccines, vaccination with HPV L2 induces antibodies that cross-neutralize diverse HPV genotypes (75,76). Vaccination with L2 peptides in animal models protects from experimental challenge by the homologous type papillo-mavirus. This protection is mediated by neutralizing antibodies (76). L2 is thus considered a promising candidate for a single antigen capable of eliciting a broadly neutralizing antibody response, which is protective against all oncogenic HPV infections and related disease. Although, these L2 vaccines are promising, the low titers of neutralizing antibodies (and especially cross-neutralizing antibodies) induced by L2 as compared with L1 VLP vaccines suggest that these L2 vaccines thus far are not optimal. Importantly, the ability of L2 vaccination to provide cross-type protection must also be demonstrated. In a recent data (Neil Christensen Richard Rodon, unpublished data) it has been found that vaccination with HPV16 L2 11-200 protects rabbits from experimental challenge with either CRPV or ROPV, two viruses that are evolutionarily highly divergent from HPV16 (77). If this is borne out in patients and the relatively low
Summary of the Data From Phase III Trials of an HPV16 L1 VLP Vaccine
Summary of the Data From Phase III Trials of an HPV16 L1 VLP Vaccine
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