A vaccine to prevent oncogenic HPV infection, or premalignant cervical lesions from progressing to cancer, would clearly offer a cost effective long-term strategy to reduce the cervical cancer burden, particularly for developing countries where effective screening programmes are not available. The encouraging experimental results obtained with testing vaccine preparations in animal models of disease have prompted both commercial and public institutions to pursue the clinical development of vaccine candidates. Recombinant DNA technology is being used to produce vaccines against HPV, and both prophylactic and therapeutic vaccines are under development.

• Viral Like Particles Vaccines (VLPs): Recombinant L1 capsid protein from HPV has the useful property of self-assembling into virus-like particles. These particles contain no viral DNA and are therefore non-infectious. More importantly, these particles stimulate the production of antibodies that bind and neutralize the infectious virus. Results from three phase I human trials with L1 VLPs have been encouraging, with excellent tolerability and high immunogenicity reported in each trial. Phase II studies are ongoing. Polypeptides of non-structural viral proteins are being added to L1 and L2 minor capsid protein in the hope that such additions will enhance protection and also confer therapeutic potential.

• Recombinant fusion proteins and peptides: Other subunit vaccine candidates based on expression of viral early antigens as fusion proteins, or synthetic peptides corresponding to immunogenic epitopes of viral proteins, are designed to have therapeutic properties to treat already infected subjects. The E6 and E7 oncoproteins of HPV are selectively expressed in premalignant lesions and cancer, and so are attractive vaccine targets. These kinds of vaccines have the capacity to induce anti-tumor responses in experimental models. Three fusion proteins and several peptides are being tested in human trials as potential therapeutic vaccines. They have proven to be safe, but their immunogenicity and efficacy has not yet been fully characterized.
  
• Live recombinant vectors: Live recombinant vaccinia viruses, engineered to express genes from HPV types 16 and 18, the most common viruses associated with cervical cancer, have been tested in therapeutic settings. Results of phase I and II trials conducted so far have been encouraging. These studies successfully demonstrated that the vaccine induces no serious side effects. However, the initial study group was too small to evaluate clinical efficacy. Live attenuated vectors, such as Salmonella, are being investigated as potential second-generation vaccines.

There are many challenges to the development of a viable HPV vaccine. It is difficult to grow HPV in a laboratory for creating conventional, attenuated vaccines. Furthermore, the presence of viral oncogenes poses a significant obstacle to development of live attenuated HPV vaccines. HPV is species specific and does not infect animals. Hence, none of the animal models completely mimics the human disease or its sexual transmission. It is therefore difficult to predict the effectiveness of HPV vaccines in human studies. HPV enters the body through mucosal cells and do not spread systemically. Therefore, an HPV vaccine will possibly have to induce a strong and sustained immune response at the genital mucosa. In this respect, nasal and oral immunization studies in animals have shown VLPs to induce antibodies in the genital mucosa, and clinical trials are now being conducted to evaluate this strategy in women. In addition, because HPV types differ significantly, antibodies raised against one type may not protect against other types, creating the need to develop multivalent vaccines. Despite these problems, more than one VLP formulation will soon be in Phase III testing as a prophylactic vaccine in a developing country context.

WHO has initiated a variety of activities aimed to accelerate the vaccine technology and to support vaccine development. A series of standard reagents are being created to be used to monitor responses to vaccination in humans and evaluating the biological effects of the vaccine. Considering that cervical cancer continues to be a serious public health problem, as public awareness of HPV infections, its transmission pathway, and the potential HPV related diseases is very low, specially in developing countries. Given the long record of prophylactic viral vaccines as a cost-effective approach to prevent infection or modify disease, an effective vaccine against oncogenic types of HPV could have a tremendous impact on the global cervical cancer burden.

Other relevant sites and links

Prevention of genital HPV infection and sequelae: Report of an external consultant's meeting. CDC, Division of STD Prevention, Dec 1999