Papillomavirus Prophylactic Vaccines: Established Successes,New Approaches

Vaccines against the human papillomaviruses (HPVs) most frequently associated with cancer of the cervix are now available. These prophylactic vaccines, based on virus-like particles (VLPs), are extremely effective, providing protection from infection in almost 100% of cases. However, the vaccines present some limitations: they are effective primarily against the HPV type present in the vaccine, are expensive to produce, and need a cold chain. Vaccines based on the minor capsid protein L2 have been very successful in animal models and have been shown to provide a good level of protection against different papillomavirus types. The potential of L2-based vaccines to protect against many types of HPVs is discussed.Papillomaviruses (PVs) make up a vast family that comprises hundreds of different viruses (30). PVs infect epithelia in humans and animals and cause benign hyperproliferative lesions, commonly called warts or papillomas, which can occasionally progress to squamous cell cancer or less commonly, adenocarcinoma (12). Cancer of the uterine cervix is caused by human papillomavirus (HPV), primarily types 16 and 18, but also a dozen other “high risk” HPV types that infect the genital mucosa. The presence of viral proteins, i.e., foreign antigens, in the cancers and precancers presents the opportunity for prevention or cure of the lesions via vaccination targeted against the viral proteins. The virus infectious cycle and the neoplastic progression from papilloma to carcinoma are broadly similar in humans and animals, and animal PVs and their hosts represent excellent model systems for HPVs, infection, and neoplastic progression (8, 13). Additionally, animal PVs have provided powerful models for antiviral vaccines (15). This is particularly true of the bovine papillomavirus types 1 and 4 (BPV), the cottontail rabbit papillomavirus (CRPV), and later of the canine oral papillomavirus (COPV).In this review, we briefly describe the virus, its structure, its genomic organization, and its proteins, review the history of the development of the current prophylactic vaccines against HPV, and discuss the requirement for new broad-spectrum prophylactic vaccines. We note that a number of preclinical vaccination studies utilizing early viral antigens (not present in a virion) protect against experimental viral challenge (9, 43). Since this presumably occurs by triggering cellular immunity that clears the virus early after the initiation of infection, prior to the induction of clinically apparent disease, we classify this approach as therapeutic vaccination. Here we focus on the late proteins, L1 and L2, key structural components of the virion, and their role in prophylactic vaccination, first in animal models and then in humans.