Human Papillomavirus
Human papillomavirus (HPV) is a small, non-enveloped deoxyribonucleic acid (DNA) virus that infects skin or mucosal cells. The circular, double-stranded viral genome is approximately 8-kb in length. The genome encodes for 6 early proteins responsible for virus replication and 2 late proteins, L1 and L2, which are the viral structural proteins.
Identification of a viral agent such as HPV as a major cause of diseases implies that prophylactic vaccines or interventions against the viral agent should prevent the disease(s) it causes. At least 13 of more than 100 known HPV genotypes can cause cancer of the cervix and are associated with other anogenital cancers and cancers of the head and neck. The two most common "high-risk" genotypes (HPV 16 and 18) cause approximately 70% of all cervical cancers. HPV was estimated to cause almost half a million cases and 250,000 deaths from cervical cancer in 2002, of which about 80% occurred in developing countries. Two "low-risk" genotypes (HPV 6 and 11) cause genital warts, a common benign condition of the external genitalia that causes significant morbidity. HPV is highly transmissible, with peak incidence soon after the onset of sexual activity, and most persons acquire infection at some time in their lives.
Initial studies in animal models showed that inoculation with species-specific papillomaviruses induced an immune response that conferred protection against homologous virus challenge. However, native papillomaviruses are not good substrates for vaccine development as they cannot be grown easily in tissue culture. Subsequent studies were initiated on the production of viral particles from expression of the structural proteins in heterologous expression systems, such as yeast or baculovirus vectors. Results showed that expression of L1 alone led to the production of virus-like particles (VLPs) which morphologically resemble the authentic HPV virions but contain no viral DNA. These VLPs are produced by self-assembly of the L1 protein when expressed in a heterologous cell substrate. In animal studies, VLPs were shown to protect against high dose experimental infection by homologous virus. HPV VLPs are highly immunogenic in mice or rabbits, and the resulting antibodies have been shown to be neutralizing and type restricted when tested in a pseudovirion neutralization assay. Immunization with denatured particles does not result in the production of neutralizing antibodies, or protect from experimental virus challenge, indicating that neutralizing epitopes are conformation dependent.