Papillomavirus prophylactic vaccines: established successes, new approaches

Abstract

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.

FIG. 1.

(A) Electron micrograph of BPV-4. Magnification, ×80,000. (Reprinted from reference with permission of the publisher.) (B) Genomic organization of a generic papillomavirus. The circular genome is represented linearly for the sake of simplicity. The viral open reading frames are represented by boxes, and the functions of their encoded viral proteins are indicated. LCR, long control region.

FIG. 2.

Prophylactic vaccination of cattle with BPV-4 VLPs (A), BPV-4 L2 protein (B), and BPV-4 L2 N terminus peptides (C). (A) Animals were vaccinated with either L1 or L1L2 VLPs. Each calf was inoculated with two doses 4 weeks apart of either 150 μg L1 VLP (each dose) or 200 μg L1L2 VLP (each dose) in Alhydrogel. Challenge virus was delivered 2 weeks after the second dose, and calves were examined for tumors at 21 weeks postchallenge. Two calves in the L1L2 VLP group developed tumors 21 weeks after challenge, but the tumors were smaller that the tumors in the control animals. (B) L2 was in a GST fusion form. Each calf was inoculated with two doses of 1 mg GST-L2 in Freund's incomplete adjuvant delivered 4 weeks apart. Challenge virus was delivered 2 weeks after the second inoculation. Calves were examined for tumors 8 weeks after challenge. (C) L2a is the N terminus of L2, comprising residues 11 to 200, in a GST fusion form; peptide 11 (Pep11) corresponds to amino acids (aa) 101 to 120; Pep14 to aa 131 to 151, and Pep16 to aa 151 to 170 of BPV-4 L2. Pep11 + Pep14 + Pep16 is an equimolar mixture of the three peptides. All peptides were conjugated to keyhole limpet hemocyanin (KLH). Each calf was inoculated with two doses of 50 μg of peptide in Alhydrogel 4 weeks apart. In the case of the Pep11 + Pep14 + Pep16 vaccine, each peptide was present at 50 μg. Challenge virus was delivered 2 weeks after the second inoculation. Calves were examined for tumors 10 weeks after challenge. In all panels, the controls are unvaccinated calves. See text for details. (Reprinted from references and and with permission of the publishers.)

FIG. 3.

Diagram depicting the polymeric L2 vaccine concept. (Courtesy of D. Lowy, reproduced with permission.). In vitro neutralization data for hyperimmune sera from rabbits vaccinated with each immunogen in Freund's adjuvant as described in Jagu et al. (46) are presented. Vaccination with the N terminus of L2 is protective against diverse papillomavirus types in association with the induction of serum antibodies that neutralize diverse papillomavirus types at low titers and the homologous type (i.e., HPV-16) at higher titers (top panel). The polymeric immunogen (bottom panel) is formed by concatenation of the N termini of L2 polypeptides derived from multiple diverse papillomavirus types. This concatenation of L2 of diverse types results in the repetitive display of epitopes with sequences conserved among types but not the type-specific epitopes. Repetitive display of B-cell epitopes is associated with enhanced antibody production. Indeed, this polymeric L2 approach results in antisera that neutralize at higher titers not only the types included in the multimeric immunogen but also other types (i.e., HPV-31 and HPV-58, boxed in red) and is associated with both a more robust and more broadly protective immune response than a monomeric L2 antigen.