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VLPs are denatured before immunization, however, they fail to induce the neutralizing antibodies. From this it is possible to conclude that the neutralizing antibodies are directed against conformationally dependent epitopes on L1 that mimic authentic virus. This model seemed most relevant to the development of prophylactic rather than therapeutic vaccine.

In collaboration with the Pasteur Institute, NCI researchers tested this model in a vaccine for cottontail rabbit papilloma virus (CRPV). A total of 39 experimental rabbits were immunized 3 times with VLPs containing CRPV L1 or L1-plus-L2 (in Freund’s adjuvant) or L1-plus-L2 (in alum) and then, with 39 controls, challenged with high-dose virus. The results indicated that 90 percent of the controls developed the expected disease, whereas 90 percent of the experimentals developed either no disease or a mild regressing disease that was very self-limited, and only one experimental developed persistent disease. In addition, about 40 percent of the controls developed invasive squamous cell cancer, but none of the experimental animals developed this. Importantly, animals inoculated with bovine L1 and L2 became infected despite high levels of BPV antibodies; the protection against CRPV was type-specific.

Researchers were able to transfer protection passively by transferring serum from immunized to unimmunized animals, thereby confirming that the neutralizing antibodies are the protective mechanism. Other laboratories have demonstrated different techniques for immunizing rabbits, including DNA transfer and the use of vaccinia vectors. The common denominator is the ability to obtain the appropriate conformationally dependent epitopes for viral capsid protein L1.

One drawback of this CRPV model is that it involves a cutaneous infection, whereas the genital HPV infections associated with cervical cancer are mucosal infections. However, an experiment with BPV type 4, which causes oral mucosal disease in cows, showed protection similar to that seen in the CRPV cutaneous system. Another experiment with canine oral papillomavirus also demonstrated very substantial protection from mucosal infection using L1 VLPs that had been expressed in insect cells. In the latter case, researchers were able to wait for as much as a year after immunization before challenge and still obtain very substantial protection, indicating a considerable duration of immunity in this mucosal model. A Rhesus monkey papillomavirus model would be superb, since it would be a mucosal infection and some monkeys develop invasive cervical cancer; however, the virus is not yet available, so this model remains theoretical rather than actual.

Serological Assay. Because there are so many types of mucosal HPVs, the vaccine against genital HPV infection should in principal be polyvalent. Some of the relevant HPVs will probably represent different serotypes. For example, genetic classification according to DNA homology shows that HPV-6 and 11 are closely related; HPV-16 and 31 are closely related; and HPV-18 and 45 are closely related. Whether they represent distinct serotype, however, remains to be established. The serotyping of HPVs is constrained by the unavailability of the appropriate conformationally dependent epitopes for the various types.

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