Human Papillomavirus Vaccine: History, Immunology, Current Status, and Future Prospects

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Abstract
The discovery of the association between infection by the human papillomavirus (HPV) and the development of cervical cancer has been the foundation for establishing HPV as the causative agent of essentially all cervical cancers and their preinvasive precursors.1 In the United States, the exact yearly costs for triage of cytologic abnormalities and HPV-related disease are unknown but likely very high. In developing nations, not only is there a shortage of resources to screen for cervical cancer and its precursors, but also once cervical cancer is diagnosed, the allocation of scarce health and economic resources may be an impediment for treatment.2 Given the large human and economic burden of cervical HPV-related disease around the world, researchers have been working over the last 2 decades to develop primary preventive strategies to avoid the establishment of a HPV infection.3 One of the areas that has received emphasis is that of vaccination against HPV both in preventive (primary prevention) and therapeutic (secondary prevention) settings. Cervical cancer is the most frequent infectious-related cancer in the world.4 The identification of the infectious agent (HPV), and a relatively good understanding of the epidemiologic risk factors for infection and the natural history of cervical dysplasia and cancer, provide a unique opportunity to execute a vaccine strategy to prevent cervical cancer and its precursors.5 Although a vaccine strategy may eventually prove to be a cost effective intervention,2 it is obvious that behavioral risk factors for the disease might be prevalent and offset the value of the vaccine in certain settings where alternative HPV types not covered by the vaccine could be conveyed to the female and result in the development of cervical cancer. The development of HPV vaccines was propelled by investigations in vitro on the immunogenicity of HPV proteins and DNA. Probably the most important contribution to the field of HPV vaccine development came in 1991, when Zhou et al showed that HPV 16 L1 capsid protein, when expressed in a recombinant system, formed viruslike particles (VLPs) that resembled native virions.6 These VLPs have proven to be highly antigenic without being pathogenic.7 Due to the ease in synthesizing these VLPs using various recombinant vectors, the biotechnology industry has vigorously propagated the interest in HPV preventive vaccines, which are based on VLPs alone. In contrast to preventive vaccines, HPV therapeutic vaccines would need to include some antigenic determinants derived from the early HPV proteins (eg, E7) rather than the late proteins that VLPs use to self-assemble. This has proved to be a much more challenging task in terms of biodelivery and response. The basis for this difficult design of either purely therapeutic HPV vaccines or the chimeric vaccines that include both early and late HPV elements as antigenic determinants and are proposed as an ideal combination to accomplish both preventive and treatment goals will be explained in a subsequent section.8 Clinical trials using preventive HPV vaccines have generated enthusiasm about the future prospects of HPV vaccines and their clinical impact.9,10 However, there are limitations currently, including restricted valency or coverage to only a few HPV types (targeted are those that cause the greatest proportion of human disease), expense, potential barriers to wide availability and acceptability in both developed and developing countries, and the potential epidemiological shift of HPV disease to currently less frequent types and variants. The immune response that HPV triggers in humans is poor compared to that elicited by other viruses.11 The infection cycle of HPV is tightly fitted to the differentiation program of its natural host, the keratinocyte.

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