Abstract and Introduction
Thirty years ago, human papillomavirus types 16 and 18 were isolated from cervical carcinomas, and it has been almost 10 years since the introduction of the first prophylactic virus-like particle (VLP) vaccine. The VLP vaccines have already impacted the reduction of pre-malignant lesions and genital warts, and it is expected that vaccination efforts will successfully lower the incidence of cervical cancer before the end of the decade. Here we summarize the historical developments leading to the prophylactic HPV vaccines and discuss current advances of next-generation vaccines that aim to overcome certain limitations of the VLP vaccines, including their intrinsic narrow range of protection, stability and production/distribution costs.
Over the last 150 years the recognition of papillomaviruses as causative agents for a number of malignancies in both animals and humans has evolved. In the 1960s sufficient evidence began accumulating demonstrating a causative role of certain human papillomaviruses (HPVs) in the development of cervical cancer beyond reasonable doubt. Numerous investigations, among them a large number of epidemiological studies, were required to reach this point. As of 2007 we stand with two successful commercial prophylactic vaccines that efficiently protect against the most prevalent oncogenic HPV types.
Early observations reported by the Italian physician Rigoni-Stern already hinted at the involvement of infectious agents in the development of cervical cancer when he suggested behavioral risks for this type of tumor. These investigations were eventually resumed in the second half of the 20th century. Not only was the risk for cervical cancer attributed to genital infection, those studies eventually acquitted some of the suspects; for example, an involvement of herpes simplex virus 2 could be ruled out.
In the 1970s HPV-6 and HPV-11 were isolated and cloned from condylomas and laryngeal papillomas, respectively. At this time, Harald zur Hausen had noted that condylomas and cervical carcinomas share a similar epidemiological pattern and this initiated the systematic hunt for novel papillomaviruses. The strategy at the time utilized Southern blot hybridization techniques under low stringency conditions using the DNA of already isolated HPV types as molecular probes. Within a few years a large number of human and animal papillomavirus genomes had been isolated.[4–7] Of the more than 200 papillomaviruses known today, many are infecting the genital epithelium and approximately 13 of them are recognized as human oncogenic viruses.
In the following years it became evident that most if not all cases of cervical cancer are associated with one of the 13 oncogenic HPV types.[9,10] Interestingly, the pattern of HPV types found in the tumors remained quite consistent over time and, likewise, the pattern is also conserved geographically, with minor deviations. Basically all epidemiological studies report the presence of HPV-16 in about half of the tumors followed by HPV-18 in approximately 18% of the samples.[11,12] This pattern closely resembles the first report of Dürst and colleagues, who already detected HPV-16 in 19 out of 41 cervical cancers from Germany, Kenya and Brazil in the early 1970s. Recently, the frequency of HPV-16/18 in cervical cancer for the time period 1940–2007 has been analyzed for 11 different countries from three different geographical regions, and it was confirmed that the involvement of the two viruses in cervical cancer development remained very stable over this long period of time. The consistency in the distribution of HPV types was of great advantage in developing prophylactic vaccines. Although the papillomavirus family is very heterogeneous and the current HPV vaccines have a quite narrow range of protection, it is also clear that there is not much diversification for existing HPV types. The number of variants for a given HPV type is low and to date these variants are not escaping vaccine-induced immunity.[13–15]
After establishing the link between HPV infections and cervical cancer development, a large number of in vitro and in vivo studies were performed that revealed the molecular patterns behind this association. Today, we have a good understanding of the molecular and cellular processes underlying the papillomavirus-induced cellular transformation, including interaction of HPV-infected cells with the host.
In the early 1990s the commercial development of today's two commercial vaccines started. The lack of an efficient system for production of papillomaviruses not only hampered the development of prophylactic vaccine antigens, but without an easy-to-handle animal model for infection, it was also not feasible to assess vaccine efficacy. In the late 1980s it was demonstrated that so-called mouse polyomavirus virus-like particles could be produced by overexpression of the VP1 capsid protein. It turned out that such an approach would also be the key for HPV vaccine development. The first production of papillomavirus virus-like particles (VLPs) was published by Zhou and colleagues followed by reports about the production of VLPs of other PVs.[17–23] Generation of PV VLPs needs little more than overexpression of the PV major capsid protein L1 and was demonstrated to be feasible in insect cells, yeast, plants, Escherichia coli (with some restrictions) and even in cell-free systems. VLPs were very valuable tools in determining the structure of the PV capsid, and in identifying putative receptors and other interaction partners but, most importantly, they provided a rational basis for prophylactic vaccine development. In the absence of systems to measure induction of virus-neutralizing antibodies, several animal models were applied to show proof of concept of VLP-based vaccination against PV. In one of these studies, Suzich et al. demonstrated by passive transfer that antibodies are able to provide protection against virus challenge. In fact, there is general consent that virus-neutralizing antibodies are the main mediators of protection in human vaccines without ruling out contribution of cellular immunity. The very pronounced type specificity of protection after VLP vaccination is, however, consistent with the neutralization pattern of serum antibodies measured in vitro.
Future Virology. 2014;9(7):633-653. © 2014 Future Medicine Ltd.