Combined human papillomavirus DNA and human papillomavirus‐like particle serologic assay to identify women at risk for high‐grade cervical intraepithelial neoplasia

Abstract

The objective of this study was to assess the utility of a second generation human papillomavirus (HPV) virus-like particle (VLP)-based ELISA as an adjunct to HPV DNA testing to identify women at risk for high-grade cervical intraepithelial neoplasia (CIN). Participants provided blood, cervical samples and interviewer-obtained questionnaire information. HPV VLPs for types 16, 18, 33, 45 and 52 were produced using a baculovirus expression system. These highly purified VLPs were used in a polymerbased ELISA test. Cases with biopsy-confirmed CIN (CIN I, n 5 237; CIN II, n 5 56; CIN III, n 5 48) and controls (n 5 351) with normal Pap smears were tested for HPV DNA by PCR and serologic response to multiple oncogenic HPV VLPs. 258/341 (76%) of cases and 230/351 (65.5%) of control patients had any type of HPV VLP antibody (OR 5 1.63, 95% CI 1.16-2.30). More cases were seropositive than controls for each individual HPV type (p < 0.001 for HPV types 16, 18, 33 and 45; p 5 0.06 for HPV 52). Reactivity to an increasing number of different HPV type-specific VLPs are associated with high-grade CIN independent of HPV DNA status. HPV VLP assays may be useful as an adjunct to HPV DNA testing in a subset of patients that needs to be defined by further studies. ' 2006 Wiley-Liss, Inc.Key words: human papillomavirus; HPV serology; cervical intraepithelial; neoplasia; predictors for disease; virus-like particles Human papillomavirus (HPV) infection has been implicated as the etiologic agent in the development of cervical intraepithelial neoplasia (CIN), and cervical cancer (for reviews see Refs. 1-3). A number of case-control and prospective studies have demonstrated a strong association between HPV and CIN of all grades. [3][4][5][6][7] Persistent genital HPV infection with specific types of HPV appears to be the predominant risk factor for progressive cervical dysplasia. 8 In addition, serologically diagnosed HPV infection has also been shown to be a risk factor for the development of cervical cancer. [9][10][11] Antibodies to conformational epitopes on synthetically produced virus-like particles (VLPs), which are similar to the HPV virion, have been shown to develop in response to infection.12-14 Serologic responses directed at type-specific epitopes on VLPs are often detectable when there is clinical evidence of disease. Serologic titers can be quantified and related to clinical disease status. 13,15,16 The use of type-specific HPV VLP antibody ELISA assays may identify women with chronic HPV infection. 15,17,18 Since the development of antibodies has been associated with persistent infection, we hypothesized that women with higher-grade CIN lesions will have a higher prevalence of HPV type-specific antibodies than women with low-grade lesions or no CIN. Thus, the aim of this study was to determine the association between HPV VLP seropositivity and the presence and grade of CIN. Material and methods Study populationStudy participants were recruited between 1992 and 1994 from gynecology, family planning, and colposcopy clinics ...

Human papillomavirus 16 and 18 L1 serology in Korean women with high-grade cervical intraepithelial neoplasia and cervical cancer

“…responses have shown that there is a strong association between HPV (mainly type 16) and cervical lesions (de Gruijl et al, 1997, Wideroff et al, 1999, Combita et al, 2002, Sasagawa et al, 1998, Sun et al, 1999, Marais et al, 2000, Einstein et al, 2007. Most have reported on both HPV DNA and VLP antibodies in all patients.…”

“…It has been suggested that HPV VLP serological assays may be useful as an additional tool for the identification of women at risk for high-grade cervical intraepithelial neoplasia (Einstein et al, 2007). Some of these prior studies were from populations with a high proportion of HIV infections (Marais et al, 2000) or in the third world (Combita et al, 2002), some studies only focused on dysplasia (Tabrizi et al, 2006, Wideroff et al, 1999, Einstein et al, 2007, some only on cancer (Combita et al, 2002, Sun et al, 1999. In addition, some have used a proper age matched controls (Combita et al, 2002).…”

Serologic response to human papillomavirus type 16 virus-like particles in Korean women with cervical precancerous and cancerous lesions

“…Recent studies have shown that the seroprevalence of antibody to HPV 16 in children younger than 11 years is 2.4% and in unselected women of 12-59 years of age it is 13% (Dunne et al, 2005;Stone et al, 2002). In a number of case-control studies, serologic responses have shown that there is a strong association between HPV and cervical lesions (de Gruijl et al, 1997;Wideroff et al, 1999;Combita et al, 2002;Einstein et al, 2007). It has been suggested that HPV VLP serologic assays may be useful as an additional tool to identify women at risk for high-grade cervical intraepithelial neoplasia (Einstein et al, 2007).…”

“…Numerous serologic studies using mainly HPV-16 VLPs (de Gruijl et al, 1997;Kirnbauer et al, 1994;Le Cann et al, 1995;Wideroff et al, 1999;Combita et al, 2002;Einstein et al, 2007) have demonstrated that infection with HPVs is followed by a serologic immune response to viral capsid proteins and that anti-VLP antibodies can be an indicator of life-time exposure to HPV infection. Seroconversion most frequently occurs between 6 and 18 months after HPV DNA detection and rarely occurs in patients with transient HPV infection (Carter et al, 2000).…”

“…In a number of case-control studies, serologic responses have shown that there is a strong association between HPV and cervical lesions (de Gruijl et al, 1997;Wideroff et al, 1999;Combita et al, 2002;Einstein et al, 2007). It has been suggested that HPV VLP serologic assays may be useful as an additional tool to identify women at risk for high-grade cervical intraepithelial neoplasia (Einstein et al, 2007). Few studies have been reported on the seroresponse to HPV-16 VLP in Korean patients with cervical lesions and the clinical significance is unclear up to date (Park et al, 1998;Park, 1996).…”