Natural immune responses against eight oncogenic human papillomaviruses in the ASCUS‐LSIL Triage Study

Abstract

Only a subset of women with human papillomavirus (HPV) infections will become seropositive, and the factors influencing seroconversion are not well-understood. We used a multiplex serology assay in women with mildly abnormal cytology results to examine seroreactivity to oncogenic HPV genotypes. An unbiased subset of women in the atypical squamous cell of undetermined significance /low-grade squamous intraepithelial lesion Triage Study (ALTS) provided blood samples at trial enrollment for serological testing. A Luminex assay based on GST-L1 fusion proteins as antigens was used to test seroreactivity against eight carcinogenic HPV genotypes (16, 18, 31, 33, 35, 45, 52, 58). We analyzed the relationship between seroprevalence in women free of precancer (N=2464) and HPV DNA status, age, sexual behavior, and other HPV-related risk factors. The overall seroprevalence was 24.5% for HPV16 L1 and ~ 20% for 18L1 and 31L1. Among women free of precancer, seroprevalence peaked in women less than 29 years and decreased with age. Type-specific seroprevalence was associated with baseline DNA detection for HPV16 (OR= 1.36, 95%CI: 1.04–1.79) and HPV18 (OR= 2.31, 95%CI: 1.61–3.32), as well as for HPV52 and HPV58. Correlates of sexual exposure were associated with increased seroprevalence across most genotypes. Women who were current or former smokers were less likely to be seropositive for all eight of the tested oncogenic genotypes. The multiplex assay showed associations between seroprevalence and known risk factors for HPV infection across nearly all tested HPV genotypes but associations between DNA- and serostatus were weak, suggesting possible misclassification of the participants’ HPV serostatus.

A Longitudinal Study of Human Papillomavirus 16 L1, E6, and E7 Seropositivity and Oral Human Papillomavirus 16 Infection

“…5 Similar to other serologic assays, the VLP-ELISAs used in this study are limited as there are no standard reference serum samples and the assay has been suggested to detect an antibody response for only 50–60% of women who previously had detectable cervical HPV DNA. 16,28,29 The VLP-ELISA utilized in this study measured the total type-specific binding IgG antibodies which include both neutralizing and non-neutralizing antibodies. Further research is needed to determine if these results may differ across other serologic assays, particularly those that restrict to neutralizing antibodies.…”

Amino acid motifs in both the major and minor capsid proteins of HPV51 impact antigenicity and infectivity

“…antibody in contemporary samples (Carter et al, 2000;Ochi et al, 2008;Pastrana et al, 2004; Syrjänen et al, 2009;Wilson et al, 2013). This is perhaps not surprising given the comparatively low rates of seroconversion following incident HPV infection (Carter et al, 2000; Syrjänen et al, 2009;Xi et al, 2002) and observations that NI antibodies are generally of low titre and may wane over time (Syrjänen et al, 2009;Wilson et al, 2013 Our objectives for this study were: (i) to generate HPV51 L1 and L2 sequences to inform the creation of representative L1 VLP and L1L2 pseudovirus antigens; (ii) to compare the antigenicity, immunogenicity and infectivity profiles with antigens based on the reference sequence; and (iii) to use appropriate antigens to compare the antibody responses generated during HPV16 and HPV51 infection. Such data should inform the structure-function relationship between the major and minor capsid proteins of an important oncogenic HPV genotype.…”

“…Most of these studies have examined HPV16 and/or HPV18 (Castellsagué et al, 2014;Lin et al, 2013;Pastrana et al, 2004;Safaeian et al, 2010;Xi et al, 2002), whilst some have expanded their investigations to evaluate other genotypes including HPV6, HPV11, HPV31, HPV33, HPV35, HPV45, HPV52 and HPV58 (Carter et al, 2000;Ochi et al, 2008;Syrjänen et al, 2009;Wilson et al, 2013). Most of these studies have made use of an immobilized L1-based target (Carter et al, 2000;Castellsagué et al, 2014;Safaeian et al, 2010;Syrjänen et al, 2009;Wilson et al, 2013;Xi et al, 2002), whilst a few have used an L1L2 pseudovirus neutralization assay (Lin et al, 2013;Ochi et al, 2008;Pastrana et al, 2004). Inter-assay agreements for measuring NI antibody responses appear to be quite poor (Safaeian et al, 2012), in contrast to studies of vaccine antibody responses (Dessy et al, 2008;Krajden et al, 2014).…”

“…Inter-assay agreements for measuring NI antibody responses appear to be quite poor (Safaeian et al, 2012), in contrast to studies of vaccine antibody responses (Dessy et al, 2008;Krajden et al, 2014). There also appears to be a poor correlation between the presence of HPV DNA and type-specific antibody in contemporary samples (Carter et al, 2000;Ochi et al, 2008;Pastrana et al, 2004;Syrjänen et al, 2009;Wilson et al, 2013). This is perhaps not surprising given the comparatively low rates of seroconversion following incident HPV infection (Carter et al, 2000;Syrjänen et al, 2009;Xi et al, 2002) and observations that NI antibodies are generally of low titre and may wane over time (Syrjänen et al, 2009;Wilson et al, 2013).…”

“…There also appears to be a poor correlation between the presence of HPV DNA and type-specific antibody in contemporary samples (Carter et al, 2000;Ochi et al, 2008;Pastrana et al, 2004;Syrjänen et al, 2009;Wilson et al, 2013). This is perhaps not surprising given the comparatively low rates of seroconversion following incident HPV infection (Carter et al, 2000;Syrjänen et al, 2009;Xi et al, 2002) and observations that NI antibodies are generally of low titre and may wane over time (Syrjänen et al, 2009;Wilson et al, 2013). Despite these potential shortcomings, individuals with high levels of type-specific NI antibodies may have a reduced risk of subsequent reinfection by that genotype (Castellsagué et al, 2014;Safaeian et al, 2010;Wilson et al, 2014).…”