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Background The authors investigated the durability of vaccine efficacy (VE) against human papillomavirus (HPV)16 or 18 infections and antibody response among nonrandomly assigned women who received a single dose of the bivalent HPV vaccine compared with women who received multiple doses and unvaccinated women. Methods HPV infections were compared between HPV16 or 18-vaccinated women aged 18 to 25 years who received one (N = 112), two (N = 62), or three (N = 1365) doses, and age- and geography-matched unvaccinated women (N = 1783) in the long-term follow-up of the Costa Rica HPV Vaccine Trial. Cervical HPV infections were measured at two study visits, approximately 9 and 11 years after initial HPV vaccination, using National Cancer Institute next-generation sequencing TypeSeq1 assay. VE and 95% confidence intervals (CIs) were estimated. HPV16 or 18 antibody levels were measured in all one- and two-dose women, and a subset of three-dose women, using a virus-like particle-based enzyme-linked immunosorbent assay (n = 448). Results Median follow-up for the HPV-vaccinated group was 11.3 years (interquartile range = 10.9–11.7 years) and did not vary by dose group. VE against prevalent HPV16 or 18 infection was 80.2% (95% CI = 70.7% to 87.0%) among three-dose, 83.8% (95% CI = 19.5% to 99.2%) among two-dose, and 82.1% (95% CI = 40.2% to 97.0%) among single-dose women. HPV16 or 18 antibody levels did not qualitatively decline between years four and 11 regardless of the number of doses given, although one-dose titers continue to be statistically significantly lower compared with two- and three-dose titers. Conclusion More than a decade after HPV vaccination, single-dose VE against HPV16 or 18 infection remained high and HPV16 or 18 antibodies remained stable. A single dose of bivalent HPV vaccine may induce sufficiently durable protection that obviates the need for more doses.

Author(s): Safaeian, Mahboobeh; Sampson, Joshua N; Pan, Yuanji; Porras, Carolina; Kemp, Troy J; Herrero, Rolando; Quint, Wim; van Doorn, Leen Jan; Schussler, John; Lowy, Douglas R; Schiller, John; Schiffman, Mark T; Rodriguez, Ana Cecilia; Gail, Mitchell H; Hildesheim, Allan; Gonzalez, Paula; Pinto, Ligia A; Kreimer, Aimee R; Costa Rica HPV Vaccine Trial (CVT) Group | Abstract: BackgroundPreviously, we demonstrated similar human papillomavirus (HPV)16/18 vaccine efficacy estimates and stable HPV16/18 antibody levels four years postvaccination in a nonrandomized analysis of women who received a varying number of doses of the bivalent HPV16/18 vaccine. Here we extend data to seven years following initial vaccination.MethodsWe evaluated HPV16/18-vaccinated women who received one (n = 134), two (n 0/1 = 193, n 0/6 = 79), or three doses (n = 2043) to a median of 6.9 years postvaccination. Cervical HPV DNA was measured with the SPF10- DEIA-LiPA PCR system; HPV16/18-specific antibody levels were measured using enzyme-linked immunosorbent assays (n = 486). Infection and immunological measures were compared across vaccine dose groups. Prevalent HPV infection at year 7 was also compared with an unvaccinated control group (UCG). All statistical tests were two-sided.ResultsAmong women in the three-dose, two-dose 0/6 , two-dose 0/1 , and one-dose groups, cumulative incident HPV16/18 infection rates (No. of events/No. of individuals) were 4.3% (88/2036, 95% confidence interval [CI] = 3.5% to 5.3%), 3.8% (3/78, 95% CI = 1.0% to 10.1%), 3.6% (7/192, 95% CI = 1.6% to 7.1%), and 1.5% (2/133, 95% CI = 0.3% to 4.9%; P = 1.00, .85, .17 comparing the two-dose 0/6 , two-dose 0/1 , and one-dose groups to the three-dose group, respectively). The prevalence of other carcinogenic and noncarcinogenic HPV types, excluding HPV16/18/31/33/45, were high and not statistically different among all dose groups, indicating that the low incidence of HPV16/18 in the one- and two-dose groups was not due to lack of exposure. At seven years, 100% of participants in all dose groups remained HPV16 and HPV18 seropositive. A non-statistically significant decrease in the geometric mean of the HPV16 antibody levels between years 4 and 7 was observed among women in the three-dose group: -10.8% (95% CI = -25.3% to 6.6%); two-dose (0/6 months) group: -17.3% (95% CI = -39.3% to 12.8%), two-dose (0/1 month) group: -6.9% (95% CI = -22.1% to 11.2%), and one-dose group: -5.5% (95% CI = -29.7% to 27.0%); results were similar for HPV18.ConclusionsAt an average of seven years of follow-up, we observed similar low rates of HPV16/18 infections and slight, if any, decreases in HPV16/18 antibody levels by dose group.

Vulvar cancer is rare, accounting for approximately 4% of gynecological malignancies worldwide [1]. However, the incidence of vulvar cancer has been increasing, particularly in young women [2, 3]. In the United States from 2000 to 2009, the incidence of vulvar cancer has significantly increased among both white and African American women; 1.4% and 0.9% annual percentage change, respectively [3]. This increase is believed to be due to a rise in human papillomavirus (HPV) infection [2, 4–6]. Worldwide, it is estimated that HPV infection is the causative agent in approximately 43% of vulvar cancers [7]. HPV 16 and 18 infections combined account for 93% of HPV-associated vulvar cancers [8]; thus, prophylactic vaccination has the potential to reduce the incidence of vulvar cancer. Two vaccines prevent HPV 16 and 18 infections at the cervix: the bivalent HPV16/18 vaccine Cervarix®, GlaxoSmithKline Vaccines [GSK]) [9] and the quadrivalent HPV6/11/16/18 vaccine (Gardasil™, Merck and Co, Inc) [10]. Data presented in abstract form for the bivalent vaccine reported a 75% reduction in HPV16/18-associated vulvar/vaginal precursor lesions (a combined endpoint) among vaccinated women compared to controls [11]. For the quadrivalent vaccine, high (>95%) vaccine efficacy (VE) against HPV16/18-associated vulvar intraepithelial neoplasia grades 1, 2, and 3 was demonstrated [10], garnering an indication from the US Food and Drug Administration (FDA) for prevention of vulvar cancer. VE against HPV16/18 infections at the vulva has yet to be reported. Efficacy against HPV16/18-associated vulvar lesions was demonstrated by both pharmaceutical vaccine trials using HPV DNA testing of vulvar lesions, which represented a small subset of the total trial population [10, 11]. Given that VE against HPV-associated lesions is the result of prevention of HPV infection, we reasoned that use of a virologic endpoint for the estimation of vulvar VE would provide additional novel information on an intermediate endpoint on the pathway to cancer. Likewise, perhaps due to the rarity of HPV-associated vulvar cancer, only 6 studies have been published on the epidemiology of vulvar HPV infection in cancer-free women [12–17] and only 1 study reported risk factors associated with high-risk HPV infection of the vulva [17]. To address the limited knowledge of vulvar VE as well as the epidemiology of vulvar HPV infection, we implemented a vulvar specimen collection at the final (year 4), randomized blinded study visit of the Costa Rica Vaccine Trial (CVT). The goals of this value-added analysis were to (1) estimate the reduction of prevalent HPV16/18 infections at the vulva compared to cervix among HPV vaccinated women compared to controls 4 years after vaccination, and (2) characterize the prevalence of and risk factors for vulvar HPV infection in the control arm of this study population.

Multidose regimens are recommended for all prophylactic subunit vaccines. Recent findings from clinical trials of an human papillomavirus virus-like particle vaccine suggest that it may be possible to develop effective single-dose subunit vaccines. The broad implications of these findings are discussed, and the importance of antigen structure and adjuvant in achieving this goal is considered. In conclusion, we argue for the inclusion of single-dose arms in future trials of vaccines, especially if they are based on induction of antibodies by virus-like displayed antigens.

Background Vaccination with minor capsid protein L2 induces antibodies that cross-neutralize diverse papillomavirus types. However, neutralizing antibody titers against the papillomavirus type from which the L2 vaccine was derived are generally higher than the titers against heterologous types, which could limit effectiveness against heterologous types. We hypothesized that vaccination with concatenated multitype L2 fusion proteins derived from known cross-protective epitopes of several divergent human papillomavirus (HPV) types might enhance immunity across clinically relevant HPV genotypes. Methods Antibody responses of mice (n = 120) and rabbits (n = 23) to vaccination with HPV-16 amino-terminal L2 polypeptides or multitype L2 fusion proteins, namely, 11-200 × 3 (HPV types 6, 16, 18), 11-88 × 5 (HPV types 1, 5, 6, 16, 18), or 17-36 × 22 (five cutaneous, two mucosal low-risk, and 15 oncogenic types), that were formulated alone or in GPI-0100, alum, or 1018 ISS adjuvants were compared with vaccination with L1 virus-like particles (VLPs), including Gardasil, a licensed quadrivalent HPV L1 vaccine, and a negative control. Mice were challenged with HPV-16 pseudovirions 4 months after vaccination. Statistical tests were two-sided. Results The HPV-16 L2 polypeptides generated robust HPV-16–neutralizing antibody responses, albeit lower than those to HPV-16 L1 VLPs, and lower responses against other HPVs. In contrast, vaccination with the multitype L2 fusion proteins 11-200 x 3 and 11-88 x 5 induced high serum neutralizing antibody titers against all heterologous HPVs tested. 11-200 × 3 formulated in GPI-0100 adjuvant or alum with 1018 ISS protected mice against HPV-16 challenge (reduction in HPV-16 infection vs phosphate-buffered saline control, P < .001) 4 months after vaccination as well as HPV-16 L1 VLPs, but 11-200 × 3 alone or formulated with either alum or 1018 ISS was less effective (reduction in HPV-16 infection, P < .001). Conclusion Concatenated multitype L2 proteins in adjuvant have potential as pan-oncogenic HPV vaccines.

The tumor suppressor p53 protein can be bound, degraded and inactivated by the human papillomavirus (HPV) E6 oncoprotein. The p53 protein's susceptibility to this oncoprotein may be influenced by the p53 codon 72 polymorphism, but the role of such a polymorphism in the development of HPV16-associated squamous cell carcinoma of the oropharynx (SCCOP) has not been established. To investigate the role of the p53 codon 72 polymorphism in the risk of HPV16-associated SCCOP, we conducted a hospital-based case-control study of 188 non-Hispanic white patients with newly diagnosed SCCOP and 342 cancer-free control subjects frequency matched by age (+/-5 years), sex, tobacco smoking status and alcohol drinking status. We found that HPV16 seropositivity was associated with an increased risk of SCCOP [adjusted odds ratio (OR), 5.7; 95% confidence interval (CI), 3.7-8.7], especially among never-smokers (adjusted OR, 14.1; 95% CI, 6.0-32.9) and among subjects with the p53 codon 72 variant genotypes [Arginine (Arg)/Proline (Pro) and Pro/Pro] (adjusted OR, 9.2; 95% CI, 4.7-17.7). A significant multiplicative interaction on the risk of SCCOP was also found between the p53 codon 72 polymorphism and HPV16 seropositivity (P = 0.05). Among never-smokers, the risk of SCCOP for those who had both HPV16 seropositivity and p53 codon 72 variant genotypes (Arg/Pro + Pro/Pro) was particularly high (adjusted OR, 22.5; 95% CI, 4.8-106.2). These findings suggest that p53 codon 72 variant genotypes modify the risk of HPV16-associated SCCOP and may be markers of genetic susceptibility to HPV16-associated SCCOP, especially among never-smokers.

Isotype-specific serum antibody responses against human papillomavirus (HPV) type 16 were evaluated by use of cross-sectional, prospective, and population-based seroepidemiologic studies. IgG1 and IgA were the most abundant isotypes. No sample contained IgG2, and

The stability over time of serum IgG antibody levels to human papillomavirus type 16 (HPV-16) was determined by comparing the HPV-16 capsid antibody levels in serial serum samples of an age-stratified random subsample of 1656 primiparous mothers resident in Helsinki who were followed until their second pregnancy, on average 29.5 months later. The correlation between the first and second pregnancy HPV-16 serum antibody levels of the same woman was high, even when >4 years had elapsed between pregnancies (r = .822). Between negativity, indeterminate results, or quartiles of positivity, the predictive values for being classified in the same category on both occasions ranged between 42% and 91%. Correlation coefficients, predictive values, and kappa coefficients between serial samples all were comparable with those of repeat analyses of the same sample, indicating that HPV capsid antibody levels are generally stable during several years of follow-up.

There is strong epidemiologic evidence for sexual transmission of high-risk genital human papillomavirus (HPV) types. However, it is unclear if infection may also be transmitted indirectly via fomites. To assess this possibility, the in vitro infectivity after desiccation was compared for pseudotype HPV-16 virions, a model for high-risk type genital HPV, and bovine papillomavirus type 1 (BPV-1), a papillomavirus known to be transmitted via fomites. The 2 viruses had similar resistance to desiccation in cell extracts, retaining approximately 100%, 50%, and 30% of infectivity when dehydrated for 1, 3, and 7 days, respectively, at room temperature. Pseudotype HPV-16 and BPV in cell extracts were completely inactivated by autoclave treatment and susceptible to 70% ethanol but were resistant to EDTA or incubation at 56 degrees C for 1 h. The data suggest that further study of nonsexual spread of high-risk genital HPV via fomites is warranted.

The epidemiologic determinants of seroreactivity to human papillomavirus (HPV) type 16 L1/L2 virus-like particles (VLPs) were assessed separately in HPV-16 DNA-positive and -negative women participating in a nested case-control study of incident cervical neoplasia. Seventy-four women with cervical HPV-16 DNA and 656 cytologically normal HPV-16 DNA-negative subjects were interviewed and tested at two time points for viral DNA and once (at the later time) for VLP seroreactivity. Among subjects who were currently HPV-16 DNA-negative, seroreactivity odds ratios increased from 2.9 for 2-5 male sex partners (vs. 0 or 1) to 5.4 for 6-9 partners and 14.0 for > or = 10. Thus, prior cervical infection may be a major determinant of seroreactivity in HPV-16 DNA-negative women. This trend was not observed in HPV-16 DNA-positive subjects. Seroreactivity was independently associated with oral contraceptive use, particularly in HPV-16 DNA-negative subjects with use for > or = 10 years. Consequently, a possible role for virus-steroid hormone interactions in seroconversion is suggested.

Background: The existence of large geographic variations in the prevalence of esophageal cancer in some countries, such as China, indicates that environmental risk factors may be important in the development of this disease. Some studies have implicated genital-mucosal strains of human papillomaviruses (HPVs) in the etiology of this cancer. Purpose: We conducted a case-control study in Shaanxi Province, China, an area with a population at high risk for esophageal cancer, to assess the association of this disease with infection by HPV type 16 (HPV16), the most common cancer-associated genital-mucosal HPV type. Methods: Ninety individuals with esophageal cancer and 121 cancer-free control subjects were identified among the patients in two hospitals in Xi'an, Shaanxi Province. The control subjects were matched to the case patients on the basis of age and sex. Blood specimens were drawn from all study subjects, and serum was isolated by routine methods. The presence of HPV16 antibodies in serum samples was determined by use of an enzyme-linked immunosorbent assay (ELISA) that used baculovirus-derived HPV16 virus-like particles as the antigen. A similar ELISA that used bovine papillomavirus type 1 (BPV1) virus-like particles as the antigen controlled for the specificity of HPV16 seroreactivity. Data from the HPV16 and the BPV1 assays were normalized with respect to results obtained in each assay with a control serum of known HPV16 seroreactivity. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to examine the association between HPV16 seroreactivity and esophageal cancer. Reported P values are two-sided. Results: The mean seroreactivity to HPV16 virus-like particles was significantly higher for the cancer patients than for the control subjects (mean value ± standard deviation = 0.85 ± 0.22 versus 0.74 ± 0.18; P

It is not known whether DNA sequence variants of human papillomavirus type 16 (HPV-16) are distinct serotypes. To examine this question, the reactivities of women's sera from Zaire (n = 97) and Denmark (n = 123) were compared in IgG-specific ELISAs based on virus-like particles (VLPs) composed of the L1 major capsid protein derived from an HPV-16 variant common in central Africa (Z-1194) or one common in northern Europe (114K). These L1s differ in seven amino acids. There was a strong correlation between reactivity in the two assays for both sets of sera (correlation coefficients, 0.73 and 0.85 for Zairian and Danish sera, respectively). In only 1 serum was there evidence for a specific reaction to one but not the other VLP variant. The results support the conclusion that the virions of strains Z-1194 and 114K are serologically cross-reactive.

An ELISA to detect serum IgG antibody response to human papillomavirus (HPV) type 16 virus-like particles (VLPs) was evaluated in a case-control study of cervical neoplasia, nested within a prospective cohort study. Subjects included 688 controls with continued normal cytology and 152 cases with confirmed incident squamous intraepithelial lesions who were tested for DNA of a broad spectrum of HPV types at cohort enrollment and follow-up. Of controls, 16.6% were seropositive compared with 30.8% and 52.4% of cases with low- and high-grade lesions, respectively. Of HPV-16 DNA-negative subjects, 16.5% were seropositive. Seropositivity increased from 22.2% in subjects who were HPV-16 DNA-positive by polymerase chain reaction once only (enrollment or follow-up) to 83.3% in those who were HPV-16 DNA-positive at both time points. These data imply that serum antibody to HPV-16 VLPs is a relatively sensitive indicator of persisting cervical HPV-16 infection.

Background Anal epidermoid carcinoma is a relatively rare tumor, but its incidence has been increasing rapidly during the past few years. Genetic material from the major oncogenic types of human papillomavirus (HPV), types 16 and 18, has regularly been demonstrated in a substantial proportion of anal cancers, suggesting an etiologic role of HPV infection. Recently, serum antibodies against HPV type 16 capsids were shown to be a serologic measure of HPV16 infection. Purpose We investigated whether serum antibodies against HPV16 capsids are associated with an increased risk of developing anal cancer. Methods Serum samples from 64 patients (48 women and 16 men) with untreated anal epidermoid cancer and from 79 age- and sex-matched healthy blood donors were analyzed for the levels of serum immunoglobulin G (IgG) against capsids of HPV16 by the enzyme-linked immunosorbent assay. The levels of serum IgG against HPV type 6 and bovine papillomavirus (BPV) capsids, as well as against HPV16 peptide antigens, were also measured. Results Whereas antibodies against HPV6 or BPV capsids were not significantly associated with anal cancer, the presence of IgG against HPV16 capsids exceeding the anti-BPV antibody levels was demonstrated among 55% (35 of 64) of the case patients but only among 4% (three of 79) of the control subjects (odds ratio [OR] = 30.4; 95% confidence interval [CI] = 8.4-161.5). Antibodies against HPV16 E2 and E7 peptides were also more common among case patients (OR = 12.8 and 95% CI = 5.4-31.5 for E2; OR = 3.0 and 95% CI = 1.4-6.7 for E7). Conclusion The results suggest that HPV16 capsid antibodies are serologic markers for anal cancer. Implication Exposure to HPV16 or related viruses appears to be a major risk factor in the majority of anal cancers.

Background In early-phase trials, a human papillomavirus 16 (HPV16) virus-like particle (VLP) vaccine has been shown to be well tolerated, immunogenic, and protective against HPV16 in women, most of whom were taking oral contraceptives. Previous studies have not determined whether HPV immunization results in specific antibody levels in the human genital tract or whether these levels might vary during contraceptive or ovulatory cycles. Therefore, we determined the levels of total and specific antibodies in the cervical secretions of women who had been immunized with HPV16 VLPs and examined the influence of the menstrual cycle and oral contraceptive use on these levels. Methods Two groups of women were immunized, seven who were taking oral contraceptives and 11 who were ovulating. After seroconversion, serum and cervical secretions were collected twice weekly for 5 weeks. Total immunoglobulins (IgG and IgA) and vaccine-specific IgGs were determined by enzyme-linked immunosorbent assay. Nonparametric statistical analyses were used to determine the statistical significance of differences in IgG levels between groups, and correlations between serum- and cervical-specific IgG levels were determined by the Spearman correlation coefficient. Results All participants developed detectable titers of anti-HPV16 VLP IgGs in their cervical secretions after immunization. The cervical titers of specific IgG and total IgGs and IgAs among participants in the contraceptive group were relatively constant throughout the contraceptive cycle. In contrast, the cervical titers of specific IgG and total IgGs and IgAs among participants in the ovulatory group varied during the menstrual cycle, being highest during the proliferative phase, decreasing approximately ninefold around ovulation, and increasing approximately threefold during the luteal phase. Serum- and cervical-specific IgG levels were correlated (r =.86) in women in the contraceptive group but not in women in the ovulatory group (r =.27). Conclusions The relatively high titer of anti-HPV16 antibodies at the cervix is promising in terms of vaccine efficacy; however, the decrease in antibody titer around ovulation raises the possibility that the HPV16 VLP vaccine might be less effective during the peri-ovulatory phase.