BACKGROUND: Results from the Costa Rica Vaccine Trial (CVT) demonstrated partial cross-protection by the bivalent human papillomavirus (HPV) vaccine, which targets HPV-16 and HPV-18, against HPV-31, -33, and -45 infection and an increased incidence of HPV-51 infection. METHODS: A study nested within the CVT intention-to-treat cohort was designed to assess high-risk HPV variant lineage-specific vaccine efficacy (VE). The 2 main end points were (1) long-term incident infections persisting for ≥2 years and/or progression to high-grade squamous intraepithelial lesions (ie, cervical intraepithelial neoplasia grade 2/3 [CIN 2/3]) and (2) incident transient infections lasting for <2 years. For efficiency, incident infections due to HPV-16, -18, -31, -33, -35, -45, and -51 resulting in persistent infection and/or CIN 2/3 were matched (ratio, 1:2) to the more-frequent transient viral infections, by HPV type. Variant lineages were determined by sequencing the upstream regulatory region and/or E6 region. RESULTS: VEs against persistent or transient infections with HPV-16, -18, -33, -35, -45, and -51 did not differ significantly by variant lineage. As the possible exception, VEs against persistent infection and/or CIN 2/3 due to HPV-31 A/B and HPV-31C variants were -7.1% (95% confidence interval [CI], -33.9% to 0%) and 86.4% (95% CI, 65.1%-97.1%), respectively (P = .02 for test of equal VE). No difference in VE was observed by variant among transient HPV-31 infections (P = .68). CONCLUSIONS: Overall, sequence variation at the variant level does not appear to explain partial cross-protection by the bivalent HPV vaccine.

BACKGROUND: Human papillomavirus vaccines prevent human papillomavirus infection and cervical precancers. The impact of vaccinating women with a current infection or after treatment for an human papillomavirus-associated lesion is not fully understood. OBJECTIVES: To determine whether human papillomavirus-16/18 vaccination influences the outcome of infections present at vaccination and the rate of infection and disease after treatment of lesions. STUDY DESIGN: We included 1711 women (18-25 years) with carcinogenic human papillomavirus infection and 311 women of similar age who underwent treatment for cervical precancer and who participated in a community-based trial of the AS04-adjuvanted human papillomavirus-16/18 virus-like particle vaccine. Participants were randomized (human papillomavirus or hepatitis A vaccine) and offered 3 vaccinations over 6 months. Follow-up included annual visits (more frequently if clinically indicated), referral to colposcopy of high-grade and persistent low-grade lesions, treatment by loop electrosurgical excisional procedure when clinically indicated, and cytologic and virologic follow-up after treatment. Among women with human papillomavirus infection at the time of vaccination, we considered type-specific viral clearance, and development of cytologic (squamous intraepithelial lesions) and histologic (cervical intraepithelial neoplasia) lesions. Among treated women, we considered single-time and persistent human papillomavirus infection, squamous intraepithelial lesions, and cervical intraepithelial neoplasia 2 or greater. Outcomes associated with infections absent before treatment also were evaluated. Infection-level analyses were performed and vaccine efficacy estimated. RESULTS: Median follow-up was 56.7 months (women with human papillomavirus infection) and 27.3 months (treated women). There was no evidence of vaccine efficacy to increase clearance of human papillomavirus infections or decrease incidence of cytologic/histologic abnormalities associated with human papillomavirus types present at enrollment. Vaccine efficacy for human papillomavirus 16/18 clearance and against human papillomavirus 16/18 progression from infection to cervical intraepithelial neoplasia 2 or greater were -5.4% (95% confidence interval -19,10) and 0.3% (95% confidence interval -69,41), respectively. Among treated women, 34.1% had oncogenic infection and 1.6% had cervical intraepithelial neoplasia 2 or greater detected after treatment, respectively, and of these 69.8% and 20.0% were the result of new infections. We observed no significant effect of vaccination on rates of infection/lesions after treatment. Vaccine efficacy estimates for human papillomavirus 16/18 associated persistent infection and cervical intraepithelial neoplasia 2 or greater after treatment were 34.7% (95% confidence interval -131, 82) and -211% (95% confidence interval -2901, 68), respectively. We observed evidence for a partial and nonsignificant protective effect of vaccination against new infections absent before treatment. For incident human papillomavirus 16/18, human papillomavirus 31/33/45, and oncogenic human papillomavirus infections post-treatment, vaccine efficacy estimates were 57.9% (95% confidence interval -43, 88), 72.9% (95% confidence interval 29, 90), and 36.7% (95% confidence interval 1.5, 59), respectively. CONCLUSION: We find no evidence for a vaccine effect on the fate of detectable human papillomavirus infections. We show that vaccination does not protect against infections/lesions after treatment. Evaluation of vaccine protection against new infections after treatment and resultant lesions warrants further consideration in future studies.

BACKGROUND: In women vaccinated against human papillomavirus (HPV), reductions in cervical disease and related procedures results in more women having intact transformation zones, potentially increasing the risk of cervical lesions caused by non-vaccine-preventable HPV types, a phenomenon termed clinical unmasking. We aimed to evaluate HPV vaccine efficacy against cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and cervical intraepithelial neoplasia grade 3 or worse (CIN3+) attributed to non-preventable HPV types in the long-term follow-up phase of the Costa Rica HPV Vaccine Trial (CVT). METHODS: CVT was a randomised, double-blind, community-based trial done in Costa Rica. Eligible participants were women aged 18-25 years who were in general good health. Participants were randomly assigned (1:1) to receive an HPV 16 and 18 AS04-adjuvanted vaccine or control hepatitis A vaccine, using a blocked randomisation method (permuted block sizes of 14, 16, and 18). Vaccines in both groups were administered intramuscularly with 0·5 mL doses at 0, 1, and 6 months. Masking of vaccine allocation was maintained throughout the 4-year randomised trial phase, after which participants in the hepatitis A virus vaccine control group were provided the HPV vaccine and exited the study; a screening-only, unvaccinated control group was enrolled. The unvaccinated control group and HPV vaccine group were followed up for 7 years, during which treatment allocation was not masked. One of the prespecified primary endpoints for the long-term follow-up phase was precancers associated with HPV types not prevented by the vaccine, defined as histologically confirmed incident CIN2+ events or CIN3+ events attributed to any HPV type except HPV 16, 18, 31, 33, and 45. Our primary analytical period was years 7-11. Primary analyses were in all participants with at least one follow-up visit and excluded participants with a previous endpoint (ie, modified intention-to-treat cohort). Safety endpoints have been reported elsewhere. This trial is registered with ClinicalTrials.gov, NCT00128661 and NCT00867464. The randomised, masked trial phase is completed; an unmasked subset of women in the HPV-vaccinated group is under active investigation. FINDINGS: Between June 28, 2004, and Dec 21, 2005, 7466 participants were enrolled (HPV vaccine group n=3727 and hepatitis A virus vaccine control group n=3739). Between March 30, 2009, and July 5, 2012, 2836 women enrolled in the new unvaccinated control group. The primary analytical cohort (years 7 to 11) included 2767 participants in the HPV vaccine group and 2563 in the unvaccinated group for the CIN2+ events endpoint assessment and 2826 participants in the HPV vaccine group and 2592 in the unvaccinated control group for the CIN3+ events endpoint assessment. Median follow-up during years 7 to 11 for women included for the CIN2+ events analysis was 52·8 months (IQR 44·0 to 60·7) for the HPV vaccine group and 49·8 months (42·0 to 56·9) for the unvaccinated control group. During years 7 to 11, clinical unmasking was observed with a negative vaccine efficacy against CIN2+ events attributed to non-preventable HPV types (-71·2% [95% CI -164·0 to -12·5]), with 9·2 (95% CI 2·1 to 15·6) additional CIN2+ events attributed to non-preventable HPV types per 1000 HPV-vaccinated participants versus HPV-unvaccinated participants. 27·0 (95% CI 14·2 to 39·9) fewer CIN2+ events irrespective of HPV type per 1000 vaccinated participants were observed during 11 years of follow-up. Vaccine efficacy against CIN3+ events attributed to non-preventable HPV types during years 7 to 11 was -135·0% (95% CI -329·8 to -33·5), with 8·3 (3·0 to 12·8) additional CIN3+ events attributed to non-preventable HPV types per 1000 vaccinated participants versus unvaccinated participants. INTERPRETATION: Higher rates of CIN2+ events and CIN3+ events due to non-preventable HPV types in vaccinated versus unvaccinated participants suggests clinical unmasking could attenuate long-term reductions in high-grade disease following successful implementation of HPV vaccination programmes in screened populations. Importantly, the net benefit of vaccination remains considerable; therefore, HPV vaccination should still be prioritised as primary prevention for cervical cancer. FUNDING: National Cancer Institute and National Institutes of Health Office of Research on Womens Health. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

The HPV vaccine has shown sustained efficacy and consistent stabilization of antibody levels, even after a single dose. We defined the HPV16-VLP antibody avidity patterns over 11 years among women who received one- or three doses of the bivalent HPV vaccine in the Costa Rica HPV Vaccine Trial. Absolute HPV16 avidity was lower in women who received one compared to three doses, although the patterns were similar (increased in years 2 and 3 and remained stable over the remaining 8 years). HPV16 avidity among women who were HPV16-seropositive women at HPV vaccination, a marker of natural immune response to HPV16 infection, was significantly lower than those of HPV16-seronegative women, a difference that was more pronounced among one-dose recipients. No differences in HPV16 avidity were observed by HPV18 serostatus at vaccination, confirming the specificity of the findings. Importantly, point estimates for vaccine efficacy against incident, six-month persistent HPV16 infections was similar between women who were HPV16 seronegative and seropositive at the time of initial HPV vaccination for both one-dose and three-dose participants. It is therefore likely that this lower avidity level is still sufficient to enable antibody-mediated protection. It is encouraging for long-term HPV-vaccine protection that HPV16 antibody avidity was maintained for over a decade, even after a single dose.

BACKGROUND: The AS04-adjuvanted HPV16/18 (AS04-HPV16/18) vaccine provides excellent protection against targeted human papillomavirus (HPV) types and a variable degree of cross-protection against others, including types 6/11/31/33/45. High efficacy against any cervical intraepithelial neoplasia grade 3 or greater (CIN3+; >90%) suggests that lower levels of protection may exist for a wide range of oncogenic HPV types, which is difficult to quantify in individual trials. Pooling individual-level data from two randomized controlled trials, we aimed to evaluate AS04-HPV16/18 vaccine efficacy against incident HPV infections and cervical abnormalities . METHODS: Data were available from the Costa Rica Vaccine Trial (NCT00128661) and Papilloma Trial Against Cancer in Young Adults trial (NCT00122681), two large-scale, double-blind randomized controlled trials of the AS04-HPV16/18 vaccine. Primary analyses focused on disease-free women with no detectable cervicovaginal HPV at baseline. RESULTS: A total of 12 550 women were included in our primary analyses (HPV arm = 6271, control arm = 6279). Incidence of 6-month persistent oncogenic and nononcogenic infections, excluding known and accepted protected types 6/11/16/18/31/33/45 (focusing on 34/35/39/40/42/43/44/51/52/53/54/56/58/59/66/68/73/70/74), was statistically significantly lower in the HPV arm than in the control arm (efficacy = 9.9%, 95% confidence interval [CI] = 1.7% to 17.4%). Statistically significant efficacy (P < .05) was observed for individual oncogenic types 16/18/31/33/45/52 and nononcogenic types 6/11/53/74. Efficacy against cervical abnormalities (all types) increased with severity, ranging from 27.7% (95% CI = 21.7% to 33.3%) to 58.7% (95% CI = 34.1% to 74.7%) for cytologic outcomes (low-grade squamous intraepithelial neoplasia lesion or greater, and high-grade squamous intraepithelial neoplasia lesion or greater, respectively) and 66.0% (95% CI = 54.4% to 74.9%) to 87.8% (95% CI = 71.1% to 95.7%) for histologic outcomes (CIN2+ and CIN3+, respectively). Comparing Costa Rica Vaccine Trial and Papilloma Trial Against Cancer in Young Adults results, there was no evidence of heterogeneity, except for type 51 (efficacy = -28.6% and 20.7%, respectively; two-sided P = .03). CONCLUSIONS: The AS04-HPV16/18 vaccine provides some additional cross-protection beyond established protected types, which partially explains the high efficacy against CIN3+.

BACKGROUND: Previously, 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. METHODS: We 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. RESULTS: Among 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. CONCLUSIONS: At 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.

BACKGROUND: The Costa Rica HPV Vaccine Trial has documented cross-protection of the bivalent HPV vaccine against HPV31/33/45 up to 7 years after vaccination, even with one dose of the vaccine. However, the durability of such protection remains unknown. Here, we evaluate the efficacy of different schedules of the vaccine against HPV31/33/45 out to 11 years postvaccination, expanding to other nontargeted HPV types. METHODS: We compared the rates of HPV infection in vaccinated women with the rates in a comparable cohort of unvaccinated women. We estimated the average vaccine efficacy (VEavg) against incident infections and tested for a change in VE over time. RESULTS: Among 3-dose women, we observed statistically significant cross-protection against HPV31/33/45 (VEavg = 64.4%, 95% confidence interval [CI] = 57.7% to 70.0%). Additionally, we observed borderline, statistically significant cross-protection against HPV35 (VEavg = 23.2%, 95% CI = 0.3% to 40.8%) and HPV58 (VEavg = 21.2%, 95% CI = 4.2% to 35.3%). There was no decrease in VE over time (two-sided Ptrend > .05 for HPV31, -33, -35, -45, and -58). As a benchmark, VEavg against HPV16/18 was 82.0% (95% CI = 77.3% to 85.7%). Among 1-dose women, we observed comparable efficacy against HPV31/33/45 (VEavg = 54.4%, 95% CI = 21.0% to 73.7%). Acquisition of nonprotected HPV types was similar between vaccinated and unvaccinated women, indicating that the difference in HPV infection rates was not attributable to differential genital HPV exposure. CONCLUSIONS: Substantial cross-protection afforded by the bivalent vaccine against HPV31/33/45, and to a lesser extent, HPV35 and HPV58, was sustained and remained stable after 11 years postvaccination, reinforcing the notion that the bivalent vaccine is an effective option for protection against HPV-associated cancers.

Bacterial vaginosis (BV) is a highly prevalent condition that is associated with adverse health outcomes. It has been proposed that BVs role as a pathogenic condition is mediated via bacteria-induced inflammation. However, the complex interplay between vaginal microbes and host immune factors has yet to be clearly elucidated. Here, we develop molBV, a 16 S rRNA gene amplicon-based classification pipeline that generates a molecular score and diagnoses BV with the same accuracy as the current gold standard method (i.e., Nugent score). Using 3 confirmatory cohorts we show that molBV is independent of the 16 S rRNA region and generalizable across populations. We use the score in a cohort without clinical BV states, but with measures of HPV infection history and immune markers, to reveal that BV-associated increases in the IL-1β/IP-10 cytokine ratio directly predicts clearance of incident high-risk HPV infection (HR = 1.86, 95% CI: 1.19-2.9). Furthermore, we identify an alternate inflammatory BV signature characterized by elevated TNF-α/MIP-1β ratio that is prospectively associated with progression of incident infections to CIN2 + (OR = 2.81, 95% CI: 1.62-5.42). Thus, BV is a heterogeneous condition that activates different arms of the immune response, which in turn are independent risk factors for HR-HPV clearance and progression. Clinical Trial registration number: The CVT trial has been registered under: NCT00128661.

Background

Human papillomavirus vaccines prevent human papillomavirus infection and cervical precancers. The impact of vaccinating women with a current infection or after treatment for an human papillomavirus-associated lesion is not fully understood.

Objectives

To determine whether human papillomavirus-16/18 vaccination influences the outcome of infections present at vaccination and the rate of infection and disease after treatment of lesions.

Study design

We included 1711 women (18-25 years) with carcinogenic human papillomavirus infection and 311 women of similar age who underwent treatment for cervical precancer and who participated in a community-based trial of the AS04-adjuvanted human papillomavirus-16/18 virus-like particle vaccine. Participants were randomized (human papillomavirus or hepatitis A vaccine) and offered 3 vaccinations over 6 months. Follow-up included annual visits (more frequently if clinically indicated), referral to colposcopy of high-grade and persistent low-grade lesions, treatment by loop electrosurgical excisional procedure when clinically indicated, and cytologic and virologic follow-up after treatment. Among women with human papillomavirus infection at the time of vaccination, we considered type-specific viral clearance, and development of cytologic (squamous intraepithelial lesions) and histologic (cervical intraepithelial neoplasia) lesions. Among treated women, we considered single-time and persistent human papillomavirus infection, squamous intraepithelial lesions, and cervical intraepithelial neoplasia 2 or greater. Outcomes associated with infections absent before treatment also were evaluated. Infection-level analyses were performed and vaccine efficacy estimated.

Results

Median follow-up was 56.7 months (women with human papillomavirus infection) and 27.3 months (treated women). There was no evidence of vaccine efficacy to increase clearance of human papillomavirus infections or decrease incidence of cytologic/histologic abnormalities associated with human papillomavirus types present at enrollment. Vaccine efficacy for human papillomavirus 16/18 clearance and against human papillomavirus 16/18 progression from infection to cervical intraepithelial neoplasia 2 or greater were -5.4% (95% confidence interval -19,10) and 0.3% (95% confidence interval -69,41), respectively. Among treated women, 34.1% had oncogenic infection and 1.6% had cervical intraepithelial neoplasia 2 or greater detected after treatment, respectively, and of these 69.8% and 20.0% were the result of new infections. We observed no significant effect of vaccination on rates of infection/lesions after treatment. Vaccine efficacy estimates for human papillomavirus 16/18 associated persistent infection and cervical intraepithelial neoplasia 2 or greater after treatment were 34.7% (95% confidence interval -131, 82) and -211% (95% confidence interval -2901, 68), respectively. We observed evidence for a partial and nonsignificant protective effect of vaccination against new infections absent before treatment. For incident human papillomavirus 16/18, human papillomavirus 31/33/45, and oncogenic human papillomavirus infections post-treatment, vaccine efficacy estimates were 57.9% (95% confidence interval -43, 88), 72.9% (95% confidence interval 29, 90), and 36.7% (95% confidence interval 1.5, 59), respectively.

Conclusion

We find no evidence for a vaccine effect on the fate of detectable human papillomavirus infections. We show that vaccination does not protect against infections/lesions after treatment. Evaluation of vaccine protection against new infections after treatment and resultant lesions warrants further consideration in future studies.

Background

Human papillomaviruses (HPV) cause over 500 000 cervical cancers each year, most of which occur in low-resource settings. Human papillomavirus genotyping is important to study natural history and vaccine efficacy. We evaluated TypeSeq, a novel, next-generation, sequencing-based assay that detects 51 HPV genotypes, in 2 large international epidemiologic studies.

Methods

TypeSeq was evaluated in 2804 cervical specimens from the Study to Understand Cervical Cancer Endpoints and Early Determinants (SUCCEED) and in 2357 specimens from the Costa Rica Vaccine Trial (CVT). Positive agreement and risks of precancer for individual genotypes were calculated for TypeSeq in comparison to Linear Array (SUCCEED). In CVT, positive agreement and vaccine efficacy were calculated for TypeSeq and SPF10-LiPA.

Results

We observed high overall and positive agreement for most genotypes between TypeSeq and Linear Array in SUCCEED and SPF10-LiPA in CVT. There was no significant difference in risk of precancer between TypeSeq and Linear Array in SUCCEED or in estimates of vaccine efficacy between TypeSeq and SPF10-LiPA in CVT.

Conclusions

The agreement of TypeSeq with Linear Array and SPF10-LiPA, 2 well established standards for HPV genotyping, demonstrates its high accuracy. TypeSeq provides high-throughput, affordable HPV genotyping for world-wide studies of cervical precancer risk and of HPV vaccine efficacy.