Immunogenicity and safety of a nine-valent human papillomavirus vaccine in women 27–45 years of age compared to women 16–26 years of age: An open-label phase 3 study

BackgroundEfficacy of the nine-valent human papillomavirus (9vHPV; HPV types 6/11/16/18/31/33/45/52/58) vaccine was demonstrated in a phase 3 study in women 16–26 years of age. We present a phase 3 immunogenicity and safety study of the 9vHPV vaccine in women 27–45 versus 16–26 years of age.MethodsThis international, open-label study (NCT03158220) was conducted in women 16–45 years of age. Participants (16–26 years, n = 570 and 27–45 years, n = 642) received a three-dose 9vHPV vaccination regimen (day 1, month 2, month 6). Month 7 geometric mean titers (GMTs) and seroconversion percentages to anti-HPV 6/11/16/18/31/33/45/52/58 were assessed. Participants were followed for safety throughout the study.ResultsAt month 7, anti-HPV 6/11/16/18/31/33/45/52/58 GMTs in women 27–45 years were compared to those in women 16–26 years of age. The primary hypothesis of non-inferiority of anti-HPV 16/18/31/33/45/52/58 GMTs in older versus younger women was met. The lower bound of the GMT ratio 95% confidence interval (27–45 years to 16–26 years) was 0.60–0.67 depending on HPV type, exceeding the non-inferiority margin of 0.5 for all HPV types. Month 7 seroconversion percentages in women 27–45 years of age were >99% for all HPV types. Injection-site and vaccine-related systemic adverse events (AEs) were observed in 87.5% and 25.1% of women 16–26 years, and 85.2% and 24.1% of women 27–45 years of age, respectively; no vaccine-related serious AEs were reported and no deaths occurred during the study.ConclusionsThe 9vHPV vaccine elicited non-inferior anti-HPV GMTs in women 27–45 years compared with women 16–26 years of age for HPV 16/18/31/33/45/52/58. The vaccine was generally well tolerated with a similar AE profile across the age groups. These data support bridging 9vHPV vaccine efficacy findings in women 16–26 years to women 27–45 years of age.Clinical trial registration NCT03158220.     

A phase III clinical study to compare the immunogenicity and safety of the 9-valent and quadrivalent HPV vaccines in men

BackgroundA nine-valent human papilloma virus (9vHPV) vaccine has been developed to prevent infections and diseases related to HPV 6/11/16/18 (as per the licensed quadrivalent HPV (qHPV) vaccine) as well as to five additional oncogenic HPV types (HPV 31/33/45/52/58). The 9vHPV vaccine has the potential to prevent 90% of cervical cancers, HPV-related anal, vaginal and vulval cancers and anogenital warts. We compared the immunogenicity and safety of the 9vHPV vaccine versus the qHPV vaccine in 16–26-year-old men.MethodsParticipants (N = 500) were randomised to receive 9vHPV or qHPV vaccines on day 1, month 2 and month 6. Serology testing was performed on day 1 and month 7. HPV type-specific antibody titres (anti-HPV 6/11/16/18/31/33/45/52/58) were determined by competitive Luminex immunoassay and expressed as geometric mean titres and seroconversion rates. Vaccine safety was also assessed.ResultsThe HPV 6/11/16/18 immune responses elicited by the 9vHPV vaccine were comparable with those elicited by the qHPV vaccine. All participants receiving the 9vHPV vaccine seroconverted for HPV 31/33/45/52/58. The 9vHPV and qHPV vaccines showed comparable safety profiles.ConclusionsIn addition to immune responses to HPV 31/33/45/52/58, a three-dose regimen of the 9vHPV vaccine elicited a similar immune response to HPV 6/11/16/18 when compared with the qHPV vaccine in men aged 16–26 years. The safety profile was also similar for the two vaccines. The results from this study support extending the efficacy findings with qHPV vaccine to 9vHPV vaccine in men aged 16–26 years.NCT02114385     

HPV infections among young MSM visiting sexual health centers in the Netherlands: Opportunities for targeted HPV vaccination

IntroductionIn 2009, girls-only HPV16/18 vaccination was introduced in the Netherlands which has achieved 46–61% uptake. Heterosexual men have benefitted from herd protection, but it is unknown whether men who have sex with men (MSM) also benefit from herd effects of the girls-only HPV16/18 vaccination program. Because MSM bear a high HPV-related disease burden, countries might consider targeted vaccination for MSM. To study possible herd effects and prior HPV exposure at a potential moment of vaccination, we assessed trends in the HPV prevalence and proportions (sero)negative for the various vaccine types among young MSM visiting sexual health centers (SHCs).MethodsWe used data from MSM included in PASSYON study years 2009–2017. In this biennial cross-sectional study among visitors of SHCs aged 16–24 years, MSM provided a penile and anal swab for HPV DNA testing (including vaccine types HPV6/11/16/18/31/33/45/52/58) and blood for HPV antibody testing (HPV16/18/31/33/45/52/58).ResultsIn total 575 MSM were included, with a median of 22 years of age and 15 lifetime sex partners and 3.5% HIV positive. Trends in penile or anal HPV prevalence during 2009–2017 were statistically non-significant for all vaccine types. Of the 455 MSM with a penile and anal swab, 360 (79%), 283 (62%) and 242 (53%) were HPV DNA negative at both anatomical sites for HPV16/18, HPV6/11/16/18 and HPV6/11/16/18/31/33/45/52/58 respectively. Among MSM who were HPV16/18 and HPV16/18/31/33/45/52/58 DNA negative and were tested for serology (n = 335 and 279 respectively), 82% and 71% were also seronegative for the respective types.DiscussionThere were no significant declines in the HPV prevalence among MSM up to eight years after introduction of girls-only HPV16/18 vaccination, indicating that MSM are unlikely to benefit largely from herd effects from girls-only vaccination. Most MSM were vaccine-type DNA negative and seronegative, suggesting that vaccination of young MSM visiting SHCs could still be beneficial.     

Safety and immunogenicity of a 9-valent HPV vaccine in females 12–26 years of age who previously received the quadrivalent HPV vaccine

ObjectivesTo assess the safety and immunogenicity of the investigational 9-valent (6/11/16/18/31/33/45/52/58) HPV (9vHPV) vaccine in prior recipients of a 3-dose regimen of quadrivalent (6/11/16/18) HPV (qHPV) vaccine.MethodsV503-006 was a randomized, double-blinded, safety/tolerability and immunogenicity study of the 9vHPV vaccine in females 12–26 years of age who were previously vaccinated with qHPV vaccine. Subjects were randomized in a 2:1 ratio to receive 3 doses of 9vHPV vaccine (n = 618) or saline placebo (n = 306) at day 1, month 2, and month 6. Systemic, injection-site and serious adverse experiences (AEs) were monitored. Serum samples were collected at day 1, month 2, and month 7. Anti-HPV 6/11/16/18/31/33/45/52/58 titers were measured using the 9-valent HPV competitive Luminex Immunoassay (cLIA).ResultsThe frequency of injection-site AEs (days 1–5 following any vaccination) was higher in the 9vHPV vaccine group than in the placebo group (91.1% and 43.9%, respectively). The frequencies of vaccine-related systemic AEs (days 1–15 following any vaccination) were generally comparable between the 2 groups (30.6% in the 9vHPV vaccine group, and 25.9% in the placebo group). One vaccine-related serious AE was reported in each of the 9vHPV vaccine and placebo groups. Few subjects (9vHPV = 0.5%; placebo = 0%) discontinued due to an AE. At 4 weeks post-dose 3, over 98% of subjects in the 9vHPV vaccine group were seropositive for HPV types 31/33/45/52/58, with marked elevations in cLIA geometric mean titers (GMTs) to these HPV types. Anti-HPV 31/33/45/52/58 GMTs were lower than in subjects administered 9vHPV vaccine who had not previously received qHPV vaccine (based on cross-study analyses); the clinical significance of this difference is unknown.ConclusionsAdministration of a 3-dose regimen of 9vHPV vaccine to adolescent girls and young women 12–26 years of age who are prior qHPV vaccine recipients is highly immunogenic with respect to HPV types 31/33/45/52/58 and generally well tolerated.     

Immunogenicity and safety of the 9-valent HPV vaccine in men

ObjectivesThis study was designed to evaluate the immunogenicity and tolerability of a prophylactic 9-valent HPV (types 6/11/16/18/31/33/45/52/58) VLP (9vHPV) vaccine in young men 16–26 years of age in comparison to young women 16–26 years of age (the population that was used to establish 9vHPV vaccine efficacy). Safety and immunogenicity data from this study will be used to bridge 9vHPV vaccine efficacy findings in 16–26 year old women to 16–26 year old men.MethodsThis study enrolled 1106 heterosexual men (HM) and 1101 women who had not yet received HPV vaccination. In addition, 313 men having sex with men (MSM) were enrolled and were evaluated separately for immunogenicity because previous results showed that antibody responses to quadrivalent HPV (types 6/11/16/18) VLP (qHPV) vaccine were lower in MSM than in HM. All subjects were administered a 3-dose regimen (Day 1, Month 2, Month 6) of 9vHPV vaccine. Serum samples were collected for anti-HPV assays. Safety information was collected for ∼12 months.ResultsThe geometric mean titers (GMTs) for HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 for HM were non-inferior to those of women at Month 7. For all vaccine HPV types, Month 7 GMTs were numerically lower in MSM than in HM. Over 99.5% of subjects were seropositive at Month 7 for each vaccine HPV type. Administration of 9vHPV vaccine to both 16–26 year old men and women was generally well tolerated.ConclusionsThese results support bridging the efficacy findings with 9vHPV vaccine in young women 16–26 years of age to men 16–26 years of age.     

Immunogenicity and safety of the 9-valent human papillomavirus vaccine in Chinese females 9–45 years of age: A phase 3 open-label study

BackgroundThe 9-valent human papillomavirus (9vHPV; HPV6/11/16/18/31/33/45/52/58) vaccine was approved for use in Chinese women aged 16–26 years in 2018. This phase 3, open-label study (NCT03903562) compared 9vHPV vaccine immunogenicity and safety in Chinese females aged 9–19 years and 27–45 years with Chinese females aged 20–26 years; we report results from day 1 through 1 month post-Dose 3. The study will continue through 54 months post-Dose 3 to assess antibody persistence in Chinese girls aged 9–19 years.MethodsParticipants aged 9–45 years received three doses of the 9vHPV vaccine. Geometric mean titers (GMTs) and seroconversion percentages for anti-HPV6/11/16/18/31/33/45/52/58 antibodies were determined by competitive Luminex immunoassay in serum samples obtained at day 1 and 1 month post-Dose 3. Adverse events (AEs) within 30 days post-vaccination and serious AEs (SAEs) occurring at any time were recorded.ResultsIn total, 1990 participants (690 aged 9–19 years; 650 aged 20–26 years; 650 aged 27–45 years) were enrolled. At 1 month post-Dose 3, >99% of participants in the per-protocol immunogenicity population seroconverted to each vaccine HPV type. Anti-HPV6/11/16/18/31/33/45/52/58 antibody GMTs in the 9–19-year age group were non-inferior to those in participants aged 20–26 years. Anti-HPV6/11/16/18/31/33/45/52/58 seroconversion percentages in the 27–45-year age group were non-inferior to those in participants aged 20–26 years. Injection-site and systemic AEs were reported by 43.3% and 50.9%, 50.5% and 57.1%, and 43.8% and 43.4% of participants aged 9–19, 20–26, and 27–45 years, respectively. There were no vaccine-related SAEs, discontinuations due to AEs, and deaths.ConclusionAntibody responses induced by 9vHPV vaccination in Chinese females aged 9–19 years and 27–45 years were non-inferior to those in Chinese females aged 20–26 years. The vaccine was generally well tolerated.ClinicalTrials.gov Identifier: NCT03903562.     

A prospective cohort study of immunogenicity of quadrivalent human papillomavirus vaccination among Alaska Native Children,Alaska, United States

ObjectiveIn the United States, HPV vaccination is routinely recommended at age 11 or 12 years; the series can be started at age 9. We conducted a cohort study to assess long-term immunogenicity of quadrivalent HPV vaccine (4vHPV) in an American Indian/Alaska Native (AI/AN) Indigenous population.MethodsDuring 2011–2014, we enrolled AI/AN girls and boys aged 9–14 years, who were vaccinated with a 3-dose series of 4vHPV. Serum specimens were collected at five time points: immediately prior to doses 2 and 3, and at one month, one year, and two years after series completion. Antibody testing was performed using a multiplex virus-like-particle-IgG ELISA for 4vHPV types (HPV 6/11/16/18).ResultsAmong 477 children (405 girls/72 boys) completing the 3-dose series, median age at enrollment was 11.2 years. Of the 477, 72 (15%) were tested before dose 2 and 70 (15%) before dose 3. Following series completion, 435 (91%) were tested at one month, 382 (80%) at one year, and 351 (74%) at two years. All tested participants had detectable antibody to 4vHPV types at all time points measured. Geometric mean concentrations (GMCs) for 4vHPV types at one month and two years post-series completion were 269.9 and 32.7 AU/ml for HPV6, 349.3 and 42.9 AU/ml for HPV11, 1240.2 and 168.3 IU/ml HPV16, and 493.2 and 52.2 IU/ml for HPV18. Among children tested after each dose, GMCs after doses 1 and 2 were 3.9 and 32.2 AU/ml for HPV6, 5.3 and 45.6 AU/ml for HPV11, 20.8 and 187.9 IU/ml for HPV16; and 6.6 and 49.7 IU/ml for HPV18. No serious adverse events were reported.ConclusionAll AI/AN children developed antibodies to all 4vHPV types after vaccination. GMCs rose after each dose, then decreased to a plateau over the subsequent two years. This cohort will continue to be followed to determine duration of antibody response.     

Immunogenicity and Safety of Human Papillomavirus-16/18 AS04-Adjuvanted Cervical Cancer Vaccine Coadministered With Combined Diphtheria-Tetanus-Acellular Pertussis–inactivated Poliovirus Vaccine to Girls and Young Women

PurposeMany countries recommend human papillomavirus (HPV) vaccination in female adolescents at an age when other vaccines are routinely administered. This open, randomized, multicenter study (108464/NCT00426361) evaluated coadministration of HPV-16/18 AS04-adjuvanted vaccine with diphtheria-tetanus-acellular pertussis–inactivated poliovirus vaccine (dTpa-IPV).MethodsHealthy females aged 10–18 years were randomized to receive HPV vaccine at months 0, 1, and 6 (n = 248), HPV vaccine coadministered with dTpa-IPV at month 0 and HPV vaccine at months 1 and 6 (n = 255), or dTpa-IPV at month 0 followed by HPV vaccine at months 1, 2, and 7 (n = 248). Immunogenicity was evaluated at months 0, 1, and 7 or 8 (depending on group). Vaccine reactogenicity and safety were also assessed.ResultsCoadministered dTpa-IPV and HPV vaccine was noninferior to dTpa-IPV alone in terms of seroprotection against diphtheria (99.2% and 100%), tetanus (100% and 100%) and poliovirus types 1, 2, and 3 (≥99.6%), and geometric mean antibody concentrations (ELISA Units/mL) for pertussis toxoid (84 vs. 75), filamentous hemagglutinin (612 and 615) and pertactin (426 and 360) at month 1. Coadministered dTpa-IPV and HPV vaccine was noninferior to HPV vaccine alone in terms of seroconversion rates for HPV-16 (99.5% and 100%) and HPV-18 (99.5% and 100%) and geometric mean antibody titers (ELISA Units/mL) for HPV-16 (15,608 and 18,965) and HPV-18 (6,597 and 6,902) at month 7. Coadministration was generally well tolerated. The reactogenicity of dTpa-IPV and the first dose of HPV vaccine was similar.ConclusionsResults from this study support coadministration of the HPV-16/18 AS04-adjuvanted vaccine with dTpa-IPV vaccine in females aged 10–18 years.     

Systematic literature review of neutralizing antibody immune responses to non-vaccine targeted high-risk HPV types induced by the bivalent and the quadrivalent vaccines

IntroductionStudies on the cross-protective effect of HPV bivalent and quadrivalent vaccines demonstrated inconsistent findings against additional HPV types covered by the nonavalent vaccine. The objective of this study was to conduct a systematic literature review to assess the consistency and durability of the cross-protective neutralizing antibody immune responses of the currently licensed bivalent and quadrivalent vaccines to non-vaccine HPV types targeted by the nonavalent vaccine (HPV 6, 11, 31, 33, 45, 52, and 58).MethodsPubMed and EMBASE databases were searched from 2008 to 2019 to identify studies reporting antibody/immune response after vaccination with either the bivalent, quadrivalent, or nonavalent vaccine. Key outcomes were seroconversion, seropositivity or geometric mean titers against HPV types 6, 11, 31, 33, 45, 52, and 58.ResultsEighteen publications met inclusion criteria, reporting on 14 interventional and five observational studies. Across all studies, immune responses to non-vaccine high-risk HPV types after bivalent vaccination were higher than baseline or quadrivalent vaccine. Nonavalent vaccine elicited near total seroconversion to HPV types 31, 33, 45, 52, and 58, with seropositivity remaining near 100% up to 24 months post-dose 1. In contrast, bivalent and quadrivalent vaccination resulted in lower seroconversion levels for non-vaccine types, which waned over time.ConclusionsThe cross-protection antibody/immune response among participants having received all three doses of bivalent or quadrivalent vaccine is not comparable to the specific response elicited by HPV vaccine types. Even in cases where a statistically significant cross-reactive immunological response is reported, long-term data on the duration of the response beyond two years are very limited. Further, the lack of a standard for assays limits comparability of results between studies.     

Antibody responses to prophylactic quadrivalent human papillomavirus vaccine at 48 months among HIV-infected girls and boys ages 9–14 in Kenya,Africa

ObjectivesHIV infected children remain at increased risk of HPV associated malignancies as they initiate sexual activity. Though they mount a vigorous immune response to the quadrivalent human papillomavirus (QHPV-6, -11,-16, and -18; Gardasil®) vaccine, durability of the immune response is uncertain. We assessed antibody responses to HPV 6, -11, -16 and -18 for up to 48 months following administration of quadrivalent human papillomavirus vaccine in HIV-infected girls and boys ages 9–14 years in Kenya.DesignOf 178 girls and boys who had previously received three doses of the quadrivalent HPV vaccine, 176 enrolled into extended follow up for 4 years. HPV antibodies to -6, -11, -16 and -18 were measured at 24, 36 and 48 months after the first vaccine dose using the total immunoglobulin G immunoassay (IgG LIA). We evaluated the magnitude and trend in HPV vaccine response and the effect of plasma HIV-1 RNA on HPV vaccine response from month 24 to month 48 of follow up.ResultsAt re-enrollment, 24 months after initial vaccination, median age of participants was 14 years (range 11–17); 167 (95%) were receiving antiretroviral therapy and 110 (66%) had plasma HIV RNA < 40 copies/mL. The rate of HPV seropositivity at 48 months was 83% for HPV-6; 80% for HPV-11; 90% for HPV-16; and 77% for HPV-18. There was a plateau in mean log10 HPV-specific antibody titer between month 24 and 48. The mean log10 HPV-type specific antibody titer for children with undetectable HIV viral load (<40) at the time of vaccination consistently remained higher for the 48 months of follow up compared to children with detectable viral load.ConclusionChildren with HIV infection may retain long term antibody response following HPV immunization. Further work to define whether HIV-infected children are protected from HPV acquisition with low levels of HPV antibodies is needed.     

Immunogenicity and safety of two novel human papillomavirus 4- and 9-valent vaccines in Chinese women aged 20–45 years: A randomized,blinded, controlled with Gardasil (type 6/11/16/18), phase III non-inferiority clinical trial

BackgroundHuman papillomavirus (HPV) infections were the main cause of anogenital cancers and warts. HPV 6/11/16/18 vaccines provide protection against the high-risk types of HPV responsible for 70% of cervical cancers and 90% of genital warts. This randomized, blinded, non-inferiority phase III trial was to determine whether immunogenicity and tolerability would be non-inferior among women after receiving two novel 4- and 9-valent HPV vaccines (4vHPV, HPV 6/11/16/18; 9vHPV, HPV 6/11/16/18/31/33/45/52/58) compared with those receiving Gardasil 4 (4-valent).Methods1680 females between 20 and 45 years were randomized in a 2:1:1 ratio to 20–26, 27–35, or 36–45 y groups. Subjects then equally assigned to receive 4vHPV, 9vHPV or Gardasil 4 (control) vaccine at months 0, 2, and 6. End points included non-inferiority of HPV-6/11/16/18 antibodies for 4vHPV versus control, and 9vHPV versus control and safety. The immunogenicity non-inferiority was pre-defined as the lower bound of 95% confidence interval (CI) of seroconversion rate (SCR) difference > ?10% and the lower bound of 95% CI of geometric mean antibody titer (GMT) ratio > 0.5.ResultsAmong the three vaccine groups, more than 99% of the participants seroconverted to all 4 HPV types. The pre-specified statistical non-inferiority criterion for the immunogenicity hypothesis was met: all the lower bounds of 95% CIs on SCR differences exceeded ?10% for each vaccine HPV type and the corresponding lower bounds of 95% CIs for GMT ratios > 0.5. Across vaccination groups, the most common vaccination reaction were injection-site adverse events (AEs), including pain, swelling, and redness. General and serious AEs were similar in the three groups. There were no deaths.ConclusionsThis study demonstrated that the novel 4- and 9-valent HPV vaccination was highly immunogenic and generally well tolerated, both of which were non-inferior to Gardasil 4 in immunogenicity and safety.     

Kinetic and HPV infection effects on cross-type neutralizing antibody and avidity responses induced by Cervarix

Background

We previously demonstrated that Cervarix^® elicits antibody responses against vaccine-related types for which clinical efficacy was demonstrated (HPV-31 and -45). Here, we evaluated the kinetics of neutralization titers and avidity of Cervarix^®-induced antibodies up to 36 months of follow-up in unexposed and HPV infected women.

Methods

A subset of women who participated in the Cost Rica HPV-16/18 Vaccine Trial had pre- and post-vaccination sera tested for antibody responses to HPV-16, -18, -31, -45, and -58 using a pseudovirion-based neutralization assay, and HPV-16 antibody avidity using an HPV-16 L1 VLP (virus-like particle)-based ELISA developed in our laboratory.

Results

In uninfected women, neutralizing antibody titers did not reach significance until after the 3rd dose for HPV-31 (month 12, p = 0.009) and HPV-45 (month 12, p = 0.003), but then persisted up to month 36 (HPV-31, p = 0.01; HPV-45, p = 0.002). Individuals infected with HPV-16 or HPV-31 at enrollment developed a significantly higher median antibody response to the corresponding HPV type after one dose, but there was not a difference between median titers after three doses compared to the HPV negative group. Median HPV-16 antibody avidity and titer increased over time up to month 12; however, the HPV-16 avidity did not correlate well with HPV-16 neutralizing antibody titers at each time point examined, except for month 6. The median avidity levels were higher in HPV-16 infected women at month 1 (p = 0.04) and lower in HPV-16 infected women at month 12 (p = 0.006) compared to the HPV negative women.

Conclusions

The persistence of cross-neutralization titers at month 36 suggests cross-reactive antibody responses are likely to persist long-term and are not influenced by infection status at enrollment. However, the weak correlation between avidity and neutralization titers emphasizes the need for examining avidity in efficacy studies to determine if high avidity antibodies play a critical role in protection against infection.     

Prevalence of human papillomavirus (HPV)-vaccine types by race/ethnicity and sociodemographic factors in women with high-grade cervical intraepithelial neoplasia (CIN2/3/AIS), Alameda County,California, United States

We evaluated racial/ethnic differences in prevalence of oncogenic HPV types targeted by the quadrivalent HPV vaccine (16/18) and nonavalent HPV vaccine (31/33/45/52/58) in women diagnosed with CIN2/3/AIS after quadrivalent HPV vaccine introduction (2008–2015). Typing data from 1810 cervical tissue specimen from HPV-IMPACT (Alameda County, California, US), a population-based CIN2/3/AIS surveillance effort, were analyzed. Using log-binomial regression, we calculated adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) comparing type prevalence by race/ethnicity, adjusted for health insurance, age, CIN2/3/AIS grade, and time period, overall and in the “early vaccine era” (2008–2011) and “later vaccine era” (2012–2015). Overall, oncogenic HPV16/18 prevalence was significantly lower among black (43%) and Hispanic (43%) women compared with white (52%) women (aPR (95% CI): 0.80 (0.70, 0.93) and 0.80 (0.70, 0.91), respectively). In 2008-2011, proportion of HPV16/18 detected was significantly lower in black (47%), Hispanic (46%), and Asian (42%) women compared to white (58%) women (aPR (95% CI): 0.80 (0.67, 0.96), 0.75 (0.63, 0.90), and 0.73 (0.58, 0.90), respectively). There were no significant differences in 2012-2015. Between the two eras, HPV16/18 prevalence declined in white (−11%), black (−9%), and Hispanic (−6%) women, and increased in Asian women (12%). Decreasing HPV 16/18 prevalence in CIN2/3/AIS lesions in white, black, and Hispanic women may suggest benefit from quadrivalent vaccination. In our unadjusted analysis of HPV31/33/45/52/58, prevalence did not differ significantly by race/ethnicity, but was significantly higher among Hispanic women (32%) compared to white women (27%) after adjustment (aPR (95%CI): 1.22 (1.02, 1.47). Prevalence was also non-significantly higher among black (32%) and Asian (33%) women. This analysis suggests that the nonavalent vaccine’s potential for impact against cervical precancers will not be lower in women of color compared to white women. These data underscore the importance of equitable vaccination in facilitating continued declines of vaccine-preventable HPV types among all women.     

Longitudinal assessment of nonavalent vaccine HPV types in a sample of sexually active African American women from ten U.S. Cities

BackgroundChronic infection with high-risk human papillomavirus is a necessary cause for cervical carcinogenesis. This study examined prevalence of nonavalent vaccine preventable HPV types over four months among sexually active women in the United States.MethodsThis sub-study obtained meta-data for 80 of the 1,365 women (18–25 years), enrolled in the BRAVO study, a randomized, open-label trial of home screening and treatment of asymptomatic bacterial vaginosis at high-risk for sexually transmitted infections conducted between 2008 and 2013. Participants were randomized to treatment or standard-of-care, and followed every 2-months for 12 months. Stored vaginal swabs from the first three visits were tested for the nine vaccine preventable HPV types using quantitative PCR. Prevalence and associated 95% confidence intervals for the HPV types were assessed using R (version 3.6.1).ResultsThe average age of the participants was 21.5 (SD ± 2.11) years, with 60% having ever been pregnant and all were African-American. Majority (71%) reported ≥ two sex partners in the prior year with 89% having unprotected vaginal sex and 45% having a new sex partner in the prior year. About 30% had ≥ one of the nine nonavalent vaccine HPV types at all three time points over a period of four months, 15% at two of any three visits, 19% at one of the three visits and 36% were negative for all nine vaccine HPV types at all time points. The most frequently detected HPV vaccine types were 52, 58, 16, and 18. The prevalence of any vaccine HPV types, and high-risk HPV types was 63.8% and 58.8%, respectively.ConclusionsOur findings suggest that HPV vaccination which is currently recommended for all unvaccinated persons through age 26 years, is likely to be more beneficial than previously thought as nonavalent HPV vaccine was not available during the time these data were collected.     

Increases in HPV-16/18 antibody avidity and HPV-specific memory B-cell response in mid-adult aged men post-dose three of the quadrivalent HPV vaccine

Strong quantitative and functional antibody responses to the quadrivalent human papillomavirus (HPV) vaccine were reported in mid-adult aged men, but there are limited data on the avidity of the antibody response and the memory B-cell response following vaccination. Although circulating antibodies induced by vaccination are believed to be the main mediators of protection against infection, evaluation of avidity of antibodies and memory B cell responses are critical for a better understanding of the vaccine immunogenicity mechanisms. Both the modified enzyme-linked immunosorbent assay (ELISA) and the enzyme-linked immunosorbent spot (ELISpot) assay are tools to measure the humoral and cellular immune responses post vaccination to characterize vaccine immunogenicity. The avidity of HPV-16 and HPV-18 specific IgG in the serum of mid-adult aged men (N = 126) who received three quadrivalent HPV vaccine doses was examined using a modified ELISA. HPV-16 memory B-cell responses were assessed via ELISpot at month 0 (prior to vaccination) and 1-month post-dose three of the vaccine (month 7). The quadrivalent vaccine induced an increase in HPV-16 and HPV-18 antibody avidity at month 7. HPV-18 avidity levels moderately correlated with anti-HPV-18 antibody titers, but no association was observed for HPV-16 antibody titers and avidity levels. The HPV-16-specific memory B-cell response was induced following three vaccine doses, however, no association with anti-HPV-16 antibody avidity was observed. Three doses of quadrivalent HPV vaccine increased antibody affinity maturation for HPV-16/18 and increased the frequency of anti-HPV-16 memory B-cells in mid-adult aged men.     

Antibody persistence and evidence of immune memory at 5 years following administration of the 9-valent HPV vaccine

BackgroundThe 9-valent HPV (9vHPV) vaccine was developed to prevent infection and disease related to 9 HPV types (HPV6/11/16/18/31/33/45/52/58) which cause approximately 90% of cervical cancers, HPV-related vulvar, vaginal and anal cancers, and genital warts worldwide. In a pivotal efficacy study, the 9vHPV vaccine prevented infection and disease due to the 9 vaccine types. Duration of protection remains to be determined. Vaccines that induce long-term protection are generally characterized by the generation of immune memory. The purpose of this report is to assess the persistence of HPV antibody response and existence of immune memory at 5 years post-vaccination.MethodsA subset of subjects (N = 150) who received 3 doses of 9vHPV vaccine at day 1, month 2 and month 6 in the pivotal efficacy study continued in a study extension and received a fourth dose of 9vHPV vaccine at month 60. Serum HPV antibody levels were measured pre-dose 4 and at 7 and 28 days post-dose 4 by competitive Luminex immunoassay. Adverse events were assessed using a vaccination report card.ResultsHPV antibodies induced following the 3-dose series of 9vHPV vaccine in the base study persisted through month 60 with seropositivity rates ranging from 77.5% to 100%. Geometric mean titers at 1 week and 1 month post-dose 4 were 1.25–4.10 and 1.65–4.88-fold higher, respectively, than levels observed 1 month following the completion of the three-dose primary series. Seropositivity rates were >99% and 100% at 1 week and 1 month post-dose 4, respectively. The fourth dose of 9vHPV vaccine was generally well tolerated.ConclusionsA three-dose regimen of the 9vHPV vaccine induced persistent HPV antibody response through 5 years post-vaccination. Administration of a fourth dose resulted in a strong anamnestic response to all 9 vaccine types. These findings suggest that the efficacy of the 9vHPV vaccine will be long lasting.Clinical Trials.gov Identifier: NCT00543543.     

Four-year follow-up of the immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine when administered to adolescent girls aged 10-14 years

PurposeLong-term immunogenicity and safety of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine when administered to adolescent girls was evaluated.MethodsThis open-label, follow-up study (NCT00316706) was conducted in 31 centers in Taiwan, Germany, Honduras, Panama, and Colombia. In the initial study (NCT00196924), 1,035 girls aged 10–14 years received the HPV-16/18 AS04-adjuvanted vaccine at 0, 1, and 6 months. Here, geometric mean titers (GMTs) of antibodies against HPV-16, HPV-18, and monophosphoryl lipid A (MPL), a component of the AS04 Adjuvant System, were reported up to month 48.ResultsIn the according-to-protocol immunogenicity cohort (N = 563), GMTs at month 48 in initially seronegative participants were 2,374.9 (95% confidence interval: 2,205.7–2,557.0) EL.U/mL for anti-HPV-16 and 864.8 (796.9–938.4) EL.U/mL for anti-HPV-18, that is, six- and threefold higher than the plateau level in a reference study demonstrating vaccine efficacy in young women (age, 15–25 years). All participants remained seropositive for anti-HPV-16 and anti-HPV-18 at month 48. Most participants (81.8%) were seropositive for anti-MPL antibodies before vaccination. Anti-MPL antibody titers in initially seropositive participants increased initially, and then declined. Most initially seronegative participants for anti-MPL seroconverted; 69.6% remained seropositive at month 48, with anti-MPL antibody titers similar to the natural background level. The vaccine was generally well tolerated. No serious adverse events were considered related to vaccination.ConclusionsIn adolescent girls, the HPV-16/18 AS04-adjuvanted vaccine produces anti-HPV-16 and anti-HPV-18 antibody titers that are maintained for up to 4 years at higher levels than those in young women in whom vaccine efficacy against cervical lesions was demonstrated.     

Immunogenicity and persistence of immunity of a quadrivalent Human Papillomavirus (HPV) vaccine in immunocompromised children

AimThe aim of this study was to determine the immunogenicity and reactogenicity of HPV vaccine in immunocompromised children.MethodsA multi-centre clinical trial was conducted in three paediatric hospitals in Australia. Unvaccinated children 5–18 years of age attending one of three paediatric hospitals with a range of specified conditions associated with immunosuppression were included. Quadrivalent HPV vaccine (Gardasil) was given to the participants and serum anti-HPV antibody levels were measured at baseline (before first dose), 7 and 24 months after the first dose of vaccine.ResultsFifty-nine participants were enrolled across the three paediatric hospitals and among those one was seropositive to types 6, 11 and 16 at baseline. Seven months after the first dose, seroconversion rates were 93.3%, 100%, 100% and 88.9% for type 6, 11, 16 and 18 respectively. The corresponding rates at 24 month follow up were 82.2%, 91.1%, 91.1% and 68.9%. The greatest increase in geometric mean titre (GMT) was for type 16, followed by type 11. GMTs declined over the following months, but remained more than fourfold higher for all serotypes compared to baseline titres at 24 months post vaccination. Injection site erythema, pain and swelling were commonly reported local adverse events and were less common after each dose. Few participants reported systemic adverse events, and minor disease flare occurred in two participants. One child developed a squamous cell oral carcinoma during follow up, but tissue was unable to be tested for HPV.ConclusionImmunosuppressed children had an adequate immunogenic response to Quadrivalent HPV vaccine regardless of age and the cause of immunosuppression. HPV related cancers occur at higher frequency and earlier in immunosuppressed patients, so early vaccination and optimal scheduling should be further studied in such children.Clinical trial registration: NCT02263703 (ClinicalTrials.gov)     

Comparing immunogenicity of the Escherichia coli-produced bivalent human papillomavirus vaccine in females of different ages

BackgroundThe safety and efficacy of a recently licensed Escherichia coli (E. coli)-produced bivalent HPV vaccine have been shown. Specific antibody levels are important indicators to evaluate the efficacy of vaccination. Therefore, we compared the immunogenicity of this HPV 16/18 vaccine in females of different ages in this study.MethodsImmunogenicity of the vaccine was analyzed in the per-protocol sets for immunogenicity (PPS-I) of a phase III trial and an immune-bridging trial. The serum samples were collected at month 0 and one month after the final dose (month 7) to assess the specific IgG antibody levels by ELISA. The seroconversion rates, geometric mean concentration (GMC), and geometric mean increase (GMI) were used to assess the immunogenicity of the test vaccine. The non-linear association of antibody levels with age was estimated via natural cubic splines and the Akaike information criterion was used to assess optimal model.ResultsBy combining the PPS-I data from the two trials, nearly all of the females seroconverted for both HPV types. In the 3-dose group, the GMC of IgG to both HPV types decreased with increasing age, especially in adolescent girls and young women. For HPV-16 and -18, the declining trend slowed down in women older than 32 and 35 years old, respectively. The GMI ranged from 648 to 80 for HPV-16 and from 218 to 42 for HPV-18. In the 2-dose group, the specific antibodies for HPV-16 and -18 peaked in girls aged 10 years with GMIs of 401 and 98, respectively, and then decreased with age.ConclusionsThe E. coli-produced bivalent HPV-16/18 vaccine induced specific antibody responses in females aged 9–45 years. The antibody levels were inversely associated with age, and the declining trends slowed down in women older than 32 or 35 years for HPV-16 and -18, respectively.     

HIV viral suppression results in higher antibody responses in HIV-positive women vaccinated with the quadrivalent human papillomavirus vaccine

ObjectiveTo evaluate the immunogenicity and safety of the quadrivalent HPV (qHPV) vaccine in HIV-positive women over 24 months.DesignBetween November 2008 and December 2012, 372 women aged 15 and older were enrolled from 14 Canadian HIV outpatient clinics in an open label cohort study. The qHPV vaccine (0.5 mL) was administered intramuscularly at months 0, 2 and 6. The primary study endpoint was seroconversion to any of the HPV types targeted by the qHPV vaccine. Antibody levels were measured at 0, 2, 7, 12, 18, and 24 months. Adverse events were recorded throughout.ResultsOf 372 participants enrolled, 310 (83%) received at least one dose of the qHPV vaccine and 277 (74%) received all three doses. Ninety-five percent (293/308) were seronegative for at least one vaccine type at baseline. The median age was 38 years (IQR 32–45, range 15–66), 36% were white, 44% black and 13% were of Indigenous origin. Seventy-two percent of participants had a suppressed HIV viral load (VL < 40 c/ml) at baseline, with a median CD4 count of 510 cells/mm³ (376–695). Month 7 HPV type-specific seroconversion rates were 99.0%, 98.7%, 98.1% and 93.6% for HPV types 6, 11, 16 and 18 respectively in the per-protocol population. Participants with suppressed HIV VL at first vaccine had a 1.74–3.05 fold higher peak antibody response compared to those without (p from 0.006 to <0.0001).ConclusionsThis study is the first to examine the qHPV vaccine in HIV-positive women out to 24 months and the first to include HIV-positive women through to age 66. The qHPV vaccine was well tolerated, and highly immunogenic. As women with suppressed viral load had higher antibody responses, planning HPV vaccination to occur when persons are virologically suppressed would be optimal for maximizing immune response. Findings provide strong evidence that older HIV-positive women can still benefit from HPV vaccination.Clinical trial registration: http://www.isrctn.com/ISRCTN33674451