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     

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.     

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.     

Efficacy of quadrivalent human papillomavirus vaccine against persistent infection and genital disease in Chinese women: A randomized,placebo-controlled trial with 78-month follow-up

BackgroundA quadrivalent human papillomavirus vaccine (qHPV; HPV6/11/16/18) has demonstrated efficacy and effectiveness worldwide. We report qHPV vaccine efficacy for up to 6.5 years after first administration among Chinese women 20–45 years of age.MethodsIn this randomized, double-blind, placebo-controlled, multicenter, Phase 3 study (NCT00834106), women were randomized 1:1 to receive 3 doses of qHPV vaccine or placebo (Day 1, Month 2, Month 6). Endo-ecto-cervical and external genital swabs were collected for HPV testing and gynecologic examinations, and cervical cytology testing were performed at Day 1 and Months 7, 12, 18, 24, 30, 42, 54, 66, and 78. Any abnormality in cytology testing would trigger colposcopy examination and cervical biopsy, if necessary. Efficacy against genital disease, persistent infection, and the composite endpoint was assessed. Primary efficacy analyses were conducted in the per-protocol efficacy (PPE) population.ResultsOf 3006 participants randomized, 2759 (91.8%) and 2374 (79%) completed the Month 30 and Month 78 visits, respectively. At Month 78, efficacy among women aged 20–45 years was 100% (95% CI: 32.3, 100; 0 vs 7 cases) and 100% (95% CI: 70.9, 100; 0 vs 14 cases) against HPV16/18-related cervical intraepithelial neoplasia Grade 2 or 3, adenocarcinoma in situ, and cervical cancer (CIN 2+) and HPV6/11/16/18-related CIN 1+, respectively, in the PPE population. The efficacy against cervical 6-month and 12-month persistent infection was 91.6% (95% CI: 66.0, 99.0) and 97.5% (95% CI: 85.1, 99.9) at Month 30 and Month 78, respectively, in the PPE population. The vaccine also reduced the rate of cervical cytology abnormalities associated with HPV6/11/16/18, with an efficacy of 94.0% (95% CI: 81.5, 98.8). The vaccine was generally well tolerated (reported separately).ConclusionThe qHPV vaccine is efficacious against endpoints of persistent infection and genital precancerous lesions in Chinese women aged 20–45 years.     

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     

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.     

Evaluation on the persistence of anti-HPV immune responses to the quadrivalent HPV vaccine in Chinese females and males: Up to 3.5 years of follow-up

BackgroundThis was an extension study of a randomized, double-blind, placebo-controlled immunogenicity and safety study of the quadrivalent human papillomavirus (qHPV) (HPV 6, 11, 16, and 18) vaccine conducted in Chinese female subjects aged 9–45 years and male subjects aged 9–15 years. To investigate the persistence of anti-HPV 6, -11, -16, and -18 responses among Chinese subjects, subjects enrolled in the base study were followed up at around month 42 (approximately 3.5 years after vaccination).MethodsAmong 600 subjects enrolled in the base study, a total of 468 subjects consented for participation in the extension study. Anti-HPV 6, -11, -16, and -18 antibodies were detected by the competitive Luminex immunoassay (cLIA) and total IgG Luminex immunoassay (IgG LIA).ResultsAmong the female subjects who received the qHPV vaccine, the proportions of subjects remained seropositive were high with both the cLIA and IgG LIA for HPV type 6, 11, and 16 through approximately 42 months following the first dose vaccination. For HPV 18, the seropositivity rate remained high as 82.0% with the IgG LIA, while it decreased to 53.6% with the cLIA, which was similar to the findings observed in other studies. The seropositivity rates remained high at month 42 for all qHPV types with both the cLIA and IgG LIA among the male subjects.ConclusionsAdministration of a 3-dose regimen of qHPV vaccine induces durable anti-HPV 6, anti-HPV 11, anti-HPV 16, and anti-HPV 18 responses among Chinese subjects for at least 3.5 years after vaccination.ClinicalTrials.gov registry: NCT01427777     

Immunogenicity and safety of the quadrivalent human papillomavirus vaccine in Chinese females aged 9 to 26 years: A phase 3, open-label,immunobridging study

BackgroundThe quadrivalent human papillomavirus (qHPV; HPV6/11/16/18) vaccine was approved for use in Chinese women aged 20–45 years in 2017. This Phase 3, open-label study (NCT03493542) aimed to assess immunogenicity and safety of the qHPV vaccine in Chinese girls aged 9–19 years versus Chinese young women aged 20–26 years; we report results from Day 1 through Month 7. The study will continue through Month 60 to assess antibody persistence in Chinese girls aged 9–19 years.MethodsParticipants aged 9–26 years received three doses of the qHPV vaccine (Day 1, Month 2, Month 6). Geometric mean titers (GMTs) and seroconversion percentages for anti-HPV6/11/16/18 antibodies were determined by competitive Luminex immunoassay (cLIA) in serum samples obtained on Day 1 and at Month 7. Injection-site adverse events (AEs) and systemic AEs within 30 days post-vaccination, and serious AEs (SAEs) occurring at any time during the study, were recorded.ResultsIn total, 766 participants (383 aged 9–19 years; 383 aged 20–26 years) were enrolled and received ≥1 vaccine dose. All participants in the per-protocol immunogenicity population of both age groups seroconverted to each of the vaccine HPV types at Month 7. Anti-HPV6/11/16/18 antibody GMTs at Month 7 in participants aged 9–19 years were non-inferior to those in participants aged 20–26 years. Injection-site AEs and systemic AEs were reported by 36.6% and 49.3% of 9–19-year-olds, and 40.7% and 54.8% of 20–26-year-olds, respectively. There were no vaccine-related SAEs. No participants discontinued the vaccine due to an AE and no deaths were reported.ConclusionAntibody responses induced by the 3-dose qHPV vaccination regimen in Chinese girls aged 9–19 years were non-inferior to those in Chinese young women aged 20–26 years. The vaccine was generally well tolerated in the study population.ClinicalTrials.gov Identifier: NCT03493542.     

Efficacy,safety, and immunogenicity of a quadrivalent HPV vaccine in Japanese men: A randomized,Phase 3, placebo-controlled study

Background

The quadrivalent (q) human papillomavirus (HPV) vaccine protects against infection and disease related to HPV types 6, 11, 16, and 18. We report efficacy, immunogenicity, and safety of qHPV vaccine in a Phase 3 study in Japanese men.

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.     

Decline of HPV infections in Scandinavian cervical screening populations after introduction of HPV vaccination programs

ObjectiveTo monitor the changes in prevalence of human papillomavirus (HPV) infections in women <50 years of age, participating in cervical screening programs of Denmark, Norway, and Sweden, before and after introduction of quadrivalent HPV (qHPV) vaccination.MethodsLiquid-based cytology samples were collected from 6538 women who attended cervical screening in Denmark, Norway, and Sweden in 2006–2008 and from 6332 similarly enrolled women in 2012–2013. Denmark started organized qHPV vaccination in 2008, Norway in 2009, and Sweden in 2012. All HPV testing and genotyping was performed using identical enrollment and analysis methods, by accredited general primer polymerase chain reaction methods with typing using the Luminex system.ResultsOverall HPV positivity declined slightly from 36.5% in 2006–2008 to 34.5% in 2012–2013. The decline was most pronounced among women 18–26 years of age: from 54.4% to 48.1% (P < 0.001). The decline was substantial for vaccine HPV types (HPV6/11/16/18: decline from 22.3% to 16.6%; P < 0.001) and was seen for both low-risk vaccine types (HPV6/11 declined from 5.0% to 2.5%) and high-risk vaccine types (HPV16/18 declined from 18.9% to 14.9%). Among women 27–50 years of age, there was no change between the time periods (22.5% and 21.6%, respectively). The significant decline in the younger age group was different in the 3 countries.ConclusionThis population-based study enrolling >12,000 women participating in cervical screening in the 3 Nordic countries before and after introduction of organized qHPV vaccination demonstrated a marked decline in HPV infection in the younger population in the 2 countries where qHPV vaccination programs started in 2008–2009, suggesting that organized HPV vaccination programs resulted in a decrease of HPV types circulating in the general population.     

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.     

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.     

Effectiveness of varying number of doses and timing between doses of quadrivalent HPV vaccine against severe cervical lesions

BackgroundBased on immunogenicity studies, a 2 dose HPV vaccination-schedule was recently recommended for girls younger than 15 years. We aimed to investigate the effectiveness of quadrivalent HPV (qHPV) vaccination against CIN2 or worse (CIN2+), by age at vaccination, number of doses, and to test whether optimal timing of 2 doses of qHPV vaccine can confer the same level of protection as the originally recommended three dose-schedule.MethodsA population-based cohort of all women aged 13–30 years, living in Denmark or Sweden during 2006–2013, was followed for qHPV vaccination status and first occurrence of CIN2+.ResultsThe study cohort comprised 2,253,561 women, of which 33% were vaccinated during follow-up, and 1.7% were diagnosed with CIN2+. Vaccination at ages 13–16 and 17–19 was associated with a reduced risk of CIN2+ after 3 doses (IRR = 0.23, 95% CI 0.11–0.49, and IRR = 0.65, 95% CI 0.41–1.03, respectively), compared to being unvaccinated. After 1 and 2 doses there was a reduced risk, but not statistically significant. Women vaccinated ages 13–16 with 2 doses, where time between first and second dose was 5 months or longer showed no difference in risk compared to 3 doses.ConclusionsWomen vaccinated with 3 doses of qHPV showed a reduced risk of CIN2+ if they were vaccinated before age 20, with a further reduced risk if vaccinated before age 17. Vaccination with 2 doses, with the second dose 5 months or longer after the first dose, did not yield an increased risk of CIN2+, compared to 3 doses.     

The safety and immunogenicity of Quadrivalent HPV (qHPV) vaccine in systemic lupus erythematosus

ObjectiveThis study evaluated the safety and immunogenicity of qHPV vaccine in SLE.MethodsSubjects: 34 women ages 19–50 years (yrs.) with mild to moderate SLE & minimally active or inactive SLE received qHPV vaccine at the standard dosing schedule.Exclusion criteria: active SLE disease (SELENA-SLEDAI > 2), history of severe SLE disease, deep venous thrombosis, on >400 mg/day of hydroxychloroquine, on >15 mg/day of prednisone, or active infections. Patients were monitored for adverse events (AE), SLE flare, generation of thrombogenic antibodies and thrombosis. Antibody (Ab) levels to HPV 6, 11, 16 & 18 were measured by HPV competitive Luminex Immunoassay and Geometric Mean Titers (GMTs) were calculated for each HPV type. Seroconversion was assessed for those seronegative at baseline.ResultsThe women in the study: African-American (79%), mean age = 38.1 years, mean age at diagnosis of SLE = 28.6 years, 35.3% had a history of smoking, 91% had 4 or more sexual partners, 50% had a history of sexually transmitted diseases, and 27.3% used condoms on a regular basis. Vaccine site reactions (VSRs) occurred in 62%, all mild. Ninety-seven percent experienced at least 1 non vaccine adverse event (nvAE) with a total of 493 nvAEs in 33 patients, of which 90% were mild and none were related to vaccine or SLE. There were 9 serious AEs, none were related to vaccine or SLE, all resolved. No patient experienced an SLE flare, thrombosis, or generation of thrombogenic antibodies. Seroconversion rate was 100% with mean GMTs comparable to Gardasil® package insert data.ConclusionIn this SLE vaccine study, qHPV vaccine was generally safe, well tolerated, and highly immunogenic.This clinical trial is registered on Clinical Trials.gov under number, NCT01741012 and was conducted under the FDA IND BB14113.     

Safety and immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine in HIV-positive women in South Africa: A partially-blind randomised placebo-controlled study

In developing countries, risk of human papillomavirus (HPV) infection may be increased by the high prevalence of human immunodeficiency virus (HIV) infection. We evaluated the safety and immunogenicity of the HPV-16/18 AS04-adjuvanted vaccine in HIV-infected women in South Africa. Asymptomatic HIV-positive women aged 18–25 years (N = 120) were stratified by CD4⁺ T-cell count and randomised (1:1) to receive HPV-16/18 vaccine (Cervarix^®; GlaxoSmithKline Vaccines) or placebo (Al[OH]₃) at 0, 1 and 6 months (double-blind). HIV-negative women (N = 30) received HPV-16/18 vaccine (open label). Anti-HPV-16/18 antibody and CD4⁺ T-cell responses, CD4⁺ T-cell count, HIV viral load, HIV clinical stage and safety were evaluated for 12 months. The safety and reactogenicity profile of the HPV-16/18 vaccine was comparable in HIV-positive and HIV-negative women. Irrespective of baseline HPV status, all HIV-positive and HIV-negative women who received the HPV-16/18 vaccine were seropositive for both HPV-16 and HPV-18 after the second vaccine dose (month 2) and remained seropositive for both antigens at month 12. Anti-HPV-16/18 antibody titres at month 12 remained substantially above levels associated with natural infection. The HPV-16/18 vaccine induced sustained anti-HPV-16/18 CD4⁺ T-cell responses in both HIV-positive and HIV-negative women. No impact of baseline CD4⁺ T-cell count or HIV viral load was observed on the magnitude of the immune response in HIV-positive women. In HIV-positive women, CD4⁺ T-cell count, HIV viral load and HIV clinical stage were unaffected by HPV-16/18 vaccine administration. In conclusion, the HPV-16/18 AS04-adjuvanted vaccine appears immunogenic and well-tolerated in women with HIV infection.     

Final report on exposure during pregnancy from a pregnancy registry for quadrivalent human papillomavirus vaccine

ObjectiveTo better describe the safety profile of pregnancy exposures to the qHPV vaccine by acquiring and analyzing post-marketing data on pregnancy outcomes.MethodsThis is a voluntary, post-marketing prenatal vaccine exposure registry. Enrollment criteria included an identifiable patient and health care provider from the United States, France, or Canada and exposure within 1 month before the date of onset of the last menstrual period or at any time during pregnancy. Outcomes of interest were pregnancy outcomes and birth defects. Prospectively reported cases were used for rate calculations.ResultsFor the 1752 prospective reports with known outcome, 1518 (86.6%) were live births, including ten twin pregnancies. Of 1527 neonates, 1444 (94.6%) had no congenital anomalies. The overall rate of spontaneous abortion was 6.7 per 100 outcomes (95% confidence interval [CI] 5.5–8.2). The prevalence of major birth defects was 2.4 per 100 live-born neonates (95% CI 1.7–3.3). There were 12 fetal deaths (0.8 per 100 outcomes, 95% CI 0.4–1.4).ConclusionRates of spontaneous abortions and major birth defects were not greater than the general population rates. Although no adverse signals have been identified to date, the qHPV vaccine is not recommended for use in pregnant women.     

Natural History of Multiple Human Papillomavirus Infections in Female Adolescents With Prolonged Follow-up

PurposeThe aim of the study was to better characterize the natural history of human papillomavirus (HPV) infections in female adolescents.MethodsFemale adolescents were enrolled in a longitudinal study. Self-vaginal samples were obtained every 3 months and tested for HPV. No participants received HPV vaccination. The findings for 40 female adolescents with the longest follow-up are reported in this study.ResultsAverage age at the time of enrollment was 15.2 years (range: 14–17; SD: .97). Mean duration of follow-up was 6.7 years (range: 4.4–9.2; SD: 1.2). In all, 32 participants (80%) reported being involved in sexual activity before their enrollment in the study; all reported being involved in sexual activity before enrollment; all reported being involved in sexual activity during follow-up. Baseline and cumulative prevalence of HPV among participants was 55% and 100%, respectively. During the study, each participant tested positive for a mean of 14 HPV types. Cumulatively, HPV 16 was detected in 29 of 40 participants (72.5%). Mean duration of high- and low-risk infections was 655.9 (median: 433) and 524.1 days (median: 334), respectively.ConclusionWith prolonged follow-up, HPV infections with multiple types were found in all participants. Most had infection with HPV-16 or HPV-18, the oncogenic types represented in current vaccines, as well as infection with other oncogenic types. These data reinforce the importance of vaccine and non-vaccine strategies for prevention of HPV infections.     

Immunogenicity and safety of a tetravalent dengue vaccine and a bivalent HPV vaccine given concomitantly or sequentially in girls aged 9 to 14 years in Mexico

Dengue is endemic in several regions, and the global incidence is increasing. The recombinant, live, attenuated, tetravalent dengue vaccine (CYD-TDV) is recommended for dengue seropositive individuals ≥ 9 years. Human papillomavirus (HPV) vaccination is recommended for girls aged 9–14 years to prevent HPV infection-related cancers. This study assessed the immunogenicity and safety of a bivalent HPV (types 16 and 18) vaccine and CYD-TDV when co-administered concomitantly or sequentially.This was a Phase IIIb, randomized, open-label, multicenter study in girls aged 9–14 years in Mexico (NCT02979535). Participants were randomized 1:1 to receive three doses of CYD-TDV 6 months apart and two doses of bivalent HPV vaccine either concomitantly with, or 1 month before (sequentially), the first 2 CYD-TDV doses. Antibody levels were measured at baseline and 28-days after each vaccine dose for all participants, using an enzyme-linked immunosorbent assay for HPV-16 and HPV-18 antibodies, and a plaque reduction neutralization test for the four dengue serotypes; results are reported only for participants who were seropositive at baseline. Safety was assessed for all randomized participants throughout the study.Of the randomized participants, 305/478 (63.8%) were seropositive for dengue at baseline: 154 in the concomitant group and 151 in the sequential group. After the last HPV vaccine dose, the antibody titers for HPV were comparable in seropositive participants between treatment groups, with between group titer ratios of 0.966 for HPV-16 and 0.999 for HPV-18. After dose 3 of CYD-TDV, antibody titers were comparable for the concomitant and sequential groups across all serotypes, with between-group ratios close to 1 (serotype 1: 0.977; serotype 2: 0.911; serotype 3: 0.921; serotype 4: 0.931).CYD-TDV and a bivalent HPV vaccine administered concomitantly or sequentially in dengue seropositive girls aged 9–14 years elicited comparable immune responses with similar safety profiles.     

Safety of a quadrivalent human papillomavirus vaccine in a Phase 3, randomized,double-blind,placebo-controlled clinical trial among Chinese women during 90 months of follow-up

Background

A quadrivalent human papillomavirus (qHPV) vaccine (HPV6/11/16/18) has demonstrated efficacy and acceptable safety in international studies. However, these studies did not include participants from mainland China, which has a substantial burden of HPV-related disease. This is the first safety report with a follow-up period of up to 90?months from a randomized, double-blind, placebo-controlled trial of qHPV vaccine in Chinese women 20–45?years of age.