A reactogenic "placebo" and the ethics of informed consent in Gardasil HPV vaccine clinical trials: A case study from Denmark.

BACKGROUND: Medical ethics guidelines require of clinical trial investigators and sponsors to inform prospective trial participants of all known and potential risks associated with investigational medical products, and to obtain their free informed consent. These guidelines also require that clinical research be so designed as to minimize harms and maximize benefits. OBJECTIVE: To examine Merck's scientific rationale for using a reactogenic aluminum-containing "placebo" in Gardasil HPV vaccine pre-licensure clinical trials. METHODS: We examined the informed consent form and the recruitment brochure for the FUTURE II Gardasil vaccine trial conducted in Denmark; and we interviewed several FUTURE II trial participants and their treating physicians. We also reviewed regulatory documentation related to Gardasil vaccine approval process and the guidelines on evaluation of adjuvants used in human vaccines. RESULTS: It was found that the vaccine manufacturer Merck made several inaccurate statements to trial participants that compromised their right to informed consent. First, even though the study protocol listed safety testing as one of the study's primary objectives, the recruitment brochure emphasized that FUTURE II was not a safety study, and that the vaccine had already been proven safe. Second, the advertising material for the trial and the informed consent forms stated that the placebo was saline or an inactive substance, when, in fact, it contained Merck's proprietary highly reactogenic aluminum adjuvant which does not appear to have been properly evaluated for safety. Several trial participants experienced chronic disabling symptoms, including some randomized to the adjuvant "placebo" group. CONCLUSION: In our view, the administration of a reactive placebo in Gardasil clinical trials was without any possible benefit, needlessly exposed study subjects to risks, and was therefore a violation of medical ethics. The routine use of aluminum adjuvants as "placebos" in vaccine clinical trials is inappropriate as it hinders the discovery of vaccine-related safety signals.

Human Papillomavirus vaccination coverage among the female population living in the state of Goiás, Brazil, 2014-2020: a time series study.

OBJECTIVE: To analyze the temporal trend of human papillomavirus (HPV) vaccination coverage among the female population aged 10 to 14 years, living in the state of Goiás, Brazil, between 2014 and 2022. METHODS: This was an ecological time series study using data from the Brazilian National Health System Information Technology Department (Departamento de Informática do Sistema Único de Saúde - DATASUS); the annual vaccination coverage rate was calculated based on the number of second doses administered; the trend of the rates was analyzed using the Prais-Winsten model. RESULTS: A total of 407,217 second doses of the quadrivalent HPV vaccine were administered to the female population aged 10-14 years, with annual vaccination coverage rates ranging from 12.3% (2019) to 30.0% (2015), and an annual percentage change (APC) of 0.7% (95%CI 0.9; 0.2; p-value = 0.030). CONCLUSION: In Góias state, the quadrivalent HPV vaccine coverage rate was below the national target (80%), showing a stationary trend in the time series.

Assessing the reduction of viral infectivity in HPV16/18-positive women after one, two, and three doses of Gardasil-9 (RIFT): Study protocol.

Human Papillomavirus (HPV) prophylactic vaccination has proven effective in preventing new infections, but it does not treat existing HPV infections or associated diseases. Hence, there is still an important reservoir of HPV in adults, as vaccination programs are mainly focused on young women. The primary objective of this non-randomized, open-label trial is to evaluate if a 3-dose regimen of Gardasil-9 in HPV16/18-positive women could reduce the infective capacity of their body fluids. We aim to assess if vaccine-induced antibodies could neutralize virions present in the mucosa, thus preventing the release of infective particles and HPV transmission to sexual partners. As our main endpoint, the E1^E4-HaCaT model will be used to assess the infectivity rate of cervical, anal and oral samples, obtained from women before and after vaccination. HPV DNA positivity, virion production, seroconversion, and the presence of antibodies in the exudates, will be evaluated to attribute infectivity reduction to vaccination. Our study will recruit two different cohorts (RIFT-HPV1 and RIFT-HPV2) of non-vaccinated adult women. RIFT-HPV1 will include subjects with an HPV16/18 positive cervical test and no apparent cervical lesions or cervical lesions eligible for conservative treatment. RIFT-HPV2 will include subjects with an HPV16/18 positive anal test and no apparent anal lesions or anal lesions eligible for conservative treatment, as well as women with an HPV16/18 positive cervical test and HPV-associated vulvar lesions. Subjects complying with inclusion criteria for both cohorts will be recruited to the main cohort, RIFT-HPV1. Three doses of Gardasil-9 will be administered intramuscularly at visit 1 (0 months), visit 2 (2 months) and visit 3 (6 months). Even though prophylactic HPV vaccines would not eliminate a pre-existing infection, our results will determine if HPV vaccination could be considered as a new complementary strategy to prevent HPV-associated diseases by reducing viral spread. Trial registration: https://clinicaltrials.gov/ct2/show/NCT05334706.

[Research progress on the differences between T and B cell responses to three different forms of human papilloma virus (HPV) vaccination].

One of the most prevalent malignancies in women is cervical cancer. Cervical cancer is mostly brought on by chronic high-risk human papillomavirus 16 (HPV16) and HPV18 infection. Currently, the widely used HPV vaccines are the bivalent Cervarix, the tetravalent Gardasil, and the 9-valent Gardasil-9.There are differences in T cell effector molecule changes, B cell antibody level, duration, age and the injection after vaccination of the three vaccines.

Effectiveness of combined approach to recurrent respiratory papillomatosis (RRP).

PURPOSE: Recent approaches for recurrent respiratory papillomatosis including local injection of bevacizumab and HPV vaccination show promise in reducing the need for frequent surgeries. In this study we propose a new combined approach of surgery, intralesional injection of 25 mg bevacizumab and HPV vaccine that can lead to resolution of RRP. MATERIAL AND METHODS: Our study involved 5 patients treated with a combination of transoral microsurgery, intralesional injection of 25 mg bevacizumab, and HPV vaccination with Gardasil 9 between April 2020 and May 2023. Standard video laryngoscopy was performed to assess the presence of papilloma and Derkay score was used to assess the severity of disease. RESULTS: All 5 patients completed the study successfully and a complete response was achieved by all. The follow-up ranged from 8 to 45 months. The mean total Derkay score before treatment was 41 (range 25 to 52) and after the combined approach was 0 both anatomically and clinically in all patients. CONCLUSIONS: This study demonstrates the effectiveness of a combined treatment approach for RRP involving surgical intervention, intralesional injection of bevacizumab, and HPV vaccination.

Immunogenicity of quadrivalent human papillomavirus vaccine among Alaska Native children aged 9-14 years at 5 years after vaccination.

BACKGROUND: Persistent human papillomavirus (HPV) infection can cause anogenital and oropharyngeal cancers. Many HPV infections and HPV-associated cancers are vaccine-preventable. Studies suggest long-term persistence of vaccine-induced antibodies. However, data are limited among Alaska Native people. METHODS: During 2011-2014, we enrolled Alaska Native children aged 9-14 years who received a 3-dose series of quadrivalent HPV vaccine (4vHPV). We collected sera at 1 month and 1, 2, 3, and 5 years post-vaccination to evaluate trends in type-specific immunoglobulin G antibody concentrations for the 4vHPV types (HPV 6/11/16/18). RESULTS: All participants (N = 469) had detectable antibodies against all 4vHPV types at all timepoints post-vaccination. For all 4vHPV types, antibody levels peaked by 1 month post-vaccination and gradually declined in subsequent years. At 5 years post-vaccination, antibody levels were higher among children who received 4vHPV at a younger age. CONCLUSIONS: Alaska Native children maintained antibodies against all 4vHPV types at 5 years post-vaccination.

Adjuvant Human Papillomavirus Vaccination in Recurrent Respiratory Papilloma Patients Older than 45.

OBJECTIVES: The primary objective was to examine the intersurgical interval (ISI) of recurrent respiratory papillomatosis (RRP) in patients older than 45 years before and after a Gardasil vaccination series. METHODS: We conducted a retrospective chart review of adult patients >45 years of age diagnosed with RRP from 2012 to 2022. Patients were excluded if they did not receive at least two doses of the Gardasil vaccine series or if they underwent two or fewer surgeries during the study period. RESULTS: Thirteen patients met the inclusion criteria, 11 males and two females. The age at initial diagnosis ranged from 46 to 80 years, with a mean of 59 years. There was a significant increase in the average ISI, from 126 ± 87 days pre-vaccination compared to 494 ± 588 days post-vaccination (p < 0.01). The average number of surgeries per patient was 6.8 ± 2.4 over an average follow-up of 49.7 ± 30.3 months. CONCLUSION: Adjuvant Gardasil use in RRP patients older than 45 years significantly increases the ISI. Current CDC recommendations include only patients ages 9 to 45, but this study provides evidence that RRP patients outside this age range may benefit from adjuvant HPV vaccination. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:3226-3229, 2024.

The eight-year long-term follow-up on the effectiveness of the quadrivalent human papillomavirus vaccine in Chinese women 20-45 years of age.

The quadrivalent human papillomavirus (4vHPV) vaccine has shown confirmative effectiveness in preventing HPV-related diseases among women and men around the globe. The phase III, randomized, double-blind efficacy study (Base study, NCT00834106) conducted in China showed 100% efficacy against HPV 16/18-related cervical intraepithelial neoplasia and efficacy against HPV persistent infection for 78 months. Participants aged 20-45 years who received three doses of 4vHPV vaccine or placebo during the base study were selected and invited for this long-term follow-up (LTFU) study to assess the long-term effectiveness of the 4vHPV vaccine in preventing HPV-related diseases. A total of 368 participants were included in this LTFU study with a median follow-up of 94 months. Among 27 participants (Vaccine vs. Placebo: 8 vs. 19) who underwent colposcopy and biopsy due to cervical cytological abnormalities or HPV infection, no HPV-16/18-related cases of cervical intraepithelial neoplasia (CIN), vulvar intraepithelial neoplasia (VIN), or vaginal intraepithelial neoplasia (VaIN) was observed in the vaccine group while two HPV-16-related cases (CIN1/VaIN) were observed in the placebo group. There were another two HPV-related cases (non-vaccine HPV types) found in the placebo group. Consistent with the findings from global studies that suggested long-term efficacy of 4vHPV vaccine, our study showed continued protective effect of 4vHPV vaccine against HPV-related precancerous diseases through a median follow-up time of 94 months with the longest follow-up time of 125 months after completing three doses of vaccination among Chinese women 20-45 years of age.

Vaccine efficacy against persistent human papillomavirus (HPV) 16/18 infection at 10 years after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a multicentre, prospective, cohort study.

BACKGROUND: A randomised trial designed to compare three and two doses of quadrivalent human papillomavirus (HPV) vaccine in adolescent girls in India was converted to a cohort study after suspension of HPV vaccination in trials by the Indian Government. In this Article, the revised aim of the cohort study was to compare vaccine efficacy of single dose to that of three and two doses in protecting against persistent HPV 16 and 18 infection at 10 years post vaccination. METHODS: In the randomised trial, unmarried girls aged 10-18 years were recruited from nine centres across India and randomly assigned to either two doses or three doses of the quadrivalent HPV vaccine (Gardasil [Merck Sharp & Dohme, Whitehouse Station, NJ, USA]; 0·5 mL administered intramuscularly). After suspension of recruitment and vaccination, the study became a longitudinal, prospective cohort study by default, and participants were allocated to four cohorts on the basis of the number vaccine doses received per protocol: the two-dose cohort (received vaccine on days 1 and 180 or later), three-dose cohort (days 1, 60, and 180 or later), two-dose default cohort (days 1 and 60 or later), and the single-dose default cohort. Participants were followed up yearly. Cervical specimens were collected from participants 18 months after marriage or 6 months after first childbirth, whichever was earlier, to assess incident and persistent HPV infections. Married participants were screened for cervical cancer as they reached 25 years of age. Unvaccinated women age-matched to the married vaccinated participants were recruited to serve as controls. Vaccine efficacy against persistent HPV 16 and 18 infections (the primary endpoint) was analysed for single-dose recipients and compared with that in two-dose and three-dose recipients after adjusting for imbalance in the distribution of potential confounders between the unvaccinated and vaccinated cohorts. This trial is registered with ISRCTN, ISRCTN98283094, and ClinicalTrials.gov, NCT00923702. FINDINGS: Vaccinated participants were recruited between Sept 1, 2009, and April 8, 2010 (date of vaccination suspension), and followed up over a median duration of 9·0 years (IQR 8·2-9·6). 4348 participants had three doses, 4980 had two doses (0 and 6 months), and 4949 had a single dose. Vaccine efficacy against persistent HPV 16 and 18 infection among participants evaluable for the endpoint was 95·4% (95% CI 85·0-99·9) in the single-dose default cohort (2135 women assessed), 93·1% (77·3-99·8) in the two-dose cohort (1452 women assessed), and 93·3% (77·5-99·7) in three-dose recipients (1460 women assessed). INTERPRETATION: A single dose of HPV vaccine provides similar protection against persistent infection from HPV 16 and 18, the genotypes responsible for nearly 70% of cervical cancers, to that provided by two or three doses. FUNDING: Bill & Melinda Gates Foundation.

Incidence and Types of Human Papillomavirus Infections in Adolescent Girls and Young Women Immunized With the Human Papillomavirus Vaccine.

Importance: Rates of human papillomavirus (HPV) infection have decreased since the introduction of HPV vaccines in populations with high vaccine uptake. Data are limited for adolescent and young adult populations in US metropolitan centers. Objective: To determine HPV infection rates in adolescent girls and young women aged 13 to 21 years in New York City following HPV vaccination. Design, Setting, and Participants: This cohort study of type-specific cervical HPV detection was conducted at a large adolescent-specific integrated health center in New York City between October 2007 and September 2019. Participants included an open cohort of adolescent girls and young adult women who received the HPV vaccine (Gardasil; Merck & Co) over a 12-year period following HPV vaccination introduction. Data analysis was concluded September 2019. Exposures: Calendar date and time since receipt of first vaccine dose. Main Outcomes and Measures: Temporal associations in age-adjusted postvaccine HPV rates. Results: A total of 1453 participants, with a mean (SD) age at baseline of 18.2 (1.4) years, were included in the cohort (African American with no Hispanic ethnicity, 515 [35.4%] participants; African American with Hispanic ethnicity, 218 [15.0%] participants; Hispanic with no reported race, 637 [43.8%] participants). Approximately half (694 [47.8%] participants) were vaccinated prior to coitarche. Age-adjusted detection rates for quadrivalent vaccine types (HPV-6, HPV-11, HPV-16, and HPV-18) and related types (HPV-31, and HPV-45) decreased year over year, with the largest effect sizes observed among individuals who had been vaccinated before coitarche (adjusted odds ratio [aOR], 0.81; 95% CI, 0.67-0.98). By contrast, detection was higher year over year for nonvaccine high-risk cervical HPV types (aOR, 1.08; 95% CI, 1.04-1.13) and anal HPV types (aOR, 1.11; 95% CI, 1.05-1.17). The largest effect sizes were observed with nonvaccine types HPV-56 and HPV-68. Conclusions and Relevance: Whereas lower detection rates of vaccine-related HPV types were observed since introduction of vaccines in female youth in New York City, rates of some nonvaccine high-risk HPV types were higher. Continued monitoring of high-risk HPV prevalence is warranted.

Immunogenicity and Safety of a Tetravalent Dengue Vaccine Administered Concomitantly or Sequentially With Quadrivalent Human Papillomavirus Vaccine in Boys and Girls 9-13 Years of Age in Malaysia: A Phase IIIb, Randomized, Open-label Study.

BACKGROUND: Incorporating dengue vaccination within existing vaccination programs could help improve dengue vaccine coverage. We assessed the immunogenicity and safety of a quadrivalent human papillomavirus (HPV) vaccine administered concomitantly or sequentially with a tetravalent dengue vaccine (CYD-TDV) in healthy children 9-13 years of age in Malaysia. METHODS: In this phase IIIb, open-label, multicenter study (NCT02993757), participants were randomized 1:1 to receive 3 CYD-TDV doses 6 months apart and 2 doses of quadrivalent HPV vaccine concomitantly with, or 1 month before (sequentially), the first 2 CYD-TDV doses. Only baseline dengue-seropositive participants received the 3 doses. Antibody levels were measured at baseline and 28 days after each injection using an enzyme-linked immunosorbent assay for HPV-6, -9, -16 and -18, and the 50% plaque reduction neutralization test for the 4 dengue serotypes; immunogenicity results are presented for baseline dengue-seropositive participants. Safety was assessed throughout the study for all participants. RESULTS: At baseline, 197 of 528 (37.3%) randomized participants were dengue-seropositive [n = 109 (concomitant group) and n = 88 (sequential group)]. After the last HPV vaccine dose, antibody titers for HPV among baseline dengue-seropositive participants were similar between treatment groups, with between-group titer ratios close to 1 for HPV-6 and 0.8 for HPV-11, -16, and -18. After CYD-TDV dose 3, dengue antibody titers were similar between treatment groups for all serotypes [between-group ratios ranged from 0.783 (serotype 2) to 1.07 (serotype 4)]. No safety concerns were identified. CONCLUSIONS: The immunogenicity and safety profiles of CYD-TDV and quadrivalent HPV vaccines were unaffected when administered concomitantly or sequentially in dengue-seropositive children.

Effectiveness of the Quadrivalent HPV Vaccine in Preventing Anal ≥ HSILs in a Spanish Population of HIV+ MSM Aged > 26 Years.

Anal squamous cell carcinoma is the most frequent virus-related non-AIDS-defining neoplasia among HIV-infected individuals, especially MSM. The objectives of this study were to analyze the effectiveness of the quadrivalent HPV (qHPV) vaccine to prevent anal ≥ high-grade squamous intraepithelial lesions (≥HSILs), external ano-genital lesions (EAGLs), and infection by qHPV vaccine genotypes in HIV+ MSM, and to study the immunogenicity of the vaccine and risk factors for ≥ HSILs. This study is nested within a randomized, double-blind, placebo-controlled trial of the qHPV vaccine, which enrolled participants between May 2012 and May 2014, with a 48-month follow-up. A vaccine or placebo was administered at 0, 2, and 6 months, and vaccine antibody titers were evaluated at 7, 12, 24, 36, and 48 months. Data were gathered at 12, 24, 36, and 48 months on sexual habits, CD4/CD8 cell/counts, HIV viral load, and the results of cytology (Thin Prep® Pap Test), HPV PCR genotyping (Linear Array HPV Genotyping Test), and high-resolution anoscopy (Zeiss 150 fc© colposcope). The study included 129 patients (mean age of 38.8 years, 40 [31%] with a history of AIDS, 119 [92.2%] receiving ART, and 4 [3.3%] with virological failure), 66 (51.2%) in vaccine arm and 63 (48.4%) in placebo arm. The vaccine and placebo groups did not differ in ≥ HSILs (14.1 vs. 13.1%, respectively, p = 0.98) or EAGL (11.1 vs. 6.8%, p = 0.4) rates during follow-up; however, a protective effect against HPV 6 was observed during the first year of follow-up in the vaccine versus placebo group (7.5% vs. 23.4%; p = 0.047). A between-arm difference (p = 0.0001) in antibodies against qHPV vaccine genotypes was observed at 7 months (76.9% in vaccine arm vs. 30.2% in placebo arm), 12 months (68.1% vs. 26.5%), 24 months (75% vs. 32.5%), 36 months (90% vs. 24.4%), and 48 months (87.2% vs. 30%). Finally, the factor associated with the risk of anal ≥ HSIL onset during the four-year follow-up was the receipt of the last dose of the vaccine less than 6 months earlier in comparison to those vaccinated for a longer period (82.4% vs. 17.6% (OR 0.869 [95% CI, 0.825-0.917]). Vaccine and placebo arms did not significantly differ in ≥ HSIL or EAGL rates or in protection against infection by HPV genotype vaccine except for HPV6 at 12 months after the first dose. A long-lasting immune response was observed in almost all the vaccinated men. The main protective factor against ≥ HSIL was to have completed the vaccination regimen more than 6 months earlier.

Public health impact and cost effectiveness of routine and catch-up vaccination of girls and women with a nine-valent HPV vaccine in Japan: a model-based study.

BACKGROUND: Combined with cancer screening programs, vaccination against human papillomavirus (HPV) can significantly reduce the high health and economic burden of HPV-related disease in Japan. The objective of this study was to assess the health impact and cost effectiveness of routine and catch-up vaccination of girls and women aged 11-26 years with a 4-valent (4vHPV) or 9-valent HPV (9vHPV) vaccine in Japan compared with no vaccination. METHODS: We used a mathematical model adapted to the population and healthcare settings in Japan. We compared no vaccination and routine vaccination of 12-16-year old girls with 1) 4vHPV vaccine, 2) 9vHPV vaccine, and 3) 9vHPV vaccine in addition to a temporary catch-up vaccination of 17-26 years old girls and women with 9vHPV. We estimated the expected number of disease cases and deaths, discounted (at 2% per year) future costs (in 2020 ¥) and discounted quality-adjusted life years (QALY), and incremental cost effectiveness ratios (ICER) of each strategy over a time horizon of 100 years. To test the robustness of the conclusions, we conducted scenario and sensitivity analyses. RESULTS: Over 100 years, compared with no vaccination, 9vHPV vaccination was projected to reduce the incidence of 9vHPV-related cervical cancer by 86% (from 15.24 new cases per 100,000 women in 2021 to 2.02 in 2121). A greater number of cervical cancer cases (484,248) and cancer-related deaths (50,102) were avoided through the described catch-up vaccination program. Routine HPV vaccination with 4vHPV or 9vHPV vaccine prevented 5,521,000 cases of anogenital warts among women and men. Around 23,520 and 21,400 diagnosed non-cervical cancers are prevented by catch-up vaccination among women and men, respectively. Compared with no vaccination, the ICER of 4vHPV vaccination was ¥975,364/QALY. Compared to 4vHPV, 9vHPV + Catch-up had an ICER of ¥1,534,493/QALY. CONCLUSIONS: A vaccination program with a 9-valent vaccine targeting 12 to 16 year-old girls together with a temporary catchup program will avert significant numbers of cases of HPV-related diseases among both men and women. Furthermore, such a program was the most cost effective among the vaccination strategies we considered, with an ICER well below a threshold of ¥5000,000/QALY.

Quadrivalent human papillomavirus vaccination successfully reduces the prevalence of vaccine-targeted genotypes in a young, vaccine-eligible-age sample of Australian females.

Background The prevalence of genital tract vaccine-type human papillomavirus (HPV) is on the decline due to high vaccine uptake through the national HPV immunisation program in Australia. The aim of this study was to investigate HPV vaccine coverage and factors associated with HPV in a vaccine-eligible sample of young Australian females. METHODS: Females aged 16-25 years were recruited into the Young Female Health Initiative study, a young women's health study, via Facebook advertising from 2012 to 2017. Sexually active participants were asked to provide a self-collected vaginal swab for the detection of HPV DNA; positive samples were genotyped. Self-reported HPV vaccination status was confirmed by the National HPV Vaccination Program Register. Outcomes of the study were HPV acquisition and genotype, HPV vaccination status and factors associated with HPV. RESULTS: Overall, 22.8% of samples (95% confidence interval (CI) 17.8-27.8%; n = 62/272) were positive for any HPV DNA, of which 19.1% (95% CI 14.4-23.8%; n = 52/272) were oncogenic types. HPV 16 was detected in three samples (1.1%; 95% CI -0.1%, 2.3%; two not HPV vaccinated and one vaccinated after sexual debut). Early sexual debut (<16 years) and multiple sexual partners were independently associated with an increased risk of any HPV. CONCLUSIONS: In a community sample of vaccine-eligible-age females with a high vaccine uptake, the prevalence of vaccine-related HPV genotypes is extremely low. Early sexual debut and multiple sexual partners are positively associated with HPV, underscoring the importance of vaccination at the routinely recommended age of 12-13 years for best vaccine impact.

The study protocol of the evaluation for the preventive efficacy of the HPV vaccine for persistent HPV16/18 infection in Japanese adult women: the HAKUOH study.

BACKGROUND: In general, human papillomavirus (HPV) vaccines have demonstrated efficacy in young women worldwide, but there is limited evidence on the efficacy of the quadrivalent HPV6/11/16/18 vaccine in adult women and no evidence of its effectiveness in Japanese adult women in particular. This study aims to evaluate the efficacy of the quadrivalent HPV6/11/16/18 vaccine for persistent HPV16/18 infection in Japanese women aged 27-45 years. METHODS: This is an interventional, nonrandomized, non-double-blind prospective cohort study designed to compare the rates of persistent HPV16/18 infection between the vaccinated arm and unvaccinated arm. The subjects will consist of all women aged 27-45 years who have normal cytology results confirmed by cervical cancer screening from May 2019 to March 2021. The follow-up time is two years. The subjects will be divided into two groups: the vaccinated group and the unvaccinated group. The study will need to enroll 600 vaccinated participants (experimental arm) and 2200 unvaccinated participants (control arm). DISCUSSION: The findings of this trial (HAKUOH study) might provide the first local evidence on the subject and be significantly useful not only to medical academia but also to the Japanese Ministry of Health, Labour and Welfare. The findings could contribute to public health improvement by providing local supportive knowledge on the prevention of HPV infection through HPV vaccination in young adult women in Japan, where active recommendations have been suspended for a long time due to adverse effects. TRIAL REGISTRATION: Trial registration number: NCT04022148 . Registration began on December 1, 2019.

Post-hoc analysis of injection-site reactions following vaccination with quadrivalent human papillomavirus vaccine in Japanese female clinical trial participants.

AIM: The quadrivalent human papillomavirus (4vHPV) vaccine has demonstrated efficacy and immunogenicity and was generally well tolerated in clinical trials conducted in Japan. We report a detailed safety analysis of injection-site reactions in female Japanese 4vHPV clinical trial participants. METHODS: This post-hoc analysis included data from 2 double-blind, placebo-controlled phase II clinical trials of a 3-dose (Day 1, Month 2, Month 6) regimen of 4vHPV vaccine in Japanese young women aged 18-26 years (N = 1021; NCT00378560) and girls aged 9-17 years (N = 107; NCT00411749). Injection-site and systemic adverse events (AEs) were monitored using vaccination report cards for 15 days after each vaccine dose; serious AEs were reported throughout the trials. Post-hoc analyses of data from these trials were performed to examine details of injection-site AEs, including day of onset, time from onset to resolution, and maximum intensity. RESULTS: Injection-site AEs were reported by 85.6% of 4vHPV vaccine recipients and 72.4% of placebo recipients, most commonly erythema, pain, pruritus, and swelling (each >5% of 4vHPV vaccine recipients). The majority of injection-site AEs had an onset within 3 days of vaccination and were mild to moderate in intensity; few 4vHPV vaccine recipients reported severe injection-site AEs (2.0% overall). All injection-site AEs resolved, and most (4vHPV: 87.5%; placebo: 92.7%) resolved within 5 days of onset. CONCLUSIONS: Most injection-site reactions are mild or moderate in intensity and of short duration. The 3-dose regimen of 4vHPV vaccine is well tolerated in Japanese female clinical trial participants based on this post-hoc analysis. These results will further support safety communication between healthcare providers and vaccine recipients regarding the HPV vaccine. TRIAL REGISTRATION: Clinicaltrials. gov: NCT00378560 and NCT00411749.

Safety and immunogenicity of the quadrivalent human papillomavirus vaccine in patients with childhood systemic lupus erythematosus: a real-world interventional multi-centre study.

OBJECTIVE: This study aimed to assess the safety and immunogenicity of the quadrivalent human papillomavirus (qHPV) vaccination in childhood-onset systemic lupus erythematosus (cSLE) patients. METHODS: Volunteer cSLE patients aged 9-20 years and healthy controls (HC) were enrolled to receive a two- or three-dose qHPV vaccination schedule from March 2014 to March 2016. Study visits were performed before the first dose, one month after the second and third doses and one year after the first dose. In each study visit, disease activity and adverse events following vaccination were analyzed, and a serum sample was collected for testing antibody concentrations. Participant recruitment was conducted in 15 Brazilian paediatric rheumatology units. Of the 256 cSLE patients included, 210 completed the two- or three-dose schedules; 15 had previously received one dose, and 18 had received two doses of the vaccine. The analysis was based on intention-to-treat so that participants who did not complete the entire study protocol were also included. RESULTS: No severe adverse events were related to the vaccination. Disease activity was generally low and remained stable or even improved. The HC presented 100% seropositivity to HPV16 and HPV18, whereas the two- and three-dose cSLE groups presented 93% and 83% versus 97% and 91%, respectively. One year after the first dose, seropositivity of the three-dose cSLE group was 91% to HPV16 and 84% to HPV18. CONCLUSIONS: HPV vaccination in cSLE patients is safe and immunogenic. Since the seropositivity to HPV16 and HPV18 was higher for the three-dose schedule group, this regimen should be recommended for cSLE patients.