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.

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.

AIDS Malignancy Consortium 054: Safety and Immunogenicity of the Quadrivalent Vaccine in Indian Women Living With HIV.

BACKGROUND: Human papillomavirus (HPV)-associated cervical cancer is a leading cause of death among Indian women. Indian women living with HIV (WLWH) may be at especially high risk. The quadrivalent HPV (qHPV) vaccine is effective in prevention of initial infection with HPV-6/11/16/18 in HIV-negative women. Little is known about previous exposure to HPV-6/11/16/18, safety, and immunogenicity of qHPV in Indian WLWH. METHODOLOGY: One hundred fifty WLWH with different CD4 levels and HIV viral load (VL) were vaccinated at 0/2/6 months at CART-CRS-IDMC, Chennai, India. Serology was performed at weeks 0, 28, and 52 for HPV-6/11/16/18 using a competitive Luminex immunoassay and for HPV-16/18 using a pseudovirion-based neutralization assay. RESULTS: Mean age was 30.8 years (range, 19-44 years). 71/87/73/81% of women were naive (sero-negative and DNA-negative) to HPV-6/11/16/18 at baseline, respectively. Among per-protocol women naive to HPV-6/11/16/18 at baseline, 100/99/99/90%, respectively, seroconverted at week 28 and 95/96/98/71% were sero-positive at week 52, respectively. Pseudovirion-based neutralization assay identified more seroconversion to HPV-18 than competitive Luminex immunoassay. There were no significant differences in the proportion seroconverting by baseline or nadir CD4 or HIV VL; however, there was a trend for increased proportion seroconverting to HPV-18 among women with higher baseline CD4 level (P = 0.052). There were no qHPV-related serious adverse events and no change in CD4 level or HIV VL among women on ART. CONCLUSIONS: qHPV vaccine was safe and immunogenic in Indian WLWH. A high proportion were naive to HPV-6/11/16/18 and may benefit from vaccination although many were married and several years post-initiation of sexual activity.

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.

Human papilloma virus (HPV) prevalence upon HPV vaccination in Swedish youth: a review based on our findings 2008-2018, and perspectives on cancer prevention.

PURPOSE: Three human papillomavirus (HPV) vaccines are available against up to nine HPV types. In Sweden, from 2012, Gardasil was offered to 10-12 year old girls through the school-based vaccination program, and as catchup vaccination for women up to 26 years. To obtain a baseline, and follow HPV vaccination effects, during 2008-2018, cervical and oral HPV prevalence were followed at a youth clinic in Stockholm, and in 2013 for comparison oral HPV prevalence was examined in high-school youth in a middle-sized county in Sweden. METHODS: In this review, we discuss all our data with cervical and oral mouthwash samples that were collected and tested for 24-27 HPV types by a bead-based multiplex assay from 2008. RESULTS: Compared with 2008-2011, with ~ 35% HPV16 and > 60% high risk (HR) HPV cervical prevalence at the youth clinic, a decrease of vaccine HPV types was observed between 2013 and 2018, with e.g., HPV16 falling to 5% in catchup vaccinated women and 15-18% in nonvaccinated women. Most common cervical HR-HPV types were HPV39, 51, 52, 56, and 59 together accounting for ~ 10% of cervical cancer, and where only HPV52 is included in Gardasil-9. At baseline 2009-2011, oral HPV prevalence was ~ 10% in unvaccinated youth at the youth clinic, but after 2013 it dropped to < 2% at the youth clinic and high schools. CONCLUSION: To conclude, Gardasil HPV types have decreased, but it is still important to follow remaining HR-HPV types and cancer development, since there is an ongoing increase in the incidence of HPV-associated tonsillar and base of tongue cancer, and cervical cancer in Sweden.

Immune responses against autologous tumor and human papilloma virus in lymph nodes from patients with penile cancer.

PURPOSE: Nearly half of penile cancers are related to human papillomavirus (HPV) infection. Investigations of tumor- and HPV-specific T cell reactivity in regional lymph nodes (LNs) from patients with penile cancer are warranted. MATERIALS AND METHODS: In this study, single-cell suspensions from LNs and peripheral blood from 11 patients with penile cancer were stained with antibodies for lymphocyte markers and analyzed by fluorescence-activated cell sorting (FACS). DNA was extracted from the tumor tissue and HPV status was investigated by PCR. RESULTS: T-cell reactivity against autologous tumor-extract and against the HPV-vaccine Gardasil® was tested by flow-cytometric assay of specific cell-mediated immune response in activated whole blood (FASCIA). CD4+/CD8+ ratios were significantly lower in HPV positive LNs (p<0.05). Immune responses to tumor extract assessed by blast transformation and expansion in vitro, of either CD4+ or CD8+ T-cells, were found in 9 of 13 LNs (69%). 5 of 6 tested patients demonstrated T cell recognition of tumor-associated antigen(s). In HPV-positive patients, dose-dependent T cell responses against L1 (late) HPV proteins (Gardasil vaccine) were demonstrated. CONCLUSIONS: LN-derived T cells from patients with penile cancer recognize tumor antigen(s) and in HPV-positive cases, there is a response against L1 (late) HPV proteins, being constituents of the Gardasil vaccine.

Cross-neutralizing antibody titres against non-vaccine types induced by a recombinant trivalent HPV vaccine (16/18/58) in rhesus macaques.

Human papillomavirus (HPV) causes not only most cervical cancers but also cancers of the vagina, vulva, penis, anus, rectum, and oropharynx. Every year, 200,000 women die of cervical cancer in the world, and China accounts for about 10%. HPV vaccines are effective in preventing HPV infections thus HPV-related cancers worldwide. Studies on the clinical trials of the 2v Cervarix™ and the 4v Gardasil® have suggested that immunization with either of these vaccines provided some level of protection against other HPV types that are closely related to the types contained in the vaccines. Here we conducted a preliminary evaluation on the ability to induce cross-neutralizing antibodies in rhesus monkeys by a 3v HPV vaccine that targets HPV16, 18, and 58 and it is specifically designed for Chinese women. We found that this vaccine is no less than Gardasil® in terms of the ability to induce NAbs against non-vaccine types of HPV in rhesus macaques. These results provided evidence from the immunogenicity point of view that the KLWS 3v HPV vaccine is a strong competitor to the imported 2v and 4v HPV vaccines currently available on the market.

WebPalestra: mudanças no Calendário Nacional de Vacinação para o ano 2018

Historicamente, diversos calendários de vacinação foram propostos pelo Programa Nacional de Imunizações em função de diferentes circunstâncias, tais como: situação epidemiológica, mudanças nas indicações das vacinas ou incorporação de novas vacinas. Para o ano de 2018, a Coordenação-Geral do Programa Nacional de Imunizações (CGPNI) informa mudanças para as seguintes vacinas do Calendário Nacional de Vacinação: vacina varicela, febre amarela e meningocócica C

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.

Serum and cervicovaginal IgG immune responses against α7 and α9 HPV in non-vaccinated women at risk for cervical cancer: Implication for catch-up prophylactic HPV vaccination.

BACKGROUND: Cervical cancer associated with high risk-human papillomavirus (HR-HPV) infection is becoming the one of the most common female cancer in many sub-Saharan African countries. First-generation immigrant African women living in Europe are at-risk for cervical cancer, in a context of social vulnerability, with frequent lack of cervical cancer screening and HPV vaccination. OBJECTIVE: Our objective was to address immunologically the issue of catch-up prophylactic HPV vaccination in first-generation African immigrant women living in France. METHODS: IgG immune responses and cross-reactivities to α7 (HPV-18, -45 and -68) and α9 (HPV-16, -31, -33, -35, -52 and -58) HPV types, including 7 HR-HPV targeted by the Gardasil-9® prophylactic vaccine, were evaluated in paired serum and cervicovaginal secretions (CVS) by HPV L1-virus-like particles-based ELISA. Genital HPV were detected by multiplex real time PCR (Seegene, Seoul, South Korea). RESULTS: Fifty-one immigrant women (mean age, 41.7 years; 72.5% HIV-infected) were prospectively included. More than two-third (68.6%) of them carried genital HPV (group I) while 31.4% were negative (group II). The majority (90.2%) exhibited serum IgG to at least one α7/α9 HR-HPV. Serum HPV-specific IgG were more frequently detected in group I than group II (100% versus 68.7%; P = 0.002). The distribution of serum and genital HPV-specific IgG was similar, but mean number of IgG reactivities to α7/α9 HR-HPV was higher in serum than CVS (5.6 IgG per woman in serum versus 3.2 in CVS; P<0.001). Rates of IgG cross-reactivities against HPV different from detected cervicovaginal HPV were higher in serum and CVS in group I than group II. Finally, the majority of groups I and II women (68.6% and 68.7%, respectively) exhibited serum or cervicovaginal IgG to Gardasil-9® HR-HPV, with higher mean rates in group I than group II (6.1 Gardasil-9® HR-HPV per woman versus 1.4; P<0.01). One-third (31.2%) of group II women did not show any serum and genital HPV-specific IgG. CONCLUSIONS: Around two-third of first-generation African immigrant women living in France showed frequent ongoing genital HPV infection and high rates of circulating and genital IgG to α7/α9 HPV, generally cross-reacting, avoiding the possibility of catch-up vaccination. Nevertheless, about one-third of women had no evidence of previous HPV infection, or showed only low levels of genital and circulating HR-HPV-specific IgG and could therefore be eligible for catch-up vaccination.

Use of real-world data for HPV vaccine trial follow-up in the Nordic region.

Post-marketing studies are commonly performed to follow-up on the safety and effectiveness of a drug or vaccine after approval has been obtained. These post-marketing studies may involve the collection of real-world data from registries and clinical biobanks in order to obtain real-world evidence. As this approach can monitor the effects of pharmaceutical products over decades, it is particularly necessary for the development of safe and effective vaccines. A long-term follow-up (LTFU) study was initiated as an extension of a phase 3 clinical study (V501-015; NCT00092534) to assess the effectiveness, immunogenicity and safety of the quadrivalent human papillomavirus (qHPV) vaccine for up to 14 years after the start of vaccination. The LTFU study included participants from Denmark, Iceland, Norway, and Sweden, and assessed qHPV vaccine effectiveness against cervical pre-cancers and cancers caused by the oncogenic HPV types 16 and 18. In particular, our study utilized Nordic national health registries, in which individual patient records were linked by a unique Personal Identity Number. Here, we describe the overall implementation and methodology of the qHPV vaccine LTFU study conducted in the Nordic region. The LTFU study format we describe here supported a comprehensive follow-up process, with near-complete retrieval of registry data and specimens from local laboratories achieved in a timely manner; therefore, we have demonstrated that such a collection is feasible and can be used to address stringent post-marketing requirements.

Brief Report: Persistence of Non-Vaccine Oncogenic HPV Genotypes in Quadrivalent HPV-Vaccinated Women Living With HIV.

BACKGROUND: Human papillomavirus (HPV) vaccines have promising safety and immunogenicity data in women living with HIV (WLWH). However, it is critical to understand the residual burden of oncogenic HPV within WLWH to inform postvaccination cervical screening needs. We assessed rates of persistent infection with nonquadrivalent HPV (qHPV) oncogenic types in a cohort of qHPV-vaccinated WLWH. SETTING: Multicentre, longitudinal cohort across Canada. METHODS: WLWH were scheduled to receive 3 doses of qHPV vaccine. Participants provided health data and HPV DNA samples. Persistent cases of HPV were defined as new HPV in samples from ≥2 consecutive visits or as HPV present in the last sample. HPV31/33/35/39/45/51/52/56/58/59/68/82 were considered to have oncogenic potential. Median follow-up time was 4 years after initial vaccine dose. RESULTS: A total of 284 participants were eligible for this analysis with 1205 person-years (PY) of follow-up (≥1 dose of vaccine, ≥1 HPV DNA result after vaccination). The highest incidence of persistent infection was with HPV51 (1.38/100 PY), followed by HPV52 (1.18/100 PY), and HPV39 (1.06/100 PY). The incidence of persistent infection with pooled HPV types added in the nonavalent vaccine (HPV31/33/45/52/58) was lower than the incidence of persistent oncogenic HPV types not contained within available vaccines (HPV35/39/51/56/59/68) (2.4/100 PY versus 3.6/100 PY, respectively). CONCLUSIONS: qHPV-vaccinated WLWH continue to face a burden of persistent oncogenic HPV infection. Although the nonavalent vaccine could alleviate some of this burden, 2 of the top 3 persistent oncogenic HPVs in this cohort are not contained within any available vaccine. This highlights the need for ongoing cervical screening in HPV-vaccinated WLWH.

The immune response to a two-dose schedule of quadrivalent HPV vaccine in 9-13 year-old girls: Is it influenced by age, menarche status or body mass index?

HPV vaccines are highly immunogenic. A two-dose schedule for 9-14 year-old is recommended. However, no data exist regarding the impact of age, menarche status and body mass index (BMI) on the immune response to a two-dose schedule. In this post-hoc analysis, we present antibody titers to HPV6/11/16/18 in 9-13 year-old girls participating in a randomized clinical trial and assigned to receive two doses of quadrivalent HPV vaccine at 6 months interval (NCT00501137). Antibody titers were measured at month 7 and 24 of the study by using a competitive Luminex immunoassay (cLIA).Both, at Month 7 and 24 the GMTs for four HPV genotypes were similar across the age bands, and did not vary significantly by menarche status. Overweight and obese girls had lower GMTs. More than 99% of girls remained seropositive for HPV 6/11/16 and 89% for HPV18 at month 24. Comprehensive data in overweight and obese vaccines are warranted.

Safety and Immunogenicity of the Quadrivalent HPV Vaccine in Japanese Boys: a Phase 3, Open-Label Study.

Human papillomavirus (HPV)-associated disease is common among men with HPV infection. A quadrivalent HPV (qHPV) vaccine has demonstrated 85.9% efficacy against HPV6/11/16/18-related, persistent (≥ 6 month) infection in a study of Japanese men aged 16-26 years old. Here, we report the results of an open-label study of the immunogenicity and tolerability of the qHPV vaccine (NCT02576054), conducted to bridge findings from Japanese men to Japanese boys aged 9-15 years old. A total of 100 boys completed a three-vaccination regimen (Day 1, and Months 2 and 6), and 99 boys were included in the primary analysis population. The rate of seroconversion at one month after vaccine Dose 3 (Month 7) was high for each type of HPV (anti-HPV6/11/16/18 seroconversion rates [95% CI]: 94.9% [85.5%, 98.3%], 99.0% [94.4%, 100.0%], 99.0% [94.5%, 100.0%], and 99.0% [94.4%, 100.0%], respectively). Moreover, anti-HPV6/11/16/18 geometric mean titers were 482.9 mMU/mL, 1052.8 mMU/mL, 3878.3 mMU/mL, and 1114.5 mMU/mL, respectively. Immune responses to the qHPV vaccine were non-inferior among Japanese boys included in the current study and compared with young Japanese men from a separate study. Injection-site reactions were the most common adverse events, and administration of the vaccine was well tolerated in Japanese boys.

Preclinical study of safety and immunogenicity of combined rubella and human papillomavirus vaccines: Towards enhancing vaccination uptake rates in developing countries.

Rubella vaccine was not part of national immunization programs (NIP) in several countries in the Middle East and North Africa (MENA), South-East Asia (SEA), and South Africa regions until the year 2000. Therefore, immunization coverage of females older than 20 years old in these countries has been the focus of national campaigns for rubella elimination in developing countries. Vaccines against human papillomavirus (HPV) are not part of NIPs in developing countries. To enhance the advantages of rubella-directed immunization campaigns and to increase HPV vaccine uptake in developing countries, this study aimed to test the stability, potency, efficacy and safety of a combined rubella and HPV vaccine. Female BALB/c mice were immunized subcutaneously with proposed combined HPV16/HPV18 VLP and rubella vaccine at weeks (W) 0, 3 then with HPV vaccine at W 7. Immunized mice developed antigen-specific antibodies against rubella and HPV significantly higher than mice immunized with rubella or HPV vaccine alone. The combined vaccine induced significantly higher splenocyte proliferation than control groups. In addition, pro-inflammatory cytokines IL-4, IL-6, IL-2, and IFNγ levels were significantly higher in mice immunized with the combined vaccine than control groups. Overall, the combined vaccine was safe and immunogenic offering antibody protection as well as eliciting a cellular immune response against rubella and HPV viruses in a single vaccine. This combined vaccine can be of great value to females above 20 years old in the SEA, MENA and South Africa regions offering coverage to rubella vaccine and a potential increase in HPV vaccine uptake rates after appropriate clinical testing.

Oral and systemic HPV antibody kinetics post-vaccination among HIV-positive and HIV-negative men.

Duration and functional aspects of the oral and systemic antibody responses following HPV vaccination in HIV-negative (HIV-) and HIV-positive (HIV+) men are not well characterized. Oral and systemic HPV-16 and HPV-18-specific antibody levels were evaluated over 18-months of follow-up, in HIV+ and HIV- men. Sera and oral gargles from 147 HIV- men, ages 27-45 and 75 HIV+ men, ages 22-61, who received 3-doses of quadrivalent HPV vaccine were tested for HPV-16 and HPV-18 antibodies at Day 1, Month 7 (1 month post-dose 3), and Month 18 (12 months post-dose 3) and HPV avidity (Day 1, and Month 7) using L1-VLP ELISA. All individuals seroconverted, regardless of HIV-status, following 3-doses of vaccine for HPV-16 and HPV-18. Serum HPV-16 and HPV-18 antibody geometric mean levels were >2-fold lower in HIV+ compared to HIV- men at Month 7 (HPV-16: 808.5 versus 2119.8 EU/mL, and HPV-18: 285.8 versus 611.6 EU/mL, p < 0.001) but not significantly different at Month 18 (HPV-16: 281.8 versus 359.7 EU/mL, p = 0.145, and HPV-18: 120.2 versus 93.4 EU/mL, p = 0.372). Post-vaccination, only oral HPV-16 antibody levels at Month 7 were significantly different between HIV+ and HIV- men (127.7 versus 177.1 EU/mg of IgG, p = 0.008). Among baseline HPV-seronegative men, circulating levels of HPV-16 and HPV-18 antibodies were up to >3 fold lower in HIV+ men, at Months 7 and 18. In contrast, levels of HPV-16 and HPV-18 antibodies after vaccination were not inferior in baseline HPV-seropositive, HIV+ men. HPV-16 and HPV-18 avidity was lower among HIV+ compared to HIV- men at Month 7 (HPV-16: 1.95 M versus 2.12 M, p = 0.027; HPV-18: 1.50 M versus 1.72 M, p < 0.001). Although differences in peak antibody levels were observed between HIV+ and HIV- men following 3 doses of vaccine, plateau antibody levels were overall comparable, and avidity was relatively high for both groups. These data indicate that the vaccine induced antibody affinity maturation in both HIV+ and HIV- men and will likely result in long-term protective immune responses.

Changes in Cervical Human Papillomavirus (HPV) Prevalence at a Youth Clinic in Stockholm, Sweden, a Decade After the Introduction of the HPV Vaccine.

Aim: This study aimed to follow the impact of human papillomavirus (HPV) catch-up and vaccination on the very high cervical HPV-prevalence in women at a youth clinic in central Stockholm during the period 2008-2018. Background: 2008-2010, cervical HPV-prevalence (69.5%) and HPV16 prevalence (34.7%) were high in non-vaccinated women at a youth clinic in Stockholm. 2013-2015, after the introduction of the quadrivalent-Gardasil® HPV-vaccine, HPV16 and HPV6 prevalence had decreased. Here, cervical HPV-prevalence was investigated 10 years after primary sampling. Material and Methods: 2017-2018, 178 cervical swabs, from women aged 15-23 years old, were tested for 27 HPV types by a bead-based multiplex method. HPV-prevalence data were then related to vaccination status and age and compared to HPV-prevalence in 615 samples from 2008 to 2010 and 338 samples from 2013 to 2015 from the same clinic, and to HPV types in 143 cervical cancer cases during 2003-2008 in Stockholm. Results: The proportion of vaccinated women increased from 10.7% (2008-2010) to 82.1% (2017-2018). The prevalence of all 27 HPVs, all high-risk HPVs (HR-HPVs) and the combined presence of the quadrivalent-Gardasil® types HPV16, 18, 6, and 11, was lower in vaccinated compared to unvaccinated women (67.4 vs. 93.3%, p = 0.0031, 60.1 vs. 86.7%, p = 0.0057 and 5.8 vs. 26.7%, p = 0.002, respectively). Furthermore, HPV16 prevalence in non-vaccinated women 2017-2018 was lower than that in 2008-2010 (16.7 and 34.7%, respectively, p = 0.0471) and similar trends were observed for HPV18 and 11. In both vaccinated and non-vaccinated women, the most common non-quadrivalent-Gardasil® vaccine HR-HPV types were HPV39, 51, 52, 56, and 59. Together they accounted for around 9.8% of cervical cancer cases in Stockholm during 2003-2008, and their prevalence tended to have increased during 2017-2018 compared to 2008-2010. Conclusion: Quadrivalent-Gardasil® vaccination has decreased HPV-vaccine type prevalence significantly. However, non-vaccine HR-HPV types remain high in potentially high-risk women at a youth clinic in Stockholm.

Long intervals between two doses of HPV vaccines and magnitude of the immune response: a post hoc analysis of two clinical trials.

The objective of this analysis was to compare the anti-HPV GMTs and their distribution after a 6-month or a 3-8 -y interval between two HPV vaccine doses. The results from two clinical trials, conducted by the same team in the same region, with serological assays performed at the same laboratory using the same ELISA methodology were compared. In the first study, 173 9-10-y-old girls and boys received two doses of 9vHPV vaccine at a 6-month interval; in the second study, 31 girls vaccinated with one dose of 4vHPV at the age of 9-14 y received a dose of 9vHPV 3-8 y later (mean 5.4 y). In both studies, blood samples were collected before and 1 month post second dose. Despite large differences in the time since the first dose, all subjects (100%) were seropositive to the common 4 HPV types (6, 11, 16 and 18) to both vaccines, with comparable GMTs and titer distributions before the second dose. One month post second dose, the GMTs increased 40-91-fold for those with a 6-month interval between doses and 60-82-fold for those with a 3-8-y interval. Titer distributions after the booster dose were comparable in the two studies. These results indicate that 2-dose HPV vaccination schedules with an interval of several years could be used for pre-adolescents. Intervals longer than 6 months may facilitate logistics for immunization programs and could be useful during periods of vaccine shortage or as a transition while the effectiveness of a one-dose schedule is being evaluated.

Durability of the neutralizing antibody response to vaccine and non-vaccine HPV types 7 years following immunization with either Cervarix® or Gardasil® vaccine.

Bivalent (Cervarix®) and quadrivalent (Gardasil®) Human Papillomavirus (HPV) vaccines demonstrate remarkable efficacy against the targeted genotypes, HPV16 and HPV18, but also a degree of cross-protection against non-vaccine incorporated genotypes, HPV31 and HPV45. These outcomes seem to be supported by observations that the HPV vaccines induce high titer neutralizing antibodies against vaccine types and lower responses against non-vaccine types. Few data are available on the robustness of the immune response against non-vaccine types. We examined the durability of vaccine and non-vaccine antibody responses in a follow up of a head-to-head study of 12-15 year old girls initially randomized to receive three doses of Cervarix® or Gardasil® vaccine. Neutralizing antibodies against both vaccine and non-vaccine types remained detectable up to 7 years following initial vaccination and a mixed effects model was used to predict the decline in antibody titers over a 15 year period. The decline in vaccine and non-vaccine type neutralizing antibody titers over the study period was estimated to be 30% every 5-7 years, with Cervarix® antibody titers expected to remain 3-4 fold higher than Gardasil® antibody titers over the long term. The antibody decline rates in those with an initial response to non-vaccine types were similar to that of vaccine types and are predicted to remain detectable for many years. Empirical data on the breadth, magnitude, specificity and durability of the immune response elicited by the HPV vaccines contribute to improving the evidence base supporting this important public health intervention. Original trial: ClinicalTrials.gov NCT00956553.