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Background The first HPV‐vaccine eligible cohorts in the Netherlands will enter the cervical screening program in 2023. However, a substantial number of young women already have had a cervical sample taken before entry into the regular screening program. This study was initiated to explore early effects of HPV vaccination on detection of cytological abnormalities in cervical samples of women younger than the screening age. Methods Results of cervical samples were obtained from the Dutch National Pathology Databank (PALGA) and were linked to the women's HPV vaccination status from the national vaccination registry (Praeventis) (N = 42,171). Occurrence of low‐grade and high‐grade squamous intraepithelial lesions or worse (LSIL and HSIL+) and high‐risk HPV positive tests (hrHPV) in the first cervical sample were compared between vaccinated and unvaccinated women by multivariable logistic regression analysis, corrected for age at cervical sampling and age of vaccination (12/13 years, ≥ = 14 years). Results For fully vaccinated women (three‐ or two‐dose schedule), statistically significant reductions were seen for all outcomes compared to unvaccinated women (hrHPV: adjusted OR, 0.70, 95% CI, 0.63–0.79; LSIL: 0.70, 0.61–0.80; HSIL+: 0.39, 0.30–0.51). Conclusions By linking nation‐wide registries on pathology and vaccination, we show significant beneficial early effects of HPV‐vaccination on LSIL, HSIL+, CIN3/AIS/carcinoma and hrHPV detection in young women upto 24 years of age who have a cervical sample taken before entry into the cervical cancer screening program. By linking nation‐wide registries on pathology and vaccination, marked reductions in low‐grade (LSIL) and high‐grade (HSIL) cytological cervical abnormalities were found in young women up to 24 years of age who were fully vaccinated against HPV and did have a cervical sample taken before entry into the cervical cancer screening program.

Initially approved as a three-dose regimen, evolving evidence has supported the efficacy of reduced-dose schedules. Single-dose HPV vaccine data among males remain scarce. This study assesses the persistence of antibodies against HPV16/18 following a single HPV vaccine dose and the immune response to a subsequent delayed dose administered at least three years later in girls and boys. This single-group descriptive study involved youth from the Quebec City area, Canada, who received a single dose of 4vHPV (girls) or 9vHPV (boys) as part of the public school-based vaccination program. A blood sample was collected 3–10 years post-initial vaccination. Girls and boys then received one 9vHPV or 2vHPV booster dose, respectively, and had a second blood draw one month later. Serological assays were conducted using M9ELISA. Four years after the initial 9vHPV dose, among 141 boys aged 12 to 14 years 96.5 % and 97.9 % had detectable antibodies against HPV16 and HPV18, respectively. Among girls aged 13 to 24 years vaccinated 3–10 years prior with one 4vHPV dose, 95.0 % (HPV16) and 93.3 % (HPV18) had detectable antibodies. One-month post-second dose administration, all participants were seropositive for HPV16/18, with significant increases in geometric mean concentrations (GMCs). A single dose induces a strong and lasting immune response in girls (4vHPV) and boys (9vHPV), with a significant antibody anamnestic boost following a second dose administered several years later. These findings indicate the potential for a single-dose or a delayed booster strategy in both sexes, and support studies showing effectiveness of single-dose schedules. The study is registered with ClinicalTrials.gov (NCT 03431246). •Single-dose HPV vaccination induces long-lasting immunogenicity in boys and girls.•High antibody persistence for HPV16/18 observed up to 3–10 years after one dose.•Delayed bivalent or nonavalent HPV booster dose increases antibody concentrations.•The study shows the potential for a single-dose or a delayed booster strategy.

Background Most European countries offer human papillomavirus (HPV) vaccination through organised immunisation programmes, but the choice of vaccine varies. We compared the expected health and economic effects of the currently used bivalent vaccine, targeting HPV-16/18, and the nonavalent vaccine, targeting seven additional genotypes, for the Netherlands. Methods We estimated the incremental impact of nonavalent versus bivalent vaccination in a cohort of 100,000 girls and 100,000 boys offered vaccination at age 10, by projecting type-specific infection risk reductions onto expected number of cervical screening outcomes, HPV-related cancers, and treatments for anogenital warts and recurrent respiratory papillomatosis (RRP). In the base-case, we assumed two-dose vaccination with 60% uptake, lifelong partial cross-protection against HPV-31/33/45 for the bivalent vaccine and EUR 25 extra cost per dose for the nonavalent vaccine. Cost-effectiveness was assessed from a healthcare provider perspective by comparing the incremental cost-effectiveness ratio (ICER) per life-year gained (LYG) with the Dutch threshold of EUR 20,000/LYG. Results Compared with bivalent vaccination, nonavalent vaccination prevents an additional 1320 high-grade cervical lesions, 70 cancers, 34,000 anogenital warts episodes and 30 RRPs and generates EUR 4.1 million discounted savings from fewer treatments. The ICER is EUR 5489 (95% credible interval: 3765; 7019)/LYG in the base-case and exceeds the cost-effectiveness threshold only if the cross-protection for the bivalent vaccine extends permanently to non-31/33/45 genotypes or if the vaccine efficacy wanes past age 20 for both vaccines. Conclusions Sex-neutral vaccination with the nonavalent vaccine is likely to be cost-effective. Long-term monitoring of type-specific vaccine effectiveness is essential because of the impact of cross-protection and waning efficacy on cost-effectiveness.

Treatment of anogenital warts (AGWs) is challenging. Candida antigen immunotherapy has been proven to be a safe and relatively effective therapeutic modality; nevertheless, some patients may experience a partial or no response. Combining Candida antigen with other immunotherapies has been proposed to improve the cure rate. Immunotherapy with human papillomavirus (HPV) vaccines has been tried with conflicting outcomes. This study aimed to  assess the efficacy and safety of intralesional Candida antigen, either alone or in combination with intralesional bivalent or quadrivalent HPV vaccines, for treating multiple AGWs. Eighty patients with multiple AGWs were included and randomly assigned to four equal groups: group A treated with intralesional Candida antigen only; group B treated with intralesional bivalent HPV vaccine (Cervarix) and Candida; group C treated with intralesional quadrivalent HPV vaccine (Gardasil) and Candida; and group D (control) treated with intralesional saline. Complete clearance of lesions was detected in 40%, 20%, and 60% of patients in Candida monotherapy, Cervarix/Candida, and Gardasil/Candida groups, respectively, whereas 40%, 60%, and 20% of patients in the three groups, respectively, showed partial response. Only 10% of the control group had a partial response. Therapeutic outcomes were significantly better in the three treatment groups compared to the control group, with no statistically significant difference between the Candida monotherapy group and the combination groups, but the response was significantly better in the Gardasil/Candida group than in the Cervarix/Candida group. No statistically significant difference was found between the studied groups regarding the development of side effects. Moreover, no recurrence was detected in any of the groups throughout the 3-month follow-up period.  Based on our results, combining intralesional HPV vaccines with Candida antigen immunotherapy may have no significant benefit for treating multiple AGWs. Candida antigen may be recommended as a relatively effective and inexpensive therapeutic modality. The combination of Gardasil and Candida was also effective but very expensive. The results of the Cervarix/Candida combination were unsatisfactory.  This clinical trial was registered and approved prospectively by the ethical review board at Faculty of Medicine, Zagazig University.

This longitudinal cohort study describes the kinetics in antibody levels after two doses of the bivalent human papillomavirus (HPV) vaccine in girls (birth cohort 2001) vaccinated in the routine Dutch vaccination program at 12 years of age, up to 7.5 years post-vaccination. Also, the antibody response one month post-vaccination of the first cohort of boys (birth cohort 2012, vaccinated at 10 years of age) eligible for HPV vaccination in the Netherlands is presented. Blood samples and questionnaire data were collected of girls and boys. HPV type-specific antibody concentrations (LU/mL) against HPV16/18/31/33/45/52/58 were assessed using a validated virus-like particle (VLP) multiplex immunoassay. For girls, antibody decays over time were modelled using the modified power-law decay model and the exponential decay model. The Geometric Mean Concentrations (GMCs) remained higher for HPV16/18 than for HPV types 31, 33, 45, 52, and 58 among girls up to 7.5 years post-vaccination. The antibody levels of HPV16 and HPV18 reached plateau values of 482 and 159 LU/mL, respectively. Mathematical modelling showed that the half-life values of HPV16/18 were 2.4- to 4.5-fold higher compared with the half-life values of the other HPV types. Among boys (aged 10 years), the GMC for HPV16 was significantly higher than among girls one month post-vaccination (aged 12 years). The GMCs of all HPV types declined over time, although the GMCs of HPV16/18 remained relatively high up to 7.5 years post-vaccination. The GMCs for HPV16/18 among boys were at least equally high as the GMCs among girls at one month post-vaccination. Further follow-up of the cohort of boys is needed to gain knowledge on long-term immune responses of young boys following bivalent HPV vaccination.

The 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. Immunogenicity 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. By 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. The 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.

In 2013, the Netherlands Pharmacovigilance Center Lareb published an overview of reports of long-lasting fatigue following bivalent HPV-vaccination (2vHPV). After an update of this overview in 2015, concerns regarding the safety of 2vHPV was picked up by the media, which led to further reports of long-lasting fatigue. Therefore, the Dutch National Institute for Public Health and the Environment (RIVM) investigated a possible association between HPV-vaccination and long-term fatigue. In this retrospective cohort study conducted in the Integrated Primary Care Information database, we investigated the occurrence of chronic fatigue syndrome (CFS), fatigue ≥6 months and 3–6 months in all girls born in 1991–2000 during the follow-up period January 1st 2007-December 31st 2014 (2007–2008 pre-vaccination and 2009–2014 post-vaccination). Patients with certain fatigue ≥6 m were asked for consent to link their primary care information with vaccination data. Incidence rates per 10,000 person years (PY) for 12–16-year-old girls were compared between pre- and post-HPV-vaccine era. A self-controlled case series (SCCS) analysis was performed using consenting vaccinated cases. A primary high-risk period of 12 months after each dose was defined. The cohort consisted of 69,429 12–16-year-old girls accounting for 2758 PY pre-vaccination and 57,214 PY post-vaccination. Differences between pre- and post-vaccination incidences (CFS: 3.6 (95% CI 0.5–25.7)/10,000 PY and 0.9 (0.4–2.1); certain fatigue ≥6 m: 7.3 (1.8–29.0) and 19.4 (16.1–23.4); certain fatigue 3–6 m: 0.0 and 16.6 (13.6–20.3), respectively) were not statistically significant. SCCS analyses in 16 consenting vaccinated cases resulted in an age-adjusted RR of 0.62 (95%CI 0.07–5.49). Fatigue ≥6 m and 3–6 m was frequently found among adolescent girls, but CFS was rarely diagnosed. No statistically significant increased incidence rates were found post-vaccination compared to similar age groups of girls pre-vaccination. The SCCS analysis included a low number of cases but revealed no elevated risk of certain fatigue ≥6 m in the high-risk period.

Demyelinating optic neuritis (DON) is a rare but sight-threatening ophthalmic condition which occasionally occurs after human papilloma virus (HPV) vaccination. We herein report a case of previously healthy 13-year-old girl who developed a bilateral refractory DON three days after the first dose of bivalent HPV vaccine. The patient experienced bilateral severe visual loss three days after HPV vaccination, and her vision was quickly deteriorated to no light perception one day after the onset of DON. Ophthalmic examination revealed sluggish pupillary light reflex and swollen optic disc in both eyes, and an emergent orbital MRI examination revealed bilateral hyperintensity and enlargement of the intraorbital optic nerve with contrast enhancement. Serological tests for aquaporin-4 IgG antibody, myelin oligodendrocyte glycoprotein IgG antibody, and other common autoantibodies were all negative. The patient showed poor response to 10 days of intravenous methylprednisolone pulse therapy (500 mg, 250 mg, and 125 mg twice per day for 4, 4, and 2 days, respectively). Hence, three-dosed subcutaneous satralizumab was used in the acute stage of DON as an adjunct therapy. Her vision gradually improved after satralizumab therapy, and increased to 20/20 and 20/32 in the right and left eye at the 3-month follow-up. To the best of our knowledge, this is the first case report of satralizumab therapy in the AQP-4 Ab and MOG-Ab dual seronegative isolated DON. Our study indicates that satralizumab may be a safe and efficient adjunct therapy which can be used in the acute stage of the refractory DON poorly responding to steroid pulse therapy.

•First comparison of the immunogenicity of the bivalent and the quadrivalent human papillomavirus (HPV) vaccines in a population of adolescent girls involved in an organized vaccination programme.•Both HPV vaccines induced the production of neutralizing antibody (NAb) to HPV31 and HPV45, besides NAbs to HPV16 and HPV18.•The bivalent HPV vaccine induced significantly higher HPV16 and HPV18 NAb titres than the quadrivalent HPV vaccine.•The bivalent HPV vaccine induced significantly more frequently and at higher titre HPV31 and HPV45 cross-NAbs than the quadrivalent HPV vaccine. Aim of this investigator-initiated study was to evaluate and compare the titres of neutralizing and cross-neutralizing antibodies (NAbs) induced by the bivalent (Cervarix®) and quadrivalent (Gardasil®) HPV vaccines in a cohort of girls aged 11–13 years from organized vaccination programmes. To this aim, HPV16 and HPV18 NAbs were measured by pseudovirion-based neutralization assays in serum collected at 1–6 months after the third vaccine dose in 107 girls vaccinated with Cervarix® and 126 vaccinated with Gardasil®, while HPV31 and HPV45 cross-NAbs were tested in the first 50 consecutive girls of both vaccine groups. The results of this study demonstrated that all vaccinated girls developed HPV16 and HPV18 NAbs, with the exception of two Gardasil® vaccinees with undetectable HPV18 NAbs. Geometric mean titres (GMTs) of both HPV16 and HPV18 NAbs were significantly higher in Cervarix® than in Gardasil® vaccinees [HPV16 NAb GMT 22,136 (95% CI, 18,811–26,073) vs 5092 (4230–6151), respectively; P<0.0001; HPV18 NAb GMT 11,962 (9536–14,363) vs 1804 (1574-2110), respectively; P<0.0001]. Cross-NAbs to HPV31 and HPV45 were detected more frequently Cervarix® (HPV31 NAb positivity rates 92.7% and 36%, respectively; P<0.05) than in Gardasil® vaccinees (HPV45 NAb positivity rates 56% and 6%, respectively; P<0.0001). The titres of cross-NAbs against HPV31 and HPV45 were also significantly higher in Cervarix® than in Gardasil® vaccinees [HPV31 NAb GMT 157.2 (95% CI, 92–269) vs 13.0 (6.5–25.8), respectively; P<0.0001; HPV45 NAb GMT 4.7 (2.1–10.2) vs 1.3 (0.3–3.1), respectively; P<0.01]. In conclusion, in adolescent girls vaccinated within organized vaccination programmes, HPV vaccines drive the generation not only of NAbs to HPV vaccine types, but also of cross-NAbs. The bivalent vaccine induced significantly higher HPV16 and HPV18 NAb titres and more frequently and at higher titre HPV31 and HPV45 cross-NAbs than the quadrivalent vaccine.

Variable intralesional immunotherapies have recently been proposed as a means of achieving a successful eradication of recurrent and recalcitrant human papillomavirus (HPV)-induced cutaneous and anogenital warts. The bivalent HPV vaccine is one of the newly proposed immunotherapeutic agents. We investigated the role of interleukin-4 (IL-4) and interferon-gamma (IFN-γ) as ex vivo immunologic predictors to estimate the response to the bivalent HPV vaccine as a potential immunotherapy for cutaneous and anogenital warts. Heparinized blood samples were withdrawn from forty patients with multiple recurrent recalcitrant cutaneous and anogenital warts and forty matched healthy control subjects. Whole blood cultures were prepared with and without bivalent HPV vaccine stimulation. Culture supernatants were harvested and stored for IL-4 and IFN-γ measurements using an enzyme-linked immunosorbent assay. A comparative analysis of IL-4 and IFN-γ levels in culture supernatants revealed a non-significant change between the patient and control groups. The bivalent HPV vaccine stimulated cultures exhibited a non-significant reduction in IL-4 levels within both groups. IFN-γ was markedly induced in both groups in response to bivalent HPV vaccine stimulation. The bivalent HPV vaccine can give a sensitive IFN-γ immune response ex vivo, superior to IL-4 and sufficient to predict both the successful eradication of HPV infection and the ultimate clearance of cutaneous and anogenital warts when the bivalent HPV vaccine immunotherapy is applied.