Prospective, multi-center post-marketing surveillance cohort study to monitor the safety of the human papillomavirus-16/18 AS04-adjuvanted vaccine in Chinese girls and women aged 9 to 45 years, 2018-2020.

Following the approval of Cervarix for the immunization of girls and women in China against high-risk human papillomavirus types 16 and 18, a non-interventional post-authorization safety study was performed. A multi-center prospective cohort study assessed safety following Cervarix vaccination of Chinese girls and women aged 9-45 years between 31 May 2018 and 3 December 2020. Adverse events following immunization (AEFIs), potential immune-mediated diseases (pIMDs), and pregnancy-related outcomes were collected up to 12 months from the third immunization or 24 months from the first immunization, whichever came first. Among 3,013 women who received 8,839 Cervarix doses, 167 (5.5%) reported ≥ 1 any AEFI, and 22 (0.7%) reported 40 serious AEFIs. During the 30 days after each dose, 147 women (4.9%) reported 211 medically attended AEFIs, including 3 serious AEFIs reported by 1 woman (0.03%). One woman reported a pIMD. Cervarix was inadvertently administered to 65 women (2.2%) within 60 days before conception or during pregnancy. Of these women, 34 (52.3%) gave birth to live infant(s) with no apparent congenital anomalies, and 1 (1.5%) woman gave birth to a live infant with a congenital anomaly. No serious AEFIs or pIMDs were considered to be related to the vaccination. In Chinese women aged 9-45 years, immunization with the Cervarix three-dose schedule was well tolerated. Overall, no safety concerns were identified, although rare adverse events may have been missed due to the study sample size.Clinical trial registration: NCT03438006.

Infection with high-risk human papillomavirus is a prerequisite for cervical cancerCervarix is a human papillomavirus-16/18 AS04-adjuvanted vaccineMulti-centre prospective cohort study to monitor safety of Cervarix immunisationSafety was monitored in 3,013 girls/women aged 9­45 years in China (8,839 doses)Cervarix was well tolerated, and no safety concerns were identified.

MOnitoring human papillomavirus Vaccine effect on Infection and cErvical diseases (MOVIE): Protocol for a cohort study using electronic health records from Yinzhou, China.

Cervical cancer is the fourth most common cancer in women, with a high disease burden worldwide. Human papillomavirus (HPV) vaccination reduces HPV-related infection and associated cervical lesions and cancers. Few studies have explored HPV vaccination impact in real-world settings in China. This study aims to monitor HPV vaccine uptake and its effects on HPV-related diseases, evaluating vaccine effectiveness in a real-world context and complementing clinical trial results. Electronic health records (EHRs) from 2010 to 2020 from the Yinzhou Regional Health Information Platform (YRHIP) will be queried/extracted to identify and monitor HPV vaccine uptake in females aged 9-45 years, and HPV-related screening and prevalence (i.e., cervical HPV infection, cervical intraepithelial neoplasia [CIN] grades 1-3, and cervical cancer) in a cohort of females aged 9-70 years. Cervical cancer screening guidelines and expert consultation will be used for intra-database validation, to determine the best algorithm for identifying HPV-related disease. Pre-launch (2010-2016) and post-launch (2018-2020) periods are predefined. A time trend analysis will be performed to describe the vaccination impact on disease prevalence and, if prerequisite conditions are met, vaccine effectiveness will be computed using logistic regression, adjusting for age, calendar year, history of screening and HPV infection. Cohort study design, outcomes validation, data linkage, and multi-step statistical analyses could provide valuable experience for designing other real-world studies in the future. The study outcomes can help inform policy-makers about uptake and HPV vaccination policy in girls and women in Yinzhou District, and provide insights on progress toward achieving goals set by the World Health Organization.

Effectiveness of maternal immunisation with a three-component acellular pertussis vaccine at preventing pertussis in infants in the United States: Post-hoc analysis of a case-control study using Bayesian dynamic borrowing.

BACKGROUND: Immunisation during pregnancy with a tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) vaccine can protect infants against pertussis between birth and paediatric vaccination. We aimed to estimate the vaccine effectiveness (VE) of third-trimester pregnancy immunisation with the three-component acellular pertussis (Td3ap) vaccine at preventing pertussis in infants <2 months in the United States (US), to support a label update. METHODS: We performed a post-hoc sub-analysis of a case-control study conducted in six US Emerging Infections Program Network states between 2011 and 2014. Our analysis included only cases and controls whose mothers were either vaccinated with Td3ap or did not receive any Tdap vaccine. The association between Td3ap maternal immunisation and pertussis in infants was assessed for US data using a frequentist method with conditional logistic regression. A robustified analysis was conducted using Bayesian dynamic borrowing of non-US data, considering a mixing-weighted prior of 90% for historical non-US VE data, and of 10% for a vague prior. VE was estimated as (1-odds ratio) × 100%. Sensitivity analyses accounting for the impact of each non-US study, different mixing weights and missing/ambiguous data were performed. RESULTS: We included 108 cases and 183 controls. Based on US data, the estimated VE of third-trimester maternal immunisation with Td3ap at preventing pertussis in infants <2 months was 78.0% (95% confidence interval: -38.0; 96.5). VE estimated by Bayesian dynamic borrowing of non-US data (with a 90% weight for historical data) was 83.4% (95% credible interval: 55.7; 92.5); sensitivity analyses produced similar VE estimates. CONCLUSIONS: Effectiveness of third-trimester pregnancy immunisation with Td3ap at preventing infant pertussis in the US is very likely to be ≥ 50% and is most likely âˆ¼ 80%. Bayesian dynamic borrowing of non-US VE data allowed overcoming the limited power (due to small sample size) of a brand-specific sub-analysis by considering additional evidence.

Challenges in synthesis of real-world vaccine effects on meningococcal serogroup B disease for 4CMenB vaccine post-licensure effectiveness studies: A systematic review.

BACKGROUND: Real-world studies on vaccine effects are diverse in terms of objectives, study setting and design, data type and scope, and analysis methods. In this review, we describe and discuss four-component meningococcal serogroup B vaccine (4CMenB vaccine, Bexsero) real-world studies with the aim of synthesizing their findings with application of standard methods. METHODS: We performed a systematic literature review of all real-world studies on 4CMenB vaccine effects on meningococcal serogroup B disease, with no restriction for population age, vaccination schedule and/or type of vaccine effect evaluated (vaccine effectiveness [VE] and vaccine impact [VI] outcomes) published since its licensure in 2013 (from January 2014 until July 2021) in PubMed, Cochrane and the grey literature. We then aimed to synthesize the findings of the identified studies through application of standard synthesis methods. RESULTS: According to reported criteria we retrieved five studies presenting estimates on 4CMenB vaccine effectiveness and impact. These studies showed great diversity in population, vaccination schedule and analysis methods mainly due to diversity in vaccine strategies and recommendations in the study settings. Directed by this diversity, no quantitative pooling methods to synthesize findings could be applied; instead we descriptively assessed study methods. We report VE estimates ranging from 59% to 94% and VI estimates ranging from 31% to 75%, representing diverse age groups, vaccination schedules and analysis methods. CONCLUSION: Both vaccine outcomes showed real-life effectiveness of 4CMenB vaccine despite differences in study methodologies and vaccination strategies. Based on appraisal of study methods, we highlighted the need for an adapted tool which facilitates synthesis of heterogenic real-world vaccine studies when quantitative pooling methods are not applicable.

Investigating Tetanus, Diphtheria, Acellular Pertussis Vaccination During Pregnancy and Risk of Congenital Anomalies.

INTRODUCTION: This observational retrospective matched cohort study evaluated the safety of a prenatal tetanus, diphtheria, acellular pertussis (Tdap) vaccination, Boostrix. We previously reported on the risk of maternal and neonatal outcomes; here we report on the risk of congenital anomalies in infants at birth through 6 months of age. METHODS: The study included pregnant Kaiser Permanente Southern California members. Women who received the Tdap vaccine on or after the 27th week of pregnancy between January 2018 and January 2019 were matched to women who were pregnant between January 2012 and December 2014 and were not vaccinated with Tdap during pregnancy. Unadjusted and adjusted relative risks (aRRs) with 95% confidence intervals were estimated by Poisson regression. Quantitative secular trend analyses, from 2011 to 2017, were conducted on congenital anomalies with a statistically significant aRR > 1. RESULTS: The analysis consisted of 16,350 and 16,088 live-born infants in the Tdap-exposed and unexposed cohorts, respectively. Of the 14 congenital anomaly body systems evaluated, 8 (eye, ear/face/neck, respiratory, upper gastrointestinal, genital, renal, musculoskeletal, integument) had statistically significant elevated aRRs, with point estimates ranging from 1.17 to 2.02. The observed elevated aRRs were consistent with their respective secular increases over time. CONCLUSION: Cautious interpretation of these findings is warranted as these increases may have resulted from improved identification and diagnosis. Furthermore, the biological plausibility of an association between maternal vaccine exposure in the third trimester of pregnancy and birth defects is low. The overall study findings support the safety of maternal immunization with Boostrix during the third trimester of pregnancy. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03463577.

Safety of tetanus, diphtheria, acellular pertussis (Tdap) vaccination during pregnancy.

The objective of this study was to evaluate the safety of prenatal tetanus, diphtheria, acellular pertussis (Tdap) vaccination. This cohort study was conducted among pregnant members at Kaiser Permanente Southern California (KPSC). The exposed cohort consisted of women who received Tdap vaccine on or after the 27th week of pregnancy between January 2018 and January 2019. The unexposed cohort consisted of matched women who were pregnant between January 2012 and December 2014 and were not vaccinated with any Tdap vaccine throughout their pregnancy. Maternal and infant characteristics and pre-specified endpoints were collected through automated data and review of the electronic health records. Unadjusted and adjusted relative risks (aRRs) with confidence intervals (CIs) were estimated by Poisson regression. Non-inferiority testing (i.e., to rule out a two-fold increase) was conducted for primary endpoints with adjustment for multiplicity. Superiority testing was conducted without multiplicity adjustment for secondary endpoints. The analysis consisted of 16,606 pairs of Tdap recipients and unexposed pregnant women. For the primary endpoints, the aRR for preeclampsia/eclampsia was 1.38 (98.75% CI:1.21-1.58) and the aRR for intrauterine infection was 1.28 (98.75% CI:1.12-1.47). These increases were consistent with the background increasing trend of these diagnoses among all pregnant women at KPSC since 2011, and the upper limit of the 98.75% CI of both aRRs did not exceed the pre-specified threshold of 2. No increased risks of small for gestational age (aRR = 1.04, 98.75% CI:0.94-1.16) or preterm delivery (aRR = 0.71, 98.75% CI:0.64-0.78) were observed. No evidence of increased risks for secondary endpoints, including poor fetal growth, preterm pre-labor rupture of membranes, stillbirth/fetal death, placental abruption, transfusion during delivery hospitalization, and neonatal death, was observed. Prenatal Tdap vaccination after the 27th week of pregnancy was not associated with increased risks of pre-specified maternal and infant outcomes, supporting the safety of Tdap vaccination during pregnancy.

Assessing the safety, impact and effectiveness of RTS,S/AS01E malaria vaccine following its introduction in three sub-Saharan African countries: methodological approaches and study set-up.

BACKGROUND: Following a 30-year development process, RTS,S/AS01E (GSK, Belgium) is the first malaria vaccine to reach Phase IV assessments. The World Health Organization-commissioned Malaria Vaccine Implementation Programme (MVIP) is coordinating the delivery of RTS,S/AS01E through routine national immunization programmes in areas of 3 countries in sub-Saharan Africa. The first doses were given in the participating MVIP areas in Malawi on 23 April, Ghana on 30 April, and Kenya on 13 September 2019. The countries participating in the MVIP have little or no baseline incidence data on rare diseases, some of which may be associated with immunization, a deficit that could compromise the interpretation of possible adverse events reported following the introduction of a new vaccine in the paediatric population. Further, effects of vaccination on malaria transmission, existing malaria control strategies, and possible vaccine-mediated selective pressure on Plasmodium falciparum variants, could also impact long-term malaria control. To address this data gap and as part of its post-approval commitments, GSK has developed a post-approval plan comprising of 4 complementary Phase IV studies that will evaluate safety, effectiveness and impact of RTS,S/AS01E through active participant follow-up in the context of its real-life implementation. METHODS: EPI-MAL-002 (NCT02374450) is a pre-implementation safety surveillance study that is establishing the background incidence rates of protocol-defined adverse events of special interest. EPI-MAL-003 (NCT03855995) is an identically designed post-implementation safety and vaccine impact study. EPI-MAL-005 (NCT02251704) is a cross-sectional pre- and post-implementation study to measure malaria transmission intensity and monitor the use of other malaria control interventions in the study areas, and EPI-MAL-010 (EUPAS42948) will evaluate the P. falciparum genetic diversity in the periods before and after vaccine implementation. CONCLUSION: GSK's post-approval plan has been designed to address important knowledge gaps in RTS,S/AS01E vaccine safety, effectiveness and impact. The studies are currently being conducted in the MVIP areas. Their implementation has provided opportunities and posed challenges linked to conducting large studies in regions where healthcare infrastructure is limited. The results from these studies will support ongoing evaluation of RTS,S/AS01E's benefit-risk and inform decision-making for its potential wider implementation across sub-Saharan Africa.

Progression from human papillomavirus (HPV) infection to cervical lesion or clearance in women (18-25 years): Natural history study in the control arm subjects of AS04-HPV-16/18 vaccine efficacy study in China between 2008 and 2016.

BACKGROUND: Cervical cancer is the third most frequent cancer in Chinese women aged 15-44 years old. Human papillomavirus (HPV) is recognized as the main etiologic agent of cervical carcinomas. This study aims to better understand the natural history of HPV infections in Chinese women aged 18-25 years. RESEARCH DESIGN AND METHODS: Data from 3,025 control arm women (AS04-HPV-16/18 vaccine trial) were analyzed to assess the probability of progression or clearance from a 6-month persistent infection (6MPI) to a cervical intraepithelial neoplasia grade 2 or greater (CIN2+), and the association with clinical determinants. Data were analyzed using univariate and multivariable Cox models. RESULTS: A total of 1,324 women with 3,814 HPV infections were included, and 65.7% of the women had at least one 6MPI. Among those 6MPI, 5.0% progressed to CIN2+, while 61.0% cleared within 6 months. The risk of progression from 6MPI to CIN2+ was substantially higher for oncogenic versus non-oncogenic HPV types. CONCLUSIONS: Oncogenic HPV infections showed lower clearance and higher risk to progress to CIN2 +. These findings observed in a population of Chinese women, confirmed previous findings from multinational studies. TRIAL REGISTRATION: The PATRICIA and AS04-HPV-16/18 vaccine trials are registered at ClinicalTrials.gov (NCT00779766 and NCT00122681).

Post-licensure observational safety study after meningococcal B vaccine 4CMenB (Bexsero) vaccination within the routine UK immunisation program.

The study investigated the safety of 4-component meningococcal serogroup B vaccination (4CMenB) in routine care. 4CMenB exposure and seizures, febrile seizures and Kawasaki disease were identified from The Health Improvement Network (THIN) database of UK electronic primary healthcare records, 2015-2018. A self-controlled case series analysis was completed. Anaphylaxis, Guillain-Barré syndrome and acute disseminated encephalomyelitis were secondary outcomes. A total of 107,231 children aged 1-18 months received ≥1 doses of 4CMenB vaccination. Most 4CMenB exposure (93%) was on the same day as other vaccines within a complete national immunisation program stage. With day 0 as day of vaccination, 43 seizures occurred in days 0-6 after 239,505 doses, and 23 febrile seizures occurred in days 0-6, and 4 Kawasaki disease cases in days 1-28 after 194,929 4CMenB doses. Adjusted incidence rate ratios including all 4CMenB exposures were 1.43 (95%CI: 1.02-2.02) for seizures and 1.72 (95%CI: 1.08-2.75) for febrile seizures. There were insufficient cases to model Kawasaki disease, and no cases of the secondary outcomes in risk periods when they may be associated with the vaccination. This study shows few cases of the outcomes after vaccination including 4CMenB with an increased risk of seizures and febrile seizures. It is not possible to attribute the finding to one specific vaccination as the majority of 4CMenB was given with other vaccinations. Trial registration: NA.

Causal inference concepts applied to three observational studies in the context of vaccine development: from theory to practice.

BACKGROUND: Randomized controlled trials are considered the gold standard to evaluate causal associations, whereas assessing causality in observational studies is challenging. METHODS: We applied Hill's Criteria, counterfactual reasoning, and causal diagrams to evaluate a potentially causal relationship between an exposure and outcome in three published observational studies: a) one burden of disease cohort study to determine the association between type 2 diabetes and herpes zoster, b) one post-authorization safety cohort study to assess the effect of AS04-HPV-16/18 vaccine on the risk of autoimmune diseases, and c) one matched case-control study to evaluate the effectiveness of a rotavirus vaccine in preventing hospitalization for rotavirus gastroenteritis. RESULTS: Among the 9 Hill's criteria, 8 (Strength, Consistency, Specificity, Temporality, Plausibility, Coherence, Analogy, Experiment) were considered as met for study c, 3 (Temporality, Plausibility, Coherence) for study a, and 2 (Temporary, Plausibility) for study b. For counterfactual reasoning criteria, exchangeability, the most critical assumption, could not be tested. Using these tools, we concluded that causality was very unlikely in study b, unlikely in study a, and very likely in study c. Directed acyclic graphs provided complementary visual structures that identified confounding bias and helped determine the most accurate design and analysis to assess causality. CONCLUSIONS: Based on our assessment we found causal Hill's criteria and counterfactual thinking valuable in determining some level of certainty about causality in observational studies. Application of causal inference frameworks should be considered in designing and interpreting observational studies.

Meta-analysis of the risk of autoimmune thyroiditis, Guillain-Barré syndrome, and inflammatory bowel disease following vaccination with AS04-adjuvanted human papillomavirus 16/18 vaccine.

PURPOSE: To assess the risk of three autoimmune diseases - autoimmune thyroiditis (AIT), Guillain-Barré syndrome (GBS), and inflammatory bowel disease (IBD) - in females following AS04-HPV-16/18 vaccination. METHODS: This meta-analysis included data from 18 randomized controlled trials, one cluster-randomized trial, two large observational retrospective cohort studies, and one case-control study. Following vaccination, a risk window of 2 years was defined for AIT and IBD and 42 days for GBS. Odds ratios (ORs) were estimated using three methods: meta-analysis inverse-variance with continuity correction (primary analysis), pooled estimate, and beta-binomial regression. RESULTS: In all studies apart from the case-control study, 154 398 exposed and 1 504 322 non-exposed subjects were included, among whom there were 141 and 1972 cases of (autoimmune) thyroiditis; 2 and 2 cases of GBS; and 43 and 401 cases of IBD, respectively. In the case-control study, there were 97 cases of AIT and 13 of GBS; matched with 802 and 130 controls, respectively. The primary analysis OR estimates were 1.46 (95% confidence interval [CI] 1.22-1.76), 11.14 (2.00-61.92), and 1.11 (0.75-1.66) for (autoimmune) thyroiditis, GBS, and IBD, respectively. CONCLUSIONS: This meta-analysis did not show an increased risk of IBD following vaccination with AS04-HPV-16/18. The 1.5-fold increased risk of (autoimmune) thyroiditis does not allow us to conclude about a causal association. For GBS, the very low number of cases and wide 95% CIs negate any firm conclusion.

Erratum to: Prevalence and Incidence of Human Papillomavirus (HPV) Infection Before and After Pregnancy: Pooled Analysis of the Control Arms of Efficacy Trials of HPV-16/18 AS04-Adjuvanted Vaccine.

[This corrects the article DOI: 10.1093/ofid/ofz486.].

Risk of herpes zoster in the Japanese population with immunocompromising and chronic disease conditions: Results from a claims database cohort study, from 2005 to 2014.

Older adults, women and patients with immunocompromised (IC) or chronic medical conditions have a higher incidence of herpes zoster (HZ) and are at higher risk of developing HZ-associated complications such as postherpetic neuralgia. The incidence rates of HZ in various IC and chronic conditions have been previously reported in a retrospective cohort study using claims data from Japanese adults. Here, we report further analyses from this cohort using univariate and multivariable Cox regression to estimate crude and adjusted hazard ratios (HRs) associated with different IC and chronic conditions. After adjusting for multiple covariates (age, sex and other coexisting medical conditions), the risk of HZ was higher in women (HR, 1.14 [95% CI, 1.11-1.17]), irrespective of age and increased with increasing age, being substantially higher in patients aged 65 years or older (HR, 3.28 [95% CI, 3.07-3.49]) when compared with those aged 18-29 years. The highest HRs were observed for the following specific IC conditions; hematopoietic stem cell transplant recipients (HR, 9.85 [95% CI, 6.80-14.28]), hematological malignancy (HR, 3.22 [95% CI, 2.54-4.09]), systemic lupus erythematosus (HR, 2.46 [95% CI, 1.45-4.15]) and inflammatory bowel disease (HR, 1.59 [95% CI, 1.14-2.21]). For most other IC and chronic medical conditions, a higher risk was also apparent though of a smaller magnitude (HRs ranging from 1.2 to <1.5). These results corroborate our previous findings and demonstrate an increased risk of HZ associated with different IC and chronic conditions.

Hepatitis B virus infection and the risk of liver disease progression in type 2 diabetic patients with potential nonalcoholic fatty liver disease: a retrospective, observational, cohort study in the United Kingdom Clinical Practice Research Datalink.

OBJECTIVE: Assess the risk of progression to cirrhosis and hepatocellular carcinoma (HCC) due to hepatitis B virus (HBV)-infection in patients with nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM). METHODS: Retrospective cohort study in the UK Clinical Practice Research Datalink with three cohorts: subjects with T2DM and HBV infection (T2DM+HBV cohort; N = 297), with T2DM without HBV-infection (T2DM cohort; N = 261 865), and with HBV-infection without T2DM (HBV cohort; N = 3630). Primary analyses were performed on the three cohorts and secondary analyses on subcohorts including patients with NAFLD diagnosis code (N = 6599). Case/outcome definitions were formulated with International Classification of Diseases/Read codes/laboratory results and classified using validated algorithms. Adjusted incidence rate ratios (IRR) were estimated with a Poisson regression model. RESULTS: When comparing the T2DM+HBV and T2DM cohorts, adjusted IRRs were 14.06 (95% confidence interval: 4.47-44.19) for cirrhosis and 2.83 (1.06-7.55) for HCC. When comparing the T2DM+HBV and HBV cohorts, adjusted IRRs were 0.68 (0.21-2.27) for cirrhosis and 1.39 (0.46-4.20) for HCC. No cirrhosis cases were identified in T2DM+NAFLD+HBV patients; IRs were 16.92/10 000 person-years (12.97-21.69) and 85.24/10 000 person-years (10.32-307.91) in the T2DM+NAFLD and NAFLD+HBV cohorts. CONCLUSION: HBV-infection increased significantly the risk for cirrhosis among T2DM patients, however, not beyond the expected incremental risk among infected non-T2DM subjects. Our approach to evaluate the role of T2DM/NAFLD and HBV-infection in liver disease progression could be applied to other settings with higher HBV prevalence.

Prevalence and Incidence of Human Papillomavirus (HPV) Infection Before and After Pregnancy: Pooled Analysis of the Control Arms of Efficacy Trials of HPV-16/18 AS04-Adjuvanted Vaccine.

OBJECTIVE: Data on human papillomavirus (HPV) prevalence around pregnancy were inconsistent. We assessed HPV prevalence before and after pregnancy, HPV incidence after pregnancy, and risk factors for HPV infection. METHOD: Data from 15 754 women in control arms of 5 AS04-HPV-16/18 vaccine efficacy trials were analyzed, including 3001 women with at least 1 pregnancy. Results of HPV deoxyribonucleic acid testing on cervical samples were available. We analyzed risk factors, including age, region, pregnancy and its outcomes, duration from pregnancy resolution to collection of first postresolution cervical sample, previous HPV infection, cigarette smoking, and number of sexual partners with Cox regression. RESULTS: Prevalence of high-risk oncogenic (hr)-HPV types was similar before and after pregnancy (20.8% vs 19.8%). Incidence of hr-HPV was 40.1 per 1000 person-years (95% confidence interval [CI], 23.4-64.2) at 0-3 months, 266.7 (95% CI, 217.4-323.7) at 3-6 months, and 95.7 (95% CI, 83.9-108.7) at >6 months after pregnancy. Risk factors associated with HPV infection after pregnancy are previous HPV infection, elective abortion, and younger age at pregnancy resolution. CONCLUSIONS: Pregnancy could not be confirmed as a risk factor for HPV infection in this population despite an increased incidence detected 3-6 months after pregnancy resolution. Most women remained HPV negative after pregnancy. CLINICAL TRIAL REGISTRATION: NCT001226810 (HPV-008 trial), NCT00294047 (HPV-015 trial), NCT00316693 and NCT00929526 (HPV-032/063 trials), and NCT00779766 (HPV-039 trial).

Risk of newly detected infections and cervical abnormalities in adult women seropositive or seronegative for naturally acquired HPV-16/18 antibodies.

BACKGROUND: Infections with human papillomavirus (HPV) types 16 and 18 account for ~70% of invasive cervical cancers but the degree of protection from naturally acquired anti-HPV antibodies is uncertain. We examined the risk of HPV infections as defined by HPV DNA detection and cervical abnormalities among women >25 years in the Human Papilloma VIrus Vaccine Immunogenicity ANd Efficacy trial's (VIVIANE, NCT00294047) control arm. METHODS: Serum anti-HPV-16/18 antibodies were determined at baseline and every 12 months in baseline DNA-negative women (N = 2687 for HPV-16 and 2705 for HPV-18) by enzyme-linked immunosorbent assay (ELISA) from blood samples. HPV infections were identified by polymerase chain reaction (PCR) every 6-months, and cervical abnormalities were confirmed by cytology every 12 months. Data were collected over a 7-year period. The association between the risk of type-specific infection and cervical abnormalities and serostatus was assessed using Cox proportional hazard models. RESULTS: Risk of newly detected HPV-16-associated 6-month persistent infections (PI) (hazard ratio [HR] = 0.56 [95%CI:0.32; 0.99]) and atypical squamous cells of undetermined significance (ASC-US+) (HR = 0.28 [0.12; 0.67]) were significantly lower in baseline seropositive vs baseline seronegative women. HPV-16-associated incident infections (HR = 0.81 [0.56; 1.16]) and 12-month PI (HR = 0.53 [0.24; 1.16]) showed the same trend. A similar trend of lower risk was observed in HPV-18-seropositive vs -seronegative women (HR = 0.95 [0.59; 1.51] for IIs, HR = 0.43 [0.16; 1.13] for 6-month PIs, HR = 0.31 [0.07; 1.36] for 12-month PIs, and HR = 0.61 [0.23; 1.61] for ASC-US+). CONCLUSIONS: Naturally acquired anti-HPV-16 antibodies were associated with a decreased risk of subsequent infection and cervical abnormalities in women >25 years. This possible protection was lower than that previously reported in 15- to 25-year-old women.

Human Papillomavirus (HPV) Vaccine Effectiveness and Potential Herd Immunity for Reducing Oncogenic Oropharyngeal HPV-16 Prevalence in the United Kingdom: A Cross-sectional Study.

BACKGROUND: Oropharyngeal cancer incidence is rapidly rising due to human papillomavirus (HPV) type 16 infection. The dearth of data on effectiveness of national female-only vaccination programs in preventing oral HPV infection and potential herd immunity in unvaccinated males has resulted in considerable controversy regarding the need to vaccinate males, especially in countries with high female vaccination coverage. METHODS: Subjects aged 0-65 years undergoing tonsillectomy for nonmalignant indications were recruited in 6 hospitals in the United Kingdom. Oral samples were collected as follows: oral rinse, tongue base, and pharyngeal wall brushes, then tonsil tissue (tonsillectomy). Vaccination data were obtained from regional health authorities. All samples were centrally tested for HPV DNA by polymerase chain reaction. RESULTS: Of 940 subjects, 243 females and 69 males were aged 12-24 years (median age, 18.6 years), with 189 (78%) females and no males vaccinated against HPV. Overall, oropharyngeal HPV-16 prevalence was significantly lower in vaccinated versus unvaccinated females (0.5% vs 5.6%, P = .04). In contrast, prevalence of any oropharyngeal HPV type was similar in vaccinated and unvaccinated females (19% vs 20%, P = .76). Oropharyngeal HPV-16 prevalence in unvaccinated males was similar to vaccinated females (0% vs 0.5%, P > .99), and lower than unvaccinated females (0% vs 5.6%, P = .08). CONCLUSIONS: Our findings indicate that the UK female-only vaccination program is associated with significant reductions in oropharyngeal HPV-16 infections. These are also the first data to suggest potential herd immunity from female-only vaccination against oropharyngeal HPV infection in contemporaneously aged males.

Burden of Herpes Zoster in the Japanese Population with Immunocompromised/Chronic Disease Conditions: Results from a Cohort Study Claims Database from 2005-2014.

INTRODUCTION: The aim of this study is to describe the disease burden and costs of herpes zoster (HZ) in the general adult Japanese population or patients with immunocompromised (IC) conditions or chronic disorders. METHODS: A retrospective cohort study of individuals aged 18-74 years was conducted using January 2005 to December 2014 records from the Japan Medical Data Center claims database. Twenty-eight IC conditions and chronic disorders were defined by diagnosis codes and/or procedures/treatments. HZ and its related complications were identified. Incidence rates (IR), frequency of HZ-related complications, healthcare resource utilization (HRU), and direct medical costs were estimated. HRU and costs were estimated on a subcohort of HZ cases occurring April 2012-January 2014. RESULTS: The overall IR of HZ in the total cohort of 2,778,476 adults was 4.92/1000 person-years (PY) [95% confidence interval (CI): 4.86-4.98] and increased with age. The IR in the IC cohort (51,818 subjects) was 8.87/1000 PY (95% CI: 8.29-9.48), ranging from 5.55/1000 PY (95% CI: 4.26-7.09) in psoriasis to 151.68/1000 PY (95% CI: 111.45-201.71) in hematopoietic stem cell transplant recipients; most IRs were in the range 6-10/1000 PY. The IRs in individuals with chronic disorders were also relatively high, in the range 5.40-12.90/1000 PY. The frequency of postherpetic neuralgia was 4.01% (95% CI: 3.72-4.33) in the total cohort and 11.73% (95% CI: 9.01-14.93) in the IC cohort. The mean [standard deviation (SD)] number of outpatient visits was 3.4 (4.9) and 5.0 (5.7), respectively, and the proportion of HZ patients hospitalized was 2.20% and 6.70%, respectively. The mean (SD) direct medical cost per HZ episode was ¥34,664 (¥54,433) and ¥55,201 (¥92,642) in the total and IC cohort, respectively. CONCLUSIONS: The elevated burden of HZ in Japanese individuals harboring IC conditions and chronic disorders documented in our study underlines the need for prevention of HZ in people with these conditions. FUNDING: GlaxoSmithKline Biologicals SA.

Effectiveness of the Oral Human Attenuated Rotavirus Vaccine: A Systematic Review and Meta-analysis-2006-2016.

BACKGROUND: Gastroenteritis caused by rotavirus accounts for considerable morbidity in young children. We aimed to assess the vaccine effectiveness (VE) of the oral rotavirus vaccine Rotarix, as measured by laboratory-confirmed rotavirus infection after referral to hospital and/or emergency departments in children aged <5 years with gastroenteritis. METHODS: We performed a systematic search for peer-reviewed studies conducted in real-life settings published between 2006 and 2016 and a meta-analysis to calculate the overall Rotarix VE, which was further discriminated through stratified analyses. RESULTS: The overall VE estimate was 69% (95% confidence interval [CI], 62% to 75%); stratified analyses revealed a non-negligible impact of factors such as study design and socioeconomic status. Depending on the control group, VE ranged from 63% (95% CI, 52% to 72%) to 81% (95% CI, 69% to 88%) for unmatched and matched rotavirus test-negative controls. VE varied with socioeconomic status: 81% (95% CI, 74% to 86%) in high-income countries, 54% (95% CI, 39% to 65%) in upper-middle-income countries, and 63% (95% CI, 50% to 72%) in lower-middle-income countries. Age, rotavirus strain, and disease severity were also shown to impact VE, but to a lesser extent. CONCLUSIONS: This meta-analysis of real-world studies showed that Rotarix is effective in helping to prevent hospitalizations and/or emergency department visits due to rotavirus infection.

Impact of history of febrile convulsions on the risk difference of febrile convulsions with the tetravalent measles-mumps-rubella-varicella vaccine: Post-hoc exploratory analysis of results from a matched-cohort study.

This post-hoc analysis of data from a matched cohort study investigated the risk of febrile convulsions (FC) 5-12 days post-first dose of measles-mumps-rubella-varicella vaccine (MMRV) in a low-risk population, compared to measles-mumps-rubella (MMR) and varicella (V) vaccines administered separately. The low-risk population excluded children with personal history of FC (Scenario 1) and children with personal or/and family history (≥1 parent/sibling) of FC (Scenario 2). Incidence of FC post-MMRV in Scenario 2 (excluding at risk children) (36.3-49.5/100,000) and post-MMR+V in the whole cohort including children with personal/family history of FC (43.6/100,000) were similar. The risk difference of FC increased by 0.2 case/100,000 in Scenario 1 and decreased by 5.3-8.6 cases/100,000 of vaccinated children in Scenario 2, compared to the whole cohort. The overall risk of FC post-first dose MMRV vaccination could be lowered by administering MMRV only to children with no personal or family history of FC.