Real-world impact and effectiveness of the quadrivalent HPV vaccine: an updated systematic literature review.

INTRODUCTION: Human papillomavirus (HPV) infection, which poses significant disease burden, is decreasing following implementation of vaccination programs. Synthesized evidence on HPV vaccine real-world benefit was published in 2016. However, long-term impact of vaccination, and how vaccination programs influence infection rates and disease outcomes, requires further examination. AREAS COVERED: We systematically reviewed observational studies on HPV vaccination within MEDLINE, EMBASE, and Google Scholar from 2016 to 2020, involving 14 years of follow-up data. We identified 138 peer-reviewed publications reporting HPV vaccine impact or effectiveness. Outcomes of interest included rates of infection at different anatomical sites and incidence of several HPV-related disease endpoints. EXPERT OPINION: The expansion of HPV vaccination programs worldwide has led to a reduction in genital infection and significant decreases in incidence of HPV-related disease outcomes. Therefore, the WHO has set goals for the elimination of cervical cancer as a public health concern. To track progress toward this requires an understanding of the effectiveness of different vaccination initiatives. However, the impact on males, and potential benefit of gender-neutral vaccination programs have not been fully explored. To present an accurate commentary on the current outlook of vaccination and to help shape policy therefore requires a systematic review of available data.

Real-world impact and effectiveness assessment of the quadrivalent HPV vaccine: a systematic review of study designs and data sources.

INTRODUCTION: Vaccine effectiveness and impact studies are typically observational, generating evidence after vaccine launch in a real-world setting. For human papillomavirus (HPV) vaccination studies, the variety of data sources and methods used is pronounced. Careful selection of study design, data capture and analytical methods can mitigate potential bias in such studies. AREAS COVERED: We systematically reviewed the different study designs, methods, and data sources in published evidence (1/2007-3/2020), which assessed the quadrivalent HPV vaccine effectiveness and impact on cervical/cervicovaginal, anal, and oral HPV infections, anogenital warts, lesions in anus, cervix, oropharynx, penis, vagina or vulva, and recurrent respiratory papillomatosis. EXPERT OPINION: The rapid growth in access to real-world data allows global monitoring of effects of different public health interventions, including HPV vaccination programs. But the use of data which are not collected or organized to support research also underscore a need to develop robust methodology that provides insight of vaccine effects and consequences of different health policy decisions. To achieve the WHO elimination goal, we foresee a growing need to evaluate HPV vaccination programs globally. A critical appraisal summary of methodology used will provide timely guidance to researchers who want to initiate research activities in various settings.

Evaluation of Heterologous Effects of Travel Vaccines in Colorectal Cancer: A Database Study and a Cautionary Tale.

Background and Aims: Recently, cholera vaccine use was shown to be associated with a reduced risk of death in patients with colorectal cancer (CRC). However, evidence on heterologous effects of travel vaccines is limited. The aim of this study was to study heterologous effects of travel vaccines in patients with CRC. Methods: We performed a retrospective database study on a cohort of CRC patients in Sweden and their postdiagnostic use of travel medications between July 2005 and December 2017. We obtained data from national registries on number of CRC diagnosis, death from CRC or other causes, age at diagnosis, and postdiagnostic use of travel vaccines and malaria prophylaxis. The Cox regression model was used to calculate incidence rate and incidence rate ratios of CRC-related and all-cause mortality by postdiagnostic travel medication status. Results: Two hundred ninety-five patients exposed to travel vaccines and malaria prophylaxis and 73,466 patients not exposed to travel medications were identified. CRC-related mortality was lowered in the exposed patients compared to the unexposed patients, irrespective of the travel medications used. The incidence rate ratios for CRC-related mortality and overall mortality were comparable. Conclusion: We postulated that patients in better health were likely to travel more frequently than patients with poor health, leading to a healthy user bias. The results suggested the same, as similar reduced mortality risks were found for all the investigated travel medications, lowering the biological plausibility of truly protective effect from post-therapeutic use of any of the travel medication studied. We advocate the use of multiple negative exposure controls and to exercise caution while drawing conclusions from travel vaccine research.

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.

Risk factors for modified vaccine effectiveness of the live attenuated zoster vaccine among the elderly in England.

BACKGROUND: The United Kingdom introduced routine vaccination with the live-attenuated zoster vaccine for 70 year-olds in 2013, with the vaccine also offered to 79 year-olds as part of a catch-up campaign. In the subsequent years, the catch-up campaign was extended to also include adults aged 78 years. We investigated 14 pre-identified potential risk factors for potential modified vaccine effectiveness. METHODS: This retrospective cohort study in England included subjects born in 1943-1946 (the routine cohort) and in 1934-1937 (the catch-up cohort). We used the Clinical Practice Research Datalink (CPRD) to identify herpes zoster (HZ) cases and the risk factors: age, gender, ethnicity, socio-economic status, asthma, type 2 diabetes, chronic obstructive pulmonary disease, smoking, body mass index, immunosuppression, history of HZ, co-administration with influenza or pneumococcal vaccine. We derived HZ incidence by risk groups, overall vaccine effectiveness (VE) and modified VE expressed as relative differences in VE from Poisson regression models. RESULTS: Overall VE was 66.8% [95% CI: 62.2; 71.0]. Two out of the 14 investigated risk factors modified the HZ VE. Notably, lower VE was observed in diabetics and in persons with a history of HZ with relative differences in VE of -22·2%, [95% CI: -39·6, -4·5] and -22·5%, [95% CI: -44·9, -0·1]. CONCLUSIONS: Live-attenuated zoster vaccine protection against HZ was lower in type 2 diabetics and in subjects with a history of HZ. Contrary to clinical trial results, age did not affect the observed VE. Further study is required to gain insights into why certain risk groups are less protected. Identifying and understanding the effect modifiers of VE is important for future vaccine development as well as vaccine recommendations.

Visual Function Response to Ocriplasmin for the Treatment of Vitreomacular Traction and Macular Hole: The OASIS Study.

Purpose: To assess the effect of ocriplasmin on visual function response (VFR) measured using visual acuity (VA) and vision-related quality of life, and to quantify the association between release of vitreomacular adhesion (VMA) at day 28 and VFR. Methods: Prespecified analysis of secondary endpoints from a randomized controlled trial. Of 220 participants with symptomatic VMA/vitreomacular traction (VMT), including VMT associated with a macular hole up to 400 µm, 146 received a single intravitreal injection of 125 µg ocriplasmin and 74 a sham injection. Based on principal components analysis results, a VFR was defined as either a VA improvement of ≥2 lines or an improvement exceeding the minimal clinically important difference (MCID) in the composite or the mental health subscale scores of the Visual Function Questionnaire (VFQ-25). The MCID was estimated using the standard error of measurement approach. The main outcome measure was the VFR at month 6, with further assessments at months 12 and 24. Results: The MCID was estimated at 3.71 points for the VFQ-25 composite score and 10.71 for the VFQ-25 mental health subscale score. A VFR occurred in 51.0% of ocriplasmin versus 23.3% of sham participants (P = 0.0001). The VFR was maintained through months 12 and 24: 53.1% and 50.3% in ocriplasmin versus 21.9% and 20.5% in sham participants, respectively (P < 0.0001). Resolution of VMA at day 28 significantly increased the odds of a VFR at each assessment period. Conclusions: Treatment with ocriplasmin compared with sham resulted in a significant improvement in VFR. The 6-month treatment effect was sustained at months 12 and 24.

Visual function response to ocriplasmin for the treatment of vitreomacular traction and macular hole.

PURPOSE: To assess the effect of an intravitreal ocriplasmin injection on visual function, measured using visual acuity (VA) and vision-related quality of life. METHODS: Post hoc analysis of prespecified secondary end-points in two multicentre, randomized, double-masked, phase 3 clinical trials. A total of 652 participants with symptomatic vitreomacular adhesion were enrolled, of whom 464 received a single intravitreal injection of 125 µg ocriplasmin and 188 received a single intravitreal placebo injection. Based on principal components analysis results, visual function response (VFR) was defined as either a VA improvement of ≥2 lines; or an improvement in the composite score of the National Eye Institute Visual Function Questionnaire (VFQ-25) exceeding the minimal clinically important difference (MCID), estimated using the standard error of measurement approach; or an improvement in the VFQ-25 driving subscale score exceeding the MCID. The main outcome measure was VFR at 6 months. RESULTS: A VFR occurred in 55.1% of the ocriplasmin group versus 34.2% of the placebo injection group (p < 0.0001). This comprised 23.7% versus 11.2% (p = 0.0003) with a ≥ 2-line VA improvement, 35.9% versus 22.7% (p = 0.0016) for the VFQ-25 composite score, and 10.2% versus 6.2% (p = 0.1697) for the driving subscale. CONCLUSION: Ocriplasmin produces a clinically meaningful visual function benefit.

Use of the nonavalent HPV vaccine in individuals previously fully or partially vaccinated with bivalent or quadrivalent HPV vaccines.

With the availability of the nonavalent human papillomavirus (HPV) vaccine, vaccinees, parents and healthcare providers need guidance on how to complete an immunization course started with the bi- or quadrivalent vaccine and whether to revaccinate individuals who have completed a full immunization course with the bi- or quadrivalent vaccine. To answer these questions three parameters should be considered: age at the start of vaccination (9 to 14 years of age versus 15 years and older, the cut-off for 2 or 3 doses schedule), the number of doses already received and the time interval between doses. Based on a number of scenarios, we propose that the 9-valent vaccine can be used to complete an incomplete vaccination regimen or might be added to a previous completed schedule to extend protection.

Quantitative benefit-risk assessment by MCDA of the quadrivalent HPV vaccine for preventing anal cancer in males.

OBJECTIVES: To quantify the benefit-risk (BR) balance of the quadrivalent human papillomavirus (qHPV) vaccine for use in males, including anal cancer prevention, by using the multicriteria decision analysis (MCDA). METHODS: Value tree and an effect table were compiled using relevant qHPV vaccine efficacy/safety data. An expert panel validated the final model inputs. RESULTS: On a scale of 0-100, the MCDA qHPV vaccine score (66) was superior to the no vaccination score (46), indicating a more favorable BR balance for the qHPV vaccine. Significant changes in weight of individual outcomes were needed to change BR balance in sensitivity analyses. The qHPV vaccine maintained a better BR profile in all alternative models. CONCLUSIONS: MCDA can be used to transparently evaluate BR balance of vaccines. The qHPV vaccine had a favorable BR balance in males. Including anal cancer as a new indication further improves the BR profile of the qHPV vaccine.

A multi-country study of intussusception in children under 2 years of age in Latin America: analysis of prospective surveillance data.

BACKGROUND: Intussusception (IS) is a form of acute intestinal obstruction that occurs mainly in infants and is usually of unknown cause. An association between IS and the first licensed rotavirus vaccine, a reassortant-tetravalent, rhesus-based rotavirus vaccine (RRV-TV), led to the withdrawal of the vaccine. New rotavirus vaccines have now been developed and extensively studied for their potential association with IS. This study aimed to describe the epidemiology and to estimate the incidence of IS in Latin American infants prior to new vaccine introduction. METHODS: Children under 2 years of age representing potential IS cases were enrolled in 16 centers in 11 Latin American countries from January 2003 to May 2005. IS cases were classified as definite, probable, possible or suspected as stated on the Brighton Collaboration Working Group guidelines. RESULTS: From 517 potential cases identified, 476 (92%) cases were classified as definite, 21 probable, 10 possible and 10 suspected for intussusception. Among the 476 definite IS cases, the median age at presentation was 6.4 months with 89% of cases aged <1 year. The male to female ratio was 1.5:1. The incidence of definite IS per 100,000 subject-years ranged from 1.9 in Brazil to 62.4 in Argentina for children <2 years of age, and from 3.8 in Brazil to 105.3 in Argentina for children aged <1 year. Median hospital stay was 4 days with a high prevalence of surgery as the primary treatment (65%). Most cases (88%) made a complete recovery, but 13 (3%) died. No clear seasonal pattern of IS cases emerged. CONCLUSIONS: This study describes the epidemiology and estimates the incidence of IS in Latin American infants prior to the introduction of new rotavirus vaccines. The incidence of IS was found to vary between different countries, as observed in previous studies. TRIAL REGISTRATION: Clinical study identifier 999910/204 (SERO-EPI-IS-204).

Safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine for cervical cancer prevention: a pooled analysis of 11 clinical trials.

A pooled analysis of the safety of the human papillomavirus (HPV)-16/18 AS04-adjuvanted cervical cancer vaccine Cervarix (GlaxoSmithKline) was performed in a cohort of almost 30,000 girls and women aged > or =10 years, 16,142 who received at least one dose of the HPV-16/18 vaccine and 13,811 who received one of three controls [Al(OH)(3) or hepatitis A vaccine (720 or 360 EU)]. Data are available for a total of 45,988 vaccine doses. Solicited local and general symptoms were recorded for seven days after each dose. Serious adverse events (SAEs), pregnancies, medically significant conditions (MSCs) and new onset of chronic diseases (NOCDs), including new onset of autoimmune diseases (NOADs), were proactively monitored. Data were analyzed by vaccine group according to age (10-14, 15-25 and >25 years) and reporting period (months 0-7, months 7-12 and >month 12). Rates of solicited local and general symptoms were higher in the HPV-16/18 vaccine group than in the control groups. However, compliance with the three-dose schedule was high and did not differ between groups (93.4% for HPV-16/18 vaccine group versus 92.5% for pooled controls). No clinically relevant differences were seen between the HPV-16/18 vaccine and pooled control groups in rates of SAEs (2.8% versus 3.1%), MSCs (19.4% versus 21.4%), NOCDs (1.7% in both groups) or NOADs (0.4% versus 0.3%). Similarly, no differences in pregnancy outcomes or rates of withdrawals due to AEs or SAEs were observed between groups. In conclusion, analysis of this large database shows the HPV-16/18 AS04-adjuvanted cervical cancer vaccine to have a favorable safety profile in women of all ages.

Analysis of adverse events of potential autoimmune aetiology in a large integrated safety database of AS04 adjuvanted vaccines.

Newly licensed vaccines against human papillomavirus (HPV) and hepatitis B (HBV), and several vaccines in development, including a vaccine against genital herpes simplex virus (HSV), contain a novel Adjuvant System, AS04, composed of 3-O-desacyl-4' monophosphoryl lipid A and aluminium salts. Given the background incidence of autoimmune disorders in some of the groups targeted for immunisation with these vaccines, it is likely that autoimmune events will be reported in temporal association with vaccination, even in the absence of a causal relationship. The objective of this integrated analysis was to assess safety of AS04 adjuvanted vaccines with regard to adverse events (AEs) of potential autoimmune aetiology, particularly in adolescents and young adults. All randomised, controlled trials of HPV-16/18, HSV and HBV vaccines were analysed in an integrated analysis of individual data (N = 68,512). A separate analysis of the HPV-16/18 vaccine trials alone was also undertaken (N = 39,160). All data were collected prospectively during the vaccine development programmes (mean follow-up of 21.4 months), and included in the analysis up to a pre-defined data lock point. Reporting rates of overall autoimmune events were around 0.5% and did not differ between the AS04 and control groups. The relative risk (AS04/control) of experiencing any autoimmune event was 0.98 (95% confidence intervals 0.80, 1.21) in the integrated analysis and 0.92 (0.70, 1.22) in the HPV-16/18 vaccine analysis. Relative risks calculated overall, for disease category or for individual events were close to 1, and all confidence intervals around the relative risk included 1, indicating no statistically significant difference in event rates between the AS04 and control groups. This integrated analysis of over 68,000 participants who received AS04 adjuvanted vaccines or controls demonstrated a low rate of autoimmune disorders, without evidence of an increase in relative risk associated with AS04 adjuvanted vaccines.