Dataset Information

Computing threshold antibody levels of protection in vaccine clinical trials: An assessment of methodological bias.

ABSTRACT: In the development of new vaccines, understanding the level of vaccine-induced antibody that is sufficient to protect against disease can simplify and expedite the development and licensing process. If there is an accepted threshold antibody level that is indicative of protection, then smaller trials measuring antibody concentration alone can be conducted to test new vaccines, instead of large efficacy studies powered on clinical outcomes. Commonly, threshold levels of protective antibody are determined from clinical efficacy trials in which clinical endpoints are measured on everyone and a small subset of participants have antibody concentrations measured. The proportion of participants with antibody below a threshold in each group in the immunogenicity subset can be compared to the proportions with disease in each group in the larger trial to find an appropriate threshold. Mathematically, this method seeks to compute an absolute threshold whereby antibody above the threshold provides complete, sterilizing immunity. However, in practice it is often understood that such thresholds may only be indicative of a relative degree of protection rather than an absolute one. Although this approach is common, the accuracy of such methods when the underlying mathematical assumptions do not hold true, has never been tested. We simulated data from clinical trial scenarios under varying assumptions of vaccine efficacy and calculated antibody thresholds of protection. We estimated the bias in the calculated thresholds derived from each scenario and showed that in many situations this method produces inflated estimates of thresholds, particularly if a vaccine induces high levels of antibody or when the underlying assumption of sterilizing immunity is violated.

SUBMITTER: Voysey M

PROVIDER: S-EPMC6128451 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Computing threshold antibody levels of protection in vaccine clinical trials: An assessment of methodological bias.

Voysey Merryn M Sadarangani Manish M Pollard Andrew J AJ Fanshawe Thomas R TR

PloS one 20180907 9

In the development of new vaccines, understanding the level of vaccine-induced antibody that is sufficient to protect against disease can simplify and expedite the development and licensing process. If there is an accepted threshold antibody level that is indicative of protection, then smaller trials measuring antibody concentration alone can be conducted to test new vaccines, instead of large efficacy studies powered on clinical outcomes. Commonly, threshold levels of protective antibody are de ...[more]

PMID: 30192787

Similar Datasets

Project description:BackgroundBias in randomized controlled trials (RCTs) can lead to underestimation or overestimation of the true effects of interventions. Surgical RCTs may suffer from the risk of bias (RoB) that is avoidable in trials of other interventions, and vice versa. We aimed to compare the adequacy of RoB assessments in surgical versus non-surgical RCTs included in Cochrane reviews and to assess the most common differences in those RoB assessments. Due to specificities of surgical trials, i.e. difficulties associated with blinding of surgical interventions, we hypothesized that assessments of surgical trials may be more adequate, compared to RCTs of non-surgical interventions.MethodsThis was a methodological study, analyzing methods of published Cochrane systematic reviews. Data were extracted from RoB tables in Cochrane reviews (judgments and accompanying explanatory comment) for the following four RoB domains used in the 2011 Cochrane RoB tool: randomization, allocation concealment, blinding of participants and personnel, and blinding of outcome assessors. We defined adequate assessments as those that were in line with instructions from the Cochrane Handbook for Systematic Reviews of Interventions. The prevalence of adequate assessments was compared in surgical versus non-surgical trials. The most common differences in both groups of reviews were presented.ResultsIn 729 analyzed Cochrane reviews, there were 10,537 included trials. The prevalence of adequate RoB judgments made by Cochrane authors ranged from 87.9, 95%CI (87.3 to 88.6%) for randomization to 70.7, 95%CI (69.8 to 71.5%) for blinding of participants and personnel. For all analyzed RoB domains, the prevalence of adequate RoB domains was higher in surgical trials than in non-surgical trials. For two RoB domains assessing blinding, this difference between surgical and non-surgical trials was statistically significant (P < 0.001), while the difference was not significant for the RoB domain regarding randomization (P = 0.124) and allocation concealment (P = 0.039, β < 0.8).ConclusionsRoB judgments were more in line with instructions from the Cochrane Handbook when Cochrane reviews assessed surgical trials, compared to those that analyzed non-surgical interventions. However, further steps are warranted to scrutinize RoB assessment in trials of both surgical and non-surgical interventions.

Project description:Hepatitis B vaccine has contributed to the reduction in hepatitis B virus infections and chronic disease globally. Screening to establish extent of vaccine induced immune response and provision of booster dose are limited in most low-and-middle income countries (LMICs). Our study investigated the extent of protective immune response and breakthrough hepatitis B virus infections among adult vaccinated healthcare workers in selected health facilities in northern Uganda. A cross-sectional study was conducted among 300 randomly selected adult hepatitis B vaccinated healthcare workers in Lira and Gulu regional referral hospitals in northern Uganda. Blood samples were collected and qualitative analysis of Hepatitis B surface antigen (HBsAg), Hepatitis B surface antigen antibody (HBsAb), Hepatitis B envelop antigen (HBeAg), Hepatitis B envelop antibody (HBeAb) and Hepatitis B core antibody (HBcAb) conducted using ELISA method. Quantitative assessment of anti-hepatitis B antibody (anti-HBs) levels was done using COBAS immunoassay analyzer. Multiple logistic regression was done to establish factors associated with protective anti-HBs levels (≥ 10mIU/mL) among adult vaccinate healthcare workers at 95% level of significance. A high proportion, 81.3% (244/300) of the study participants completed all three hepatitis B vaccine dose schedules. Two (0.7%, 2/300) of the study participants had active hepatitis B virus infection. Of the 300 study participants, 2.3% (7/300) had positive HBsAg; 88.7% (266/300) had detectable HBsAb; 2.3% (7/300) had positive HBeAg; 4% (12/300) had positive HBeAb and 17.7% (53/300) had positive HBcAb. Majority, 83% (249/300) had a protective hepatitis B antibody levels (≥10mIU/mL). Hepatitis B vaccine provides protective immunity against hepatitis B virus infection regardless of whether one gets a booster dose or not. Protective immune response persisted for over ten years following hepatitis B vaccination among the healthcare workers.

Project description:BackgroundClinical trials on Traditional Chinese Medicine (TCM) should be registered in a publicly accessible international trial register and report on all outcomes. We systematically assessed and evaluated TCM trials in registries with their subsequent publications.ObjectiveTo describe the characteristics of TCM trials, estimate bias risk and outcome-reporting bias in clinical trials.Data sources and study selectionFifteen trial registries were searched from their inception to July 2012 to identify randomised trials on TCM including Chinese herbs, acupuncture and/or moxibustion, cupping, tuina, qigong, etc.Data extractionWe extracted data including TCM specialty and treated disease/conditions from the registries and searched for subsequent publications in PubMed and Chinese databases. We compared information in the registries of completed trials with any publications focusing on study design, sample size, randomisation, bias risk including reporting bias from the register protocol.Results1096 registered randomised trials were identified evaluating TCM, of which 505 were completed studies (46.1%). The most frequent conditions were pain (13.3%), musculoskeletal (11.7%), nervous (8.7%), digestive (7.1%), circulatory (6.5%), respiratory (6.3%), mental and behavioural disorders (6.2%) and cancer (6.0%). The trial register data identified parallel, phase II/III randomised trials with sample size estimations and blinding, but limited information about randomisation (sequence generation and allocation concealment). Comparing trial registration data of 115 completed trials (22.8%) with their subsequent 136 publications, inconsistencies were identified in one or more of the following: sample size (11%), outcome assessor blinding (37.5%), primary outcomes (29%) and safety (28%) reporting.ConclusionsIncreasing numbers of clinical trials investigating a variety of TCM interventions have been registered in international trial registries. The study design of registered TCM trials has improved in estimating sample size, use of blinding and placebos. However, selective outcome reporting is widespread and similar to conventional medicine and therefore study conclusions should be interpreted with caution.

Dataset Information

Computing threshold antibody levels of protection in vaccine clinical trials: An assessment of methodological bias.

Publications

Computing threshold antibody levels of protection in vaccine clinical trials: An assessment of methodological bias.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets