scholarly journals Principal surrogates in context of high vaccine efficacy

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Andrea Callegaro ◽  
Fabian Tibaldi ◽  
Dean Follmann
Keyword(s):  
Vaccine Efficacy ◽  
Meta Analysis ◽  
Principal Stratification ◽  
Simulation Experiments ◽  
Correlates Of Protection ◽  
Vaccine Trials ◽  
Simulation Results ◽  
The Impact ◽  
Statistical Solutions ◽  
Very High

Abstract Objectives The use of correlates of protection (CoPs) in vaccination trials offers significant advantages as useful clinical endpoint substitutes. Vaccines with very high vaccine efficacy (VE) are documented in the literature (95% or above). Callegaro, A., and F. Tibaldi. 2019. “Assessing Correlates of Protection in Vaccine Trials: Statistical Solutions in the Context of High Vaccine Efficacy.” BMC Medical Research Methodology 19: 47 showed that the rare infections observed in the vaccinated groups of these trials poses challenges when applying conventionally-used statistical methods for CoP assessment such as the Prentice criteria and meta-analysis. The objective of this work is to investigate the impact of this problem on another statistical method for the assessment of CoPs called Principal stratification. Methods We perform simulation experiments to investigate the effect of high vaccine efficacy on the performance of the Principal Stratification approach. Results Similarly to the Prentice framework, simulation results show that the power of the Principal Stratification approach decreases when the VE grows. Conclusions It can be challenging to validate principal surrogates (and statistical surrogates) for vaccines with very high vaccine efficacy.

Principal Surrogates in Context of High Vaccine Efficacy

2019 ◽  
Author(s):  
Andrea Callegaro ◽  
Tibaldi Fabian ◽  
Dean Follmann
Keyword(s):  
Statistical Methods ◽  
Simulation Study ◽  
Vaccine Efficacy ◽  
Principal Stratification ◽  
Clinical Endpoint ◽  
Correlates Of Protection ◽  
The Impact ◽  
Very High

Abstract Background: The use of correlates of protection (CoPs) in vaccination trials offers significant advantages as useful clinical endpoint substitutes. Vaccines with very high vaccine efficacy (VE) are documented in the literature (95% or above). Callegaro and Tibaldi, (2019) showed that the rare infections observed in thevaccinated groups of these trials poses challenges when applying conventionally-used statistical methods for CoP assessment such as the Prentice criteria and meta-analysis.Methods: In this paper, we extended Callegaro and Tibaldi, (2019) simulation study by evaluating the impact of high VE on the Principal stratification approach.Results: Similarly to the Prentice framework, we showed that the power decreases when the VE grows. It follows that it can be challenging to validate a principal surrogate (and a statistical surrogate) when rare infections are observed in the vaccinated groups.

scholarly journals Epitope-Specific Serological Assays for RSV: Conformation Matters

Vaccines ◽  
2019 ◽  
Vol 7 (1) ◽  
pp. 23 ◽  
Author(s):  
Emily Phung ◽  
Lauren Chang ◽  
Kaitlyn Morabito ◽  
Masaru Kanekiyo ◽  
Man Chen ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Antigenic Site ◽  
Immune Monitoring ◽  
Effective Vaccine ◽  
F Protein ◽  
Correlates Of Protection ◽  
Vaccine Trials ◽  
Antigenic Sites ◽  
Syncytial Virus ◽  
The Impact

Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in children and older adults. An effective vaccine must elicit neutralizing antibodies targeting the RSV fusion (F) protein, which exists in two major conformations, pre-fusion (pre-F) and post-fusion (post-F). Although 50% of the surface is shared, pre-F contains highly neutralization-sensitive antigenic sites not present on post-F. Recent advancement of several subunit F-based vaccine trials has spurred interest in quantifying and understanding the protective potential of antibodies directed to individual antigenic sites. Monoclonal antibody competition ELISAs are being used to measure these endpoints, but the impact of F conformation and competition from antibodies binding to adjacent antigenic sites has not been thoroughly investigated. Since this information is critical for interpreting clinical trial outcomes and defining serological correlates of protection, we optimized assays to evaluate D25-competing antibodies (DCA) to antigenic site Ø on pre-F, and compared readouts of palivizumab-competing antibodies (PCA) to site II on both pre-F and post-F. We show that antibodies to adjacent antigenic sites can contribute to DCA and PCA readouts, and that cross-competition from non-targeted sites is especially confounding when PCA is measured using a post-F substrate. While measuring DCA and PCA levels may be useful to delineate the role of antibodies targeting the apex and side of the F protein, respectively, the assay limitations and caveats should be considered when conducting immune monitoring during vaccine trials and defining correlates of protection.

scholarly journals The Impact of Serotype Cross-Protection on Vaccine Trials: DENVax as a Case Study

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 674
Author(s):  
Maíra Aguiar ◽  
Nico Stollenwerk
Keyword(s):  
Vaccine Efficacy ◽  
Careful Consideration ◽  
Dengue Vaccine ◽  
Serious Adverse Events ◽  
Post Vaccination ◽  
Vaccine Trials ◽  
Long Time ◽  
Health Need ◽  
The Impact ◽  
Over Time

There is a growing public health need for effective preventive interventions against dengue, and a safe, effective and affordable dengue vaccine against the four serotypes would be a significant achievement for disease prevention and control. Two tetravalent dengue vaccines, Dengvaxia (CYD-TDV—Sanofi Pasteur) and DENVax (TAK 003—Takeda Pharmaceutical Company), have now completed phase 3 clinical trials. Although Dengvaxia resulted in serious adverse events and had to be restricted to individuals with prior dengue infections, DENVax has shown, at first glance, some encouraging results. Using the available data for the TAK 003 trial, we estimate, via the Bayesian approach, vaccine efficacy (VE) of the post-vaccination surveillance periods of 12 and 18 months. Although better measurement over a long time was expected for the second part of the post-vaccination surveillance, variation in serotype-specific efficacy needs careful consideration. Besides observing that individual serostatus prior to vaccination is determinant of DENVax vaccine efficacy, such as for Dengvaxia, we also noted, after comparing the VE estimations for 12- and 18-month periods, that vaccine efficacy is decreasing over time. The comparison of efficacies over time is informative and very important, and brings up the discussion of the role of temporary cross-immunity in dengue vaccine trials and the impact of serostatus prior to vaccination in the context of dengue fever epidemiology.

scholarly journals The O-Ag Antibody Response to Francisella Is Distinct in Rodents and Higher Animals and Can Serve as a Correlate of Protection

Pathogens ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1646
Author(s):  
Lauren E. Shoudy ◽  
Prachi Namjoshi ◽  
Gabriela Giordano ◽  
Sudeep Kumar ◽  
Jennifer D. Bowling ◽  
...  
Keyword(s):  
Vaccine Efficacy ◽  
Low Dose ◽  
High Sensitivity ◽  
High Dose ◽  
Live Vaccine Strain ◽  
Plasma Samples ◽  
Vaccine Candidates ◽  
Correlates Of Protection ◽  
Vaccine Trials ◽  
Bona Fide

Identifying correlates of protection (COPs) for vaccines against lethal human (Hu) pathogens, such as Francisella tularensis (Ft), is problematic, as clinical trials are currently untenable and the relevance of various animal models can be controversial. Previously, Hu trials with the live vaccine strain (LVS) demonstrated ~80% vaccine efficacy against low dose (~50 CFU) challenge; however, protection deteriorated with higher challenge doses (~2000 CFU of SchuS4) and no COPs were established. Here, we describe our efforts to develop clinically relevant, humoral COPs applicable to high-dose, aerosol challenge with S4. First, our serosurvey of LVS-vaccinated Hu and animals revealed that rabbits (Rbs), but not rodents, recapitulate the Hu O-Ag dependent Ab response to Ft. Next, we assayed Rbs immunized with distinct S4-based vaccine candidates (S4ΔclpB, S4ΔguaBA, and S4ΔaroD) and found that, across multiple vaccines, the %O-Ag dep Ab trended with vaccine efficacy. Among S4ΔguaBA-vaccinated Rbs, the %O-Ag dep Ab in pre-challenge plasma was significantly higher in survivors than in non-survivors; a cut-off of >70% O-Ag dep Ab predicted survival with high sensitivity and specificity. Finally, we found this COP in 80% of LVS-vaccinated Hu plasma samples as expected for a vaccine with 80% Hu efficacy. Collectively, the %O-Ag dep Ab response is a bona fide COP for S4ΔguaBA-vaccinated Rb and holds significant promise for guiding vaccine trials with higher animals.

scholarly journals The Impact of Serotype Cross-Protection on Vaccine Trials: DENVax as a Case Study

2020 ◽  
Author(s):  
Maíra Aguiar ◽  
Nico Stollenwerk
Keyword(s):  
Vaccine Efficacy ◽  
Careful Consideration ◽  
Dengue Vaccine ◽  
Serious Adverse Events ◽  
Post Vaccination ◽  
Vaccine Trials ◽  
Long Time ◽  
Health Need ◽  
The Impact ◽  
Over Time

There is a growing public health need for effective preventive interventions against dengue, and a safe, effective and affordable dengue vaccine against the four serotypes would be a significant achievement for disease prevention and control. Two tetravalent dengue vaccines, Dengvaxia (Sanofi Pasteur) and DENVax (Takeda Pharmaceutical Company), have now completed phase 3 clinical trials. While Dengvaxia resulted in serious adverse events and is restricted to individuals with prior dengue infections, DENVax has shown, at first glance, some encouraging results. Using the available data for the TAK 003 trial, we estimate, via the Bayesian approach, vaccine efficacy (VE) of the post-vaccination surveillance periods. Although better measurement over long time was expected for the second part of the post-vaccination surveillance, variation in serotype-specific efficacy needs careful consideration. Besides observing that individual serostatus prior to vaccination is determinant of DENVax vaccine efficacy, we also compare the VE estimations for 12 and 18 months and we observe that the efficacy is decreasing over time. The comparison of efficacies over time is informative and very important, bring up the discussion of the role of temporary cross-immunity in dengue vaccine trials and the impact of serostatus prior to vaccination in the context of dengue fever epidemiology.

scholarly journals Pneumococcal vaccination in adults at very high risk or with established cardiovascular disease: systematic review and meta-analysis

2020 ◽  
Author(s):  
Miguel Marques Antunes ◽  
Gonçalo S Duarte ◽  
Dulce Brito ◽  
Margarida Borges ◽  
João Costa ◽  
...  
Keyword(s):  
Systematic Review ◽  
Cardiovascular Disease ◽  
High Risk ◽  
Observational Studies ◽  
Meta Analysis ◽  
Pneumococcal Vaccination ◽  
Significant Heterogeneity ◽  
All Cause Mortality ◽  
The Impact ◽  
Very High

Abstract Aims There are several guidelines that recommend pneumococcal vaccination (PPSV23 and/or PCV13) in adults with a history of cardiovascular disease (established heart failure, coronary disease, and cerebrovascular disease) or at a very high risk of cardiovascular disease. However, there is no randomized controlled trial (RCT) systematic review that evaluates the impact of vaccination on all-cause mortality compared to no vaccination in this particular population. Our objective is to conduct a systematic review and meta-analysis of the impact of pneumococcal vaccination in the referred population. Methods and results We searched CENTRAL and MEDLINE for relevant RCTs and observational studies. Data were screened, extracted, and appraised by two independent reviewers. We pooled results using a random effects model, and used hazard ratios (HRs) with 95% confidence intervals (CIs) to assess measure of effect. The primary outcome was all-cause mortality and we assessed the confidence in the evidence using the GRADE framework. No RCTs were found. Seven observational studies were included for analyses. Pooled results from five studies enrolling a total of 163 756 participants showed a significant decrease in all-cause mortality (HR 0.78, 95% CI 0.73–0.83, very low confidence), without statistically significant heterogeneity (χ2 test P = 0.21; I2 = 32%). Conclusions Pneumococcal vaccination was associated with a 22% decrease of all-cause mortality in patients with cardiovascular disease or at a very high cardiovascular risk. However, limitations due to study design and the serious risk of bias in three of the included studies leads to a decreased level of result confidence.

scholarly journals Modeling as a Tool for Transboundary Aquifer Assessment Prioritization

Water ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 2685
Author(s):  
Ashley E. P. Atkins ◽  
Saeed P. Langarudi ◽  
Alexander G. Fernald
Keyword(s):  
System Dynamics Model ◽  
Dynamics Model ◽  
Simulation Experiments ◽  
Transboundary Aquifer ◽  
Information Reporting ◽  
Aquifer Systems ◽  
System Components ◽  
Simulation Results ◽  
The Impact ◽  
Transboundary Aquifers

Transboundary aquifers are critical global water supplies facing unprecedented threats of depletion; existing efforts to assess these resources do not adequately account for the complexities of transboundary human and physical system interactions to the determinant of the impact of assessment outcomes. This study developed a system dynamics model with natural, human, and technical system components for a section of the transboundary Mesilla Basin/Conejos-Médanos aquifer to evaluate the following dynamic hypothesis: how and when information from a transboundary aquifer assessment is reported and perceived, in scenarios where two countries follow identical and different timeframes, dynamically impacts the behaviors of the shared aquifer. Simulation experiments were conducted to quantitatively assess the dynamics of transboundary aquifer assessment information reporting and perception delays. These critical feedbacks have not previously been incorporated practically in simulation and analysis. Simulation results showed that the timing and content of reporting can change the dynamic behavior of natural, human, and technical components of transboundary aquifer systems. This study demonstrates the potential for modeling to assist with prioritization efforts during the data collection and exchange phases to ensure that transboundary aquifer assessments achieve their intended outcomes.

Correlation-Based Meta-Analytic Structural Equation Modeling: Effects of Parameter Covariance on Point and Interval Estimates

2018 ◽  
Vol 22 (4) ◽  
pp. 892-916 ◽  
Author(s):  
Shu Fai Cheung ◽  
Rong Wei Sun ◽  
Darius K.-S. Chan
Keyword(s):  
Structural Equation Modeling ◽  
Random Effects ◽  
Structural Equation ◽  
Meta Analysis ◽  
Real Data ◽  
Equation Modeling ◽  
Path Coefficient ◽  
Data Sets ◽  
Simulation Results ◽  
The Impact

More and more researchers use meta-analysis to conduct multivariate analysis to summarize previous findings. In the correlation-based meta-analytic structural equation modeling (cMASEM), the average sample correlation matrix is used to estimate the average population model. Using a simple mediation model, we illustrated that random effects covariation in population parameters can theoretically bias the path coefficient estimates and lead to nonnormal random effects distribution of the correlations. We developed an R function for researchers to examine by simulation the impact of random effects in other models. We then reanalyzed two real data sets and conducted a simulation study to examine the magnitude of the impact on realistic situations. Simulation results suggest parameter bias is typically negligible (less than .02), parameter bias and root mean square error do not differ across methods, 95% confident intervals are sometimes more accurate for the two-stage structural equation modeling approach with a diagonal random effects model, and power is sometimes higher for the traditional Viswesvaran-Ones approach. Given the increasing popularity of cMASEM in organizational research, these simulation results form the basis for us to make several recommendations on its application.

scholarly journals Modeling COVID-19 vaccine efficacy and coverage towards herd-immunity in the Basque Country, Spain

2021 ◽  
Author(s):  
Nico Stollenwerk ◽  
Javier Mar ◽  
Joseba Bidaurrazaga Van-Dierdonck ◽  
Oliver Ibarrondo ◽  
Carlo Estadilla ◽  
...  
Keyword(s):  
Vaccine Efficacy ◽  
Basque Country ◽  
Severe Disease ◽  
Herd Immunity ◽  
Dose Administration ◽  
Vaccine Trials ◽  
The Impact ◽  
Sterilizing Immunity ◽  
Full Immunization

Vaccines have measurable efficacies, obtained first from vaccine trials. However, vaccine efficacy is not a static measure upon licensing, and the long term population studies are very important to evaluate vaccine performance and impact. COVID-19 vaccines were developed in record time and although the extent of sterilizing immunity is still under evaluation, the currently licensed vaccines are extremely effective against severe disease, with vaccine efficacy significantly higher after the full immunization schedule. We investigate the impact of vaccines which have different efficacies after first dose and after the second dose administration schedule, eventually considering different efficacies against severe disease as opposed to overall infection. As a proof of concept, we model the vaccine performance of hospitalization reduction at the momentary scenario of the Basque Country, Spain, with population in a mixed vaccination setting, giving insights into the population coverage needed to achieve herd immunity in the current vaccination context.

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