Endpoint For Vaccine Trials Research Articles

Exploring Natural Immune Responses to Shigella Exposure Using Multiplex Bead Assays on Dried Blood Spots in High-Burden Countries: Protocol From a Multisite Diarrhea Surveillance Study.

Molecular diagnostics on human fecal samples have identified a larger burden of shigellosis than previously appreciated by culture. Evidence of fold changes in immunoglobulin G (IgG) to conserved and type-specific Shigella antigens could be used to validate the molecular assignment of type-specific Shigella as the etiology of acute diarrhea and support polymerase chain reaction (PCR)-based microbiologic end points for vaccine trials. We will test dried blood spots collected at enrollment and 4 weeks later using bead-based immunoassays for IgG to invasion plasmid antigen B and type-specific lipopolysaccharide O-antigen for Shigella flexneri 1b, 2a, 3a, and 6 and Shigella sonnei in Shigella-positive cases and age-, site-, and season-matched test-negative controls from all sites in the Enterics for Global Health (EFGH) Shigella surveillance study. Fold antibody responses will be compared between culture-positive, culture-negative but PCR-attributable, and PCR-positive but not attributable cases and test-negative controls. Age- and site-specific seroprevalence distributions will be identified, and the association between baseline antibodies and Shigella attribution will be estimated. The integration of these assays into the EFGH study will help support PCR-based attribution of acute diarrhea to type-specific Shigella, describe the baseline seroprevalence of conserved and type-specific Shigella antibodies, and support correlates of protection for immunity to Shigella diarrhea. These insights can help support the development and evaluation of Shigella vaccine candidates.

BCG-induced protection against Mycobacterium tuberculosis infection: Evidence, mechanisms, and implications for next-generation vaccines.

SummaryThe tuberculosis (TB) vaccine Bacillus Calmette‐Guérin (BCG) was introduced 100 years ago, but as it provides insufficient protection against TB disease, especially in adults, new vaccines are being developed and evaluated. The discovery that BCG protects humans from becoming infected with Mycobacterium tuberculosis (Mtb) and not just from progressing to TB disease provides justification for considering Mtb infection as an endpoint in vaccine trials. Such trials would require fewer participants than those with disease as an endpoint. In this review, we first define Mtb infection and disease phenotypes that can be used for mechanistic studies and/or endpoints for vaccine trials. Secondly, we review the evidence for BCG‐induced protection against Mtb infection from observational and BCG re‐vaccination studies, and discuss limitations and variation of this protection. Thirdly, we review possible underlying mechanisms for BCG efficacy against Mtb infection, including alternative T cell responses, antibody‐mediated protection, and innate immune mechanisms, with a specific focus on BCG‐induced trained immunity, which involves epigenetic and metabolic reprogramming of innate immune cells. Finally, we discuss the implications for further studies of BCG efficacy against Mtb infection, including for mechanistic research, and their relevance to the design and evaluation of new TB vaccines.

Likelihood-Based Methods for Assessing Principal Surrogate Endpoints in Vaccine Trials

When evaluating principal surrogate biomarkers in vaccine trials, missingness in potential outcomes requires prediction using auxiliary variables and/or augmented study design with a close-out placebo vaccination (CPV) component. The estimated likelihood approach, which separates the estimation of biomarker distribution from the maximization of the estimated likelihood, has often been adopted. Here we develop a likelihood-based approach that jointly estimates the two parts and describe the methods for selecting auxiliary variables as risk predictors and/or biomarker predictors. Through numerical studies, we observe that in a standard trial design without a CPV component, the two methods achieve similar performance in estimation of the risk model and the marker model. However, for trials augmented with a CPV component, using the likelihood-based method achieves better estimation performance compared to the estimated likelihood method. Moreover, in the presence of a large number of covariates from which to select, the ML method achieves comparable or better performance compared to the EL method in both designs. While the CPV component has not yet been implemented in existing vaccine trials, our results have applications in the planning of future vaccine trials. We illustrate the method using data from a dengue vaccine trial.

Analyzing Vaccine Trials in Epidemics With Mild and Asymptomatic Infection.

Vaccine efficacy against susceptibility to infection (VES), regardless of symptoms, is an important endpoint of vaccine trials for pathogens with a high proportion of asymptomatic infection, because such infections may contribute to onward transmission and long-term sequelae, such as congenital Zika syndrome. However, estimating VES is resource-intensive. We aimed to identify approaches for accurately estimating VES when limited information is available and resources are constrained. We modeled an individually randomized vaccine trial by generating a network of individuals and simulating an epidemic. The disease natural history followed a “susceptible-exposed-infectious/symptomatic (or infectious/asymptomatic)-recovered” model. We then used 7 approaches to estimate VES, and we also estimated vaccine efficacy against progression to symptoms (VEP). A corrected relative risk and an interval-censored Cox model accurately estimate VES and only require serological testing of participants once, while a Cox model using only symptomatic infections returns biased estimates. Only acquiring serological endpoints in a 10% sample and imputing the remaining infection statuses yields unbiased VES estimates across values of the basic reproduction number (R0) and accurate estimates of VEP for higher R0 values. Identifying resource-preserving methods for accurately estimating VES and VEP is important in designing trials for diseases with a high proportion of asymptomatic infection.

High-throughput data analysis and data integration for vaccine trials

Rational vaccine development can benefit from biomarker studies, which help to predict, optimize and evaluate the immunogenicity of vaccines and ultimately provide surrogate endpoints for vaccine trials. Systems biology approaches facilitate acquisition of both simple biomarkers and complex biosignatures. Yet, evaluation of high-throughput (HT) data requires a plethora of tools for data integration and analysis. In this review, we present an overview of methods for evaluation and integration of large amounts of data collected in vaccine trials from similar and divergent molecular HT techniques, such as transcriptomic, proteomic and metabolic profiling. We will describe a selection of relevant statistical and bioinformatic approaches that are frequently associated with systems biology. We will present data dimension reduction techniques, functional analysis approaches and methods of integrating heterogeneous HT data. Finally, we will provide a few examples of applications of these techniques in vaccine research and development.

Comment on Clinical Development of Candidate HIV Vaccines: Different Problems for Different Vaccines

Comment on Clinical Development of Candidate HIV Vaccines: Different Problems for Different Vaccines

Nucleic Acid Assay System for Tier II Laboratories and Moderately Complex Clinics to Detect HIV in Low‐Resource Settings

There is a clear need for an instrument-free molecular diagnostic system for detecting human immunodeficiency virus type 1 (HIV-1) RNA or DNA that can be used in developing countries. Such a test could be used for early diagnosis of HIV-1 infection during infancy and could serve as a surrogate end point for vaccine trials. We developed the IsoAmp HIV-1 assay (BioHelix Corporation), which targets the HIV-1 gag gene with use of isothermal reverse-transcription helicase-dependent amplification chemistry. The IsoAmp HIV assay uses a disposable amplicon containment device with an embedded vertical-flow DNA detection strip to detect the presence of HIV-1 amplicons. The vertical-flow DNA detection strip has a control line to validate the performance of the device and a test line to detect the analyte. The analyte is detected by a sandwich immunoassay for reporter moieties on a capture probe and a detection probe. The control line consists of the detection probe reporter moiety conjugated to the vertical-flow DNA detection strip. The preliminary limit of detection of the IsoAmp HIV assay was evaluated by testing serial dilutions of HIV-1 armored RNA (Assuragen). We found that 21 (75%) of 28 assays yielded positive results when 50 copies of HIV-1 armored RNA were input into the IsoAmp HIV reaction.

Type-specific duration of human papillomavirus infection: implications for human papillomavirus screening and vaccination.

Understanding the duration of human papillomavirus (HPV) infection may help find suitable end points for vaccine trials and testing intervals in screening studies. We studied genotype-specific infection duration among 2462 women enrolled in the Ludwig-McGill cohort study. Cervical specimens collected every 4-6 months were tested by a polymerase chain reaction protocol. Actuarial techniques were used to estimate the duration of HPV infection and to investigate the influence of age, number of sexual partners, and coinfection with multiple HPV types. At enrollment, the prevalence of infection with high-risk HPV types was 10.6%, and the prevalence of infection with low-risk HPV types was 6.1%; incidence rates were 6.1 and 5.0 infections per 1000 women-months, respectively. Prevalent infections took longer to clear than incident infections (mean time to clearance, 18.6 months vs. 13.5 months). The mean duration of incident infection with high- and low-risk HPV varied according to the analytic approach used to measure this variable and showed considerable variation by HPV type (range, 5.1-15.4 months). Age and number of partners did not influence infection duration, whereas coinfection was associated with increased infection duration. The mean duration of HPV-16 monoinfection was 11.0 months, and the mean duration of HPV-16 coinfection was 15.4 months. There was considerable variation among HPV types with regard to the duration of infection. Coinfection with multiple types contributed to an increased infection duration.

ASSESSING SURROGATE ENDPOINTS IN VACCINE TRIALS WITH CASE-COHORT SAMPLING AND THE COX MODEL.

Assessing immune responses to study vaccines as surrogates of protection plays a central role in vaccine clinical trials. Motivated by three ongoing or pending HIV vaccine efficacy trials, we consider such surrogate endpoint assessment in a randomized placebo-controlled trial with case-cohort sampling of immune responses and a time to event endpoint. Based on the principal surrogate definition under the principal stratification framework proposed by Frangakis and Rubin [Biometrics58 (2002) 21-29] and adapted by Gilbert and Hudgens (2006), we introduce estimands that measure the value of an immune response as a surrogate of protection in the context of the Cox proportional hazards model. The estimands are not identified because the immune response to vaccine is not measured in placebo recipients. We formulate the problem as a Cox model with missing covariates, and employ novel trial designs for predicting the missing immune responses and thereby identifying the estimands. The first design utilizes information from baseline predictors of the immune response, and bridges their relationship in the vaccine recipients to the placebo recipients. The second design provides a validation set for the unmeasured immune responses of uninfected placebo recipients by immunizing them with the study vaccine after trial closeout. A maximum estimated likelihood approach is proposed for estimation of the parameters. Simulated data examples are given to evaluate the proposed designs and study their properties.

Endpoints in vaccine trials.

In this paper we discuss statistical considerations regarding endpoints in preventive vaccine trials. Brief discussion is given to preclinical, Phase I, and Phase II trials, with the bulk of attention paid to endpoint choice and analysis in Phase III efficacy trials. In addition to traditional efficacy measures of vaccine effects for immunized individuals, consideration is given to waning, strain specific efficacy, correlates of protective immunity, postinfection endpoints, and cluster randomized trials.

Twenty years of outpatient respiratory syncytial virus infection: a framework for vaccine efficacy trials.

Respiratory syncytial virus (RSV) is the most important viral respiratory pathogen of infancy and childhood. Much has been written about inpatients with severe disease. Inpatients, however, represent only a minority of RSV-infected children. We studied the characteristics of symptomatic outpatient RSV infection in healthy children to gain a better understanding of RSV disease and to provide a background for the testing of intervention strategies in children without high-risk conditions. A total of 1113 children were followed during 20 consecutive RSV seasons. Signs and symptoms of respiratory infection were monitored. Cultures were obtained for febrile upper respiratory infection, acute otitis media, and lower respiratory infection (LRI). Rates of febrile upper respiratory infection, acute otitis media, LRI, and hospitalization were calculated. Given those rates, numbers of children needed to demonstrate efficacy of a vaccine product were calculated. Mild disease from RSV infection lacked some of the classic features of RSV infection seen in hospitalized children. Involvement of the lower respiratory tract was, however, noted to be much higher in RSV infection than it was in infection with other viral respiratory pathogens. LRI was, therefore, considered the best candidate endpoint for vaccine trials. A product with 60% efficacy could be proven, with a power of 0.8, to be efficacious with as few as 1500 infants. RSV infection is common and often involves the lower respiratory tract, even in outpatients. Our 20-year study of RSV infection provides a basis for calculation of sample sizes to be used in trials of vaccine candidates.

Endpoints for Vaccine Trials: Conference Summary

AIDS Research and Human RetrovirusesVol. 11, No. 10 Endpoints for Vaccine Trials: Conference SummaryConference on Advances in AIDS Vaccine Development—1994MICHAEL S. ASCHER and HAYNES W. SHEPPARDMICHAEL S. ASCHERSearch for more papers by this author and HAYNES W. SHEPPARDSearch for more papers by this authorPublished Online:16 Mar 2009https://doi.org/10.1089/aid.1995.11.1315AboutSectionsPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail "Endpoints for Vaccine Trials: Conference Summary." , 11(10), pp. 1315–1316FiguresReferencesRelatedDetails Volume 11Issue 10Oct 1995 To cite this article:MICHAEL S. ASCHER and HAYNES W. SHEPPARD.Endpoints for Vaccine Trials: Conference Summary.AIDS Research and Human Retroviruses.Oct 1995.1315-1316.http://doi.org/10.1089/aid.1995.11.1315Published in Volume: 11 Issue 10: March 16, 2009PDF download