Vaccine Trials (vaccine + trials)

Distribution by Scientific Domains


Selected Abstracts


Chop-Lump Tests for Vaccine Trials

BIOMETRICS, Issue 3 2009
Dean Follmann
Summary This article proposes new tests to compare the vaccine and placebo groups in randomized vaccine trials when a small fraction of volunteers become infected. A simple approach that is consistent with the intent-to-treat principle is to assign a score, say,W, equal to 0 for the uninfecteds and some postinfection outcome X,> 0 for the infecteds. One can then test the equality of this skewed distribution of,W,between the two groups. This burden of illness (BOI) test was introduced by Chang, Guess, and Heyse (1994,,Statistics in Medicine,13, 1807,1814). If infections are rare, the massive number of 0s in each group tends to dilute the vaccine effect and this test can have poor power, particularly if the,X's are not close to zero. Comparing,X,in just the infecteds is no longer a comparison of randomized groups and can produce misleading conclusions. Gilbert, Bosch, and Hudgens (2003,,Biometrics,59, 531,541) and Hudgens, Hoering, and Self (2003,,Statistics in Medicine,22, 2281,2298) introduced tests of the equality of,X,in a subgroup,the principal stratum of those "doomed" to be infected under either randomization assignment. This can be more powerful than the BOI approach, but requires unexaminable assumptions. We suggest new "chop-lump" Wilcoxon and,t -tests (CLW and CLT) that can be more powerful than the BOI tests in certain situations. When the number of volunteers in each group are equal, the chop-lump tests remove an equal number of zeros from both groups and then perform a test on the remaining,W's, which are mostly >0. A permutation approach provides a null distribution. We show that under local alternatives, the CLW test is always more powerful than the usual Wilcoxon test provided the true vaccine and placebo infection rates are the same. We also identify the crucial role of the "gap" between 0 and the,X's on power for the,t -tests. The chop-lump tests are compared to established tests via simulation for planned HIV and malaria vaccine trials. A reanalysis of the first phase III HIV vaccine trial is used to illustrate the method. [source]


Sensitivity Analyses Comparing Outcomes Only Existing in a Subset Selected Post-Randomization, Conditional on Covariates, with Application to HIV Vaccine Trials

BIOMETRICS, Issue 2 2006
Bryan E. Shepherd
Summary In many experiments, researchers would like to compare between treatments and outcome that only exists in a subset of participants selected after randomization. For example, in preventive HIV vaccine efficacy trials it is of interest to determine whether randomization to vaccine causes lower HIV viral load, a quantity that only exists in participants who acquire HIV. To make a causal comparison and account for potential selection bias we propose a sensitivity analysis following the principal stratification framework set forth by Frangakis and Rubin (2002, Biometrics58, 21,29). Our goal is to assess the average causal effect of treatment assignment on viral load at a given baseline covariate level in the always infected principal stratum (those who would have been infected whether they had been assigned to vaccine or placebo). We assume stable unit treatment values (SUTVA), randomization, and that subjects randomized to the vaccine arm who became infected would also have become infected if randomized to the placebo arm (monotonicity). It is not known which of those subjects infected in the placebo arm are in the always infected principal stratum, but this can be modeled conditional on covariates, the observed viral load, and a specified sensitivity parameter. Under parametric regression models for viral load, we obtain maximum likelihood estimates of the average causal effect conditional on covariates and the sensitivity parameter. We apply our methods to the world's first phase III HIV vaccine trial. [source]


Regulatory T cells in human geohelminth infection suppress immune responses to BCG and Plasmodium falciparum

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 2 2010
Linda J. Wammes
Abstract Chronic helminth infections induce T-cell hyporesponsiveness, which may affect immune responses to other pathogens or to vaccines. This study investigates the influence of Treg activity on proliferation and cytokine responses to BCG and Plasmodium falciparum -parasitized RBC in Indonesian schoolchildren. Geohelminth-infected children's in vitro T-cell proliferation to either BCG or pRBC was reduced compared to that of uninfected children. Although the frequency of CD4+CD25hiFOXP3+ T cells was similar regardless of infection status, the suppressive activity differed between geohelminth-infected and geohelminth-uninfected groups: Ag-specific proliferative responses increased upon CD4+CD25hi T-cell depletion in geohelminth-infected subjects only. In addition, IFN-, production in response to both BCG and parasitized RBC was increased after removal of CD4+CD25hi T cells. These data demonstrate that geohelminth-associated Treg influence immune responses to bystander Ag of mycobacteria and plasmodia. Geohelminth-induced immune modulation may have important consequences for co-endemic infections and vaccine trials. [source]


Dissecting cytotoxic T,cell responses towards the NY-ESO-1 protein by peptide/MHC-specific antibody fragments

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2004
Gerhard Held
Abstract NY-ESO-1 is a germ cell antigen aberrantly expressed by different tumor types that elicits strong humoral and cellular immune responses, representing one of the most promising candidates for vaccination of cancer patients. A detailed analysis of CD8+ T,cells generated in vaccine trials using NY-ESO-1-derived peptides (157,165 and 157,167) revealed that the dominant immune response was directed against a cryptic epitope (159,167) diverting the immune response from tumor recognition. Only CTL reactivity to the NY-ESO-1157,165 peptide appeared to be capable of lysing NY-ESO-1/HLA-A0201-expressing tumor cells. To study the process of NY-ESO-1 peptide presentation by tumor cells in more detail we generated a high-affinity (KD=60,nM) antibody fragment that specifically recognizes the NY-ESO-1157,165 peptide/HLA-A0201 complex. Peptide variants such as the NY-ESO-1157,167 peptide or the cryptic NY-ESO-1159,167 peptide were not recognized. The antibody fragment blocked in a dose-dependent fashion the recognition of NY-ESO-1/HLA-A2-positive tumor cells by NY-ESO-1157,165 peptide-specific CD8+ T,cells. This antibody fragment is a novel reagent that binds with TCR-like specificity to the NY-ESO-1157,165/HLA-A2 complex thus distinguishing between CTL responses against immunological meaningful or cryptic NY-ESO-1-derived peptides. It may therefore become a useful monitoring tool for the development of NY-ESO-1-based cancer vaccines. [source]


A miniaturized assay for influenza neuraminidase-inhibiting antibodies utilizing reverse genetics-derived antigens

INFLUENZA AND OTHER RESPIRATORY VIRUSES, Issue 5 2009
Matthew R. Sandbulte
Background, Antibodies to neuraminidase (NA) contribute to protection during influenza virus infection, but NA inhibition (NI) titers are not routinely analyzed in vaccine trials. One reason is the cumbersome nature of the conventional thiobarbituric acid (TBA) NI assay, which uses chemical methods to quantify free sialic acid following incubation of NA with substrate in the presence of serum. In addition, the assay is complicated by the need to use virus of a hemagglutinin (HA) subtype novel to the host to detect NA-specific antibodies only. Objectives, Our primary objectives were to miniaturize the colorimetric NI assay to a format suitable for quantitative analysis of large numbers of samples, and validate the specificity and sensitivity of the miniaturized format with ferret and human sera. An additional aim was to use reverse genetics to construct HA-mismatched viral reagents bearing NA of recent influenza A vaccine strains and H6 HA. Results, Analysis of ferret antisera by the miniaturized assay demonstrated sensitivity and specificity comparable with the conventional assay. Similar increases in the NI titers in sera from vaccinated human volunteers were measured in miniaturized and conventional assays. Inactivated and live-attenuated vaccines increased NI titers against a given subtype at approximately the same rate. Conclusions, The reagents and miniaturized format of the TBA method described here provide a platform for practical serological monitoring of functional antibodies against NA. [source]


Bad blood: The Tuskegee syphilis study and legacy recruitment for experimental AIDS vaccines

NEW DIRECTIONS FOR ADULT & CONTINUING EDUCATION, Issue 105 2005
Kimberly Sessions Hagen
For African Americans, medical research often connotes exploitation and cruelty, making recruiting African Americans to participate in HIV vaccine trials particularly daunting. But infusing adult education principles into such efforts is both increasing African American participation and helping heal the legacy of the Tuskegee experiment. [source]


Protective immunization of calves against Ostertagia ostertagi using fourth stage larval extracts

PARASITE IMMUNOLOGY, Issue 9-10 2010
A. M. HALLIDAY
Summary ConA lectin was used to isolate glycoproteins from detergent extracts of fourth stage Ostertagia ostertagi larvae. This preparation contained proteins additional to those observed in a similar fraction prepared from adult O. ostertagi. Two vaccine trials were conducted with this preparation, and sub-fractions thereof, in groups of 6,8 worm-free calves. All groups were challenged with 50 000 O. ostertagi larvae 1 week after the final immunization, and protection was assessed by comparing the egg and worm counts of the immunized groups with their respective controls. Immunization with the ConA-binding antigen or its sub-fractions induced high titre serum antibody responses. In the first trial, the cumulative egg count of the group immunized with unfractionated antigen was 60% lower than the corresponding control value, and worm counts were 47% lower. In the second trial, the cumulative egg counts of the vaccinated groups ranged from 70% to 85% lower than the corresponding controls, with worm counts up to 64% lower. It was concluded that detergent-soluble, ConA-binding extracts prepared from O. ostertagi fourth stage larvae contained protective immunogens that were as effective as the best antigens published for O. ostertagi to date. [source]


Chop-Lump Tests for Vaccine Trials

BIOMETRICS, Issue 3 2009
Dean Follmann
Summary This article proposes new tests to compare the vaccine and placebo groups in randomized vaccine trials when a small fraction of volunteers become infected. A simple approach that is consistent with the intent-to-treat principle is to assign a score, say,W, equal to 0 for the uninfecteds and some postinfection outcome X,> 0 for the infecteds. One can then test the equality of this skewed distribution of,W,between the two groups. This burden of illness (BOI) test was introduced by Chang, Guess, and Heyse (1994,,Statistics in Medicine,13, 1807,1814). If infections are rare, the massive number of 0s in each group tends to dilute the vaccine effect and this test can have poor power, particularly if the,X's are not close to zero. Comparing,X,in just the infecteds is no longer a comparison of randomized groups and can produce misleading conclusions. Gilbert, Bosch, and Hudgens (2003,,Biometrics,59, 531,541) and Hudgens, Hoering, and Self (2003,,Statistics in Medicine,22, 2281,2298) introduced tests of the equality of,X,in a subgroup,the principal stratum of those "doomed" to be infected under either randomization assignment. This can be more powerful than the BOI approach, but requires unexaminable assumptions. We suggest new "chop-lump" Wilcoxon and,t -tests (CLW and CLT) that can be more powerful than the BOI tests in certain situations. When the number of volunteers in each group are equal, the chop-lump tests remove an equal number of zeros from both groups and then perform a test on the remaining,W's, which are mostly >0. A permutation approach provides a null distribution. We show that under local alternatives, the CLW test is always more powerful than the usual Wilcoxon test provided the true vaccine and placebo infection rates are the same. We also identify the crucial role of the "gap" between 0 and the,X's on power for the,t -tests. The chop-lump tests are compared to established tests via simulation for planned HIV and malaria vaccine trials. A reanalysis of the first phase III HIV vaccine trial is used to illustrate the method. [source]


A Bayesian Semiparametric Joint Hierarchical Model for Longitudinal and Survival Data

BIOMETRICS, Issue 2 2003
Elizabeth R. Brown
Summary This article proposes a new semiparametric Bayesian hierarchical model for the joint modeling of longitudinal and survival data. We relax the distributional assumptions for the longitudinal model using Dirichlet process priors on the parameters defining the longitudinal model. The resulting posterior distribution of the longitudinal parameters is free of parametric constraints, resulting in more robust estimates. This type of approach is becoming increasingly essential in many applications, such as HIV and cancer vaccine trials, where patients' responses are highly diverse and may not be easily modeled with known distributions. An example will be presented from a clinical trial of a cancer vaccine where the survival outcome is time to recurrence of a tumor. Immunologic measures believed to be predictive of tumor recurrence were taken repeatedly during follow-up. We will present an analysis of this data using our new semiparametric Bayesian hierarchical joint modeling methodology to determine the association of these longitudinal immunologic measures with time to tumor recurrence. [source]