Biomedical subjects

Ivan S F Chan

Publications and source records attributed to Ivan S F Chan.

8 recordsLinked to original sources

PubMed2003

Decline in varicella-zoster virus (VZV)-specific cell-mediated immunity with increasing age and boosting with a high-dose VZV vaccine.

The safety and immunogenecity of a booster dose of live attenuated varicella-zoster virus (VZV) vaccine was evaluated in 196 healthy subjects, >or=60 years old, who had already received a VZV vaccine >5 years before. This repeat booster dose was well tolerated. Cell-mediated immunity (CMI) to VZV was measured by an interferon-gamma (IFN-gamma) enzyme-linked immunosorbent spot-forming cell (ELISPOT) assay and a limiting dilution responder cell frequency (RCF) assay. Prevaccination responses decreased as a function of increasing age but were detectable in all subjects by use of the IFN-gamma ELISPOT assay. In most subjects, VZV-specific CMI was increased at 6 weeks postvaccination. The magnitude of the vaccine-induced IFN-gamma ELISPOT response was inversely related to prevaccination values. Although there was a significant correlation between the IFN-gamma ELISPOT and RCF assays, the ELISPOT assay had greater sensitivity and a wider dynamic range. A live attenuated VZV vaccine is safe and immunogenic in an elderly population, and the vaccine-induced immunity may be monitored by the IFN-gamma ELISPOT assay.

Age Factors↗

PubMed2003

Measurement of cell-mediated immunity with a Varicella-Zoster Virus-specific interferon-gamma ELISPOT assay: responses in an elderly population receiving a booster immunization.

An interferon-gamma ELISPOT assay has been developed for assessment of cellular immune responses to Varicella-Zoster Virus (VZV) in large, multi-center clinical vaccine trials. We show that the assay performed best when testing peripheral blood mononuclear cells (PBMCs) that had been isolated and then frozen on the same day as blood was drawn, and that freezing PBMCs from blood that was stored overnight before processing resulted in dramatically reduced responses. This assay was used to monitor cell-mediated immunity (CMI) in response to a booster immunization with an investigational live, attenuated VZV vaccine in an elderly population that had been vaccinated 8-10 years previously. The booster vaccine elicited a 1.6- to 1.7-fold rise in the VZV-specific cellular immune response as measured by the ELISPOT assay. The increase from pre to post booster vaccination response was more pronounced (approximately 2.2-fold rise) in a subset of subjects who had received two prior immunizations with a live, attenuated vaccine.

Aged↗

PubMed2003

A cautionary note on exact unconditional inference for a difference between two independent binomial proportions.

Fisher's exact test for comparing response proportions in a randomized experiment can be overly conservative when the group sizes are small or when the response proportions are close to zero or one. This is primarily because the null distribution of the test statistic becomes too discrete, a partial consequence of the inference being conditional on the total number of responders. Accordingly, exact unconditional procedures have gained in popularity, on the premise that power will increase because the null distribution of the test statistic will presumably be less discrete. However, we caution researchers that a poor choice of test statistic for exact unconditional inference can actually result in a substantially less powerful analysis than Fisher's conditional test. To illustrate, we study a real example and provide exact test size and power results for several competing tests, for both balanced and unbalanced designs. Our results reveal that Fisher's test generally outperforms exact unconditional tests based on using as the test statistic either the observed difference in proportions, or the observed difference divided by its estimated standard error under the alternative hypothesis, the latter for unbalanced designs only. On the other hand, the exact unconditional test based on the observed difference divided by its estimated standard error under the null hypothesis (score statistic) outperforms Fisher's test, and is recommended. Boschloo's test, in which the p-value from Fisher's test is used as the test statistic in an exact unconditional test, is uniformly more powerful than Fisher's test, and is also recommended.

Humans↗

PubMed2002

Use of statistical models for evaluating antibody response as a correlate of protection against varicella.

In vaccine clinical trials, humoral antibody responses are often used to measure the effect of a vaccine because they correlate with a vaccine's protective efficacy against the target disease. While the concept of a correlate of protection usually refers to establishing a protective level of antibody titre, identifying a clear-cut value is often impossible because vaccine efficacy is not related solely to the antibody titre. We propose examining the relationship between disease protection and the whole distribution of antibody responses rather than a single cut-off level. In particular, we use failure-time models to estimate the relationship between long-term disease breakthroughs and primary antibody responses after vaccination. We apply these models to show that the varicella antibody response measured by glycoprotein enzyme-linked immunosorbent assay 6 weeks after vaccination strongly correlate with protection against varicella (chickenpox); we used 7-year follow-up data from children who received one dose of a live attenuated varicella (Oka/Merck) vaccine. In addition, we explore the potential use of these models to predict long-term disease breakthrough rates and to estimate the predicted vaccine efficacy of a similar varicella vaccine made with a modified manufacturing process.

Antibodies, Viral↗

PubMed2002

A comparison of safety, tolerability and immunogenicity of Oka/Merck varicella vaccine and VARILRIX in healthy children.

This study compared safety, tolerability, and immunogenicity of the Oka/Merck varicella vaccine and VARILRIX [Oka-RIT strain SmithKline Beecham Biologicals] in healthy children 12-24 months of age. Subjects were randomized in this double blind study to receive either a single dose of Oka/Merck varicella vaccine, (approximately 50,000 plaque forming units (PFU), Group A or approximately 16,000 PFU, Group B) or 1 dose of VARILRIX, (approximately 40,000 PFU/dose, Group C). Safety profiles in each treatment group were similar. The proportions of subjects achieving a 6-week postvaccination titer> or = 5 gpELISA units in Groups A, B or C were 97.1, 95.2 and 85.6%, respectively.

Antibodies, Viral↗

PubMed2002

Response to recombinant hepatitis B vaccine in children and adolescents with chronic renal failure.

BACKGROUND: Diminished antibody responses to the dosage of hepatitis B (HB) vaccine indicated for healthy adults has led to a greater dosage recommendation (40 microg of HB surface antigen [HBsAg]) for adults with chronic renal failure (CRF), but an appropriate dosage for children with CRF has not been established. METHODS: Seventy-eight children and adolescents with CRF (22 patients, predialysis; 42 patients, chronic dialysis therapy; 14 renal transplant recipients) aged 1 to 19 years (mean, 10.1 years) were enrolled onto a study to test a three 20-microg dose course of the HB vaccine Recombivax HB (Merck & Co, Inc, West Point, PA). RESULTS: The vaccine was well tolerated; no patient had a serious adverse event attributable to vaccine, and no patient withdrew from the study because of an adverse event. Overall, 91% of 66 patients administered three doses had a protective titer of 10 mIU/mL or greater for antibody against HBsAg (anti-HBs) and a geometric mean titer (GMT) of 733 mIU/mL, with seroprotection rates and GMTs among predialysis, dialysis, and renal transplant patients of 100% (4,140 mIU/mL), 94% (419 mIU/mL), and 64% (152 mIU/mL), respectively. All (100%) predialysis patients had a 10-mIU/mL or greater anti-HBs titer after only two doses of vaccine compared with 64% of dialysis patients and 50% of transplant recipients. Eighty-eight percent of 57 fully vaccinated patients tested 12 months after the first dose retained a 10-mIU/mL or greater anti-HBs titer. CONCLUSION: A regimen of three 20-microg doses of Recombivax HB is suitably immunogenic for children with CRF not administered immunosuppressive medication. When possible, at least two, and preferably all three, doses of vaccine should be administered before progression to end-stage renal disease.

Adolescent↗

PubMed2002

Power and sample size determination for noninferiority trials using an exact method.

Noninferiority studies are frequently conducted to justify the development of new drugs and vaccines that have been shown to offer better safety profiles, easier administration, or lower cost while maintaining similar efficacy as compared to the standard treatment. Recently, exact methods have been developed to address the concern that existing asymptotic methods for analyzing and planning noninferiority may fail because of small sample size or because of skewed or sparse data structure. In this paper, we explore the use of exact methods in determining sample size and power for noninferiority studies that focus on the difference of two proportions. The methodology for sample size and power calculations is developed based on an exact unconditional test of noninferiority. We illustrate this exact method using a clinical trial example in childhood nephroblastoma and briefly discuss the optimal sample-size allocation strategy. This exact unconditional method performs very well in various scenarios and compares favorably to its asymptotic counterpart in terms of sensitivity. Therefore, it is a very desirable tool for planning noninferiority trials, especially in situations where asymptotic methods are likely to fail.

Algorithms↗

PubMed2002

Inverse relationship between six week postvaccination varicella antibody response to vaccine and likelihood of long term breakthrough infection.

BACKGROUND: We used the large clinical database that supported the development of Oka/ Merck varicella vaccine to study the relationship between the primary varicella antibody response, as determined by gpELISA, an enzyme-linked immunosorbent assay that detects antibodies to varicella-zoster virus (VZV) glycoprotein, and the subsequent risk of postvaccination breakthrough varicella. METHODS: We vaccinated 1,164 healthy children with a single dose of varicella vaccine containing 2900 to 9000 plaque-forming units/dose. The primary immune response to vaccination was determined by gpELISA 6 weeks after vaccination. Subjects were followed annually for 7 years to ascertain cases of breakthrough varicella. RESULTS: The estimated vaccine efficacy among children with a 6-week postvaccination antibody titer of > or = 5 gpELISA units was 95.5% (95% confidence interval, 94.2%, 96.8%) compared with 83.5% (95% confidence interval, 76.9%, 89.5%) for subjects with a titer of <5 gpELISA units. Children with a 6-week postvaccination antibody titer of <5 gpELISA units were 3.5 times more likely than those with a titer of > or = 5 gpELISA units to develop breakthrough varicella. CONCLUSIONS: We identified a 6-week postvaccination antibody titer of > or = 5 gpELISA units as an approximate correlate of protection. In addition we established an accelerated failure time model based on log normal hazard that predicted varicella breakthrough rates based on the distribution of 6-week postvaccination varicella antibody titers.

Antibodies, Viral↗