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.

Vaccination with measles, mumps and rubella vaccine and varicella vaccine: safety, tolerability, immunogenicity, persistence of antibody and duration of protection against varicella in healthy children.

BACKGROUND: Administration of M-M-R II (Measles, Mumps and Rubella Virus Vaccine, Live) and VARIVAX [Varicella Virus Vaccine Live (Oka/Merck)] given concomitantly at separate injection sites during the same office visit could increase vaccine compliance by reducing the number of health care visits for immunizations. We compared the safety and immunogenicity of M-M-R II and VARIVAX given concomitantly at separate sites (Group A) with administration of the two vaccines 6 weeks apart (Group B) as well as the persistence of varicella antibody and the duration of protection afforded by varicella vaccine. METHODS: A total of 603 healthy children, ages 12 months to 6 years, with no history of measles, mumps, rubella, varicella and zoster or vaccination against these diseases, were randomized to either Group A or B and were followed for clinical reactions and serologic responses to all four viral components. Children were enrolled from August through December, 1993. Subjects were followed for 5 years to evaluate persistence of varicella antibody and breakthrough varicella rates. We compared breakthrough rates to expected attack rates in unvaccinated children to produce estimates of vaccine efficacy. RESULTS: Both vaccine regimens were generally well-tolerated. There were no significant differences between the groups in the rates of fever, injection site reactions or rashes after vaccination. Seroconversion rates and geometric mean titers for measles, mumps and rubella were not significantly different between groups. The varicella seroconversion rate and percentage with glycoprotein-based ELISA titers > or = 5.0 units were similar between the two groups (99.5 and 92.5% vs. 100 and 94.8% for Groups A and B, respectively), but the geometric mean titers were statistically significantly different (13.2 for Group A and 17.9 for Group B). Varicella antibody persistence rates were >98 to 100% during 6 years of follow-up in both groups. Compared with historical rates, varicella vaccine efficacy during 5 years was estimated to be 90.5% (95% confidence interval, 86.2%, 95.0%) and 88.9% (95% confidence interval, 83.7%, 93.7%) in Groups A and B, respectively. CONCLUSIONS: Administration of M-M-R II and VARIVAX concomitantly at separate injection sites or 6 weeks apart was generally well-tolerated and immunogenic in healthy children 12 months to 6 years of age. VARIVAX administered with M-M-R II induced persistent immunity and long-term protection against breakthrough varicella infection.

Influence of genotype on the natural history of untreated proliferative sickle retinopathy--an angiographic study.

The natural history of untreated proliferative sickle retinopathy (PSR) has been observed in 35 patients (40 eyes) with homozygous sickle cell (SS) disease and in 112 patients (114 eyes) with sickle cell-haemoglobin C (SC) disease over a mean follow-up period of 4.5 years (range 0.5-14.0 years). In both genotypes progression of PSR was most frequent between ages 20 and 39 years. Spontaneous regression was more common in SS disease (p = 0.01), and more likely to proceed to complete non-perfusion. In SC disease PSR tended to be stable in patients aged 40 and over, and non-perfused PSR lesions were significantly more likely to reperfuse (p = 0.01) than in SS disease. In both genotypes regression was not influenced by size or elevation of the PSR lesion. The tendency for PSR to regress in SS disease suggests that treatment is unnecessary in SS patients aged 40 and over.

A functionally significant allelic polymorphism in a T cell receptor V beta gene segment.

The effect of an allelic polymorphism in the BV1S1 gene segment on recognition of major histocompatibility complex (MHC)-peptide complexes by a specific T cell receptor (TCR) was studied using RBL 2H3 cells transfected with TCR-CD3 zeta chimeric receptors. An HLA-A2-restricted human immunodeficiency virus (HIV) pol-specific cytotoxic T lymphocyte (CTL) clone utilizing the BV1S1A2 gene in combination with AV2S1A2 was identified and the extracellular domains of the TCR were fused to CD3 zeta. In degranulation assays RBL 2H3 transfectants expressing this receptor maintained the specificity of the parental CTL clone. The allelic variant BV1S1A1N1 containing a glutamine for histidine substitution at position 48 in the loop of the second complementarity-determining region was generated by site-directed mutagenesis. Transfection of this molecule as a CD3 zeta chimera together with the original AV2S1A2 CD3 zeta molecule resulted in cell surface expression of both chains but a loss of recognition of HLA-A2 HIV pol peptide-pulsed targets. The effect of this polymorphism on MHC-peptide recognition supports current models of TCR MHC-peptide interaction and provides evidence for a functional role for polymorphism in the TCRV genes.

Absence of mutations in the Gs alpha and Gi2 alpha genes in sporadic parathyroid adenomas and insulinomas.

1. Activating mutations of the alpha-subunits of the Gs and Gi2 proteins give rise to the oncogenes gsp and gip2, respectively, which are found in a variety of endocrine tumours. 2. In this study the polymerase chain reaction and direct sequencing have been used to screen a small sample of parathyroid adenomas and insulinomas for these mutations. 3. No mutations were identified in nine insulinomas and 13 parathyroid adenomas screened for gsp, and 11 parathyroid adenomas and four insulinomas screened for gip2. In addition, two gastrinomas from patients with multiple endocrine neoplasia type 1 were found to be negative for both oncogenes. 4. This is the first report of screening for gip2 in parathyroid adenomas and gsp/gip2 in insulinomas, and it extends the range of tumours examined for these oncogenes.

Laser photocoagulation for proliferative retinopathy in sickle haemoglobin C disease.

The effect of sectoral, scatter laser photocoagulation on proliferative sickle retinopathy (PSR) was investigated by reviewing fluorescein angiograms of 88 sickle cell-haemoglobin C patients enrolled in a controlled, randomised trial. Follow-up was for a median period of 2.9 years. Complete infarction of all PSR in an eye occurred in 7 of 74 treated eyes and 2 of 60 control eyes. Treatment resulted in significantly greater regression (decrease in number or size of PSR lesions) in eyes of patients aged < 25 years at enrollment but not in eyes of patients > or = 25 years at enrollment. Infarction of individual PSR lesions was significantly more common in treated eyes. Treated PSR was significantly more likely to infarct if small (< 15 degrees circumferential involvement) and if flat rather than elevated. New PSR was significantly less likely to develop in treated eyes.

Engagement of a T cell receptor by major histocompatibility complex irrespective of peptide.

T cell receptors (TCR) identify target cells presenting a ligand consisting of a major histocompatibility complex molecule (MHC) and an antigenic peptide. A considerable amount of evidence indicates that the TCR contacts both the peptide and the MHC components of the ligand. In fully differentiated T cells the interaction between the peptide and the TCR makes the critical contribution to eliciting a cellular response. However, during the positive selection of thymocytes the contribution of peptide relative to MHC is less well established. Indeed it has been suggested that the critical interaction for positive selection is between the TCR and the MHC molecule and that peptides can be viewed as either allowing or obstructing this contact. This predicts that a given TCR is capable of engaging multiple MHC/peptide complexes. In this study a system is described which detects simply engagement of the TCR by MHC/peptide complexes rather than the functional outcome of such interactions. Using this approach the extent to which peptides can influence contacts between the TCR and the MHC molecule has been examined. The results show that the TCR does in fact engage a wide range of ligands in an MHC-restricted but largely peptide-independent manner, suggesting that only a few peptides are able to prevent the TCR from contacting the MHC molecule.

Childhood vaccination against varicella: persistence of antibody, duration of protection, and vaccine efficacy.

OBJECTIVE: To document the duration of protection afforded by Oka/Merck varicella vaccine over a 7-year period. STUDY DESIGN: The subjects were healthy children 1 to 12 years of age originally enrolled in clinical studies to evaluate the primary immune response to varicella vaccine 6 weeks after vaccination. Each was monitored for antibody persistence, breakthrough infection, and household exposure to varicella to produce estimates of vaccine efficacy. RESULTS: The 6-year cumulative varicella antibody persistence rate was 99.5% (95% CI: 98.9%, 100.0%). The annual breakthrough rate through 7 years ranged from 0.2% to 2.3% per year; the estimated cumulative event rate was 6.5%. Comparison of the observed average annual breakthrough rate with the age-adjusted expected annual incidence rate of varicella in unvaccinated children corresponded to an estimated vaccine efficacy of 93.8% to 94.6%. Eighty vaccinated children were exposed to varicella in the household, resulting in 8 (10%) cases of infection. When compared with the historical attack rate of 86.8% in unvaccinated susceptible persons exposed to varicella in the household, this yields an estimated vaccine efficacy of 88.5% (95% CI: 80.9%, 96.1%). Varicella cases in vaccinated children generally were mild. CONCLUSION: The live attenuated varicella vaccine is highly effective in inducing persistent immunity and long-term protection against breakthrough varicella infection.

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.

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.

Laser photocoagulation for proliferative retinopathy in sickle haemoglobin C disease

The effect of sectoral, scatter laser photocoagulation on proliferative sickle retinopathy (PSR) was investigated by reviewing florescein angiograms of 88 sickle cell-haemoglobin C patients enrolled in a controlled, randomised trial. Follow-up was for a median period of 2.9 years. Complete infarction of all PSR in an eye occurred in 7 of 74 treated eyes and 2 0f 60 control eyes. Treatment resulted in significantly greater regression (decrease in number and size of PSR lesions) in eyes of patients aged <25 years at enrollment but not in eyes of patients> or = 25 years at enrollment. Infarction of the individual PSR lesions was significantly more common in treated eyes. Treated PSR was significantly more likely to infarct if small (< 15 degrees circumferential involvement) and if flat rather than elevated. New PSR was significantly less likely to develop in treated eyes.