A quadrivalent measles, mumps, rubella and varicella vaccine would facilitate universal immunization against all 4 diseases, improve compliance and immunization rates and decrease the number of ...injections given to children and visits to physicians' offices.
To evaluate 1- and 2-dose regimens of a combined measles, mumps, rubella and varicella vaccine (ProQuad, referred to as MMRV) manufactured with a varicella component of increased potency.
In this partially blind, multicenter study, 480 healthy 12- to 23-month-old children were randomized to receive either MMRV and placebo or M-M-RII and VARIVAX. Injections were given concomitantly at separate sites. Subjects randomized to receive MMRV and placebo received a second dose of MMRV 90 days later. Subjects were followed for 42 days after each vaccination for adverse experiences. Immunogenicity was evaluated 6 weeks after each vaccination.
Measles-like rash and fever during days 5-12 were more common after the first dose of MMRV (rash, 5.9%; fever, 27.7%) than after M-M-RII and VARIVAX (rash, 1.9%; fever, 18.7%). The incidence of other adverse events were similar between groups. Response rates were >90% to all vaccine components in both groups. Geometric mean titers to measles and mumps were significantly higher after 1 dose of MMRV than after administration of M-M-RII and VARIVAX. The second dose of MMRV elicited slight to moderate increases in measles, mumps and rubella antibody titers and a substantial increase in varicella antibody titer (from 13.0 to 588.1 glycoprotein antigen-based enzyme-linked immunosorbent assay units/mL).
A 1- or 2-dose regimen of MMRV is generally well-tolerated when administered to 12- to 23-month-old children and has a safety and immunogenicity profile similar to that of M-M-RII and VARIVAX administered concomitantly.
In the United States, children receive primary doses of M-M-RII (Merck & Co, Inc, West Point, PA) and Varivax (Merck & Co, Inc) beginning at 12 months, often at the same health care visit. Currently ...a second dose of M-M-RII is given to 4- to 6-year-old children, to increase vaccination rates and to reduce the number of individuals without detectable antibodies. A second dose of a varicella-containing vaccine may result in similar benefits.
To demonstrate that ProQuad (measles, mumps, rubella, and varicella virus vaccine live; Merck & Co, Inc) may be given in place of a second dose of M-M-RII or second doses of M-M-RII and Varivax for 4- to 6-year-old children.
Four- to 6-year-old children who had been immunized previously with M-M-RII and Varivax were assigned randomly to receive either ProQuad and placebo (N = 399), M-M-RII and placebo (N = 195), or M-M-RII and Varivax (N = 205) and were then monitored for safety and immunogenicity.
ProQuad was generally well tolerated. Similarity (noninferiority) was demonstrated in postvaccination antibody responses to measles, mumps, and rubella between recipients of ProQuad and all recipients of M-M-RII and in responses to varicella between recipients of ProQuad and recipients of Varivax. Postvaccination seropositivity rates for antibodies against all 4 viruses were nearly 100% in all 3 groups. Small fold increases were observed for measles, mumps, and rubella antibody titers. In contrast, substantial boosts in varicella antibody titers were observed among recipients of a second dose of varicella vaccine, administered as ProQuad or Varivax.
ProQuad may be used in place of a second dose of M-M-RII or second doses of M-M-RII and Varivax for 4- to 6-year-old children.
301 healthy adult volunteers were randomized to one of three treatment groups: inactivated hepatitis A vaccine alone; inactivated hepatitis A vaccine with immune globulin (Ig) concurrently; or Ig ...alone. The first two treatment groups received a second dose of hepatitis A vaccine at week 24. Anti-HAV was measured 4, 8, 12, 24 and 28 weeks after the primary immunization. When comparing subjects receiving inactivated hepatitis A vaccine alone to those receiving vaccine and Ig, the seropositivity rates were not significantly different at 4, 8, 12 and 28 weeks, but at week 24 the seropositivity rate was lower in the group receiving both vaccine and Ig compared to the group receiving vaccine alone (92.0% compared to 97.0%). At weeks 8, 12 and 24 the geometric mean titers (GMTs) were significantly lower for subjects receiving both vaccine and Ig. The GMTs were not significantly different after the second dose of vaccine. At all time points, the lower serum antibody concentrations observed in subjects receiving both inactivated hepatitis A vaccine and Ig were nevertheless substantially higher than the cutoff for assay seropositivity and much higher than after Ig alone; these differences are therefore clinically insignificant.
Acidic fibroblast growth factor (aFGF) is markedly stabilized by heparin. Partially due to the heterogeneity of heparin preparations, the nature of the aFGF polyanion binding site is still ...ill-defined. We have, therefore, investigated a wide variety of well-defined polyanions in terms of their ability to stabilize human recombinant aFGF (15-154) against thermal denaturation. The specificity of the interaction between aFGF and polyanions is shown to be remarkably weak with a surprising number of polyanions (including small phosphorylated and sulfated compounds as well as highly charged biopolymers) able to induce physical stability. Temperature-dependent fluorescence and circular dichroism measurements show that many of these polyanionic compounds stabilize aFGF to the same extent as heparin. The ability of these agents to protect the three free thiol groups of aFGF from copper-catalyzed oxidation was also explored and significant protection was observed. The extent and electrostatic requirements of the protein's polyanion binding site were probed by the use of a series of well-defined heparin fragments and differentially phosphorylated inositol compounds. A tetrasaccharide fragment of heparin is the smallest unit of heparin capable of stabilizing aFGF against thermal denaturation. Increasing phosphorylation of inositol compounds (up to six phosphate groups per molecule) enhances the thermal stability of aFGF. These results are discussed in the context of a model of human aFGF based on the X-ray crystal structure of the bovine protein and previous studies by others of the heparin binding site of both acidic and basic FGF.
A combination measles, mumps, rubella, and varicella vaccine (ProQuad, Merck & Co., Inc, West Point, PA) was evaluated in five clinical trials. Use of ProQuad would result in fewer injections for ...children and would facilitate universal immunization against all four diseases.
To describe the combined results obtained from the studies conducted during the clinical development program for ProQuad.
A total of 5833 healthy children, 12-23 months of age, and 399 healthy children, 4-6 years of age, received 1 or 2 doses of ProQuad in five controlled clinical trials. M-M-R II and VARIVAX were used as the control for most studies. Safety was evaluated for six weeks postvaccination and immunogenicity was assessed six weeks after each dose by a sensitive assay (ELISA or gpELISA).
A single dose of ProQuad in 12- to 23-month-old children was shown to be as immunogenic as a single dose of M-M-R II and VARIVAX and was generally well tolerated. ProQuad can be used concomitantly with other vaccines (hepatitis B and Hoemophilus influenzoe b). A higher rate of fever was reported after 1 dose of ProQuad compared to M-M-R II and VARIVAX, but fever episodes were transient without long-term sequelae. Both a 2-dose regimen of ProQuad in 12- to 23-month-olds and use of ProQuad in place of M-M-R II at 4-6 years were shown to be immunogenic and well tolerated. The incidence of adverse experiences following a second dose of ProQuad was lower than that following the initial dose.
A single dose of ProQuad is as immunogenic as M-M-R II and VARIVAX and is well tolerated in a 1- or 2-dose schedule. ProQuad should easily fit into the routine immunization schedule.
The design of an aqueous formulation for acidic fibroblast growth factor (aFGF) requires an understanding of the type of compounds that can either directly or indirectly stabilize the protein. To ...this end, spectrophotometric turbidity measurements were initially employed to screen the ability of polyanionic ligands, less specific compounds, and variations in solution conditions (temperature and pH) to stabilize aFGF against heat-induced aggregation. It was found that in addition to the well-known protection of aFGF by heparin, a surprisingly wide variety of polyanions (including small sulfated and phosphorylated compounds) also stabilizes aFGF. These polyanionic ligands are capable of raising the temperature at which the protein unfolds by 15-30 degrees C. Many commonly used excipients were also observed to stabilize aFGF in both the presence and the absence of heparin. High concentrations of some of these less specific agents are also able to increase the temperature of aFGF thermal unfolding by as much as 6-12 degrees C as shown by circular dichroism and differential scanning calorimetry. Other compounds were found which protect the chemically labile cysteine residues of aFGF from oxidation. Aqueous formulations of aFGF were thus designed to contain both a polyanionic ligand that enhances structural integrity by binding to the protein and chelating agents (e.g., EDTA) to prevent metal ion-catalyzed oxidation of cysteine residues. While room-temperature storage (30 degrees C) leads to rapid inactivation of aFGF in physiological buffer alone, several of these aFGF formulations are stable in vitro for at least 3 months at 30 degrees C. Three aFGF topical formulations were examined in an impaired diabetic mouse model and were found to be equally capable of accelerating wound healing.
In 2005, the National Institutes of Health (NIH) chronic graft-versus-host disease (cGVHD) consensus project provided diagnosis and staging criteria, based mostly on clinical experience and expert ...opinion. These criteria were revised in 2014, aiming to provide enhanced specificity and clarity. However, the impact of 2014 changes to the original NIH cGVHD severity scoring criteria has not been reported. In this study, 284 patients, prospectively enrolled on the National Cancer Institute's cross-sectional cGVHD natural history study, were scored using the 2005 NIH cGVHD criteria and then rescored according to the 2014 modifications. In comparing the two criteria, 2014 cGVHD global severity scoring resulted in a tendency toward being categorized as milder scores (75 vs. 72% of severe score per 2014, p = 0.0009), with a statistically significant shift in NIH liver and lung scores toward milder categories (p < 0.0001). 2005 and 2014 NIH global severity scores showed a significant association with reduced grip strength (p < 0.0001), reduced joint range of motion (p = 0.0003), and the subspecialist evaluation score (p < 0.0001). Poor survival prediction of the severe NIH lung score is also retained in the new criteria (p = 0.0012). These findings support the use of 2014 cGVHD scoring criteria in continuous efforts to develop better classification systems.
Introduction
Chronic Graft-versus-Host Disease (cGvHD) is a complication of allogeneic stem cell transplantation. 2005 NIH Staging Criteria (SC) of cGvHD emerged as result of an international effort ...to provide uniform standards for clinicians and researchers. In 2014, NIH cGvHD SC were revised based on gathered scientific evidence. This study assessed the impact of 2014 revision of NIH cGvHD SC on Organ and Global Score distributions, and associations to functional and quality of life measures (QOL).
Methods
Patients (pts) with cGvHD participating in a natural history study of cGvHD (NCT00092235) between October 2004 and November 2016 were evaluated and followed for survival. NIH cGvHD organ and global severity scores (0-3) were prospectively assigned using the 2005 NIH cGvHD SC. Supervised by a physician experienced in cGvHD, two selected team members rescored pts retrospectively with the 2014 SC based on the original 2005 NIH cGvHD scoring forms and data obtained from assessments by clinician subspecialists. A total of 284 pts were evaluated. Distributions of organ-specific and global severity scores measured by the 2005 and 2014 NIH cGvHD SC were compared. 2014 NIH cGvHD SC were tested for associations with functional and QOL measures: Lee symptom scale (LSS), Short Form 36 (SF36), 2-minute walk test (2MW), grip strength (GS), joint range of motion (ROM), Human Activity Profile (HAP), mean Subspecialist Evaluation Score (mSSE), and Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), using the model established by Baird et al. to validate the original 2005 NIH SC in a subset of this cohort (BBMT 2013; 19:632). Survival analysis was performed to determine potential predictors of overall survival.
Results
Pts had a median age of 46 yrs (range 19-71); 37% were receiving moderate and 40% high levels of systemic immunosuppression. Pts scored by 2014 NIH SC tended to have slightly lower global severity scores in comparison to 2005 NIH SC (75% vs 72% pts with severe cGvHD). Lung and liver scores tended to be lower, 2014 NIH cGvHD organ-specific and global severity scores are shown in Table 1. 2014 NIH skin score was associated with reduced GS and ROM (both p<0.0001) and higher LSS (p=0.0001) and mSSE (p<0.0001). 2014 NIH lung score showed significant associations with lower values for 2MW, SF36 physical component summary score (PCS), and HAP maximum activity score (MAS), as well as higher mSSE (all p<0.0001) and a trend towards association with reduced GS (p=0.002). 2014 NIH global severity score (24% moderate, 72% severe in this population) was positively associated with mSSE (p<0.0001) and showed trends toward association with higher LSS and lower HAP adjusted activity score (AAS).
Five-year overall survival in this cohort was 70.9% (95% CI: 64.8-76.1%) with a median potential follow-up of 79 months. The final Cox survival model included 2014 NIH Lung score (3 vs 0-2, HR=2.67, 95% CI: 1.47-4.84; p=0.0012), time from cGvHD diagnosis to consent (4+ yrs vs <4 yrs, HR=0.53, 95% CI: 0.31-0.94, p=0.028), and Karnofsky performance status (KPS, 80-100% vs <80%, HR=0.48, 95% CI: 0.30-0.77; p=0.0020). In the analysis of the 2005 NIH cGvHD SC, Baird and colleagues reported a Cox survival model including 2005 NIH lung score, time from cGvHD diagnosis to consent, and absolute eosinophil count, but not KPS.
The associations between NIH Global score and the NIH lung score and patient-reported outcome measures are similar to those in the Baird et al. analysis of 2005 NIH cGvHD SC. In contrast to Baird et al. statistically significant associations are now seen between global severity, skin score and lung scores and performance-based measures including GS and 2MW. This suggests that scoring refinements introduced in 2014 have strengthened the validity of the NIH SC.
Conclusions
In this cross-sectional cohort severely affected by cGvHD, the 2014 NIH cGvHD SC organ-specific and global scores were associated with functional and QOL measures, and likely reflect cGvHD burden. Refinements in describing lung and liver cGvHD resulted in lower scores for these organs using the 2014 NIH cGvHD SC compared to the 2005 NIH cGvHD SC. These findings illustrate that 2014 NIH cGvHD SC are valid measures for cGvHD-related burden and warrant study within both clinical care and prospective trials.
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No relevant conflicts of interest to declare.
Abstract Between 2004 and 2010, 189 adult patients were enrolled on the National Cancer Institute's cross-sectional chronic graft-versus-host disease (cGVHD) natural history study. Patients were ...evaluated by multiple disease scales and outcome measures, including the 2005 National Institutes of Health (NIH) Consensus Project cGVHD severity scores. The purpose of this study was to assess the validity of the NIH scoring variables as determinants of disease severity in severely affected patients in efforts to standardize clinician evaluation and staging of cGVHD. Out of 189 patients enrolled, 125 met the criteria for severe cGVHD on the NIH global score, 62 of whom had moderate disease, with a median of 4 (range, 1-8) involved organs. Clinician-assigned average NIH organ score and the corresponding organ scores assigned by subspecialists were highly correlated ( r = 0.64). NIH global severity scores showed significant associations with nearly all functional and quality of life outcome measures, including the Lee Symptom Scale, Short Form-36 Physical Component Scale, 2-minute walk, grip strength, range of motion, and Human Activity Profile. Joint/fascia, skin, and lung involvement affected function and quality of life most significantly and showed the greatest correlation with outcome measures. The final Cox model with factors jointly predictive for survival included the time from cGVHD diagnosis (>49 versus ≤49 months, hazard ratio HR = 0.23; P = .0011), absolute eosinophil count at the time of NIH evaluation (0-0.5 versus >0.5 cells/μL, HR = 3.95; P = .0006), and NIH lung score (3 versus 0-2, HR = 11.02; P < .0001). These results demonstrate that NIH organs and global severity scores are reliable measures of cGVHD disease burden. The strong association with subspecialist evaluation suggests that NIH organ and global severity scores are appropriate for clinical and research assessments, and may serve as a surrogate for more complex subspecialist examinations. In this population of severely affected patients, NIH lung score is the strongest predictor of poor overall survival, both alone and after adjustment for other important factors.
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