Safety, tolerability and immunogenicity of concomitant injections in separate locations of M-M-R II, VARIVAX and TETRAMUNE in healthy children vs. concomitant injections of M-M-R II and TETRAMUNE followed six weeks later by VARIVAX.

OBJECTIVES AND STUDY DESIGN: The primary objectives of this study were to compare immunologic responses, antibody persistence, safety and varicella breakthrough rates when VARIVAX (varicella vaccine) is given at the same time as M-M-R II (measles, mumps, rubella vaccine) and TETRAMUNE (conjugate Haemophilus influenzae type b, diphtheria, tetanus and whole cell pertussis vaccine) at separate injection sites (Group A) vs. VARIVAX given 6 weeks after M-M-R II and TETRAMUNE (Group B). Six hundred nine healthy children, 12 to 23 months of age, were randomized to one of two treatment (immunization) groups (Group A and Group B). Blood for antibody titers was drawn on the day of immunization, 6 weeks after each injection and 1 year later. Local and systemic adverse reactions were recorded. Exposure and cases of varicella were documented through a 1-year follow-up period. RESULTS: Measles, mumps and rubella seroconversion rates and geometric mean titers (GMTs) were similar for both treatment groups. Varicella seroconversion rates were also similar between groups. However, varicella GMTs and percent with a varicella-protective level [> or =5.0 glycoprotein (gp) enzyme-linked immunosorbent assay (ELISA) units] did not meet the prespecified criteria for similarity were lower for Group A (GMT 10.5; 82.8% > or =5.0 gp ELISA units) than for Group B (GMT 14.5; 91.2% > or =5.0 gp ELISA units). The GMTs between groups for other antibodies were similar. At the 1-year follow-up antibody titers were comparable in both groups and breakthrough varicella cases appeared generally similar. There were fewer local adverse events (AEs) at the VARIVAX injection sites (9.8% and 2.9%, Group A and B, respectively) than at the TETRAMUNE sites (27.9% and 24.0%). Systemic AEs were not statistically different when M-M-R II was administered alone (8.6%) or concomitantly with VARIVAX (8.9%). When VARIVAX was given alone AEs were 1.8%. The rate of fever > or =102 degrees F after M-M-R II and TETRAMUNE administered together was 10.7% on Days 0 to 3 and 23.7% on Days 7 to 21. When VARIVAX was administered alone, the rate of fever was 5.4% on Days 0 to 3 (P = 0.018) and 10.8% on Days 7 to 21 (P<0.001). CONCLUSION: Because the varicella titers were comparable and varicella breakthrough rates generally similar at 1 year in both groups, we expect that the concomitant administration of VARIVAX with M-M-R II and TETRAMUNE has clinical effectiveness similar to that with VARIVAX 6 weeks after the administration of these other two vaccines. VARIVAX appears to be less reactogenic than M-M-R II and TETRAMUNE.

Regulation of malic enzyme synthesis by insulin triiodothyronine, and glucagon in liver cells in culture.

Cells isolated from the livers of 17- to 19-day-old chick embryos were maintained in a chemically defined culture medium. During 3 days in culture the activity of malic enzyme, a measure of its concentration, was stimulated 2-, 23-, or 77-fold by insulin, triiodothyronine, or insulin plus triiodothyronine, respectively. Glucagon blocked the stimulation caused by insulin plus triiodothyronine. Changes in the relative synthesis of immunologically isolated malic enzyme were similar in magnitude and direction to the changes in enzyme activity. Degradation of malic enzyme was unaffected by the three hormones. Both soluble protein and malic enzyme were degraded with a t1/2 of about 30 hours. In cells preincubated for 2 days with insulin, synthesis of malic enzyme was stimulated 4.5-fold within 3 hours after adding triiodothyronine and reached an apparent new steady state after 24 to 30 hours. If the rate of enzyme synthesis was dependent on the concentration of cytoplasmic malic enzyme messenger RNA, then this messenger RNA appeared to have a t1/2 of about 18 hours. Glucagon rapidly and specifically inhibited synthesis of malic enzyme in preinduced cells, suggesting an action at the level of translation or cytoplasmic messenger RNA processing.

On ferritin heterogeneity. Further evidence for heteropolymers.

Tissue ferritins from the horse, rat, and human consist of multiple isoferritins some of which are common to more than one tissue in the same individual. Subunit analyses indicate that the ferritins from all three species are similarly composed of only two types of subunit with an approximate Mr of 21,000 and 19,000, designated H and L. The relative amounts of these subunits vary progressively throughout the isoferritin spectrum. Amino acid analyses and tryptic peptide maps indicate that the H and L subunits have extensive sequence homologies and that both are species-specific. Both subunits have been identified as the primary products of apoferritin synthesis in a wheat germ lysate programmed by rat liver mRNA. These results substantiate our proposal (Adelman, T. G., Arosio, P., and Drysdale, J. W. (1975) Biochem. Biophys. Res. Commun. 63, 1056-1062) that tissue ferritins are not unique homopolymers but families of hybrid molecules consisting of different proportions of two subunit types.