Gary S. Marshall

Safety and Immunogenicity of a Combination: Measles, Mumps, Rubella and Varicella Vaccine (ProQuad®)

Background: A combination measles, mumps, rubella, and varicella vaccine (ProQuad®, Merck & Co., Inc, West Point, PA) was evaluated in 5 clinical trials. Use of ProQuad® would result in fewer injections for children and would facilitate universal immunization against all 4 diseases. Objective: To describe the combined results obtained from the studies conducted during the clinical development program for ProQuad®. Methods: 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 5 controlled clinical trials. M-M-R®II and VARIVAX® were used as the control for most studies. Safety was evaluated for 6 weeks postvaccination and immunogenicity was assessed 6 weeks after each dose by a sensitive assay (ELISA or gpELISA). Results: 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 Haemophilus influenzae 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. Conclusions: 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.

Immunogenicity and Safety of H influenzae Type b–N meningitidis C/Y Conjugate Vaccine in Infants

BACKGROUND: Meningococcal disease incidence is highest in children younger than 2 years of age, yet there is no US-licensed vaccine for this age group. A phase III study evaluated the immunogenicity and safety of an investigational Haemophilus influenzae type b (Hib)–Neisseria meningitidis serogroups C and Y-tetanus toxoid conjugate vaccine (HibMenCY). MATERIALS AND METHODS: A total of 4180 infants were randomly assigned to receive the HibMenCY at the ages of 2, 4, 6, and 12 to 15 months or the licensed Hib tetanus toxoid conjugate vaccine (ActHIB) at 2, 4, and 6 months and Hib conjugated to N meningitidis outer membrane protein (PedvaxHIB) at 12 to 15 months. Routinely scheduled vaccines were coadministered. Serum bactericidal activity using human complement and anti–polyribosylribitol phosphate antibodies were assessed in 991 subjects. Local and systemic adverse reactions were recorded for 4 days after each dose. RESULTS: The percentage of HibMenCY recipients with serum bactericidal assay using human complement titers of 1:8 or higher after dose 3 was 98.8% for N meningitidis serogroup C (MenC) and 95.8% for N meningitidis serogroup Y (MenY). After dose 4, the percentages were 98.5% and 98.8%, respectively. The percentage of HibMenCY recipients with postdose 3 anti-polyribosylribitol phosphate antibody levels of ≥1.0 μg/mL was noninferior to that of control (96.3% vs 91.2%). After dose 4, MenC and MenY serum bactericidal assay using human complement antibody titers increased 12-fold over pre–dose 4 levels. Incidence of pain, redness, and swelling at the HibMenCY injection sites tended to be lower than with Hib type b after the first 3 doses and after the fourth dose. Rates of systemic symptoms were similar across groups. CONCLUSIONS: The HibMenCY was immunogenic against MenC and MenY and induced anti–polyribosylribitol phosphate antibody levels noninferior to those of licensed Hib conjugate vaccine. The safety profile of the HibMenCY was clinically acceptable and comparable to Hib conjugate vaccine.

Differential diagnosis of chronic fatigue in children : behavioral and emotional dimensions

A battery of self-report questionnaires and structured diagnostic interviews was administered to 20 children and adolescents who presented to a pediatric specialty clinic with chronic fatigue. Matched groups of healthy and depressed control subjects (aged 8 to 19 years) were also studied. Criteria were established to identify those items in the assessment battery that reliably differentiated among the three groups. Analysis of item content suggested several clusters of characteristics that discriminated among the subject groups, including life changes, cognitive difficulties, negative self-attributions, social relationship disruption, and somatic symptom presentation. The results suggest that certain psychological factors can discriminate chronic fatigue from depressive symptomatology, as well as normal functioning. Items discriminating among groups are presented in an organized questionnaire format to assist with the understanding and assessment of pediatric chronic fatigue cases.

Cytomegalovirus Seroprevalence in Women Bearing Children in Jefferson County, Kentucky

Symptomatic congenital cytomegalovirus (CMV) disease occurs almost exclusively in infants born to seronegative mothers who acquire the virus during pregnancy. This study sought to determine patterns of CMV immunity in women of childbearing age at one center participating in a national study. Cord blood specimens from 100 consecutive deliveries at each of three hospitals were tested for CMV-specific IgG. Mean age of women in this sample was 25.7 years; 76% were white, 60% were from middle and upper socioeconomic status, 64% were married, and 57% had other living children. Overall seroprevalence rate was 62%. Univariate analysis showed strong associations between seropositivity and lower socioeconomic status, non-white race, and age younger than 25 years (odds ratios, 4.4, 3.9, and 2.5, respectively). Stratification by socioeconomic status and race eliminated the effect of age. Stratification by socioeconomic status markedly reduced the effect of race, whereas stratification by race only moderately reduced the effect of lower socioeconomic status, which was the strongest predictor of seropositivity (odds ratio, 3.4). Seroprevalence was lowest among older white women of middle and upper socioeconomic status (47% seropositive). Development of longitudinal regional seroprevalence data will facilitate interpretation of data generated by the National CMV Registry.

Immunogenicity, Safety, and Tolerability of a Hexavalent Vaccine in Infants

BACKGROUND: DTaP5-IPV-Hib-HepB is a fully liquid investigational hexavalent vaccine directed against 6 diseases. METHODS: This multicenter, open-label, comparator-controlled, phase III study randomly assigned healthy infants 2-to-1 as follows: group 1 received DTaP5-IPV-Hib-HepB, PCV13, and RV5 at 2, 4, and 6 months of age followed by DTaP5, Hib-OMP, and PCV13 at 15 months of age; group 2 received DTaP5-IPV/Hib, PCV13, and RV5 at 2, 4, and 6 months of age, with HepB at 2 and 6 months of age, followed by DTaP5, Hib-TT, and PCV13 at 15 months of age. RESULTS: Overall, 981 participants were vaccinated in group 1 and 484 in group 2. Immune responses in group 1 to all antigens contained in DTaP5-IPV-Hib-HepB 1 month after dose 3 and for concomitant rotavirus vaccine were noninferior to those in group 2, with the exception of antipertussis filamentous hemagglutinin (FHA) geometric mean concentrations (GMCs). Vaccine response rates for FHA were noninferior to control. After the toddler dose, group 1 immune responses were noninferior to group 2 for all pertussis antigens. Solicited adverse event rates after any dose were similar in both groups, with the exceptions of increased injection-site erythema, increased fever, and decreased appetite in group 1. Fever was not associated with hospitalization or seizures. CONCLUSIONS: The safety and immunogenicity of DTaP5-IPV-Hib-HepB are comparable with the analogous licensed component vaccines. Decreased FHA GMCs and increased injection-site reactions and fever are unlikely to be clinically significant. DTaP5-IPV-Hib-HepB provides a new combination vaccine option aligned with the recommended US infant immunization schedule.

Clinical and Epidemiological Aspects of Rotavirus Infection

Rotavirus is a major worldwide cause of infant morbidity and mortality, and disease burden in the US is substantial. Vaccination is the only practical way to gain control over rotavirus disease. Prevention through the universal use of improved live oral vaccines is on the horizon.

PROCESSING OF HUMAN CYTOMEGALOVIRUS GLYCOPROTEIN B IN RECOMBINANT ADENOVIRUS-INFECTED CELLS

Intracellular processing of human cytomegalovirus (HCMV) glycoprotein B (gB; gpUL55) expressed by a recombinant adenovirus (Ad-gB) was studied in human A549 cells as processing events could affect immunogenicity when such viruses are used as live-recombinant vaccines. Cleavage of [35S]methionine-labelled gp13O into gp93 and gp55 reached a maximum after a 3 h chase. Cleavage was completely inhibited by brefeldin A, suggesting that processing normally occurs as a late Golgi or post-Golgi event. Uncleaved gp 130 remained completely sensitive to endo-beta-N-acetylglucosaminidase H (Endo-H) in untreated cells following long chase periods, indicating high-mannose oligosaccharides at all of the 18 N-linked glycosylation sites (Asn-X-Ser/Thr) and retention in the endoplasmic reticulum. Endo-H analysis of gp55 from swainsonine-treated and untreated cells was consistent with glycosylation at all three potential sites, with two oligosaccharides remaining sensitive to Endo-H and one being processed to Endo-H resistance. The heavily glycosylated N-terminal gp93 subunit was not detected by [35S]methionine-labelling but was easily detected along with gp55 after labelling with [3H]mannose. No cleavage of gp 130 was observed in analogous pulse-chase radiolabelling of Ad-gB-infected human fibroblasts, even though these cells are permissive for HCMV replication and can process the native gB molecule. Processing of gB in recombinant adenovirus-infected A549 cells was generally similar to that previously reported for native gB in HCMV-infected fibroblasts.

Correlates of high grade and low grade Haemophilus influenzae bacteremia.

Routine use of the Isolator 1.5 Microbial Tube® lysis direct plating blood culture system at our institution since November, 1983, provided a unique opportunity to study bacteremia in children from a quantitative perspective. In a 3-year period, 90 episodes of Haemophilus influenzae bacteremia occurred in immunocompetent outpatients; 83 of these met the criteria for study. Patients with high grade bacteremia (>100 colony-forming units/ml) were more likely to have meningitis than those with low grade bacteremia (<100 colony-forming units/ ml); conversely low grade bacteremia patients were more likely to have cellulitis or arthritis. Of 38 meningitis patients those with high grade bacteremia (n = 25) had a significantly shorter duration of illness before presentation than those with low grade bacteremia (median, 1 vs. 3 days; P < 0.006). In addition high grade bacteremia patients had significantly lower white blood cell counts (median, 11.4 vs. 17.3 × 103/ mm3; P ≤ 0.007) and absolute neutrophil counts (5.5 vs. 11.1 × 103/mm3; P ≤ 0.01). Only 1 of 8 meningitis patients who were pretreated with appropriate antibiotics had high colony counts compared to 7 of 8 matched controls (P = 0.04).

Use of standardized patients to examine physicians' communication strategies when addressing vaccine refusal: A pilot study

Vaccine refusal is increasingly reported but few direct observations of the communication between physicians and parents skeptical about vaccines have been made. In a pilot study, a standardized patient posing as an expectant mother (standardized mother, SM) opposed to immunization met with blinded community physicians under the pretext of prenatal interviews. Persuasive communication strategies were scored using a standardized questionnaire. Recorded transcripts were evaluated for compliance with American Academy of Pediatrics recommendations for handling vaccine refusal. Nine encounters were conducted, representing 16% of pediatric and 3% of family practices in the area. Physicians scored high on listening, maintaining eye contact, spending time with the SM, using understandable terms, and avoiding a paternalistic posture. Lower scores were obtained on encouraging questions, checking for understanding, validating the importance of the SMs concerns, and assessing knowledge about vaccines. The median recorded encounter lasted 19 min. SMs represent a novel strategy for studying physician/parent communication about vaccines.

Common Variable Immunodeficiency Presenting With Persistent Parvovirus B19 Infection

Parvovirus B19 infection in healthy hosts is self-limited, but persistent infection has been described in patients with cellular immune defects. A 6-year-old boy presented with a 6-month history of weight loss and malaise and a 1-month history of fever and polyarticular arthritis. Parvovirus DNA was detected in plasma at 10 300 copies/mL. Levels of immunoglobulin (Ig)G, IgA, IgM, IgG-1, and IgG-2 were low, and antibody responses to vaccine antigens were impaired. HIV antibody and DNA polymerase chain reaction were negative, and the patient had normal immunophenotype, mitogen stimulation response, CD40 ligand and inducible costimulator expression, transmembrane activator and CAML interactor sequencing, genomic analysis, and fluorescent in situ hybridization for deletions at 22q11.2. Common variable immunodeficiency was diagnosed and replacement therapy with immune globulin intravenous was initiated. The parvovirus DNA level declined by half over 3 months and was undetectable at 15 months. Constitutional symptoms improved but arthritis persisted and eosinophilic fasciitis eventually developed. This case demonstrates that persistent parvovirus infection may be a presenting feature of humoral immune deficiency and can mimic juvenile rheumatoid arthritis. The infection may respond to immune globulin intravenous therapy.