Clinical trials of varicella vaccine in healthy adolescents and adults.

Adolescents and adults have an increased risk of severe and, rarely, fatal varicella. Increased risk of exposure of susceptible teens and adults occurs because of the more common use of day care and nursery programs, and more common exposure of health care workers to herpes zoster. The exposure of susceptible parents to their own children represents an important hazard. Live attenuated varicella vaccine requires two doses to be adequately immunogenic in adults. Safety and clinical tolerability have been well documented, and persistent antibody protection from infection and virtual absence of early herpes zoster infections are inferred from encouraging preliminary data.

Reactogenicity and immunogenicity of a three-component acellular pertussis vaccine administered as the primary series to 2, 4 and 6 month old infants in the United States.

Five hundred and fifty-seven infants received either an acellular pertussis (DTaP) vaccine containing pertussis toxoid (PT), filamentous hemagglutinin (FHA) and pertactin (PRN) or one of two commercially available whole-cell pertussis (DTP) vaccines at 2, 4 and 6 months. One month after the third immunization, IgG antibody values to pertussis toxoid, filamentous hemagglutinin and PRN were significantly greater following DTaP than either DTP (P < 0.05). When reactions within 48 h after all three doses of vaccine were combined, fever 101 degrees, > or = moderate fussiness, > or = moderate pain, swelling 10 mm, and erythema 10 mm occurred less often after DTaP compared with DTP-Connaught (P < 0.001). The same adverse events were also less after DTaP compared with DTP-Lederle (P < 0.05), except for erythema 10 mm. This three-component DTaP vaccine produced fewer adverse events and greater antibody values to PT, FHA and PRN in comparison with either licensed DTP vaccine when given as the primary series.

Antibody response of low birth weight infants to Haemophilus influenzae type b polyribosylribitol phosphate-outer membrane protein conjugate vaccine.

OBJECTIVE: To evaluate the effectiveness in low birth weight (LBW) infants of the currently recommended immunization schedule for conjugated Haemophilus influenzae type b (HIB) vaccine. METHODS: We quantified antibody responses in 36 preterm infants with a mean birth weight of 1060 g and a mean gestational age of 28 weeks. Infants were immunized with 0.5 mL of HIB vaccine at 2 and 4 months' postnatal age. Specific HIB antibodies were quantified on cord blood, immediately before each immunization and 2 months after the last immunization. RESULTS: Even though the geometric mean titers increased significantly during the study period, they were still markedly lower than values reported in term infants. After the second immunization, only 24 infants (67%) attained antibody concentrations of more than 0.25 micrograms/mL, defined as seropositivity. Also, only 53% of infants achieved antibody concentrations of more than 1.0 micrograms/mL compared with 92% as reported in term infants. Stepwise logistic regression identified gestational age of 27 weeks or less and the amount of intravenous immunoglobulin received as the significant variables influencing the antibody response after the first immunization. The incidence of side effects was negligible. CONCLUSIONS: We conclude that LBW infants, and especially those born at 27 or less weeks' gestation, do not respond as effectively to the HIB vaccine. We speculate that reevaluation of the current immunization schedule may be required for very LBW infants.

Safety and cellular and humoral immune responses of a booster dose of varicella vaccine 6 years after primary immunization.

Four hundred nineteen children and adolescents immunized with live varicella vaccine 4-6 years earlier were enrolled in a study to evaluate the safety and immune response to a booster dose containing approximately 3300 pfu of virus. Of the subjects, 99% (414/419) maintained antibody to varicella zoster virus (VZV) with a geometric mean titer of 25.7 and mean stimulation index (SI) for VZV-specific lymphoproliferation response of 40.3 +/- 5.3 (SE). Some 7-10 days after the booster immunization, seropositivity rates increased to 100% (302/302), and GMT was 143.6 (anamnestic response). At 6 weeks after the booster inoculation, a subset of subjects had 100% seropositivity (74/74) with a GMT of 218.8 and an SI of 58.6. After 3 months, seropositivity was 100% (358/358), GMT was 119.0, and SI was 61.4.

Comparison of a three-component acellular pertussis vaccine with a whole-cell pertussis vaccine in 15- through 20-month-old infants.

OBJECTIVE: To compare the immunogenicity and reactogenicity of a diphtheria and tetanus toxoids and three-component acellular pertussis vaccine (DTaP) with a diphtheria and tetanus toxoids and whole-cell pertussis vaccine (DTwP) when administered as a booster dose to infants 15 through 20 months of age. DESIGN: Randomized, double-blind, comparative study. SETTING: Three pediatric practices (two private; one hospital-based). PARTICIPANTS: One hundred and sixty-five healthy 15- through 20-month old infants. SELECTION PROCEDURES AND INTERVENTIONS: Infants were randomly assigned in a 2:1 ratio to receive vaccine from a single lot of DTaP or from commercially available DTwP. DTaP contained 25 micrograms of pertussis toxoid, 25 micrograms of filamentous hemagglutinin, 8 micrograms of pertactin (69-kilodalton outer membrane protein), 25 flocculating units of diphtheria toxoid, and 10 flocculating units of tetanus toxoid per 0.5-mL dose. DTwP contained one half the concentrations of diphtheria and tetanus toxoids compared with DTaP and a pertussis component with a potency of 4 U/0.5-mL dose. Serum samples were obtained on the day of immunization and 4 weeks later. Adverse reactions were recorded by parents for 7 days after immunization. An interval history was obtained 4 weeks after immunization. MEASUREMENTS AND RESULTS: IgG antibody to pertussis toxoid, filamentous hemagglutinin, pertactin, diphtheria toxoid, and tetanus toxoid was measured by an indirect enzyme-linked immunosorbent assay (ELISA) method. One month after immunization, the geometric mean antibody levels after DTaP compared with DTwP were: pertussis toxoid, 70.6 vs 28 ELISA U/mL (P = .003); filamentous hemagglutinin, 183.4 vs 43 ELISA U/mL (P < .001); pertactin, 216 vs 49.9 ELISA U/mL (P < .001); diphtheria, 14.1 vs 14.9 IU/mL (P = .74); and tetanus, 11.9 vs 14.8 IU/mL (P = .089). After immunization with DTaP, most local and systemic adverse experiences were significantly fewer compared with DTwP (P < .05). CONCLUSIONS: This three-component DTaP vaccine demonstrates significantly greater immune responses to pertussis toxoid, filamentous hemagglutinin, and pertactin, equivalent immune responses to diphtheria and tetanus toxoids, and significantly less reactogenicity compared with a licensed DTwP.

Immunization of children with acute lymphoblastic leukemia with live attenuated varicella vaccine without complete suspension of chemotherapy.

A total of 44 children with acute lymphoblastic leukemia were immunized against chickenpox with the Oka/Merck strain live attenuated varicella vaccine. Of these children, 24 continued oral chemotherapy with 6-mercaptopurine during the immunization period and 20 had suspension of all chemotherapy for 1 week before and 1 week after the vaccine. Seroconversion, as determined by the detection of fluorescent antibody to membrane antigens, occurred in 91% and did not differ between patients continuing 6-mercaptopurine from those in whom chemotherapy was suspended. Fever and/or rash occurred in less than one third of vaccinated children. Unexpected reactions occurred in two vaccinated children, one from each group, both of whom had low absolute lymphocyte counts (less than 750/microL) on the day of immunization. Vaccine-induced immunity appeared effective in preventing or modifying chickenpox after exposure to natural disease.

Natural killing of varicella-zoster virus (VZV)-infected fibroblasts in normal children, children with VZV infections, and children with Hodgkin's disease.

We studied mononuclear cell (MNC)-mediated natural killing (NK) of varicella-zoster virus (VZV)-infected fibroblasts in normal children, children with VZV infections, and children with Hodgkin's disease. NK activity was tested in 18 hr 51Cr release assays. NK activity for adults was significantly higher than that for children 1-3 years old or 4-6 years old (p less than 0.05). Serological status did not affect NK activity. NK activity in normal children was not increased 4-6 weeks after immunization with varicella vaccine. Seven normal children with natural varicella showed significantly higher NK activity against VZV-infected and uninfected targets. Eight immunosuppressed children with herpes zoster showed significantly reduced NK activity within 72 hours of the onset of herpes zoster. However, their NK activity rose to the normal level one to two weeks later. Children with Hodgkin's disease had low NK activity. These results suggested that NK cells might play an initial defensive role in VZV infections, and that low NK activity in immunocompromised hosts might contribute to their high incidence of herpes zoster.

Rotavirus serotype-specific neutralizing activity in human milk.

A plaque reduction neutralization assay was used to determine rotavirus serotype-specific neutralizing activity in human breast milk from 25 mothers of upper socioeconomic background and 20 mothers of a lower socioeconomic status. Levels of neutralizing activity, as well as those of rotavirus-specific antibodies detected by enzyme-linked immunosorbent assay (ELISA), were comparable for each socioeconomic group. Overall, neutralizing activity in human milk was detected in the majority of samples and can be increased many months postpartum. The prevalence of neutralization antibodies (titers, greater than or equal to 1:10) was 77% against Wa (serotype 1), 86% against SA-11 (serotype 3), and 75% against NCDV (bovine) rotavirus. Rotavirus-specific IgA and IgG antibodies detected by ELISA (titers, greater than or equal to 1:10) were present in 35% and 55% of breast milks, respectively. Sequential analysis of repeated breast milk samples from five individual mothers revealed that rotavirus neutralizing activity fluctuated over time, with high activity observed in one mother's milk at 18 months postpartum. Mothers who breast-fed for six months or more tended to have higher milk neutralizing titers against rotavirus.

Combination measles, mumps, rubella and varicella vaccine.

A comparative clinical trial was conducted in 15- to 17-month-old healthy children to compare an investigational combination measles, mumps, rubella, varicella (MMRV) vaccine v standard measles, mumps, rubella vaccine followed 6 weeks later with the varicella (MMR + V) vaccine. Both the MMRV and MMR + V vaccine schedules stimulated virtually 100% seroconversion for all component viruses. Mean antibody titers were similar for each virus component in the two vaccine groups. Clinical reactivity postimmunization was also similar with 25% to 29% morbilliform rashes, 12% to 25% mild papulovesicular (varicella) rashes, and 12.5% to 18% temperature elevations above 38.3 degrees C (101 degrees F). Antibodies to measles, mumps, and rubella viruses were persistent at 1 year of follow-up in both groups. Varicella antibody was persistent in 8/10 originally seronegative MMRV vaccinees and 5/5 MMR + V vaccine recipients tested. One MMRV vaccine recipient had a household exposure to chickenpox during the year postvaccination that resulted in a subclinical boost in varicella antibody titer. Two children in the MMR + V vaccine group had close varicella exposures; mild varicella (20 lesions) developed in one. There were no known exposures to natural measles, mumps, or rubella. Three of four MMRV vaccinees with low titer antibody to varicella prior to immunization had greater than fourfold increases in antibodies after vaccination. The combination MMRV vaccine is an immunogenic, safe, and cost-effective approach to varicella immunization of healthy children. Continued work is needed to select the appropriate dose of varicella component, to assure higher persistence rate of varicella antibody.

Varicella vaccine studies in healthy children and adults.

Immunization of normal children and adults with Oka strain live varicella vaccine from several manufacturers has been studied in our laboratory and elsewhere. This paper summarizes clinical trials designed to obtain information on minimum dose immunogenicity pre- and postexposure prophylaxis, immunization of various age groups, and booster immunizations for seropositive individuals. These studies documented a 94% to 100% seroconversion rate with 95% to 100% persistence of antibodies at 3 to 4 years. Protective efficacy was more than 90%, and the vaccine was successful in preventing varicella when a high dose was given postexposure. Clinical reactions were limited to temperature elevations and minor papulovesicular rashes that occurred in 5% to 10% of vaccinees. Herpes zoster has been absent in vaccinated healthy individuals.

The combination measles, mumps, rubella and varicella vaccine in healthy children.

A clinical trial was conducted to compare the combination measles, mumps, rubella, varicella vaccine (MMRV) and the standard measles, mumps, rubella vaccine and subsequent varicella vaccine (MMR + V) in 15 to 17 month old healthy children. Both the MMRV and MMR + V schedules stimulated virtually 100% seroconversion for all component viruses. Mean antibody titers were similar for each virus component in the two vaccine groups. Clinical reactivity post immunization was also similar with 25-29% morbilliform rashes, 12-25% mild papulovesicular (varicella) rashes, and 12.5-18% temperature elevations above 101 degrees F. Antibodies to measles, mumps, and rubella viruses were persistent in 8/10 originally seronegative MMRV vaccinees and 5/5 MMR + V recipients tested. On MMRV recipient had a household exposure to chickenpox during the year postvaccination that resulted in a subclinical boost in varicella antibody titer. Two children in the MMR + V group had close varicella exposures: one developed mild varicella (20 lesions). There were no known exposures to natural measles, mumps, or rubella. Three of four MMRV vaccinees with low titer antibody to varicella prior to immunization had greater than four-fold rises in antibodies. The combination measles, mumps, rubella, varicella vaccine is an immunogenic, safe and cost effective approach to varicella immunization of healthy children.

Human polymorphonuclear leukocyte-mediated cytotoxicity against varicella-zoster virus-infected fibroblasts.

Polymorphonuclear leukocytes (PMN) were studied for their ability to mediate cytotoxicity against varicella-zoster virus (VZV)-infected and uninfected human fibroblasts in 51Cr release assays. PMN were capable of mediating antibody-dependent cellular cytotoxicity (ADCC) against VZV-infected targets. Maximal ADCC was obtained with effector-to-target ratios of 100:1 and 18 h of incubation. Percent 51Cr release for 26 normal adults was 14.1 +/- 0.6 (mean +/- standard error) in the presence of pooled human seropositive sera (final dilution, 1:100) and 0.5 +/- 0.6 in the presence of pooled human seronegative sera. Addition of phorbol myristate acetate (PMA) enhanced PMN-mediated cytotoxicity against VZV-infected and uninfected targets. PMA-stimulated cytotoxicity was optimal with PMA concentrations of 200 ng/ml and effector-to-target ratios of 10:1, and antibody was not required; killing was detected as early as 3 h after incubation and was maximal after 18 h. Highly purified PMN were capable of mediating both ADCC and PMA-stimulated lysis. Catalase completely inhibited PMA-stimulated PMN cytotoxicity, but had no effect on PMN-mediated ADCC. PMN from patients with chronic granulomatous disease were capable of mediating ADCC, but not PMA-stimulated killing, against VZV-infected targets. Thus, PMN could kill VZV-infected targets by two different mechanisms: ADCC, which required antibody but not hydrogen peroxide (H2O2), and PMA-stimulated cytotoxicity, which required H2O2 but not antibody.

Varicella vaccine trials in healthy children. A summary of comparative and follow-up studies.

Beginning in 1979, OKA and KMcC strains of varicella zoster virus (VZV) vaccine were administered to 369 healthy seronegative children in a sequence of ten comparative clinical trials. Postimmunization clinical reactivity was minimal with the OKA vaccines but was unacceptably high (32%) with the KMcC passage-40 vaccine. Ninety-three percent to 100% immunogenicity was noted by fluorescent antibody assay and in vitro lymphocyte proliferation to VZV antigens. Follow-up studies demonstrated persistence of antibody and in vitro lymphocyte proliferation responses and protection or modification of infection nine to 48 months after immunization. Only five episodes of mild varicella occurred in children in whom seroconversion had occurred. These episodes were noted after at least 281 known varicella exposures. Vaccine virus reactivation as zoster had not occurred in any child.

Susceptibility of vaccine strains of varicella-zoster virus to antiviral compounds.

Using a plaque reduction assay, we determined the 50% effective doses of six antiviral compounds against low- and high-passage viruses of the KMcC and Oka strains of varicella-zoster virus vaccine. The potency, as indicated by the ranges of 50% effective doses (micrograms per milliliter) of the antiviral compounds, in decreasing order was as follows: (E)-5-(2-bromovinyl)-2'-deoxyuridine, 0.0007 to 0.0035; 1-(2'-flouro-2-deoxy-beta-D-arabinofuranosyl)-5-iodocytosine, 0.0063 to 0.0091; aphidicolin, 0.092 to 0.180; acyclovir, 0.79 to 1.81; vidarabine, 0.62 to 2.10; and phosphonoformic acid, 8.18 to 16.4. Susceptibility to the various antiviral compounds was independent of passage level or strain. These data, along with the available in vivo data, indicate that varicella-zoster virus vaccine infections requiring antiviral therapy most probably would be treated as effectively as would natural varicella infections.

HCMV envelope antigens induce both humoral and cellular immunity in guinea pigs.

Antibody and cellular immunity were measured in guinea pigs immunized with whole virion, with nucleocapsids of human cytomegalovirus or with solubilized antigens containing virus envelope proteins. All the three types of immunogens induced the production of humoral antibody as well as cytomegalovirus (CMV)-specific cellular immunity. In immunization experiments envelope antigen was as effective as immunization with whole virion.

Serum levels of IgA1 and IgA2 in children and in patients with IgA deficiency.

Serum levels of IgA1 and IgA2 were measured by solid phase radioimmunoassay in samples from 110 children between 3 months and 10 years of age. Both IgA1 and IgA2 were detectable in all samples, and both IgA1 and IgA2 increased with increasing age. The percent of total serum IgA that was IgA2 did not change with age and was the same in samples from children (15.05 +/- 10.2%) as in samples from adults (15.86 +/- 7.98%). The proportion of serum IgA that was IgA2 was much less variable within sibships than within the group at large (P less than 0.005). In the 16 patients with IgA deficiency, the proportion of serum IgA that was IgA1 or IgA2 was highly variable. IgA2 constituted more than 50% of the IgA in 5 patients and less than 7% of the IgA in an additional 5 patients. These findings suggest that regulation of serum concentrations of IgA1 and IgA2 is complex and influenced by genetic factors and probably other unidentified factors.

Tobramycin sulfate elimination in premature infants.

The elimination pharmacokinetics of tobramycin sulfate was studied in 25 newborn infants of birth weight 0.7 to 4.7 kg during 31 treatment episodes. The peak serum concentrations after a 2.5 mg/kg dose were usually within the therapeutic range of 5 to 10 micrograms/ml; however, the serum predose trough values were elevated above the theoretical safe limit of 2 micrograms/ml. Because of the prolonged serum elimination half-lives, a calculated extended dosage interval, sometimes greater than 24 hours, was necessary to obtain a predose trough of less than or equal to 2 micrograms/ml. The serum elimination half-lives inversely correlated with gestational age, extrauterine age, birth weight, and creatinine clearance. The very low ratio of tobramycin renal clearance to creatinine renal clearance was virtually constant and indicated a probable tubular reabsorption of tobramycin. A general dosage schedule based on birth weight was derived from the data. An alternative formula was derived to enable prediction of the tobramycin elimination half-life based on a combination of birth weight, gestational age, and extrauterine age for an infant younger than 7 days of age.

Live attenuated varicella vaccine: the KMcC strain in healthy children.

The KMcC strain of live, attenuated varicella-zoster virus vaccine was studied in healthy children as a preliminary step toward varicella vaccine studies with this strain in children with leukemia. Forty-three children were immunized: 26 with the 40th passage vaccine and 17 with the 50th passage. Studies included surveillance for clinical reactivity, oropharyngeal excretion of vaccine virus, viruria, and viremia. Antibody responses were assayed by fluorescent antibody to membrane antigens and immune adherence hemagglutination. Cell-mediated immune responses were assayed by lymphocyte proliferation to varicella-zoster virus specific antigens. There was 100% seroconversion to the KMcC passage 40 and 50 vaccines (by fluorescent antibody to membrane antigen assay). Every child studied developed in vitro lymphocyte proliferation to varicella-zoster virus antigens. Papular skin lesions, probably vaccine related, occurred in 31% of the 40th passage vaccinees but in only 6% of the 50th passage vaccinees. The 50th passage KMcC strain vaccine is sufficiently immunogenic and safe to initiate clinical studies with leukemia patients.

Antibody-dependent cell-mediated cytotoxicity against varicella-zoster virus-infected targets.

Antibody-dependent cell-mediated cytotoxicity (ADCC) against cryopreserved varicella-zoster virus-infected human foreskin fibroblasts was detected in a 51Cr release assay. Target cells, samples of seropositive or seronegative sera, and mononuclear cells obtained by Ficoll-Hypaque centrifugation of human peripheral blood were added to microtiter plate wells and allowed to incubate at 37 degrees C for 4 h. Fibroblasts infected for 48 to 96 h were susceptible to ADCC. Effector cells from seropositive and seronegative normal children were equally active in the assay. Antibody titers were determined by testing serial dilutions of sera in the ADCC assay. Zoster immune globulin had a titer of 204,800. Sera from 40 naturally seropositive individuals were compared by assays for ADCC and fluorescent antibody to membrane antigen. All sera that were negative by fluorescent antibody to membrane antigen (less than 2) were also negative by ADCC (less than 20). All sera that were positive by fluorescent antibody to membrane antigen were also positive by ADCC, but titers of individual sera were frequently 5 to 20 times higher in the ADCC assay.

Simultaneous bilateral central catheters: a safe technique.

Optimal central catheter care includes restriction usage for blood sampling and blood product administration on enhance continued sterility, but our experience with 25 children receiving bone marrow transplants after cytoreduction challenges this concept. Prior to transplantation, bilateral percutaneous subclavian vein silastic catheters were inserted without incident, one utilized for continuous nutritional support in caloric quantity to assure body weight maintenance, and the contralateral catheter utilized for daily venous sampling plus administration of medications including blood products. Patients subsequently entered a protective environment and bi-weekly surveillance cultures were monitored. Nutritional therapy was given for 876 days through 53 catheters. One patient developed culture-proven sepsis, an organism first cultured from the skin. The patient complication rate of 4% and the per diem rate of 0.11% in this immunocompromised population compares favorably to the 10.5 and 0.32% incidence we previously reported for 200 children with unilateral catheters. These data demonstrate that bilateral central catheters can be safely utilized in children for nutrition and sampling.