Safety and immunogenicity of live varicella virus vaccine in children with human immunodeficiency virus type 1

Live varicella virus vaccine was administered to 10 stable human immunodeficiency virus type 1 (HIV-1)-infected children. Subjects were monitored for adverse reactions, HIV-1 plasma levels, CD4 T cell counts and immune responses. The vaccine was well-tolerated. Varicella-zoster virus-specific lymphocyte proliferative responses were detected in all subjects by 4 weeks and in 9 of 10 subjects 1 year after vaccination.     

Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than five years of age for prevention of pneumonia

OBJECTIVE: To determine the effectiveness of the Wyeth heptavalent pneumococcal conjugate vaccine against clinical and radiograph-confirmed pneumonia in children. METHODS: The heptavalent CRM(197) pneumococcal conjugate vaccine (PCV) was given to infants at 2, 4, 6 and 12 to 15 months of age in a randomized, double blind trial. Children were randomized to receive either the CRM(197) PCV (vaccine group) or the meningococcal type C CRM(197) conjugate vaccine (control group). The primary outcome of this trial was invasive pneumococcal disease. In addition children with the clinical diagnosis of pneumonia in the study population were identified through review of automated inpatient, emergency and outpatient databases. The subset of the cohort of these children who had chest radiographs obtained at the time of diagnosis was identified, and the original reading of their radiographs by the radiologist was obtained from automated databases. Rates of clinically diagnosed pneumonia, of pneumonia with a radiograph obtained regardless of result, of pneumonia with positive radiograph (consolidation, empyema or parenchymal infiltrate) and of pneumonia with only perihilar infiltrates were compared between vaccinated and nonvaccinated groups. In addition risk of disease pneumonia was evaluated by race and ethnicity. RESULTS: The incidence of a first pneumonia episode in the control group was 55.9 per 1000 person-years. A radiograph was obtained in 61% of episodes, a positive radiograph in 21% and perihilar findings in an additional 5%. In per protocol follow-up of children given PCV, first episodes of all clinically diagnosed pneumonia were reduced by 4.3% [95% confidence interval (CI), -3.5, 11.5%, = 0.27], episodes with a radiograph were reduced by 9.8% (CI 0.1, 18.5%, < 0.05) and episodes with a positive radiograph were reduced by 20.5% (CI 4.4, 34.0, = 0.02). In the intent to treat analysis including all episodes after randomization, episodes with a positive radiograph were reduced by 17.7%, =.01). The greatest impact was in the first year of life with a 32.2% reduction and a 23.4% reduction in the first 2 years, but only a 9.1% reduction in children >2 years of age. Asians, blacks and Hispanics were at higher risk of pneumonia than were whites, but there was no evidence of ethnic variation in PCV effectiveness. Ten of the 11 cases of pneumococcal pneumonia with a positive blood culture were in the control group. CONCLUSION: The pneumococcal conjugate vaccine tested was effective in reducing the risk of pneumonia in young children.     

Group A streptococcal infection in children younger than three years of age

We evaluated 758 sick children younger than 3 years of age for Group A beta-hemolytic streptococcal (GABHS) upper respiratory infection (URI) to determine the usual clinical presentation of the disease in this age group, indications for culture and the optimal site(s) from which to isolate the organism. GABHS infection was documented in 35 subjects (4.6%). The classic presentation (as proposed in the 1940s) of GABHS URI in children younger than 3 years of age was not confirmed by this study. In 32 of the GABHS cases there were pharyngitis, common cold symptoms or both, and these were associated with acute otitis media 10 times and with otitis media with effusion 3 times. Clinical impetigo was associated with GABHS URI (4 of 32 cases). GABHS URI would not have been documented in 6 of 32 cases if cultures of the anterior nares had not been performed. Children between 18 and 36 months of age were more likely to have GABHS disease than were younger children. Hoarseness and vomiting occurred less frequently in children younger than 36 months with GABHS infection than in those of that age who had non-beta-hemolytic streptococcal illnesses. A history of two or more siblings at home or a family member with a recent streptococcal infection and the presence of irritability, a reddened throat or palate or uvular edema were each associated with GABHS URI. We concluded that sick children between 18 and 36 months of age with a reddened throat should have cultures taken of the throat and anterior nares for GABHS.(ABSTRACT TRUNCATED AT 250 WORDS)     

Failure of the conjugate pneumococcal vaccine to prevent recurrent bacteremia in a child with human immunodeficiency virus disease

Patients with advanced HIV disease have a poor response to some immunizations. A case is presented of a Class C1 HIV-infected child who suffered three episodes of Streptococcus pneumoniae serotype 6B bacteremia despite having received the heptavalent conjugate and 23-valent polysaccharide pneumococcal vaccines. Clinicians should expect some vaccine failures with the heptavalent conjugate vaccine in children with advanced HIV disease.     

Safety and immunogenicity of three doses of a Neisseria meningitidis A + C diphtheria conjugate vaccine in infants from Niger

BACKGROUND: High rates of endemic disease and recurrent epidemics of serogroup A and C meningococcal meningitis continue to occur in sub-Saharan Africa. A meningococcal A + C polysaccharide diphtheria-toxoid-conjugated vaccine may address this issue. METHODS: In Niger three doses of a bivalent meningococcal A + C diphtheria-toxoid-conjugated vaccine (MenD), containing 1, 4 or 16 microg of each polysaccharide per dose, administered at 6, 10 and 14 weeks of age, were compared with Haemophilus influenzae type b-tetanus toxoid-conjugated (PRP-T) vaccine given with the same schedule or with a meningococcal A + C polysaccharide vaccine (MenPS) given at 10 and 14 weeks of age. One blood sample was taken at the time of enrollment (6 weeks of age) and another was taken 4 weeks after the primary series. RESULTS: All doses of MenD were well-tolerated. After the primary series a higher proportion of infants had detectable serum bactericidal activity against serogroup A for each dose of MenD (from 94% to 100%) than for MenPS (31%) or H. influenzae type b-tetanus toxoid-conjugated vaccine (18.9%); P < or = 0.05. Significant differences were also observed for serogroup C MenD 4 microg or MenD 16 microg (100%) vs. MenPS (69.7%) or Haemophilus influenzae type b-tetanus toxoid-conjugated vaccine (24.3%); P < or = 0.05. When MenPS vaccine was given to 11-month-old children, the immune response measured by both enzyme-linked immunosorbent assay and serum bactericidal assay was greater in those previously immunized with MenD than in those immunized with MenPS vaccine. CONCLUSION: MenD was safe among infants in Niger, and immunization led to significantly greater functional antibody activity than with MenPS. The 4-microg dose of MenD for both the A and C serogroups has been selected for further studies.     

Safety and immunogenicity of heptavalent pneumococcal CRM197 conjugate vaccine in infants and toddlers.

OBJECTIVES: The objectives of this study were (1) to determine the safety and immunogenicity of heptavalent pneumococcal CRM197 conjugate (PNCRM7) vaccine in infants and (2) to determine the effect of concurrent hepatitis B immunization during the primary series and the effect of concurrent diphtheria and tetanus toxoid and acellular pertussis [DTaP (ACEL-IMUNE)] and conjugate CRM197 Haemophilus influenzae type b [HbOC (HibTITER) immunization at time of the booster dose on the safety and immunogenicity of PNCRM7and these other concurrently administered vaccines. METHODS: This was a randomized double-blinded study in 302 healthy infants in the Northern California Kaiser Permanente (NCKP) Health Plan. Infants received either PNCRM7 vaccine or meningococcal group C conjugate vaccine as a control at 2, 4 and 6 months of age and a booster at 12 to 15 months of age. Study design permitted the evaluation of immunology and safety of concurrent administration of routine vaccines. Antibody titers were determined on blood samples drawn before and 1 month after the primary series and the booster dose. RESULTS: After the third dose of PNCRM7 geometric mean concentrations (GMCs) ranged from 1.01 for serotype 9V to 3.72 microg/ml for serotype 14. More than 90% of all subjects had a post-third dose titer of > or =0.15 microg/ml for all serotypes, and the percentage of infants with a post-third dose titer of > or =1.0 microg/ml ranged from 51% for type 9V to 89% for type 14. After the PNCRM7 booster dose, the GMCs of all seven serotypes increased significantly over both post-Dose 3 and pre-Dose 4 antibody levels. In the primary series there were no significant differences in GMCs of pneumococcal antibodies between the subjects given PN-CRM7 alone or concurrently with hepatitis B vaccine. At the toddler dose concurrent administration of PNCRM7 and DTaP and HbOC resulted in a near conventional threshold for statistical significance of a post-Dose 4 GMC for serotype 23F [alone 6.75 mirog/ml vs. concurrent 4.11 microg/ml (P = 0.057)] as well as significantly lower antibody GMCs for H. influenza polyribosylribitol phosphate, diphtheria toxoid, pertussis toxin and filamentous hemagglutinin. For all antigens there were no differences between study groups in defined antibody titers that are considered protective. CONCLUSION: We conclude that PNCRM7 vaccine was safe and immunogenic. When this vaccine was administered concurrently at the booster dose with DTaP and HbOC vaccines, lower antibody titers were noted for some of the antigens when compared with the antibody response when PNCRM7 was given separately. Because the GMCs of the booster responses were all generally high and all subjects achieved similar percentages above predefined antibody titers, these differences are probably not clinically significant.     

Safety and immunogenicity of pneumococcal conjugate vaccine in combination with diphtheria,tetanus toxoid,pertussis and Haemophilus influenzae type b conjugate vaccine

BACKGROUND: Pneumococcal polysaccharide/protein conjugate vaccines (PnCV) are immunogenic and effective in infancy. However, an addition to the nine currently recommended vaccine injections during the first year of life of African children may be a deterrent to participation in a PnCV program. Thus we have evaluated the safety and immunogenicity of a 9-valent PnCV (Wyeth Lederle Pediatrics and Vaccines) mixed with diphtheria, tetanus toxoid, cell pertussis and type b (TETRAMUNE). METHODS: Healthy Gambian infants were randomized at the age of 2 months to receive three doses 1 month apart of either (1) placebo reconstituted in TETRAMUNE in the right thigh (control) or (2) PnCV in the left thigh and TETRAMUNE in the right thigh (separate) or (3) PnCV reconstituted in TETRAMUNE as a single injection in the right thigh (combined). The vaccines were given together with routine Expanded Program on Immunization vaccines. Adverse reactions were recorded after vaccination, and antibody concentrations were measured by enzyme-linked immunosorbent assays. RESULTS: Local induration and tenderness were observed more commonly at the site of injection of TETRAMUNE than at the site of injection with PnCV after each dose of vaccination. Swelling at the site of injection was encountered more frequently at the site of administration of TETRAMUNE than at the site of administration PnCV ( P< 0.00001 for Doses 1 and 2 and P< 0.0009 for Dose 3). Swelling at the site of administration of TETRAMUNE mixed with PnCV was comparable with that observed for TETRAMUNE alone. Although most mothers reported that the babies "felt hot" 24 h after each injection, febrile reactions (temperature, >or=38 degrees C) were infrequent and resolved with antipyretics. Geometric mean titer for anti-polyribosylribitol phosphate antibody was 11.6 microg/ml [95% confidence limits (95% CI), 9.2, 14.6] in the control group and comparable with 13.3 microg/ml (95% CI 11.0, 16.0) in the combined group and significantly higher at 17.9 microg/ml (95% CI 14.7, 21.9; P= 0.01) in the separate group. Geometric mean concentrations of serotype-specific pneumococcal antibodies were higher in the combined group than the separate group for all nine serotypes. Antibody responses to diphtheria and pertussis antigens were similar in all groups. Anti-tetanus toxoid antibody concentrations were lowest in the combined group (6.66 IU/ml, 95% CI 5.77, 7.68 in the control group; 5.15 IU/ml, 95% CI 4.39, 6.03 in the combined group; P= 0.02). However, all vaccinees achieved protective antibody values. CONCLUSION: The combination of TETRAMUNE and PnCV is safe and immunogenic.     

Reduced effectiveness of Haemophilus influenzae type b conjugate vaccine in children with a high prevalence of human immunodeficiency virus type 1 infection

BACKGROUND: Haemophilus influenzae type b (Hib) conjugate vaccines have successfully reduced the burden of invasive Hib disease in developed countries; however, their effectiveness in countries with a high incidence of pediatric HIV-1 is unknown. METHODS: The effectiveness of Hib conjugate vaccine was prospectively evaluated in South African children. The burden of invasive Hib disease in children < 1 year old was compared in 2 cohorts. The first cohort included 22,000 African children born in 1997 [969 (4.45%) of whom were estimated to be HIV-1-infected] who were not vaccinated with Hib conjugate vaccine. This group was compared with 19,267 children [1162 (6.03%) of whom were estimated to be HIV-1 infected] vaccinated at 6, 10 and 14 weeks of age with an Hib conjugate vaccine [TETRAMUNE (polyribosylribitol phosphate-CRM(197)-diphtheria-tetanus toxoids-whole cell pertussis)] between March, 1998, and June, 1999. RESULTS: The estimated burden of invasive Hib disease in nonimmunized HIV-1-infected children < 1 year of age was 5.9-fold [95% confidence interval (95% CI), 2.7 to 12.6] higher than in HIV-1-uninfected children. The overall estimated effectiveness of Hib conjugate vaccine in fully vaccinated children <1 year of age was 83.2% (95% CI 60.3 to 92.9). Vaccine effectiveness was significantly reduced in HIV-1-infected [43.9% (95% CI -76.1 to 82.1)] compared with uninfected children [96.5% (95% CI 74.4 to 99.5); P < 10(-5)]. Among three of the fully vaccinated HIV-1-infected children who developed invasive Hib disease, the anti-Hib polyribosylribitol phosphate serum antibody concentrations were 0.23, 0.25 and 0.68 microg/ml. CONCLUSION: Although the Hib conjugate vaccine was less effective among HIV-1-infected than among uninfected children, it was 83% effective in preventing overall invasive Hib disease and therefore should be considered for inclusion in the routine vaccination schedule by other African countries.     

Quantitative and qualitative antibody response to pneumococcal conjugate vaccine among African human immunodeficiency virus-infected and uninfected children

OBJECTIVE: To determine the quantitative and qualitative antibody responses to a pneumococcal conjugate vaccine (PnCV) in human immunodeficiency virus (HIV)-exposed infected and uninfected children. METHODS: Children were randomized to receive either a PnCV or placebo at 6, 10 and 14 weeks of age. PnCV serotype-specific antibody concentrations were measured by a standard enzyme immunoassay (EIA) and a 22F modified EIA (22F EIA) on single serum samples drawn at 21-42 days post-dose 3. Functional activities of the serotype-specific antibody to serotypes 6B, 19F and 23F were measured with an opsonophagocytic assay (OPA). RESULTS: The geometric mean antibody concentrations (GMC) were similar in HIV-infected and HIV-uninfected PnCV recipients for 7 of the 9 vaccine serotypes. In placebo recipients, the GMCs were significantly higher in HIV-infected than in uninfected children for 7 of the serotypes. In HIV-infected PnCV recipients, the GMCs were lower for 5 of the serotypes in children with severe acquired immunodeficiency syndrome than in children who were asymptomatic or mildly symptomatic with acquired immunodeficiency syndrome. HIV-infected PnCV recipients were less likely to have measurable functional antibody (OPA titer > or =1/8) to all 3 studied serotypes (6B, 19F and 23F) than in HIV-uninfected children. HIV-infected children required a higher concentration of anticapsular antibody to achieve 50% of the maximum uptake of labeled Streptococcus pneumoniae in the OPA assay than HIV-uninfected children for 2 of the 3 serotypes, although this was significant only for serotype 6B (P = 0.0005). CONCLUSION: HIV-infected children have similar quantitative antibody responses but poorer qualitative antibody responses to the PnCV.     

Tolerability and immunogenicity of an eleven-valent pneumococcal conjugate vaccine in healthy toddlers

BACKGROUND: A need to increase the serotype coverage of pneumococcal conjugate vaccines exists. The use of a single carrier protein may cause overload of the carrier and decrease the immune response by not providing sufficient carrier-specific T helper cell support. A vaccine composed of a mixture of tetanus- and diphtheria-conjugated polysaccharides (PS) is a potential solution to this issue. OBJECTIVES: The aim of this study was to assess the tolerability and immunogenicity in healthy toddlers of an 11-valent pneumococcal conjugate vaccine that uses both tetanus and diphtheria toxoids as carriers. We explored the effect of an aluminum adjuvant on safety and immunogenicity by comparing the vaccine with and without adjuvant. METHODS: Twenty Finnish and 23 Israeli toddlers received the conjugate vaccine with or without aluminum adjuvant. Safety data were recorded for 5 days after vaccination. Sera were obtained before and 28 days after the immunization. IgG antibodies to the 11 vaccine-type PSs were determined by enzyme immunoassay. RESULTS: No serious adverse events occurred. The formulation with the adjuvant tended to induce fewer local but more systemic reactions than the non-adjuvant-containing formulation. Both vaccine formulations induced significant IgG increases for the vaccine-specific PSs. Types 3 and 7F were the most immunogenic; antibodies reached a concentration of 1 microg/ml in all individuals. Conjugates of types 6B, 14 and 23F were the weakest immunogens; antibodies reached the concentration of 1 microg/ml in 36, 27 and 32% of the individuals in the nonadjuvant group and in 53, 38 and 53% in the adjuvant group, respectively. CONCLUSIONS: An 11-valent mixed carrier pneumococcal conjugate vaccine is safe and immunogenic in toddlers. The use of an adjuvant do not seem to offer any significant benefit.     

Lymphocyte subsets in children younger than 2 years old: normal values in a population at risk for human immunodeficiency virus infection and diagnostic and prognostic application to infected children.

Data were collected prospectively from 116 children younger than 2 years old who were seen at the Duke Pediatric AIDS Clinical Trials Unit for known human immunodeficiency virus seropositivity. Forty-six (40%) of these children were human immunodeficiency virus-infected and 70 were not infected. Using 3-month blocks, 10th, 50th and 90th percentiles were calculated for the CD4+ and CD8+ cell counts, percentage of lymphocytes positive for CD4 and CD8 and T4:T8 ratios. Results from the infected and uninfected children were compared. By 3 to 6 months of age the infected patients had significantly lower CD4+ counts, percentage CD4+ cells and T4:T8 ratios, whereas the percentage of CD8+ lymphocytes was significantly higher. Absolute CD8+ counts were approximately the same in infected and uninfected children through age 2 years. Most infected children had one or more abnormal lymphocyte subset results (less than the 10th percentile for uninfected patients) by age 2: 83% had an abnormal CD4+ percentage; 78% had an abnormal T4:T8 ratio; and 67% had an abnormal CD4+ count. All 13 children who had an opportunistic infection (at any age) had an abnormal CD4+ percentage before age 2 years, and 12 of 13 had a low absolute CD4+ count or T4:T8 ratio. Among patients who died 10 of 11 had 1 or more low CD4+ count, 9 of 11 had an abnormal CD4+ percentage and 8 of 11 an abnormal T4/T8 ratio.     

Safety of botulinum toxin type A in children younger than 2 years

BackgroundBotulinum toxin type A (BoNT-A) has been used in many indications and is licensed for the treatment of spasticity in children older than 2 years. However, there are few reports of BoNT-A treatment in patients younger than 2 years of age.AimsTo review retrospectively the safety data from all infants treated with botulinum toxin type A (BoNT-A) before 2 years of age in a paediatric neurology unit.MethodsThere were 74 infants: 28 received the first dose before 1 year of age, and 46 between the ages of 1 and 2 years.ResultsIn the first year of life, the most frequent indication was obstetric brachial palsy (OBP) (71.4% of cases) and in the second year, cerebral palsy (CP) (73.9%). Both Botox^® and Dysport^®, the two commercially-available BoNT-A products in Spain, were used. The average starting dose by session was 6.55 U/kg body weight Botox in infants in their first year of life, and 8.4 U/kg body weight Botox and 21.1 U/kg body weight Dysport in the second year of life. Only 3.6% of cases treated in the first year and 6.5% of those treated in the second experienced adverse events (AEs), which consisted of mild weakness or tiredness lasting 1–4 days.ConclusionsBoNT-A has a good safety profile in infants younger than 2 years old. AEs are similar to those found in older children.