Safety, vaccine virus shedding and immunogenicity of trivalent, cold-adapted, live attenuated influenza vaccine administered to human immunodeficiency virus-infected and noninfected children.

OBJECTIVE: To assess the safety of live, attenuated influenza vaccine (LAIV) administered to relatively asymptomatic or mildly symptomatic HIV-infected children and non-HIV-infected children. METHODS: Twenty-five non-HIV and 24 HIV-infected children (CDC Class N or A1,2) were enrolled into this double blind, placebo-controlled study. Children were randomized within each HIV status group to one of two dosing regimens: Regimen 1, Dose 1 = LAIV, Dose 2 = placebo, Dose 3 = LAIV; or Regimen 2, Dose 1 = placebo, Dose 2 = LAIV, Dose 3 = LAIV. Study doses were separated by 28 to 35 days. Reactogenicity events within 10 days and adverse events within 28 to 35 days after each study dose were recorded. Blood HIV RNA concentrations, CD4 counts and CD4% were measured throughout the study on HIV-infected children. Quantitative influenza cultures were performed on nasal aspirates collected periodically from all children up to 28 to 35 days after each study dose. Influenza isolates were assessed for retention of the temperature-sensitive phenotype. Serum influenza HAI antibodies were measured before and after each LAIV vaccination. RESULTS: No significant differences were found in rates of reactogenicity events and vaccine-related adverse events after placebo or the first dose of LAIV within each HIV status group, nor were differences found between HIV-infected and HIV-uninfected children after each dose of LAIV. Overall none of the HIV-infected children experienced a significant LAIV-related serious adverse event or influenza-like illness, making the one sided 95% CI of such a serious event occurring after LAIV 0 to 12%. No significant changes in geometric mean HIV RNA concentrations, CD4 counts or CD4% or prolonged or increased quantity of LAIV virus shedding occurred in HIV-infected children after receiving either dose of LAIV. All recovered influenza isolates retained the temperature-sensitive phenotype. After two doses of LAIV, 83% of the non-HIV-infected and 77% of the HIV-infected children had a > or = 4-fold rise in influenza antibody to at least one of the three LAIV strains. CONCLUSION: If relatively healthy HIV-infected children become exposed to LAIV inadvertently, then serious adverse outcomes would not be expected to occur frequently.

Prospective, randomized, placebo-controlled evaluation of the safety and immunogenicity of three lots of intranasal trivalent influenza vaccine among young children.

BACKGROUND: Trivalent formulations of an experimental, cold-adapted, intranasal influenza (CAIV) vaccine have been shown to be safe, immunogenic and efficacious in young children. METHODS: We evaluated the safety and immunogenicity of three consistency lots of CAIV in children 12 to 36 months of age randomized to one of five groups: Groups 1, 2 and 3 received separate lots containing A/Shenzhen/227/95 (H1N1), A/Wuhan/359/95(H3N2) and B/Harbin/7/94-like viral strains. Group 4 received an earlier efficacy trial lot which included a different H1N1 strain (A/Texas/36/91-like); and Group 5 received placebo. We performed strain-specific serum hemagglutination inhibition antibody levels against type A (H3N2 or H1N1) or type B as appropriate. RESULTS: Overall 474 children received 2 doses, 2 months apart. Each lot was well-tolerated, and there were no significant group differences between consistency lots in the proportion of children with fever and local or systemic reactions after vaccination. The 3 consistency lots were not statistically different with regard to immunogenicity as measured by seroconversion or absolute geometric mean titer. Immune responses were more robust among initially seronegative children and for H3N2 and B strains than for H1N1 strains. After 2 doses of vaccine 97, 84 and 62% had hemagglutination inhibition titers > or = 1/32 against A/H3N2, B and H1N1 strains, respectively. For A/H3N2 only, immune responses after 1 dose of vaccine are similar to those seen after 2 doses. CONCLUSIONS: Each consistency lot of CAIV is as or more immunogenic than a lot used in a large efficacy trial.

Cost-effectiveness analysis of an intranasal influenza vaccine for the prevention of influenza in healthy children.

OBJECTIVE: Intranasal influenza vaccine has proven clinical efficacy and may be better tolerated by young children and their families than an injectable vaccine. This study determined the potential cost-effectiveness (CE) of an intranasal influenza vaccine among healthy children. METHODS: We conducted a CE analysis of data collected between 1996 and 1998 during a prospective 2-year efficacy trial of intranasal influenza vaccine, supplemented with data from the literature. The CE analysis included both direct and indirect costs. We enrolled 1602 healthy children aged 15 to 71 months in year 1, 1358 of whom were enrolled in year 2. One or 2 doses of intranasal influenza vaccine or placebo were administered to measure the cost per febrile influenza-like illness (ILI) day avoided. RESULTS: During the 2-year study period, vaccinated children had an average of 1.2 fewer ILI fever days/child than unvaccinated children. In an individual-based vaccine delivery scenario with vaccine given twice in the first year and once each year thereafter at an assumed base case total cost of $20 for the vaccine and its administration (ie, per dose), CE was approximately $30/febrile ILI day avoided. CE ranged from $10 to $69/febrile ILI day avoided at $10 to $40/dose, respectively. In a group-based delivery scenario, vaccination was cost saving compared with placebo and remained so if vaccine cost was <$28 (the break-even price per dose). In the individual-based scenario, vaccination was cost saving if vaccine cost was <$5. In this scenario, nearly half of lost productivity in the vaccine group was attributable to vaccine visits, which overshadowed the relatively modest savings in ILI-associated costs averted. CONCLUSIONS: Routine use of intranasal influenza vaccine among healthy children may be cost-effective and may be maximized by using group-based vaccination approaches. cost-effectiveness, influenza, vaccine, children.

Pneumococcal and influenza immunization and human immunodeficiency virus load in children.

OBJECTIVE: HIV-infected children receiving influenza vaccine, pneumococcal vaccine and both vaccines concurrently were studied to examine the effect of immunization on plasma HIV viral load. METHODS: Thirteen children received immunizations: pneumococcal vaccine, 5; pneumococcal and influenza vaccines, 7; and influenza vaccine, 1. Most patients (12 of 13) were receiving combination reverse transcriptase inhibitor antiretroviral therapy without protease inhibitors at the time of immunization. Baseline plasma HIV RNA was determined 1 month prior (11 of 13), 2 weeks prior (12 of 13) and on the day of immunization (12 of 13). Plasma HIV RNA was assayed at 2 weeks (11 of 13), 4 weeks (12 of 13) and 3 months (5 of 13) after immunization. T cell activation markers (HLA-DR+, CD38+ and CD45RO+, CD28+) were examined for both CD4+ and CD8+ lymphocytes on the day of immunization and 2 weeks after immunization for 11 children. RESULTS: Only one child developed a >0.5-log increase in viral load at any time after immunization. There was no correlation between an increase in viral load and antibody response to pneumococcal vaccine. At least one activation marker increased (> 10%) for two children receiving pneumococcal vaccine and two children receiving pneumococcal and influenza vaccines. One of these children experienced an increase in viral load. CONCLUSION: Immunization with pneumococcal and influenza vaccines, alone or in combination, is rarely associated with a significant increase in HIV plasma RNA in children receiving combination antiretroviral therapy.

Correlates of immune protection induced by live, attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine.

The authors conducted a 2-year, multicenter, double-blind, placebo-controlled efficacy field trial of live, attenuated, cold-adapted, trivalent influenza vaccine administered by nasal spray to children 15-71 months old. Overall, vaccine was 92% efficacious at preventing culture-confirmed infection by influenza A/H3N2 and influenza B. Because influenza A/H1N1 did not cause disease during the years in which this study was conducted, the authors sought to determine vaccine efficacy and correlates of immune protection against experimental challenge with 107 TCID50 of attenuated H1N1 (vaccine strain) by intranasal spray. Prechallenge assessments included serum hemaglutination-inhibiting (HAI) antibody and nasal wash IgA antibody to H1N1. Vaccine was 83% efficacious (95% confidence interval, 60%-93%) at preventing shedding of H1N1 virus after challenge. Any serum HAI antibody or any nasal wash IgA antibody was correlated with significant protection from H1N1 infection as indicated by vaccine-virus shedding, and high efficacy against H1N1 challenge was demonstrated.

Parapharyngeal abscess due to cat-scratch disease.

The spectrum of illness attributed to cat-scratch disease (CSD) continues to expand. Although a common cause of cervical adenitis in children, CSD has not been associated as a cause of deep fascial space infections of the head and neck. We describe a child with extensive parapharyngeal adenitis and abscesses due to CSD confirmed by histological and serological evaluations.

Efficacy of vaccination with live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine against a variant (A/Sydney) not contained in the vaccine.

OBJECTIVE: To determine the safety, immunogenicity, and efficacy of revaccination of children with live attenuated influenza vaccine. STUDY DESIGN: A 2-year multicenter, double-blind, placebo-controlled, efficacy field trial of live attenuated, cold-adapted trivalent influenza vaccine administered by nasal spray to children. This report summarizes year 2 results, a year in which the epidemic strain of influenza A/Sydney was not well matched to the vaccine strains. Each year, vaccine strains were antigenically equivalent to the contemporary inactivated influenza vaccine. In year 2, a single intranasal revaccination was administered. Active surveillance for influenza was conducted during the influenza season by means of viral cultures. Influenza cases were defined as illnesses with wild-type influenza virus isolated from respiratory secretions. RESULTS: In year 2, 1358 (85%) children, 26 to 85 months of age, returned for revaccination. The intranasal vaccine was easily accepted, well tolerated, and immunogenic. Revaccination resulted in 82% to 100% of the vaccinated children in a subset studied for immunogenicity being seropositive as compared with 26% to 65% of placebo recipients, depending on the influenza strain tested. No serious adverse events were associated with the vaccine. In addition to the strains in the vaccine, antibody was induced to the variant strain A/Sydney/H3N2. In year 2, influenza A/Sydney/H3N2, a variant not contained in the vaccine, caused 66 of 70 cases of influenza A; nonetheless, intranasal vaccine was 86% efficacious in preventing A/Sydney influenza. Eight cases of lower respiratory tract disease were associated with A/Sydney influenza; all cases were in the placebo group. CONCLUSIONS: This live attenuated, cold-adapted influenza vaccine was safe, immunogenic, and efficacious against influenza A/H3N2 (including a variant, A/Sydney, not contained in the vaccine) and influenza B. The characteristics of this vaccine make it suitable for routine use in children to prevent influenza.

The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children.

BACKGROUND: Influenzavirus vaccine is used infrequently in healthy children, even though the rates of influenza in this group are high. We conducted a multicenter, double-blind, placebo-controlled trial of a live attenuated, cold-adapted, trivalent influenzavirus vaccine in children 15 to 71 months old. METHODS: Two hundred eighty-eight children were assigned to receive one dose of vaccine or placebo given by intranasal spray, and 1314 were assigned to receive two doses approximately 60 days apart. The strains included in the vaccine were antigenically equivalent to those in the inactivated influenzavirus vaccine in use at the time. The subjects were monitored with viral cultures for influenza during the subsequent influenza season. A case of influenza was defined as an illness associated with the isolation of wild-type influenzavirus from respiratory secretions. RESULTS: The intranasal vaccine was accepted and well tolerated. Among children who were initially seronegative, antibody titers increased by a factor of four in 61 to 96 percent, depending on the influenza strain. Culture-positive influenza was significantly less common in the vaccine group (14 cases among 1070 subjects) than the placebo group (95 cases among 532 subjects). The vaccine efficacy was 93 percent (95 percent confidence interval, 88 to 96 percent) against culture-confirmed influenza. Both the one-dose regimen (89 percent efficacy) and the two-dose regimen (94 percent efficacy) were efficacious, and the vaccine was efficacious against both strains of influenza circulating in 1996-1997, A(H3N2) and B. The vaccinated children had significantly fewer febrile illnesses, including 30 percent fewer episodes of febrile otitis media (95 percent confidence interval, 18 to 45 percent; P<0.001). CONCLUSIONS: A live attenuated, cold-adapted influenzavirus vaccine was safe, immunogenic, and effective against influenza A(H3N2) and B in healthy children.

School-based clusters of meningococcal disease in the United States. Descriptive epidemiology and a case-control analysis.

OBJECTIVE: To evaluate the epidemiologic features and risk factors for multiple cases of meningococcal disease in schools. DESIGN: Population-based prospective evaluation and case-control study of clusters of meningococcal disease that occurred in schools from January 1989 to June 1994. SETTING: Surveillance conducted through state health departments in the United States. MAIN OUTCOME MEASURES: Descriptive epidemiology of school-based clusters of meningococcal disease and determinants of their occurrence. RESULTS: We identified 22 clusters of meningococcal disease in 15 states. The estimated incidence of secondary meningococcal disease among schoolchildren aged 5 to 18 years was 2.5 per 100000 population, a relative risk of 2.3 (95% confidence interval [CI], 1.6-3.3). The median number of students per cluster was 2 (range, 2-4). Of 30 subsequent cases, 10 (33%) occurred 2 or fewer days after the index case, and 22 (73%) occurred 14 or fewer days after the index case. Among the 8 schools with 2 or more cases, 50% of the additional cases occurred 2 or more days after the second case. Secondary schools (grades 7 through 12) accounted for 15 (75%) of 20 cluster schools compared with 9 (45%) of 20 matched control schools (P<.05). In 16 (73%) of 22 clusters, interaction between case patients was noted. The index patient in cluster schools was more likely than the controls to have participated in a school-based group activity 14 or fewer days before illness (matched odds ratio, 7.0; 95% CI, 0.9-57). CONCLUSIONS: Three quarters of the school clusters occurred in secondary schools, with over 70% of subsequent cases occurring within 2 weeks of the index case. Rapid initiation of a chemoprophylaxis program after 2 cases of meningococcal disease in a school would have potentially prevented 50% of subsequent cases in the clusters described.

Epidemiology of invasive pneumococcal disease in southern California: implications for the design and conduct of a pneumococcal conjugate vaccine efficacy trial.

Population-based prospective surveillance of invasive pneumococcal disease was done in Southern California from 31 March 1992 to 1 April 1995; 814 cases were identified, for an incidence of 12.5/100,000 persons/year. The incidence among persons < or = 2, < or = 5, and > or = 65 years of age was 145, 72, and 32/100,000, respectively. More than 95% of cases included bacteremia; incidence of meningitis was 0.8/100,000. Among children < or = 2 years of age, 79% of isolates were obtained in the outpatient setting, compared with 16% of isolates among persons > or = 15 years of age. Eighty percent of isolates were serotypes included in heptavalent pneumococcal conjugate vaccines currently being evaluated. Children < or = 2 years of age were at highest risk of having an isolate resistant to penicillin. Among resistant isolates, high-level resistance increased from 4% to 21% over a 3-year period. Prospective epidemiologic data are needed to perform a protective efficacy trail of pneumococcal conjugate vaccines in infants, among whom most invasive pneumococcal disease is vaccine-preventable.

Cat-scratch disease--Connecticut, 1992-1993.

A prospective population-based surveillance system was established to characterize the epidemiology of cat-scratch disease (CSD) among residents of Connecticut who were reported to the state health department with a diagnosis of suspected CSD. During 1992 and 1993, 246 persons met the case definition, for an average statewide annual incidence of 3.7/100,000 persons. The median age of patients with CSD was 14 years (range, 1-64), and 52% were female. The age-specific attack rate was highest among persons < 10 years of age (9.3/100,000) and decreased with increasing age. Symptoms in addition to adenopathy were noted by 74% of case-patients. Eleven percent of all case-patients were hospitalized. There were no deaths. Most patients with clinically diagnosed CSD developed an immunologic response to Bartonella species. Our data suggest that although CSD is primarily a disease of younger persons, the age spectrum is wider than was commonly appreciated.

Multistate case-control study of maternal risk factors for neonatal group B streptococcal disease. The Active Surveillance Study Group.

Risk factors for early onset disease (EOD) caused by Group B streptococci (GBS) that are the foundation of prevention guidelines were identified in studies conducted in a few hospital centers. We investigated cases of EOD identified through laboratory-based active surveillance during 1991 and 1992 in a multistate population of 17 million. Ninety-nine cases were compared with 253 controls matched for hospital, date of birth and birth weight. Prematurity (< 37 weeks of gestation) was present in 28% of cases; 53% of case mothers had rupture of membranes > 12 hours; and 48% reported intrapartum fever. The incidence of EOD in each surveillance area was higher among blacks. By multivariate analysis, case mothers were more likely than controls to have rupture of membranes before labor onset (adjusted odds ratio 8.7, P < 0.001), intrapartum fever (adjusted odds ratio 11.9, P < 0.001), and history of urinary infection during pregnancy (adjusted odds ratio 4.3, P < 0.05). Young maternal age was also associated with risk of disease. Three-fourths of case mothers had intrapartum fever, < 37 weeks of gestation and/or prolonged rupture of membranes, indicators previously used to select high risk women for intrapartum chemoprophylaxis. Our findings extend data from single hospitals and suggest prenatal screening and selective intrapartum chemoprophylaxis of high-risk mothers could potentially prevent the majority of EOD in the United States.

Duration of antibody response after meningococcal polysaccharide vaccination in US Air Force personnel.

The long-term kinetics of the immunologic response after vaccination of adults with Neisseria meningitidis polysaccharide vaccine is unknown. Total meningococcal anti-capsular antibody response (measured by ELISA) and serum bactericidal activity after routine vaccination with quadrivalent meningococcal vaccine were evaluated in US Air Force personnel. In a retrospective cross-sectional study, blood samples were obtained from approximately 40 personnel before vaccination, at 1 and 4-6 months, and at 2, 3, 4, 6, 8, and 10 years after vaccination. Total anti-group A and -group C capsular antibody levels and bactericidal activity peaked 1 month after vaccination and declined substantially by 2 years. At each interval, significantly higher levels of total antibody and bactericidal activity were detected than before vaccination. Anti-capsular antibodies and bactericidal activity persisted for up to 10 years after immunization. These and further studies on the serologic measure of protection against meningococcal disease are important for evaluation of candidate vaccines and development of recommendations for immunization.

Cat scratch disease in Connecticut. Epidemiology, risk factors, and evaluation of a new diagnostic test.

BACKGROUND: Although cat scratch disease is commonly diagnosed in patients who have unexplained regional lymphadenopathy after encounters with cats, its epidemiology and the risk factors for disease are not clearly defined, and there is no generally accepted diagnostic test. METHODS: We conducted a physician survey to identify cases of cat scratch disease occurring over a 13-month period in cat owners in Connecticut. We interviewed both the patients (or their parents) and controls matched for age who owned cats. Serum from the patients was tested for antibodies to Rochalimaea henselae with a new, indirect fluorescent-antibody test. RESULTS: We identified 60 patients with cat scratch disease and 56 age-matched subjects. Patients were more likely than controls to have at least one pet kitten 12 months old or younger (odds ratio, 15), to have been scratched or bitten by a kitten (odds ratio, 27), and to have had at least one kitten with fleas (odds ratio, 29). A conditional logistic-regression analysis found that in kitten-owning households, patients were more likely than controls to have been scratched or bitten by a cat or kitten (odds ratio, 12.4; 95 percent confidence interval, 1.0 to 150). Of 45 patients, 38 had serum samples with titers of 1:64 or higher for antibody to R. henselae, as compared with 4 of 112 samples from controls (P < 0.001). The positive predictive value of the serologic test was 91 percent. Of 48 serum samples from patients' cats, 39 were positive for antibodies to R. henselae, as compared with positive samples from 11 of 29 control cats (P < 0.001). CONCLUSIONS: Cat scratch disease is strongly associated with owning a kitten, and fleas may be involved in its transmission. The serologic test for rochalimaea may be useful diagnostically, and our results suggest an etiologic role for this genus.

Group B streptococcal disease in the United States, 1990: report from a multistate active surveillance system.

Group B streptococcal (GBS) disease is the most common cause of neonatal sepsis and meningitis in the United States. It is also an important cause of morbidity among pregnant women and adults with underlying medical conditions. Because most states have not designated GBS disease as a reportable condition, previous estimates of the incidence of GBS disease were based on studies from single hospitals or small geographic areas. This report summarizes the results of population-based active surveillance for invasive GBS disease in counties within four states that had an aggregate population of 10.1 million persons in 1990. A case of GBS disease was defined as isolation of group B streptococcus from a normally sterile anatomic site in a resident of one of the surveillance areas. Age- and race-adjusted projections to the U.S. population suggest that > 15,000 cases and > 1,300 deaths due to GBS disease occur each year. The projected age- and race-adjusted national incidence is 1.8/1,000 live births for neonatal GBS disease and 4.0/100,000 population per year for adult GBS disease. Intrapartum chemoprophylaxis for pregnant women at risk for delivering infants with GBS disease is the most effective strategy available for prevention of neonatal disease. Development of effective GBS vaccines may prevent GBS disease in both infants and adults. Ongoing surveillance for GBS disease is important for targeting preventive measures and determining their effectiveness.

Dandy-Walker malformation in Ellis-van Creveld syndrome.

We report on 2 Old Order Amish patients with Ellis-van Creveld (EvC) syndrome and the Dandy-Walker malformation; a similar case is noted in the literature. Pedigree analysis of our patients documents extensive inbreeding in successive generations. Considering the rarity of EvC syndrome and Dandy-Walker malformation as isolated malformations, the appearance of both in our 2 patients plus the patient in the literature suggests that Dandy-Walker malformation may be a manifestation in the EvC syndrome. However, in this isolate the coincidental occurrence of 2 rare recessive traits cannot be excluded.