Comparison of the efficacy and safety of live attenuated cold-adapted influenza vaccine, trivalent, with trivalent inactivated influenza virus vaccine in children and adolescents with asthma

BACKGROUND: Despite their potential for increased morbidity, 75% to 90% of asthmatic children do not receive influenza vaccination. Live attenuated influenza vaccine (LAIV), a cold-adapted, temperature-sensitive, trivalent influenza vaccine, is approved for prevention of influenza in healthy children 5 to 19 years of age. LAIV has been studied in only a small number of children with asthma. METHODS: Children 6 to 17 years of age, with a clinical diagnosis of asthma, received a single dose of either intranasal CAIV-T (an investigational refrigerator-stable formulation of LAIV; n = 1114) or injectable trivalent inactivated influenza vaccine (TIV; n = 1115) in this randomized, open-label study during the 2002-2003 influenza season. Participants were followed up for culture-confirmed influenza illness, respiratory outcome, and safety. RESULTS: The incidence of community-acquired culture-confirmed influenza illness was 4.1% (CAIV-T) versus 6.2% (TIV), demonstrating a significantly greater relative efficacy of CAIV-T versus TIV of 34.7% (90% confidence interval [CI] 9.4%-53.2%; 95% CI = 3.9%-56.0%). There were no significant differences between treatment groups in the incidence of asthma exacerbations, mean peak expiratory flow rate findings, asthma symptom scores, or nighttime awakening scores. The incidence of runny nose/nasal congestion was higher for CAIV-T (66.2%) than TIV (52.5%) recipients. Approximately 70% of TIV recipients reported injection site reactions. CONCLUSIONS: CAIV-T was well tolerated in children and adolescents with asthma. There was no evidence of a significant increase in adverse pulmonary outcomes for CAIV-T compared with TIV. CAIV-T had a significantly greater relative efficacy of 35% compared with TIV in this high-risk population.     

Efficacy and safety of a live attenuated, cold-adapted influenza vaccine, trivalent against culture-confirmed influenza in young children in Asia

BACKGROUND: This study was designed to evaluate the efficacy and safety of cold-adapted influenza vaccine, trivalent (CAIV-T) against culture-confirmed influenza in children 12 to <36 months of age during 2 consecutive influenza seasons at multiple sites in Asia. METHODS: In year 1, 3174 children 12 to <36 months of age were randomized to receive 2 doses of CAIV-T (n = 1900) or placebo (n = 1274) intranasally > or =28 days apart. In year 2, 2947 subjects were rerandomized to receive 1 dose of CAIV-T or placebo. RESULTS: Mean age at enrollment was 23.5 +/- 7.4 months. In year 1, efficacy of CAIV-T compared with placebo was 72.9% [95% confidence interval (CI): 62.8-80.5%] against antigenically similar influenza subtypes, and 70.1% (95% CI: 60.9-77.3%) against any strain. In year 2, revaccination with CAIV-T demonstrated significant efficacy against antigenically similar (84.3%; 95% CI: 70.1-92.4%) and any (64.2%; 95% CI: 44.2-77.3%) influenza strains. In year 1, fever, runny nose/nasal congestion, decreased activity and appetite, and use of fever medication were more frequent with CAIV-T after dose 1. Runny nose/nasal congestion after dose 2 (year 1) and dose 3 (year 2) and use of fever medication after dose 3 (year 2) were the only other events reported significantly more frequently in CAIV-T recipients. CONCLUSIONS: CAIV-T was well tolerated and effective in preventing culture-confirmed influenza illness over multiple and complex influenza seasons in young children in Asia.     

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.     

Safety of the intranasal, trivalent, live attenuated influenza vaccine (LAIV) in children with intermittent wheezing in an open-label field trial

BACKGROUND: Safety of the intranasal, trivalent, live attenuated influenza vaccine (LAIV) in children with asthma is unknown. A previous report showed an "asthma signal" in children aged 18-35 months. METHODS: Healthy children aged 1.5-18 years with history of intermittent wheezing received single annual LAIV doses during a 4-year trial. Rates of medically-attended acute respiratory illnesses, including acute asthma exacerbation, during 0-14 and 0-42 days post-LAIV were compared with respective reference periods (before day 0 and after 14 or 42 days). To assess the risk of new-onset asthma, LAIV recipients without history of wheezing were analyzed. RESULTS: During each of the 4 years, 454, 656, 656, and 430 children, respectively, with intermittent wheezing who received LAIV had no increased risk for medically-attended acute respiratory illnesses, including asthma exacerbation. First-dose LAIV recipients, including those aged 1.5-4 years, and those receiving 2-4 consecutive annual doses had no increased risk. Children with parents' report of intermittent wheezing and those with administrative database codes for asthma during 2 prior years had no increased risk. During the 4 years, 2952, 3092, 2953, and 2478 children without history of wheezing had no increased risk of new-onset asthma. CONCLUSIONS: LAIV administration in children aged 1.5-18 years with history of intermittent wheezing was safe, and was not associated with increased risk for medically-attended acute respiratory illnesses, including acute asthma exacerbation. This was true for the first and 2-4 consecutive annual doses. Parents' report of intermittent wheezing was reliable. First-dose LAIV was not associated with new-onset asthma in children without history of wheezing.     

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.     

Safety of cold-adapted live attenuated influenza vaccine in a large cohort of children and adolescents

OBJECTIVE: To determine the safety of cold-adapted trivalent intranasal influenza virus vaccine (CAIV) in children and adolescents. STUDY DESIGN: A randomized, double blind, placebo-controlled safety trial in healthy children age 12 months to 17 years given CAIV (FluMist; MedImmune Vaccines, Inc.) or placebo (randomization, 2:1). Children <9 years of age received a second dose of CAIV or placebo 28 to 42 days after the first dose. Enrolled children were then followed for 42 days after each vaccination for all medically attended events. Prespecified outcomes included 4 prespecified diagnostic groups and 170 observed individual diagnostic categories. The relative risk and the 2-sided 90% confidence interval were calculated for each diagnostic group and individual category by clinical setting, dose and age. More than 1500 relative risk analyses were performed. RESULTS: A total of 9689 evaluable children were enrolled in the study. Of the 4 prespecified diagnostic categories (acute respiratory tract events, systemic bacterial infection, acute gastrointestinal tract events and rare events potentially associated with wild-type influenza), none was associated with vaccine. Of the biologically plausible individual diagnostic categories, 3, acute gastrointestinal events, acute respiratory events and abdominal pain, had different analyses that demonstrated increased and decreased relative risks, making their association with the vaccine unlikely. For reactive airway disease a significant increased relative risk was observed in children 18 to 35 months of age with a relative risk of 4.06 (90% confidence interval, 1.29 to 17.86) in this age group. The individual diagnostic categories of upper respiratory infection, musculoskeletal pain, otitis media with effusion and adenitis/adenopathy had at least one analysis that achieved a significant increased risk ratio. All of these events were infrequent. CONCLUSION: CAIV was generally safe in children and adolescents. The observation of an increased risk of asthma/reactive airway disease in children <36 months of age is of potential concern. Further studies are planned to evaluate the risk of asthma/reactive airway disease after vaccine.     

Safety of the trivalent,cold-adapted influenza vaccine (CAIV-T) in children

The trivalent, cold-adapted influenza vaccine (CAIV-T, FluMist, Aviron, Mountain View, CA) is a live attenuated influenza virus vaccine that is administered by nasal spray. CAIV-T is efficacious in preventing influenza virus infection. The vaccine was submitted to the Food and Drug Administration for licensure in healthy children and adults. Universal immunization is being considered in children, and an effective vaccine with minimal adverse reactions is thus required. The published studies on the safety of CAIV-T in children reviewed in this article were clinical trials sponsored by the National Institutes of Health (NIH) conducted in children from 1975 to 1991, clinical trials from 1991 to 1993 sponsored by a cooperative agreement between NIH and Wyeth-Ayerst Research, and clinical trials from 1995 to the present sponsored by a cooperative agreement between NIH and Aviron. Safety assessments included the occurrence of: 1) specific influenza-like symptoms, unexpected symptoms, and use of medications within the first 10 days after vaccination; 2) acute illness and use of medication within 11 to 42 days postvaccination; 3) serious adverse events and rare events within 42 days after vaccination; 4) healthcare utilization within 14 days after vaccination; and 5) acute respiratory symptoms with annual sequential vaccine doses. CAIV-T was safe and well-tolerated. Transient, mild respiratory symptoms were observed in a minority (10%-15%) of children and primarily with the first CAIV-T dose. Vomiting and abdominal pain occurred in fewer than 2 percent of CAIV-T recipients. The gastrointestinal symptoms were mild and of short duration. An excess of illness or use of medication was not observed after the 10th day of vaccination. Sequential annual doses of CAIV-T were well-tolerated and not associated with increased reactogenicity. CAIV-T did not cause an increase in healthcare utilization. Thus CAIV-T is safe in healthy children and should complement the use of inactivated influenza vaccine, trivalent (IIV-T) in children with underlying chronic conditions.     

Repeated immunization of children with inactivated and live attenuated influenza virus vaccines: safety,immunogenicity, and protective efficacy

Annual immunization of healthy children with live attenuated or inactivated influenza virus vaccine currently is under consideration in an attempt to reduce influenza-associated morbidity and mortality in children and the impact of influenza in the community. However, few studies have assessed the effects of this practice. Available data from studies conducted in children and adults provide reassurance that repeated annual immunization is safe and effective. Although the frequencies of significant responses to immunization (such as significant rise in titer or evidence of vaccine virus infection) are lower among persons who were immunized previously when compared with persons immunized for the first time, no consistent increases or decreases in serum antibody levels achieved after immunization or in the level of protective efficacy have been noted. Additional data regarding the effects of annual immunization are needed, and continued efforts to develop improved vaccines for the prevention of influenza are indicated.     

Effect of concurrent viral infection on systemic and local antibody responses to live attenuated and enhanced-potency inactivated poliovirus vaccines.

OBJECTIVE--To determine the effect of an asymptomatic nonpolioviral infection on the immune response to poliovirus vaccines. DESIGN--Open comparative trial. SETTING--Well-child clinic at The Children's Hospital of Buffalo, NY. PARTICIPANTS--Twenty-seven healthy infants infected with nonpolioviruses and 27 healthy controls matched for age and vaccine group. INTERVENTIONS--Trivalent oral attenuated poliovirus vaccine or enhanced potency inactivated vaccine administered at ages 4 and 12 months. MEASUREMENTS/MAIN RESULTS--Neutralizing antibody to poliovirus serotypes 1, 2, and 3 were determined in the serum and nasopharyngeal secretion samples obtained at ages 4, 5, 12, and 13 months. The IgA antibody titers for polioviruses 1, 2, and 3 were measured in nasopharyngeal secretion samples during the same periods. Antibody responses to poliovirus vaccines were similar in coinfected subjects and healthy controls at ages 5 and 13 months, except for serum neutralizing antibody that was significantly elevated in the controls compared with coinfected subjects (geometric mean [+/- SD] antibody titers, 12.7 +/- 1.6 vs 11.5 +/- 1.7). Concurrent viral infections affected the immune response in recipients of the oral poliovirus vaccine and the enhanced-potency inactivated poliovirus vaccine similarly. The immune response to polioviruses 1 and 3 were more adversely affected by coinfection than was the immune response to poliovirus 2. CONCLUSION--Concurrent asymptomatic viral infections minimally impaired the immune response to poliovirus vaccines. The adverse effects of coinfection were considered clinically insignificant.     

Duration of protection provided by live attenuated influenza vaccine in children

BACKGROUND: Reliable availability of influenza vaccine before October could enable the vaccination of many children who might not otherwise be vaccinated. METHODS: Available data for children were analyzed to describe protection provided by live attenuated influenza vaccine (LAIV) for greater than 5 months postvaccination. RESULTS: Four studies conducted in children aged 6 months to 18 years were identified. Culture-confirmed efficacy against A/H1N1 and A/H3N2 strains at 9-12 months postvaccination was 77% [95% confidence interval (CI): 53-89%] to 100% (95% CI: 68-100%) and through a second influenza season without revaccination was 56% (95% CI: 31-73%) and 57% (95% CI: 6-82%), respectively. Against B strains, 1 study demonstrated 86% (95% CI: 59-95%) efficacy at 5-7 months. Another study demonstrated 27% (95% CI: -62% to 67%) efficacy at 9-12 months compared with 74% (95% CI: 39-89%) at 1 to <5 months during a period of antigenic drift for circulating B strains. A third study estimated 50% (95% CI: -49% to 83%) efficacy against influenza B strains through a second season without revaccination. CONCLUSIONS: In children, live attenuated influenza vaccine provided sustained protection against influenza illness caused by antigenically similar strains. Efficacy at 1 to <5 months postvaccination was comparable to that at 9-12 months for A/H1N1 and A/H3N2 strains and at 5-7 months for B strains. Meaningful efficacy was seen through a second season without revaccination, although at a lower level than during the first 12 months postvaccination.     

Direct and total effectiveness of the intranasal, live-attenuated, trivalent cold-adapted influenza virus vaccine against the 2000-2001 influenza A(H1N1) and B epidemic in healthy children

BACKGROUND: The efficacy of the intranasal, live-attenuated, trivalent cold-adapted influenza virus vaccine (CAIV-T) against influenza A(H3N2) and B infections in healthy persons is established, but its effectiveness against natural influenza A(H1N1) infection is unknown. OBJECTIVE: To assess the effectiveness of CAIV-T in healthy children during the 2000-2001 influenza A(H1N1) and B epidemic. DESIGN: Community-based, nonrandomized, open-label trial from August 1998 through April 2001. SETTING: Intervention and comparison communities in central Texas. PARTICIPANTS: Healthy children, aged 1.5 to 18 years, from the intervention communities received a single dose of CAIV-T at least 1 time or more in 1998, 1999, and/or 2000. MAIN OUTCOME MEASURES: The incidence of medically attended acute respiratory illnesses during the 2000-2001 influenza epidemic was compared in 3794 health plan CAIV-T recipients with age-eligible, health plan nonrecipients in the intervention communities for direct effectiveness (n = 9325), and with those in the 2 comparison communities for total effectiveness (n = 16,264). RESULTS: The 2281 CAIV-T recipients in 2000 had significant direct protection against medically attended acute respiratory illness of 18% to 20% during the biphasic influenza A(H1N1) and B epidemic, and 17% to 26% during influenza A(H1N1) predominance. The 931 recipients of CAIV-T in 1999 containing influenza A/Beijing/262/95(H1N1) and B/Beijing/184/93-like viruses had persistent heterovariant protection against the 2000-2001 influenza A/New Caledonia/20/99(H1N1) and B/Sichuan/379/99 variants. The 616 recipients of a single CAIV-T dose in 1999 only, including those younger than 5 years with no prior natural exposure to influenza A(H1N1) viruses, showed persistent protection. CONCLUSION: Healthy children who received CAIV-T in 2000 or 1999 were protected against new variants of influenza A(H1N1) and B in the 2000-2001 influenza epidemic.     

Augmented antibody response to live attenuated measles vaccine in children with Plasmodium falciparum parasitaemia

The impact of malarial infection on the humoral immunological response to measles virus antigen was studied in 184 children aged 8-19 months in Guinea-Bissau. Pre- and post-immunization measles serology was performed using dried blood on absorbent paper and the ELISA technique. Blood smears obtained at the time of vaccination and 2 and 4 weeks afterwards were examined for malaria parasites. Pre-vaccination antibodies to measles were found in 44 out of 184 children (24%). Plasmodium falciparum was identified in 62 of the 132 initially non-immune children who completed the study. The rate of seroconversion was 127 out of 132 (96%). Post-immunization measles antibody titres were significantly higher in the vaccinees with P. falciparum than in those without malaria parasites in the blood.     

Humoral and cellular immune responses in children given annual immunization with trivalent inactivated influenza vaccine

BACKGROUND: There have been no prior reports of the frequency of circulating influenza-specific, interferon gamma-producing memory CD4+ and CD8+ T-cells in healthy children who have received multiple influenza immunizations. METHODS: We evaluated 21 previously immunized children, ages 3 to 9 years, before and 1 month after administration of trivalent inactivated influenza vaccine. Frequencies of influenza-specific CD4+ and CD8+ T-cells stimulated with trivalent inactivated influenza vaccine or A/Panama (H3N2) virus were determined by flow cytometry, and antibody responses to vaccine strains and a drifted H3N2 strain were measured by hemagglutination inhibition assay and neutralizing antibody assays. RESULTS: Mean change in CD4+ and in CD8+ T-cell frequencies after immunization was 0.01% (P > 0.39) with postimmunization CD4+ frequencies higher than CD8+ frequencies. Children with more previous vaccinations had a higher baseline frequency of CD4+ T-cells (P = 0.0002) but a smaller increase or even a decline from baseline after immunization (P = 0.003). An association between age and change in frequency was not detected. Baseline geometric mean titers (GMTs) and seroprotection rates were significantly higher in older children against A/Panama (neutralizing baseline GMT, P = 0.0488) and A/New Caledonia (hemagglutination inhibition baseline GMT and seroprotection, P < 0.0297). Baseline GMTs against B/Hong Kong were not associated with age or quantity of prior vaccinations. CONCLUSIONS: These findings suggest that children may plateau in CD4+ T-cell responses to influenza antigens with repeated exposures and that the number of exposures may play a large role in building a memory CD4+ T-cell response to influenza A, perhaps independently from age.