Live attenuated influenza vaccine in children

Live attenuated influenza vaccine (LAIV) offers a novel approach to influenza vaccination and is approved for healthy individuals 5 to 49 years of age. In placebo-controlled studies in children, LAIV was 73 to 93 percent efficacious, and protection lasted more than 12 months. In head-to-head studies in children, LAIV demonstrated a 35 to 53 percent reduction in influenza attack rates compared with injectable influenza vaccine (TIV) for matched strains. Compared with TIV, LAIV has demonstrated broader serum antibody responses, particularly against mismatched influenza A. The most common adverse events are runny nose and nasal congestion. Increased rates of asthma events were observed in young children. Additional large-scale safety and efficacy studies in young children, including a formal risk-benefit assessment, are ongoing. The results of these analyses will guide potential future use in young children.     

Live attenuated influenza virus vaccine trial in children.

Thirty-four children received intranasally a live attenuated influenza A virus vaccine, and were then followed for six months to evaluate the vaccine safety, immunogenicity, and efficacy. All but one of the 31 children with hemagglutination inhibition (HI) titers less than 64 before inoculation responded with at least a four-fold rise in antibody titer to a single dose of vaccine. One child required two doses. Seven (21%) of the vaccinees also responded with production of nasal neutralizing antibody. The vaccine was well tolerated with few clinical reactions. Two vaccinees developed fever possibly attributable to the vaccine. No transmission of the vaccine virus to any of the 25 unvaccinated contact children was demonstrable. Five months after this vaccine trial an influenza epidemic due to a heterologous influenza A strain occurred in the community. During this outbreak acute febrile and/or respiratory illness occurred in 12 or 52% of the contact controls, and in six or 19% of the vaccinees. In two of these six vaccinees, influenza A infection was confirmed by at least a four-fold increase in HI titer. This study suggests this study suggests that this vaccine is safe, easily administered, highly immunogenic in children, and is protective against a heterologous strain epidemic in the community.     

Superior relative efficacy of live attenuated influenza vaccine compared with inactivated influenza vaccine in young children with recurrent respiratory tract infections

BACKGROUND: Young children have a high incidence of influenza and influenza-related complications. This study compared the efficacy and safety of cold-adapted influenza vaccine, trivalent (CAIV-T) with trivalent inactivated influenza vaccine (TIV) in young children with a history of recurrent respiratory tract infections (RTIs). METHODS: Children 6 to 71 months of age were randomized to receive 2 doses of CAIV-T (n = 1101) or TIV (n = 1086), 35 +/- 7 days apart before the start of the 2002-2003 influenza season and were followed up for culture-confirmed influenza, effectiveness outcomes, reactogenicity, and adverse events. RESULTS: Overall, 52.7% (95% confidence interval [CI] = 21.6%-72.2%) fewer cases of influenza caused by virus strains antigenically similar to vaccine were observed in CAIV-T than in TIV recipients. Greater relative efficacy for CAIV-T was observed for the antigenically similar A/H1N1 (100.0%; 95% CI = 42.3%-100.0%) and B (68.0%; 95% CI = 37.3%-84.8%) strains but not for the antigenically similar A/H3N2 strains (-97.1%; 95% CI = -540.2% to 31.5%). Relative to TIV, CAIV-T reduced the number of RTI-related healthcare provider visits by 8.9% (90% CI = 1.5%-15.8%) and missed days of school, kindergarten, or day care by 16.2% (90% CI = 10.4%-21.6%). Rhinitis and rhinorrhea, otitis media, and decreased appetite were the only events that were reported more frequently in CAIV-T subjects. There was no difference between groups in the incidence of wheezing after vaccination. CONCLUSIONS: CAIV-T was well tolerated in these children with RTIs and demonstrated superior relative efficacy compared with TIV in preventing influenza illness.     

The use of inactivated influenza vaccine in children

The impact of influenza in the very young appears to be comparable to that in the elderly. Influenza vaccine strategy is changing to reflect that impact. Currently, the broader recommendations include vaccination with trivalent inactivated influenza vaccines (TIVs) for children aged 6 to 59 months. This article reviews TIV safety, immunogenicity, and efficacy in children, current vaccine recommendations, and vaccine administration and dosage.     

Antibody responses after inactivated influenza vaccine in young children

BACKGROUND: The frequency and duration of antibody responses after trivalent inactivated influenza vaccine (TIV) in young children are not well defined and assume greater importance with the expanded recommendations for vaccine use in children aged 6 months-5 years. METHODS: Forty-three children aged 6-23 months were vaccinated with TIV in the fall of 2002. At enrollment the majority of children were seronegative to one or more of the vaccine antigens and had no previously documented influenza. Postvaccination sera were collected in the subsequent fall and winter seasons. Acute antibody responses to TIV were determined using standardized hemagglutination inhibition (HAI) and neutralization assays. In calculating the duration of responses, sequential sera were analyzed to the last available sera, to the point at which antibody became undetectable, or to intercurrent influenza infection. RESULTS: Forty-three subjects contributed 121 sera that were analyzed for HAI responses to TIV. Four-fold HAI rises after 2 doses of TIV in naive individuals were seen in 13 (72%) to H3N2, 22 (92%) to H1N1, and 15 (60%) to influenza B. Fewer 4-fold rises were seen in those with preexisting antibody. The results of microneutralization assays to H3N2 correlated well with HAI results. The time for antibody to decay to one-half of the postvaccination titer (t1/2) was approximately 126 days for H1N1 and 258 days for H3N2. CONCLUSIONS: Although not all children responded with 4-fold rises in antibody or achieved the putative protective titer of > or =1:32, the half-life of antibody suggested that children immunized in the fall should have immune responses sustained throughout the ensuing influenza season.     

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.     

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.     

Prophylactic effect of inactivated influenza vaccine on young children

BACKGROUND: The effectiveness of inactivated influenza vaccine in healthy infants and young children has been controversial. The aim of this study was to determine the prophylactic effect of inactivated influenza vaccine in young children. METHODS: Eighty-six healthy infants and children younger than 7-years-old were immunized by a subcutaneous injection of inactivated influenza vaccine before the 1999/2000 influenza season. Ninety-four age-matched children were randomly assigned as the control. These children were followed-up from January to April, 2000. A diagnosis of influenza A virus infection was made rapidly by a positive result of the the enzyme immunoassay membrane test using enzyme-conjugated monoclonal antibodies specific for a conserved epitope of influenza A nucleoprotein. The incidence of influenza A infection was compared and statistically assessed. RESULTS: The prevalence of influenza A virus infection, diagnosed by the influenza A rapid detection test, was 5.8% in the vaccine group and 17.0% in the control group, that is significantly lower in the vaccine receiving group than the non-receiving group (P = 0.016). However, four out of five infected children in the vaccine group were younger than 2-years-old. CONCLUSION: We conclude that inactivated influenza vaccine reduces the incidence of influenza A virus infection in 2-6-year-old children.     

Live attenuated varicella vaccine in healthy 12- to 24-month-old children

We studied live attenuated Oka/Merck varicella vaccine in 147 seronegative children 12 to 24 months of age and their 94 seronegative older siblings 2 to 12 years of age. The vaccine side effects were mild, consisting of a papular rash in 15 of 147 (10.2%) children 12 to 24 months and seven of 94 (7.4%) siblings. In a subset of 12- to 24-month-old children, modified fluorescent antibody test for membrane antigen was not detectable at seven days postimmunization but was detectable in 50% by 14 days and in 100% by 21 days. Within 6 weeks, 96.6% of children 12 to 24 months and 94.7% of siblings seroconverted. The geometric mean titer did not vary with age at immunization. One-year blood samples were obtained from 70 children 12 to 24 months of age who seroconverted; 92.9% retained detectable antibody. The geometric mean titer had decreased from 55.7 to 18.6. Of these 70 children, 34% had been exposed to varicella since immunization, and two cases of varicella were observed in seroconverters. Both cases were mild, with less than 50 vesicles. Oka/Merck varicella vaccine appears to be safe, highly immunogenic, and protective against 96% of exposures to natural varicella during the first year after vaccination in infants. Those cases of varicella that develop in immunized children appear substantially reduced in severity.     

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.     

Measuring antibody responses to a live attenuated influenza vaccine in children

BACKGROUND: Hemagglutination inhibition (HAI) assay is the standard method for evaluating inactivated influenza vaccines, but no standard assay has been established for evaluating live attenuated influenza vaccines (LAIV). LAIV containing A/Beijing/262/95(H1N1) induced low serum HAI antibody responses to the antigenic variant, A/New Caledonia/20/99(H1N1) in a serologic study but provided protection against the A/New Caledonia-like viruses in a community study. Neutralization and HAI assays were compared by measuring H1N1 cross-reactive antibody responses to the LAIV in children. METHODS: Sera were collected from 50 children 1-8 years of age before vaccination and 4-6 weeks after each dose of the LAIV. Antibody titers to the 3 vaccine viruses were measured by the HAI assay, whereas antibody titers against the H1N1 vaccine virus (A/Beijing/262/95) and 2 H1N1 antigenic variants (A/Shenzhen/227/95 and A/New Caledonia/20/99) were measured by the HAI and neutralization assays. RESULTS: Initially seronegative participants were more likely to develop HAI seroconversion responses to the 3 vaccine viruses than the baseline seropositive participants (77% versus 14% for H1N1, 100% versus 20% for H3N2, 100% versus 19% for B, P < 0.01, Fisher's exact test). For the H1N1 cross-reactive antibody responses, seroconversion rates measured by the neutralization assay were significantly higher than those measured by the HAI assay (95% versus 78%, P = 0.0485 for A/Beijing/262/95; 75% versus 24%, P < 0.0001 for A/Shenzhen/227/95; 51% versus 5%, P < 0.0001 for A/New Caledonia/20/99). CONCLUSIONS: The neutralization assay was more sensitive than the HAI assay for measuring H1N1 antibody responses after vaccination of children with the LAIV and may provide a better correlate of clinical protection provided by the LAIV.     

Trivalent, inactivated influenza virus vaccine in children with sickle cell disease

School-aged children with sickle cell disease who were administered a single dose of trivalent, inactivated influenza virus vaccine had serum antibody titers comparable to titers achieved in the two-dose trials carried out in 1978. The proportion exhibiting titers of 1:32 or greater ranged from 84% to 68% for the three antigens. Preschool children with sickle cell disease received two doses of the same vaccine four weeks apart and their postimmunization titers to each of the antigens were slightly lower. The vaccine, which contained 15 micrograms of hemagglutinin to each of three influenza viruses, A (H1N1), A (H3N2), and B, in a volume of 0.5 mL, was adequately immunogenic for schoolchildren who probably had been primed by previous natural infection. Younger children who received the same quantity in two divided doses four weeks apart had slightly lower but acceptable titers and tolerated the injections with few side reactions.     

Effectiveness of inactivated influenza vaccine for prevention of otitis media in children

OBJECTIVE: The objective of this study was to evaluate the effectiveness of inactivated influenza vaccine in preventing acute otitis media (AOM) and otitis media with effusion (OME) in children aged 6 to 60 months who attend day care. STUDY DESIGN: This prospective, single-blind study was conducted in 8 day care centers in Ankara, Turkey. One hundred nineteen (61 vaccinated and 58 unvaccinated against influenza) healthy children were examined at study entry and at 6-week intervals for 6 months by the same 2 otorhinolaryngologists who were blinded about the vaccination status of the children. The frequency of AOM and OME is compared between the 2 groups and the effect of influenza season on frequency of episodes was evaluated. Based on national influenza laboratory data, the influenza season was determined to be the period between December 15, 2003, and January 31, 2004. RESULT: The frequencies of AOM, OME and total otitis media episodes in vaccinated children were 2.3%, 22.8% and 25.2%, respectively, and these frequencies were 5.2%, 31.1% and 36.3% in the unvaccinated group. The difference was statistically significant (P < 0.01). This difference was especially prominent in the influenza season (P < 0.05). CONCLUSION: Influenza vaccine is effective in reducing AOM and OME episodes in 6- to 60-month-old day care children, especially during influenza season.     

Live attenuated human rotavirus vaccine, Rotarix

Rotavirus infections are the leading cause of severe gastroenteritis in young children worldwide. Recently two new rotavirus vaccines have entered the world market. This review provides a summary of the rationale, development, and evaluation of one of these vaccines, Rotarix. Rotarix is a live oral rotavirus vaccine developed from a single protective human strain following multiple passages in tissue culture to attenuate the strain. The vaccine is administered as two oral doses at approximately 2 and 4 months of age. Large safety and efficacy trials have shown the vaccine is safe, not associated with intussusception, and effective against the most common circulating human serotypes. Efficacy against severe rotavirus gastroenteritis and hospitalization have ranged from 85 to 100 percent.     

Evaluation of clinical and immunological effects of inactivated influenza vaccine in children with asthma

Although annual influenza vaccinations are recommended by many authorities, some doctors may be reluctant to vaccinate asthmatic children because of the risk of inducing bronchial reactivity and exacerbating the asthma. In this study, the effect of split influenza vaccine on clinical symptoms, airway responsiveness and its influence on T lymphocytes was evaluated. Twenty-one asthmatic children with stable asthma were recruited and divided into two groups. Eleven patients who received the influenza vaccine formed the vaccination group and 10 patients who received a placebo formed the placebo group. Forced expiratory volume in 1 s ( FEV ₁), airway response (PC₂₀ methacholine, PC₂₀ = provocation concentration causing a 20% fall in FEV ₁) and the T lymphocyte subset ratio (Th1/Th2) were recorded on day 1 pre-vaccination and day 14 post-vaccination. Patients were also asked to record their peak expiratory flow (PEF) every morning and evening and to complete daily symptom scores over the period of 2 weeks. There were no significant changes in PC₂₀, FEV ₁, PEF variability, symptom scores and the Th1/Th2 ratio between the vaccination and placebo groups between day 1 pre-vaccination and day 14 post-vaccination. Similar results of PEF variability and asthma symptom score were obtained when the analysis was restricted to the day 1 pre-vaccination and day 3 post-vaccination. Immunization with split influenza vaccine does not exacerbate asthma in children either with a clinical or immunological effect. These results suggest that children with stable asthma can safely be immunized with a split influenza vaccine.