Efficacy and Safety of 1 and 2 Doses of Live Attenuated Influenza Vaccine in Vaccine-Naive Children Efficacy of a Russian-backbone live attenuated influenza vaccine among children in Senegal: a randomised, double-blind, placebo-controlled trial Efficacy of a Russian-backbone live attenuated influenza vaccine among young children in Bangladesh: a randomised, double-blind, placebo-controlled trial Influenza Vaccine Effectiveness in the United States During 2012–2013: Variable Protection by Age and Virus Type Live attenuated versus inactivated influenza vaccine in infants and young children. Superior Relative Efficacy of Live Attenuated Influenza Vaccine Compared With Inactivated Influenza Vaccine in Young Children With Recurrent Respiratory Tract Infections Safety, Efficacy, and Effectiveness of Cold-Adapted Influenza Vaccine-Trivalent Against Community-Acquired, Culture-Confirmed Influenza in Young Children Attending Day Care Effectiveness of Non-Adjuvanted Pandemic Influenza A Vaccines for Preventing Pandemic Influenza Acute Respiratory Illness Visits in 4 U.S. Communities The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children. Efficacy and Safety of a Live Attenuated, Cold-Adapted Influenza Vaccine, Trivalent Against Culture-Confirmed Influenza in Young Children in Asia Vaccine Effectiveness Against Laboratory-Confirmed Influenza in Children 6 to 59 Months of Age During the 2003–2004 and 2004–2005 Influenza Seasons Effectiveness of the 2012/13 Trivalent Live and Inactivated Influenza Vaccines in Children and Adolescents in Saxony-Anhalt, Germany: A Test-Negative Case-Control Study 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 Live attenuated seasonal and pandemic influenza vaccine in school-age children: a randomized controlled trial. Randomized evaluation of live attenuated vs. inactivated influenza vaccines in schools (RELATIVES) cluster randomized trial: Pilot results from a household surveillance study to assess direct and indirect protection from influenza vaccination. Association of vaccine handling conditions with effectiveness of live attenuated influenza vaccine against H1N1pdm09 viruses in the United States. Live Attenuated Versus Inactivated Influenza Vaccine in Hutterite Children Correlation of Cellular Immune Responses with Protection against Culture-Confirmed Influenza Virus in Young Children
Background : We investigated the efficacy and safety of 1 versus 2 doses of live attenuated influenza vaccine ( LAIV ) in influenza vaccine – naive children aged 6 to < 36 months . Patients / Methods : Subjects were r and omized to 1 of 4 regimens in year 1 : 2 doses LAIV , 1 dose LAIV , excipient placebo , or saline placebo . In year 2 , LAIV recipients were to receive 1 dose of LAIV and placebo recipients were to receive saline placebo . Because of an unintended treatment allocation error in year 2 , 1 block of subjects who were r and omized to LAIV received saline placebo and 1 block who were r and omized to placebo received LAIV . Results : In year 1 , vaccine efficacy versus placebo among recipients of 2 and 1 doses of LAIV was 73.5 % and 57.7 % , respectively , against antigenically similar strains . In year 2 , absolute efficacy of a single dose of LAIV was 73.6 % and 65.2 % , respectively , in recipients of 2 and 1 doses of LAIV in year 1 . Year 2 efficacy was 57.0 % in subjects who received 2 doses of LAIV in year 1 and placebo in year 2 . Safety and tolerability of LAIV were consistent with previous studies . Reactogenicity was similar between placebo groups . Seroconversion rates were significantly higher in the 2-dose versus the 1-dose LAIV group in year 1 and in both LAIV groups versus placebo in years 1 and 2 . Conclusions : One dose of LAIV provided clinical ly significant protection against influenza in young children previously unvaccinated against influenza ; 2 doses provided additional protection . Protection after 2 doses in year 1 persisted through a second season without revaccination . LAIV excipients were not a major contributor to reactogenicity . These benefits provide support for increased use of LAIV in children ≥2 years of age Summary Background Live attenuated influenza vaccines have been shown to significantly reduce influenza in diverse population s of children , but no efficacy studies have been done in re source -poor tropical setting s. In Senegal , we assessed the efficacy and safety of a live attenuated influenza vaccine based on Russian-derived master donor viruses and licensed as a single dose . Methods In this double-blind , placebo-controlled , parallel group , single-centre trial done near Niakhar , Senegal , generally healthy children aged 2–5 years were r and omly allocated ( 2:1 ) to receive a single intranasal dose of masked trivalent live attenuated influenza vaccine or placebo . The allocation sequence was computer-generated by PATH with block sizes of three . The manufacturer provided vaccine and placebo in coded vials to preserve blinding . Participants were monitored through the predictable influenza season in Senegal for adverse events and signs and symptoms of influenza using weekly home visits and surveillance in clinics . The primary outcome was symptomatic laboratory-confirmed influenza caused by any strain and occurring from 15 days post-vaccination to the end of the study . The primary analysis was per protocol . This study is registered with Clinical Trials.gov , number NCT01854632 . Findings Between May 23 , and July 1 , 2013 , 1761 children were r and omly assigned , 1174 to receive live attenuated influenza vaccine and 587 to receive placebo .  The per- protocol set included 1173 vaccinees and 584 placebo recipients followed up to Dec 20 , 2013 . Symptomatic influenza was laboratory-confirmed in 210 ( 18 % ) of 1173 recipients of live attenuated influenza vaccine and 105 ( 18 % ) of placebo recipients , giving a vaccine efficacy of 0·0 % ( 95 % CI −26·4 to 20·9 ) . Adverse events were balanced between the study groups . Two girls who had received live attenuated influenza vaccine died , one due to anasarca 12 days postvaccination and one due to malnutrition 70 days postvaccination . Interpretation Live attenuated influenza vaccine was well tolerated in young children in Senegal , but did not provide protection against influenza . Further study in such population s , which might experience extended periods of influenza circulation , is warranted . Funding US Centers for Disease Control and Prevention and Bill & Melinda Gates Foundation Summary Background The rates of influenza illness and associated complications are high among children in Bangladesh . We assessed the clinical efficacy and safety of a Russian-backbone live attenuated influenza vaccine ( LAIV ) at two field sites in Bangladesh . Methods Between Feb 27 and April 9 , 2013 , children aged 2–4 years in urban Kamalapur and rural Matlab , Bangladesh , were r and omly assigned in a 2:1 ratio , according to a computer-generated schedule , to receive one intranasal dose of LAIV or placebo . After vaccination , we monitored children in weekly home visits until Dec 31 , 2013 , with study clinic surveillance for influenza illness . The primary outcome was symptomatic , laboratory-confirmed influenza illness due to vaccine-matched strains . Analysis was per protocol . The trial is registered with Clinical Trials.gov , number NCT01797029 . Findings Of 1761 children enrolled , 1174 received LAIV and 587 received placebo .  Laboratory-confirmed influenza illness due to vaccine-matched strains was seen in 93 ( 15·8 % ) children in the placebo group and 79 ( 6·7 % ) in the LAIV group . Vaccine efficacy of LAIV for vaccine-matched strains was 57·5 % ( 95 % CI 43·6–68·0 ) . The vaccine was well tolerated , and adverse events were balanced between the groups . The most frequent adverse events were tachypnoea ( n=86 in the LAIV group and n=54 in the placebo group ) , cough ( n=73 and n=43 ) , and runny nose ( n=68 and n=39 ) , most of which were mild . Interpretation This single-dose Russian-backbone LAIV was safe and efficacious at preventing symptomatic laboratory-confirmed influenza illness due to vaccine-matched strains . LAIV programmes might reduce the burden of influenza illness in Bangladesh . Funding The Bill & Melinda Gates Foundation Background . During the 2012–2013 influenza season , there was cocirculation of influenza A(H3N2 ) and 2 influenza B lineage viruses in the United States . Methods . Patients with acute cough illness for ≤7 days were prospect ively enrolled and had swab sample s obtained at outpatient clinics in 5 states .  Influenza vaccination date s were confirmed by medical records . The vaccine effectiveness ( VE ) was estimated as [ 100 % × ( 1 − adjusted odds ratio ) ] for vaccination in cases versus test-negative controls . Results . Influenza was detected in 2307 of 6452 patients ( 36 % ) ; 1292 ( 56 % ) had influenza A(H3N2 ) , 582 ( 25 % ) had influenza B/Yamagata , and 303 ( 13 % ) had influenza B/Victoria . VE was 49 % ( 95 % confidence interval [ CI ] , 43%–55 % ) overall , 39 % ( 95 % CI , 29%–47 % ) against influenza A(H3N2 ) , 66 % ( 95 % CI , 58%–73 % ) against influenza B/Yamagata ( vaccine lineage ) , and 51 % ( 95 % CI , 36%–63 % ) against influenza B/Victoria . VE against influenza A(H3N2 ) was highest among persons aged 50–64 years ( 52 % ; 95 % CI , 33%–65 % ) and persons aged 6 months–8 years ( 51 % ; 95 % CI , 32%–64 % ) and lowest among persons aged ≥65 years ( 11 % ; 95 % CI , −41 % to 43 % ) . In younger age groups , there was evidence of residual protection from receipt of the 2011–2012 vaccine 1 year earlier . Conclusions . The 2012–2013 vaccines were moderately effective in most age groups . Cross-lineage protection and residual effects from prior vaccination were observed and warrant further investigation BACKGROUND Universal vaccination of children 6 to 59 months of age with trivalent inactivated influenza vaccine has recently been recommended by U.S. advisory bodies . To evaluate alternative vaccine approaches , we compared the safety and efficacy of intranasally administered live attenuated influenza vaccine with those of inactivated vaccine in infants and young children . METHODS Children 6 to 59 months of age , without a recent episode of wheezing illness or severe asthma , were r and omly assigned in a 1:1 ratio to receive either cold-adapted trivalent live attenuated influenza vaccine ( a refrigeration-stable formulation of live attenuated intranasally administered influenza vaccine ) or trivalent inactivated vaccine in a double-blind manner . Influenza-like illness was monitored with cultures throughout the 2004 - 2005 influenza season . RESULTS Safety data were available for 8352 children , and 7852 children completed the study according to the protocol . There were 54.9 % fewer cases of cultured-confirmed influenza in the group that received live attenuated vaccine than in the group that received inactivated vaccine ( 153 vs. 338 cases , P<0.001 ) . The superior efficacy of live attenuated vaccine , as compared with inactivated vaccine , was observed for both antigenically well-matched and drifted viruses . Among previously unvaccinated children , wheezing within 42 days after the administration of dose 1 was more common with live attenuated vaccine than with inactivated vaccine , primarily among children 6 to 11 months of age ; in this age group , 12 more episodes of wheezing were noted within 42 days after receipt of dose 1 among recipients of live attenuated vaccine ( 3.8 % ) than among recipients of inactivated vaccine ( 2.1 % , P=0.076 ) . Rates of hospitalization for any cause during the 180 days after vaccination were higher among the recipients of live attenuated vaccine who were 6 to 11 months of age ( 6.1 % ) than among the recipients of inactivated vaccine in this age group ( 2.6 % , P=0.002 ) . CONCLUSIONS Among young children , live attenuated vaccine had significantly better efficacy than inactivated vaccine . An evaluation of the risks and benefits indicates that live attenuated vaccine should be a highly effective , safe vaccine for children 12 to 59 months of age who do not have a history of asthma or wheezing . ( Clinical Trials.gov number , NCT00128167 [ Clinical Trials.gov ] . ) 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 r and omized 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 OBJECTIVE . The goal was to evaluate the safety , tolerability , and efficacy of an investigational , refrigerator-stable formulation of live attenuated influenza vaccine ( cold-adapted influenza vaccine-trivalent ) against culture-confirmed influenza , acute otitis media , and effectiveness outcomes in young children in day care over 2 consecutive influenza seasons . METHODS . Children 6 to < 36 months of age who were attending day care were assigned r and omly in year 1 to receive 2 doses of vaccine or placebo intranasally , 35 ± 7 days apart . In year 2 , subjects received 1 dose of the same treatment as in year 1 . RESULTS . A total of 1616 subjects ( vaccine : 951 subjects ; placebo : 665 subjects ) in year 1 and 1090 subjects ( vaccine : 640 subjects ; placebo : 450 subjects ) in year 2 were able to be evaluated for efficacy . The mean age at first vaccination was 23.4 ± 7.9 months . In year 1 , the overall efficacy of the vaccine against influenza subtypes similar to the vaccine was 85.4 % ; efficacy was 91.8 % against A/H1N1 and 72.6 % against B. In year 2 , the overall efficacy was 88.7 % ; efficacy was 90.0 % against H1N1 , 90.3 % against A/H3N2 , and 81.7 % against B. Efficacy against all episodes of acute otitis media associated with culture-confirmed influenza was 90.6 % in year 1 and 97.0 % in year 2 . Runny nose or nasal discharge after dose 1 in year 1 was the only reactogenicity event that was significantly more frequent with cold-adapted influenza vaccine-trivalent ( 82.3 % ) than placebo ( 75.4 % ) . CONCLUSIONS . Cold-adapted influenza vaccine-trivalent was well tolerated and effective in preventing culture-confirmed influenza illness in children as young as 6 months of age who attended day care We estimated the effectiveness of four monovalent p and emic influenza A ( H1N1 ) vaccines ( three unadjuvanted inactivated , one live attenuated ) available in the U.S. during the p and emic . Patients with acute respiratory illness presenting to inpatient and outpatient facilities affiliated with four collaborating institutions were prospect ively recruited , consented , and tested for influenza . Analyses were restricted to October 2009 through April 2010 , when p and emic vaccine was available . Patients testing positive for p and emic influenza by real-time RT-PCR were cases ; those testing negative were controls . Vaccine effectiveness was estimated in logistic regression models adjusted for study community , patient age , timing of illness , insurance status , enrollment site , and presence of high-risk medical conditions .  P and emic virus was detected in 1,011 ( 15 % ) of 6,757 enrolled patients . Fifteen ( 1 % ) of 1,011 influenza positive cases and 1,042 ( 18 % ) of 5,746 test-negative controls had record-verified p and emic vaccination > 14 days prior to illness onset . Adjusted effectiveness ( 95 % confidence interval ) for p and emic vaccines combined was 56 % ( 23 % , 75 % ) . Adjusted effectiveness for inactivated vaccines alone ( 79 % of total ) was 62 % ( 25 % , 81 % ) overall and 32 % ( −92 % , 76 % ) , 89 % ( 15 % , 99 % ) , and −6 % ( −231 % , 66 % ) in those aged 0.5 to 9 , 10 to 49 , and 50 + years , respectively . Effectiveness for the live attenuated vaccine in those aged 2 to 49 years was only demonstrated if vaccination > 7 rather than > 14 days prior to illness onset was considered ( 61%∶ 12 % , 82 % ) . Inactivated non-adjuvanted p and emic vaccines offered significant protection against confirmed p and emic  influenza-associated medical care visits in young adults 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 Background : This study was design ed 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 r and omized to receive 2 doses of CAIV-T ( n = 1900 ) or placebo ( n = 1274 ) intranasally ≥28 days apart . In year 2 , 2947 subjects were rer and omized 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 OBJECTIVE . The goal was to estimate the effectiveness of influenza vaccination  against laboratory-confirmed influenza during the 2003–2004 and 2004–2005 influenza seasons in children 6 to 59 months of age . METHODS . We conducted a case-control study with children with medically attended , acute respiratory infections who received care in an inpatient , emergency department , or outpatient clinic setting during 2 consecutive influenza seasons . All children residing in Monroe County , New York , Davidson County , Tennessee , or Hamilton County , Ohio , were enrolled prospect ively at the time of acute illness and had nasal/throat swabs tested for influenza with cultures and /or polymerase chain reaction assays . Children with laboratory-confirmed influenza were case subjects and children who tested negative for influenza were control subjects . Child vaccination records from the parent and the child 's physician were used to determine and to vali date influenza vaccination status . Influenza vaccine effectiveness was calculated as ( 1 − adjusted odds ratio ) × 100 . RESULTS . We enrolled 288 case subjects and 744 control subjects during the 2003–2004 season and 197 case subjects and 1305 control subjects during the 2004–2005 season . Six percent and 19 % of all study children were fully vaccinated according to immunization guidelines in the respective seasons . Full vaccination was associated with significantly fewer influenza-related inpatient , emergency department , or outpatient clinic visits in 2004–2005 ( vaccine effectiveness : 57 % ) but not in 2003–2004 ( vaccine effectiveness : 44 % ) . Partial vaccination was not effective in either season . CONCLUSIONS . Receipt of all recommended doses of influenza vaccine was associated with halving of laboratory-confirmed influenza-related medical visits among children 6 to 59 months of age in 1 of 2 study years , despite suboptimal matches between the vaccine and circulating influenza strains in both years A live attenuated influenza vaccine has been available in Germany since the influenza season 2012/13 , which is approved for children aged 2 - 17 years . Using data from our laboratory-based surveillance system , we described the circulation of influenza and non-influenza respiratory viruses during the influenza season 2012/13 in Saxony-Anhalt . We estimated the effectiveness of live and inactivated trivalent influenza vaccines in preventing laboratory-confirmed cases among children and adolescents . From week 40/2012 to 19/2013 , sentinel paediatricians systematic ally swabbed acute respiratory illness patients for testing of influenza and 5 non-influenza viruses by PCR . We compared influenza cases and influenza-negative controls . Among children aged 2 - 17 years , we calculated overall and vaccine type-specific effectiveness against laboratory-confirmed influenza , stratified by age group ( 2 - 6 ; 7 - 17 years ) . We used multivariable logistic regression to adjust estimates for age group , sex and month of illness . Out of 1,307 specimens , 647 ( 35 % ) were positive for influenza viruses and 189 ( 15 % ) for at least one of the tested non-influenza viruses . For vaccine effectiveness estimation , we included 834 patients ( mean age 7.3 years , 53 % males ) in our analysis . Of 347 ( 42 % ) influenza-positive specimens , 61 ( 18 % ) were positive for A(H1N1)pdm09 , 112 ( 32 % ) for A(H3N2 ) and 174 ( 50 % ) for influenza B virus . The adjusted overall vaccine effectiveness including both age groups was 38 % ( 95 % CI : 0.8 - 61 % ) . The adjusted effectiveness for inactivated vaccines was 37 % ( 95 % CI : -35 - 70 % ) and for live vaccines 84 % ( 95 % CI : 45 - 95 % ) . Effectiveness for the live vaccine was higher in 2 - 6 year-old children ( 90 % , 95 % CI : 20 - 99 % ) than in children aged 7 - 17 years ( 74 % , 95 % CI : -32 - 95 % ) . Our study of the strong influenza season in 2012/13 suggests a high preventive effect of live attenuated influenza vaccine especially among young children , which could not be reached by inactivated vaccines . We recommend the use of live attenuated influenza vaccines in children unless there are contraindications 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 r and omized , 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 BACKGROUND The novel influenza A(H1N1pdm09 ) virus emerged in North America in early 2009 and rapidly spread worldwide . In this study we report the efficacy of the live attenuated monovalent H1N1pdm09 vaccine and 2009 - 10 seasonal influenza vaccine in a r and omized double-blind placebo-controlled trial . METHODS We enrolled 703 children aged 7 - 11 . Each child was r and omly allocated in the ratio 3:2 to receive one dose of live attenuated monovalent H1N1pdm09 vaccine or saline placebo between November 2009 and January 2010 , followed after 3 - 10 weeks by independent r and om allocation to one dose of live attenuated trivalent 2009 - 10 seasonal influenza vaccine or saline placebo in the same ratio . Children were followed up through September 2010 with biweekly telephone calls and symptom diaries . Seasonal and p and emic influenza infections were confirmed by virologic testing of nose and throat swabs collected during acute respiratory illnesses . RESULTS Overall , 30 children had confirmed influenza including 3 ( 0.43 % ) H1N1pdm09 , 10 ( 1.4 % ) seasonal A(H3N2 ) , and 17 ( 2.4 % ) influenza B. There were no significant differences in incidence rates of H1N1pdm09 or A(H3N2 ) between the four study arms , but receipt of the seasonal influenza vaccine was associated with a significant reduction in risk of influenza B ( p<0.01 ) . Vaccine efficacy against confirmed H1N1pdm09 infection associated with receipt of the monovalent H1N1pdm09 vaccine was 65 % ( 95 % confidence interval , CI : -281 % , 97 % ) . Vaccine efficacies against confirmed seasonal influenza A(H3N2 ) and B infection associated with receipt of the seasonal influenza vaccine were 31 % ( 95 % CI : -138 % , 80 % ) and 96 % ( 95 % CI : 67 % , 99 % ) respectively . CONCLUSIONS Vaccine efficacy was consistent with other studies of the monovalent H1N1pdm09 vaccine and seasonal influenza vaccines . Our study was underpowered to provide precise estimates of vaccine efficacy due to low incidence of influenza A viruses during the study period BACKGROUND Children are key drivers of influenza transmission . Vaccinating school age children decreases influenza in the community . OBJECTIVE To pilot-test the methods for a future trial to compare the direct and indirect benefits of inactivated influenza vaccine ( IIV ) vs. live attenuated influenza vaccine ( LAIV ) in preventing influenza infection . METHODS During the 2013 - 14 influenza vaccination campaign , we piloted an open-label cluster r and omized trial involving 10 elementary schools in Peterborough , Ontario , Canada . We r and omized schools on a 1:1 basis to have students receive  IIV  or LAIV . We invited a subset of vaccinated students and their households to participate in a surveillance sub- study , which involved completing daily symptom diaries during influenza season and collecting mid-turbinate swabs from symptomatic individuals to detect influenza infection . The main outcome measure was confirmed influenza infection using a real-time reverse transcriptase polymerase chain reaction ( PCR ) assay . RESULTS One hundred and nineteen households ( 166 students and 293 household members ) participated . During 15 weeks of surveillance , we detected 22 episodes of PCR-confirmed influenza ( 21 influenza A/H1N1 and 1 influenza B ) . The incidence of influenza per 1000 person-days was 1.24 ( 95 % CI , 0.40 - 2.89 ) for IIV-vaccinated students , compared to 0.13 ( 95 % CI , 0.003 - 0.72 ) for LAIV-vaccinated students ; the incidence rate ratio was 0.10 ( 95 % CI , 0.002 - 0.94 ) . Similarly , the incidence of influenza per 1000 person-days was 1.33 ( 95 % CI , 0.64 - 2.44 ) for IIV household members , compared to 0.47 ( 95 % CI , 0.17 - 1.03 ) for LAIV household members ; the incidence rate ratio was 0.36 ( 95 % CI , 0.11 - 1.08 ) . The overall incidence rate ratio ( combining students and household members ) was 0.27 ( 95 % CI , 0.09 - 0.69 ) . CONCLUSIONS Household surveillance involving participant monitoring and reporting of symptoms and self- collection of mid-turbinate swabs is feasible . A larger study is required to vali date the suggestion that vaccinating children with LAIV might confer more protection against influenza for both children and their household contacts , compared to IIV . TRIAL REGISTRATION Clinical Trials.gov NCT01995851 PURPOSE This analysis examined potential causes of the lack of vaccine effectiveness ( VE ) of live attenuated influenza vaccine ( LAIV ) against A/H1N1pdm09 viruses in the United States ( US ) during the 2013 - 2014 season . Laboratory studies have demonstrated reduced thermal stability of A/California/07/2009 , the A/H1N1pdm09 strain utilized in LAIV from 2009 through 2013 - 2014 . METHODS Post hoc analyses of a 2013 - 2014 test-negative case-control ( TNCC ) effectiveness study investigated associations between vaccine shipping conditions and LAIV lot effectiveness . Investigational sites provided the LAIV lot numbers administered to each LAIV recipient enrolled in the study , and the vaccine distributor used by the site for commercially purchased vaccine . Additionally , a review was conducted of 2009 - 2014 pediatric observational TNCC effectiveness studies of LAIV , summarizing effectiveness by type/subtype , season , and geographic location . RESULTS From the 2013 to 2014 TNCC study , the proportion of  LAIV recipients  who  tested positive for H1N1pdm09  was significantly higher among children who received a lot released between August 1 and September 15 , 2013 , compared with a lot shipped either earlier or later ( 21 % versus 4 % ; P<0.01 ) . A linear relationship was observed between the proportion of subjects testing positive for H1N1pdm09 and outdoor temperatures during truck unloading at distributors ' central locations . The review of LAIV VE studies showed that in the 2010 - 2011 and 2013 - 2014 influenza seasons , no significant effectiveness of LAIV  against H1N1pdm09 was demonstrated for the trivalent or quadrivalent formulations of LAIV in the US , respectively , in contrast to significant effectiveness against A/H3N2 and B strains during 2010 - 2014 . CONCLUSIONS This study showed that the lack of VE observed with LAIV in the US against H1N1pdm09 viruses was associated with exposure of some LAIV lots to temperatures above recommended storage conditions during US distribution , and is likely explained by the increased susceptibility of the A/California/7/2009 ( H1N1pdm09 ) LAIV strain to thermal degradation . CLINICAL TRIAL REGISTRY NCT01997450 Influenza is a major cause of morbidity and mortality , result ing in excess hospitalization and death ( 13 ) . Data from longitudinal studies suggest that children are an important source of community transmission of influenza ( 48 ) . Vaccinating children against influenza not only protects them but can also provide indirect benefit through herd protection ( that is , reducing the risk for influenza in susceptible persons by rendering immunity in others ) ( 916 ) . However , the choice of vaccine that best achieves herd protection remains uncertain ( 17 , 18 ) . Intranasal live attenuated influenza vaccine ( LAIV ) has been reported to provide 55 % greater protection against influenza in children than inactivated influenza vaccine ( IIV ) ( 19 , 20 ) . Vaccinating children with LAIV compared with IIV should provide better community protection because of better direct protection of children and better indirect effects of herd protection . This question is of public health importance , particularly given differences in recommendations on preferential use of LAIV ( 2123 ) . Most comparative influenza vaccine studies assess direct protection only ( 24 ) . Underst and ing the comprehensive benefit of LAIV versus IIV requires evaluation of both direct and indirect effects . This is best addressed through a r and omized , controlled trial ; however , r and om assignment of the children of entire communities to vaccination with LAIV versus IIV is not possible in most setting s. Hutterite colony members live communally and are relatively isolated from cities and towns , and influenza is regularly introduced into these colonies . This offers an opportunity to test the effect of vaccinating children with LAIV versus IIV on community protection in a cluster r and omized trial ( 11 ) . We hypothesized that a 70 % or greater uptake of trivalent LAIV compared with a similar uptake of trivalent IIV among healthy children and adolescents would reduce laboratory-confirmed influenza by 50 % in the LAIV versus IIV group . A 50 % risk reduction was selected on the basis of a previous trial showing a 55 % direct risk reduction in children who received LAIV compared with IIV ( 19 ) . We also hypothesized that this would translate to a reduction in influenza-associated outcomes . Methods Study Colonies Residents of Hutterite colonies within 150 km of design ated cities or towns in Alberta and Saskatchewan , Canada , were enrolled and followed from 22 October 2012 through 20 May 2015 . Each colony was approached annually regarding whether it would enroll for the next influenza season . Colonies were excluded if the children did not receive any routine vaccinations or if local public health policy was to offer influenza immunization to persons beyond high-risk children ( for example , those with cystic fibrosis ) . Hutterite colonies are small communities ( for example , 70 to 120 residents ) with single-family dwellings and communally shared buildings , such as the kitchen , dining hall , and school . Hutterite families shop in nearby towns for supplies and clothing not available in the colony . The children attend school in the colony . Vaccinated Children Healthy Hutterite children aged 36 months to 15 years ( ages when they attend school ; age 15 years is when Hutterite children are considered to have reached maturity ) were eligible to be vaccinated . Exclusion criteria included anaphylactic reaction to a previous LAIV or trivalent influenza vaccine ; known IgE-mediated hypersensitivity to eggs manifested as hives , swelling of the mouth and throat , difficulty breathing , hypotension , or shock ; history of asthma ; medically diagnosed or treated wheezing within 42 days before enrollment ; GuillainBarr syndrome within 8 weeks of a previous influenza vaccine ; anaphylactic reaction to any vaccine component ; pregnancy ; household contact with a severely immunocompromised person who was being cared for in a protective environment ; and use of aspirin or salicylate-containing products within 30 days before enrollment . Other Hutterite Colony Members All other residents of Hutterite colonies were eligible to participate as nonvaccine recipients and could receive an influenza vaccine outside of the trial . Ethics approval was obtained at McMaster University , the University of Calgary , and the University of Saskatchewan . Participants gave written consent . Participants provided consent for children , and assent was also directly sought from children aged 7 to 15 years . Interventions In the LAIV group , healthy children aged 36 months to 15 years received a 0.2-mL dose of intranasal LAIV ( FluMist [ MedImmune ] ) recommended for the 2012 to 2013 ( influenza A/California/7/2009[H1N1]pdm09 , influenza A/Victoria/361/2011[H3N2 ] , and influenza B/Wisconsin/1/2010like viruses ) , 2013 to 2014 ( influenza A/California/7/2009[H1N1]pdm09 , influenza A/Victoria/361/2011[H3N2 ] , and influenza B/Massachusetts/2/2012like viruses ) , or 2014 to 2015 influenza seasons ( influenza A/California/7/2009[H1N1]pdm09 , influenza A/Texas/50/2012[H3N2 ] , and influenza B/Massachusetts/2/2012like viruses ) . In the IIV group , healthy children aged 36 months to 15 years received a 0.5-mL intramuscular injection of IIV ( Vaxigrip [ Sanofi Pasteur ] ) recommended for the 3 influenza seasons . In both LAIV and IIV groups , previously unvaccinated children younger than 9 years at the time of immunization received a second dose of the vaccine 4 weeks after the first dose . Blinding and Allocation A statistician assigned colonies , using a r and om-number generator , within each of 5 geographic regions where participating Hutterite colonies were located to control for regional differences in influenza circulation . Allocation was to 1 of the 2 study groups ( LAIV or IIV ) in a 1:1 ratio . To minimize bias , we gave precedence to achieving a balance of colonies within strata or health regions as opposed to balancing overall cluster numbers between groups . We reduced the possibility of enrollment bias by allocating LAIV or IIV status to colonies after participant enrollment . Colonies were not r and omly assigned again in the second and third year of the trial so that vaccine allocation remained the same over the entire study . In the event of a colony withdrawal , another colony from the same study region that met eligibility criteria was selected as a replacement and allocated to the same group as the colony that had withdrawn . Arrangements for vaccine shipment from the manufacturer to depots were made by an intermediary clinical trials research organization that received the r and omization code from the statistician . To maintain blinding , children allocated to LAIV received a concurrent 0.5-mL saline injection to mimic IIV . Those allocated to IIV received a 0.2-mL dose of intranasal saline . Among children younger than 9 years who had never previously received seasonal influenza vaccine , those allocated to LAIV received a concurrent 0.5-mL intramuscular injection of sterile saline with the first and second dose of intranasal LAIV . Those in the IIV group received concurrent 0.2-mL doses of intranasal saline administered 4 weeks apart . For blinding purpose s , different teams were used to vaccinate children or assess outcomes . Vaccines were prepared by nurses behind a privacy screen in the preparation room in the Hutterite colony . Surveillance staff , who assessed outcomes , were not involved in vaccination and were blinded to allocation status . Investigators , study coordinators , study monitors , and the data and safety monitoring board were all blinded . Follow-up The start date of the surveillance period for influenza was defined as 1 or more cases of laboratory-confirmed influenza in 2 consecutive weeks from public health surveillance regions that occurred at least 2 weeks after completion of study vaccination in a study colony ; the stop date was defined as no cases of laboratory-confirmed influenza for 2 consecutive weeks in colonies within the health region . Participants were assessed twice weekly by using a st and ardized checklist of self- or parent-reported symptoms or signs . If any new symptoms were reported , the participant was contacted directly by research staff , who confirmed the symptoms and obtained flocked nasal swabs if 2 or more of the following symptoms were present : fever ( temperature 38C ) , cough , nasal congestion , sore throat , headache , sinus problems , muscle aches , fatigue , ear ache or infection , or chills . We provided thermometers for study participants . Outcomes The primary outcome was laboratory-confirmed influenza A or B in all participants , the assessment of which began 2 weeks after vaccination to ensure adequate time for development of an immune response . For participants with 2 or more signs and symptoms , influenza was confirmed on the basis of detecting viral RNA in respiratory sample s through duplex real-time reverse transcriptase polymerase chain reaction ( RT-PCR ) . This test targeted the matrix gene for influenza A virus and the nonstructural gene for influenza B virus ( 25 ) . All specimens with positive results on RT-PCR were then tested by using Centers for Disease Control and Prevention primers capable of differentiating wild-type from vaccine strains . We also assessed antimicrobial prescriptions , influenza-like illness ( defined as a temperature 38.0C and cough ) ( 26 ) , medically attended visits for respiratory illness , school- or work-related absenteeism , emergency department visits , hospital admissions , and deaths . Although we had originally planned to capture hospitalizations , we decided before data collection to consider emergency department visits as a separate outcome from hospital admission . Further , we initially planned to analyze outcomes , including physician-diagnosed otitis media , lower respiratory tract infection , and pneumonia , but a reduction in re sources limited our ability to vali date these outcomes . We captured all hospitalizations and deaths and reported the number of events in each study group , but because of low numbers , we did not conduct analyses . Adverse ABSTRACT The highly sensitive gamma interferon ( IFN-γ ) enzyme-linked immunosorbent spot ( ELISPOT ) assay permits the investigation of the role of cell-mediated immunity ( CMI ) in the protection of young children against influenza . Preliminary studies of young children confirmed that the IFN-γ ELISPOT assay was a more sensitive measure of influenza memory immune responses than serum antibody and that among seronegative children aged 6 to < 36 months , an intranasal dose of 107 fluorescent focus units ( FFU ) of a live attenuated influenza virus vaccine ( CAIV-T ) elicited substantial CMI responses . A commercial inactivated influenza virus vaccine elicited CMI responses only in children with some previous exposure to related influenza viruses as determined by detectable antibody levels prevaccination . The role of CMI in actual protection against community-acquired , culture-confirmed clinical influenza by CAIV-T was investigated in a large r and omized , double-blind , placebo-controlled dose-ranging efficacy trial with 2,172 children aged 6 to < 36 months in the Philippines and Thail and . The estimated protection curve indicated that the majority of infants and young children with ≥100 spot-forming cells/106 peripheral blood mononuclear cells were protected against clinical influenza , establishing a possible target level of CMI for future influenza vaccine development . The ELISPOT assay for IFN-γ is a sensitive and reproducible measure of CMI and memory immune responses and contributes to establishing requirements for the future development of vaccines against influenza , especially those used for children
BACKGROUND This systematic review and meta- analysis describes and consoli date s findings from all studies that assessed the effectiveness of live-attenuated influenza vaccine ( LAIV )  against laboratory-confirmed influenza since the 2009 p and emic in children and young adults .