Published online December 1, 2006
PEDIATRICS Vol. 118 No. 6 December 2006, pp. 2298-2312 (doi:10.1542/peds.2006-0725)
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ARTICLE

Safety, Efficacy, and Effectiveness of Cold-Adapted Influenza Vaccine-Trivalent Against Community-Acquired, Culture-Confirmed Influenza in Young Children Attending Day Care

Timo Vesikari, MDa, Douglas M. Fleming, MB, ChB, PhDb, Javier F. Aristegui, MDc, Andre Vertruyen, MDd, Shai Ashkenazi, MDe, Ruth Rappaport, PhDf, Jonathan Skinner, PhDf, Melanie K. Saville, MB, BSg, William C. Gruber, MDf, Bruce D. Forrest, MDf for the CAIV-T Pediatric Day Care Clinical Trial Network

a Tampere University Medical School, Tampere, Finland
b Northfield Health Centre, Birmingham, United Kingdom
c Hospital de Basurto, Bilbao, Spain
d St Vincentius Hospital, Antwerp, Belgium
e Schneider Children’s Hospital, Petah Tikva, Israel
f Wyeth Vaccines Research, Pearl River, New York
g Wyeth Vaccines Research, Taplow, United Kingdom


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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 randomly 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.

Key Words: influenza • cold-adapted influenza vaccine-trivalent • children

Abbreviations: AE—adverse event • AOM—acute otitis media • CAIV-T—cold-adapted influenza vaccine-trivalent • CI—confidence interval • LAIV—live attenuated influenza vaccine • PCR—polymerase chain reaction • PP—per protocol • TIV—trivalent influenza vaccine

Influenza is a major cause of serious respiratory illness and acute otitis media (AOM) in young children and is associated with significant public health and socioeconomic burdens through excess hospitalizations, clinic and outpatient visits, antibiotic prescriptions, and lost parental workdays.1–6 Influenza-associated hospitalization rates for children <2 years of age are comparable to those seen for elderly persons and adults at high risk for complications of influenza.7–13 During an influenza season, up to 33% of emergency department visits for children <12 months of age8 and 20% of excess hospitalizations for children <3 years of age12 have been attributed to influenza infection.

High influenza attack rates and the propensity to shed larger amounts of influenza virus for longer periods than older children and adults indicate that young children are significant reservoirs of influenza in the community.14–17 Children attending day care frequently experience the highest influenza attack rates2,18; however, influenza is underdiagnosed frequently in this age group.19 Routine immunization of young children may provide communitywide benefits by reducing the transmission of influenza to susceptible populations, decreasing the overall community disease burden, and reducing the overall economic burden of influenza.20,21

Inactivated trivalent influenza vaccine (TIV) is recommended in the United States for use in children 6 months to <5 years of age.22 Few efficacy studies using TIV in young children have been published. Estimates of TIV efficacy against influenza illness range from 12% to 83% and vary according to age, circulating influenza virus strains, level of disease burden, and other variables.23 Variability in TIV efficacy and effectiveness against AOM has also been observed.23–27

The frozen formulation of live attenuated influenza vaccine (LAIV) (FluMist; MedImmune, Gaithersburg, MD) was approved in the United States in 2003 for healthy persons 5 to 49 years of age. A new, refrigerator-stable formulation of LAIV, referred to as cold-adapted influenza vaccine-trivalent (CAIV-T), is currently in development. The clinical trial described here evaluated the safety, tolerability, and efficacy of CAIV-T against culture-confirmed influenza, during 2 consecutive influenza seasons, in children 6 to <36 months of age who were attending day care. Vaccine efficacy against AOM and certain effectiveness outcomes were also determined.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Design
This prospective, randomized, double-blind, placebo-controlled, multicenter trial was conducted over 2 consecutive influenza seasons at 70 clinical centers located in Belgium, Finland, Israel, Spain, and the United Kingdom, between October 2, 2000, and May 31, 2002. The study was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. The study protocol and all subsequent amendments were approved by the human ethics committees, institutional review boards, and any regional or national ethics committees at participating centers.

Participants
Eligible subjects were children who were 6 to <36 months of age at the time of enrollment and who were in good health, as determined by medical history and physical examination. Children were required to be attending day care for a minimum of 12 hours/week. Eligibility to participate in the second year of the trial required continued good health and completion of the primary dosing series and surveillance in year 1. Written informed consent was obtained from the parent or guardian of each child. Exclusion criteria for both years included any serious chronic disease, Down syndrome or other cytogenetic disorders, immunosuppression or a household member with immunosuppression, receipt of immunoglobulin in the previous 6-month period, receipt of any investigational vaccine or agent 1 month before enrollment or any influenza treatment within the 2 weeks before enrollment, documented history of hypersensitivity to egg or egg protein, clinically confirmed respiratory illness with wheezing within 2 weeks before enrollment, receipt of aspirin within 2 weeks before enrollment, receipt of any live virus vaccine within 1 month before enrollment, and previous influenza vaccination (year 1) or off-protocol influenza vaccination (year 2).

Vaccine and Placebo
CAIV-T was manufactured and release-tested by Wyeth Vaccines Research (Marietta, PA) and consisted of 3 cold-adapted, attenuated, reassortant strains, representing the hemagglutinin and neuraminidase antigens of the A/New Caledonia/20/99 (H1N1), A/Sydney/05/97 (H3N2), and B/Yamanashi/166/98 influenza strains for the first year of the study and the hemagglutinin and neuraminidase antigens of the A/New Caledonia/20/99 (H1N1), A/Panama/2007/99 (H3N2), and B/Victoria/504/2000 influenza strains for the second year of the study. Each 0.2-mL dose of CAIV-T was formulated to contain ~107 median tissue culture dose (or equivalent fluorescent units in year 2) of each of the 6:2 influenza reassortant virus strains. After manufacture, the vaccine was stored frozen and then shipped to the study sites at 2°C to 8°C, at which temperature it was stored until just before administration.

The hemagglutinin and neuraminidase antigens of the wild-type influenza strains used to generate the type A/H1N1 and type B vaccine reassortants for the year 1 CAIV-T formulation were antigenically representative of virus recommended by the World Health Organization for the 2000/2001 influenza season in the Northern Hemisphere. Because of industrywide technical problems encountered in the production of the recommended H3N2 A/Panama/2007/99 (A/Moscow/10/99-like) vaccine strain,28 a decision was made to use the H3N2 vaccine strain (A/Sydney/05/97) recommended for the previous 1999/2000 season in the year 1 CAIV-T formulation. This decision was based on the antigenic similarity of the hemagglutinin antigen with that of A/Panama/2007/99, the circulation of A/Sydney/05/97-like viruses before the 2000/2001 season,29 and previous clinical trials with a frozen formulation of CAIV-T that demonstrated both cross-reactive antibody development (as measured with a hemagglutinin-inhibiting antibody assay) and efficacy against mismatched influenza A/H3N2 virus.30 The A/Sydney/05/97 antigens matched the antigens used in commercial TIV for that season. The vaccine composition for year 2 consisted of vaccine strains that were antigenically representative of the World Health Organization 2001/2002 Northern Hemisphere composition recommendations.31 Placebo consisted of sterile physiologic saline solution manufactured by Wyeth Vaccines Research.

In year 1, subjects were assigned randomly to receive a primary series of 2 doses of either CAIV-T or placebo, in a 3:2 ratio, 35 ± 7 days apart. In year 2, all subjects received a single dose of either CAIV-T or placebo according to their year 1 treatment assignments. In both years, study subjects, their parents or guardians, and the clinical personnel were unaware of the treatment being administered. CAIV-T and placebo were supplied in single-dose, identically packaged sprayers labeled with the codes to which subjects were assigned. The total single-dose volume of 0.2 mL (~0.1 mL into each nostril) of vaccine or placebo was administered intranasally with the spray applicator intended for commercial use. The first dose of the primary series was administered on study day 0, after informed consent had been obtained.

Surveillance for Influenza Illness
Surveillance for influenza-like illness was based on regular telephone contacts, clinic visits, or home visits (as applicable). In both years, contact started 11 days after receipt of the first study dose (day 0) and continued weekly through completion of the first (May 31, 2001) or second (May 31, 2002) season surveillance period.

A nasal swab sample was required if subjects exhibited fever (rectal temperature of ≥38°C or axillary temperature of ≥37.5°C), wheezing, shortness of breath, pulmonary congestion, pneumonia, or ear infection (suspected or diagnosed AOM). A nasal swab sample was also required if subjects showed ≥2 of the following: runny nose or nasal congestion (rhinorrhea), sore throat (pharyngitis), cough, muscle aches, chills, headache, irritability, decreased activity, or vomiting. A viral culture was also obtained at the investigators’ discretion.

Nasal specimens were cultured in Madin-Darby canine kidney monolayer cultures, and typing was determined by immunostaining positive cultures with influenza type A-specific and type B-specific monoclonal antibodies. Nasal specimens were cultured and typed in the Department of Virology at the University of Turku (Turku, Finland). Positive specimens were shipped to Wyeth Vaccines Research (Pearl River, NY) for additional identification. Subtype identification and antigenic characterization were performed for 78.3% of all influenza-positive isolates in year 1, by the Centers for Disease Control and Prevention (Atlanta, GA), with serologic techniques. In year 2, identification assays, including polymerase chain reaction (PCR) assays and sequencing of HA1 gene fragments, were performed by Wyeth Vaccines Research with methods similar to those described previously for H3N2 and B viruses.32,33 In the second season, wild-type B/Hong Kong/1351/02 strain cocirculated32,34 and was associated with difficulties in serotyping. PCR analyses and HA1 sequencing methods were used for subtype identification and antigenic characterization of 99.0% of all influenza-positive isolates in year 2, whereas only 87.6% of isolates were identifiable with serologic testing. All strain-specific efficacy analyses in year 2 were based on PCR analyses, with serotyping confirmation when possible. Influenza-positive specimens obtained within 28 days after any vaccine dose were tested to determine whether they were CAIV-T-like or wild-type (community acquired).

AOM
An ear examination was performed if the subject developed symptoms suggesting AOM. AOM was defined as a visually abnormal tympanic membrane (with regard to color, position, and/or mobility) suggesting an effusion in the middle ear cavity, concomitant with ≥1 of the following signs and/or symptoms of acute infection: fever (rectal temperature of ≥38°C or axillary temperature of ≥37.5°C), earache, irritability, diarrhea, vomiting, acute otorrhea not caused by external otitis, or other symptoms of respiratory infection.35,36 An episode of febrile otitis media was defined as an episode of AOM in a child with a documented fever (rectal temperature of ≥38°C or axillary temperature of ≥37.5°C), and an episode of influenza-associated AOM was defined as an episode of AOM in a child with a positive culture for influenza virus. An episode of AOM in a study participant was included in the efficacy analysis if it complied with the definition of AOM given above, occurred ≥15 days after receipt of the first dose of vaccine or placebo, and occurred during the period in which influenza virus was isolated in each country.

Effectiveness Outcomes
The ability of CAIV-T, relative to placebo, to reduce the burden of respiratory illness in children attending day care was determined by evaluating the reduction in the following predefined end points during the influenza season: (1) the incidence of a parent or guardian taking time off from paid work at least once to care for the child during the current influenza-like illness, (2) the total number of days of paid work missed for parents or guardians, (3) the total number of days missed from day care as a result of influenza-like illness, (4) the incidence of ≥1 outpatient or emergency department visit because of acute febrile and/or respiratory illness, (5) the incidence of ≥1 prescription of antibiotics as a result of influenza-like illness, and (6) the number of days of treatment with an antibiotic prescribed as a result of the influenza-like illness.

Safety Assessment
After each study vaccination, parents and legal guardians were asked to record information on a diary card regarding axillary or rectal temperature, runny nose/nasal congestion, sore throat, cough, vomiting, activity level, appetite, irritability, headache, chills, muscle pain, and the use of antipyretic medications (for prophylaxis or treatment), as well as any unscheduled physician visits and medications, for 11 consecutive days, including the day of vaccination (day 0). An adverse event (AE) was defined as any clinically significant event, including but not limited to (1) events that required any prescription or nonprescription medication within 11 days after vaccination, (2) events that required an unscheduled health care provider visit and/or health care provider consultation within 11 days after vaccination, (3) events that resulted in study termination, or (4) any other clinically significant event that occurred at any time during the course of the study. Serious AEs, including hospitalizations, were monitored and collected through the end of the influenza season in each year of the study.

Statistical Analyses
Sample size estimates were based on assumed attack rates of culture-confirmed influenza in the placebo and CAIV-T groups of 12% and 3%, respectively (as observed in a previous trial of LAIV in older children30) and a subject discontinuation rate of ≤25%. A sample size of 1100 children that were able to be evaluated (with 3:2 randomization) permitted ≥90% power that the lower limit of the 95% confidence interval (CI) of efficacy over the first season would be ≥45%. The planned sample size for this study provided ≥80% power to detect frequency differences between the CAIV-T and placebo groups ranging from 4.3% to 8.2%.

The randomization schedule was generated by Wyeth Vaccines Research. Study product for year 1 was labeled with 1 of 5 letter codes, namely, A, H, or M (CAIV-T) or B or K (placebo). Each subject was assigned the next sequential number by the study site investigator and received study product for the treatment assigned to that subject number, according to a preprinted randomization allocation list provided to the study site by Wyeth Vaccines Research. The number sequence was concealed until interventions were assigned. Two efficacy populations were defined for both seasons, that is, the intent-to-treat population (all subjects who received ≥1 dose of study vaccine or placebo in year 1 or who received a single dose of study vaccine or placebo at the start of year 2) and the per-protocol (PP) population (subjects who received both vaccinations, or a single vaccination in year 2, to which they were assigned; who received no live viral vaccine within 28 days of any study vaccination; and who had no major protocol violations).

The primary efficacy end point was the efficacy of a primary series of 2 doses of CAIV-T, relative to placebo, against culture-confirmed influenza caused by subtypes antigenically similar to those contained in the vaccine in the first season. Secondary efficacy end points included the efficacy of 2 doses of CAIV-T against culture-confirmed influenza caused by any community-acquired subtypes in season 1; efficacy of CAIV-T against culture-confirmed influenza caused by subtypes antigenically similar to those contained in the vaccine and against any subtype in year 2; efficacy against all episodes of AOM, febrile AOM (first and all episodes), and influenza-associated AOM (first and all episodes) in both years; and improvement in effectiveness outcomes.

Vaccine efficacy was estimated as vaccine efficacy = 1 – (C/NC)/(P/NP), where NC is the number of subjects who received CAIV-T, C is the number of CAIV-T subjects who were case subjects, NP =is the number of subjects who received placebo, and P is the number of placebo subjects who were case subjects. For these estimates, conditional on the total number of cases, 95% CIs were obtained from the binomial distribution. For the purpose of estimating efficacy, only the first episode of each kind of illness for each subject was taken into account, unless otherwise indicated.

An episode of AOM was defined as one in which ≥30 days had passed since the onset of the previous episode. Estimates of efficacy (with 95% CIs) of CAIV-T, relative to placebo, against first episodes of AOM associated with a positive culture for influenza virus antigenically similar to virus contained in the vaccine and AOM associated with fever were calculated for the PP population. Estimates of efficacy of CAIV-T, relative to placebo, against all episodes of AOM, all febrile AOM, and all influenza-associated AOM were based on the hazard ratio estimated from the Andersen-Gill model for multiplicative hazards of recurrent events, with treatment as the only effect.

For effectiveness end points, relative effectiveness was defined in the same manner as for vaccine efficacy against influenza, that is, relative effectiveness = 1 – IC/IP, where IC and IP are incidence rates for CAIV-T and placebo, respectively, in the PP population. For the variables that were not defined as incidence variables, the rates IC and IP were defined as the quotient of the total number of days of missed work or days of antibiotic treatment, as appropriate, divided by the total number of days of surveillance. CIs at the 95% level for relative effectiveness were computed from the binomial distribution, as for vaccine efficacy.

Because the circulation of influenza and its resulting impact on the community vary according to region, the analyses of efficacy for effectiveness end points were conducted with events that occurred during the influenza season of each country, for more accurate assessment of the true impact of the vaccine on these end points. The influenza season within each country was defined as the period from the time of isolation of the first wild-type influenza-positive culture among study participants after vaccination through the time of the last identification of an influenza-positive culture in that country.

All subjects who received any dose of study vaccine were included in the analysis of safety. For the analysis of safety according to dose, subjects were analyzed according to the vaccine that they actually received (as treated), CAIV-T or placebo. For analyses of the safety population that included >1 dose, subjects who received ≥1 dose of CAIV-T were classified as "CAIV-T" and subjects who received only placebo were classified as "placebo." For AEs within 11 days after vaccination, the incidence rates for each body system and for each event for the 2 treatment groups were compared by using Fisher’s exact test (2-sided). For the summary of reactogenicity events, P values were obtained by using Fisher’s exact test. Mild, moderate, and severe fevers were defined with axillary temperatures of ≥37.5°C, ≥38.6°C, and ≥40.0°C, respectively. These cutoff points were considered equivalent to rectal temperatures of ≥38.0°C, ≥39.1°C, and ≥40.0°C, respectively. Subjects whose temperature was measured orally were analyzed with the same fever cutoff points as for rectal temperature measurements. Subjects whose temperature was measured aurally or whose method of measurement was unknown were analyzed with the most conservative fever cutoff points (ie, those for axillary temperature measurements). These conversions were similar to those used in a previously published efficacy trial of LAIV.37


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Subjects
Enrollment began on October 2, 2000, before the start of the first influenza season, and was completed on November 18, 2000. A total of 1784 subjects, at 70 sites, prospectively underwent random assignment to 1 of 2 study groups, in a 3:2 ratio (CAIV-T/placebo). All doses of CAIV-T or placebo in the primary series were administered by December 29, 2000. Participant flow, including withdrawals and reasons for exclusion from the efficacy analysis during year 1, is summarized in Fig 1.


Figure 1
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  		FIGURE 1 Participant flow, including reasons for withdrawal and exclusion from the PP analysis in year 1. ITT indicates intent to treat. a Subjects might have been excluded for >1 reason. b In year 2, 1119 subjects who had received both doses of study vaccine or placebo received a single dose of the same treatment they had received in year 1.

 
A total of 1735 subjects (97.3%) completed year 1; of the 49 subjects (2.7%) who withdrew during year 1, most did so at parental request (1.2%) or were lost to follow-up monitoring (1.0%). Four subjects (2 in the CAIV-T group and 2 in the placebo group) withdrew during year 1 because of AEs; 3 of these AEs were judged to be not related to study medication, and 1 (idiopathic thrombocytopenic purpura in a placebo recipient) was judged to be probably not related to study medication.

In year 2, 1119 subjects, at 62 sites, who completed year 1 successfully (ie, received both doses of study vaccine according to the protocol) received a single dose of the same treatment they had received in year 1. Clinical supply of CAIV-T for year 2 was not available until the end of November in 2001; all vaccine doses in year 2 were administered between December 3 and December 21, 2001. A total of 1112 subjects (99.4%) completed the study; 7 subjects (1 in the CAIV-T group and 6 in the placebo group) were lost to follow-up monitoring during year 2. No subjects withdrew from the study in year 2 because of AEs. An additional 22 subjects (17 in the CAIV-T group and 5 in the placebo group) were excluded from the PP efficacy analysis in year 2 because of major protocol violations.

A total of 1616 subjects (90.6%), including 951 CAIV-T recipients (89.8%) and 665 placebo recipients (91.7%), were included in the primary analysis of efficacy in season 1 (2000/2001). Baseline demographic characteristics for the PP efficacy population are presented in Table 1. A total of 4210 nasal swabs were collected during 4717 illness visits in season 1, and conclusive culture results (whether positive or negative for influenza) were obtained for 98.7% of the swabs. Fifty-six samples failed to yield results, primarily because of culture contamination by fungus or other agents. During the first season, an average of 2.34 and 2.38 swabs per subject were collected from CAIV-T and placebo recipients, respectively. In season 2, 1537 nasal swabs were collected during 1651 illness visits; conclusive results were obtained for 98.4% of swabs, of which 12.8% were determined to be positive for influenza. Swab rates in season 2 were 1.33 and 1.44 swabs per subject for CAIV-T and placebo recipients, respectively.


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  		TABLE 1 Demographic Characteristics of Subjects in Years 1 and 2 (PP Efficacy Population)

 
Culture-Confirmed Influenza
Influenza strains that were circulating in the community during the 2 seasons are summarized in Table 2. During the first season, all circulating influenza strains matched the vaccine strains, and most illnesses were caused by influenza A/H1N1 and influenza B strains. During the second season (2001/2002), a variety of influenza strains were circulating in the community, with clinical disease being caused by all 3 of the vaccine-like strains of influenza (A/H1N1, A/H3N2, and B). In addition, illness was caused by 2 influenza B strains that emerged from a different influenza B lineage and were antigenically distinct from the influenza B vaccine virus.


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  		TABLE 2 Strains of Community-Acquired Influenza Virus

 
Vaccine efficacy against culture-confirmed influenza is summarized in Table 3. In year 1, the overall efficacy of CAIV-T against community-acquired subtypes of influenza virus antigenically similar to those in the vaccine was 85.4% (95% CI: 74.3%–92.2%), with efficacy for individual vaccine strains of 91.8% (95% CI: 80.8%–97.1%) against A/New Caledonia/20/99-like (H1N1) viruses and 72.6% (95% CI: 38.6%–88.9%) against B/Sichuan/379/99-like viruses. In year 1, only 1 case of A/Panama/2007/99-like (H3N2) virus was detected in a placebo recipient; therefore, efficacy could not be assessed. The vaccine also provided similar protection in year 1 against all wild-type influenza strains, regardless of antigenic similarity to the vaccine, with efficacy of 85.9% (95% CI: 76.4%–92.0%). In a posthoc analysis, efficacy against any antigenically similar strain was 90.8% (95% CI: 69.6%–98.2%) and 83.6% (95% CI: 66.9%–92.6%) for subjects 12 to 23 months and ≥24 months of age, respectively. For subjects 6 to <12 months of age, the numbers of influenza cases were too small (2 CAIV-T recipients and 5 placebo recipients) to allow reliable evaluation of efficacy against antigenically similar strains; however, significant efficacy was demonstrated against any influenza strain in this age group (83.4%; 95% CI: 12.7%–98.3%).


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  		TABLE 3 Efficacy of CAIV-T Against Culture-Confirmed Influenza Illness According to Influenza Strain

 
In year 2, CAIV-T demonstrated protective efficacy similar to that in year 1, including against the A/New Caledonia/20/99-like virus, against which subjects had received 2 doses in year 1. In year 2, efficacy against influenza illness caused by influenza strains antigenically similar to those in the vaccine was 88.7% (95% CI: 82.0%–93.2%). In contrast to year 1, circulation of wild-type A/H3N2 influenza virus was more prevalent in year 2, as evidenced by the high attack rate among placebo recipients. In year 2, efficacy of CAIV-T against each of the individual vaccine strains was found to be 90.0% (95% CI: 56.3%–98.9%), 90.3% (95% CI: 82.9%–94.9%), and 81.7% (95% CI: 53.7%–93.9%) for the H1N1 A/New Caledonia/20/99-like viruses, H3N2 A/Panama/2007/99-like viruses, and B/Victoria/504/00-like viruses, respectively.

Influenza seasons according to country began as early as December 1, 2000 (Israel), and ended as late as May 31, 2001 (Spain), in year 1. In year 2, influenza seasons began on December 14, 2001 (Spain), and ended on April 18, 2002 (Finland and Israel). Table 4 summarizes efficacy against culture-confirmed influenza in both seasons according to country. In year 1, statistically significant efficacy against influenza strains antigenically similar to those in the vaccine was observed on a country basis in Israel, Finland, and the United Kingdom. Each of these countries had a placebo attack rate of ~16%. In Belgium and Spain, much lower attack rates were observed, and vaccine efficacy could not be determined.


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  		TABLE 4 Efficacy of CAIV-T Against Culture-Confirmed Influenza Illness According to Country (PP Efficacy Population)

 
In the second season (2001/2002), a much more significant influenza epidemic occurred, with high placebo attack rates of ≥30% being seen in Belgium, Israel, and Spain and with substantial attack rates also being observed in Finland (16.3%) and the United Kingdom (18.6%). Statistically significant efficacy was observed in all countries in year 2. Overall, strain-specific attack rates were 3.1% (A/H1N1), 22.4% (A/H3N2), and 7.3% (B). In year 2, all A/H1N1 and A/H3N2 virus isolates were identified as antigenically similar to the vaccine. However, only 29 (62%) of 47 influenza B isolates were identified as antigenically similar to the vaccine; 17 (36%) were identified as antigenically not similar to the vaccine, and the antigenic relatedness of 1 remaining isolate (from a CAIV-T recipient) could not be determined. Twelve (67%) of these 18 isolates came from children in Israel, and most were B/Hong Kong/1351/02-like. The emergence of these divergent strains was reflected in a lower efficacy estimate against any community-acquired strains, particularly in Israel. The attack rates for these 17 identified divergent strains were 1.1% and 2.2% in CAIV-T and placebo recipients, respectively; however, efficacy did not achieve statistical significance (50.8%; 95% CI: –43.0% to 84.1%).

AOM
Efficacy of CAIV-T against all AOM end points is summarized in Table 5. The efficacy of CAIV-T against all episodes of influenza-associated AOM was high (90.6% and 97.0% reduction in incidence in years 1 and 2, respectively). However, no difference between groups in the incidence of all episodes of AOM, first episode of febrile AOM, or all episodes of febrile AOM in either year was seen.


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  		TABLE 5 Efficacy of CAIV-T Against AOM, Febrile AOM, and AOM Associated With Influenza Illness Antigenically Similar to the Vaccine (PP Efficacy Population)

 
Effectiveness Outcomes
Effectiveness of CAIV-T against socioeconomic end points was most apparent in year 2, when the overall placebo attack rate for influenza was 30.9%. CAIV-T was effective against all socioeconomic end points in year 2 and effective against some in year 1, despite the lower influenza attack rate in placebo recipients (Table 6). During season 2 (2001/2002), CAIV-T reduced significantly the need for a parent or guardian to take time off from work by 45.1%, days of work lost by 47.5%, days of missed day care by 36.3%, and days of antibiotic use for influenza illness by 24.0%. Furthermore, the results demonstrated the substantial effect of vaccination with CAIV-T on severe disease, as reflected by a 35.1% reduction in the number of subjects with ≥1 emergency department visit during the second season.


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  		TABLE 6 Effectiveness of CAIV-T for Socioeconomic End Points (PP Efficacy Population)

 
Safety Evaluation
Reactogenicity events are summarized in Table 7. Runny nose or nasal discharge was observed in a marginally but statistically significantly greater proportion of CAIV-T recipients (82.3%), compared with placebo recipients (75.4%), after the first dose in year 1 (P = 0.001). No other significant differences in reactogenicity events after any dose in either year were observed, although the CAIV-T group had greater incidence of headache (15.0% vs 8.9%; P = .070) and fever of >37.5°C (32.0% vs 27.8%; P = .098) after the first dose in year 1. For children <24 months of age, chills were reported less frequently by CAIV-T recipients than placebo recipients after dose 1 in year 1 (0% vs 16.7%; P = .029), and runny nose or nasal discharge was more frequent in CAIV-T recipients after dose 2 (81.3% vs 74.6%; P = .035). No other significant differences in reactogenicity events in children <24 months of age were observed.


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  		TABLE 7 Reactogenicity Events Reported Within the First 11 Days After Each Dose of CAIV-T or Placebo

 
Similar proportions of subjects in the CAIV-T (36.4%) and placebo (35.4%) groups (P = .688) reported ≥1 AE within 11 days after the first vaccination in year 1, and the proportions reporting AEs within each body system were also similar. AEs reported most frequently among CAIV-T and placebo recipients after the first study dose included fever (8.7% and 7.2%, respectively), rhinitis (8.2% and 8.0%), cough (6.4% and 7.9%), otitis media (5.8% and 4.0%), and upper respiratory tract infection (4.3% and 4.6%). The AEs reported most frequently after dose 1 among CAIV-T and placebo recipients 6 to <12 months of age were diarrhea (5.6% and 2.9%, respectively), bronchospasm (0% and 5.7%), cough (5.6% and 4.3%), rhinitis (9.6% and 4.3%), upper respiratory tract infection (9.6% and 7.1%), fever (15.2% and 11.4%), and otitis media (9.6% and 5.7%). Similar AE profiles were observed within 11 days after the second vaccination in year 1 and the single vaccination in year 2. With the exception of bronchospasm after the second vaccination (P = .016), there were no statistically significant differences in the proportions of subjects in each treatment group who experienced each of these events (all P > .10). Lower respiratory tract illnesses reported as AEs were infrequent and were similar between treatment groups after the first (pneumonia: 3 CAIV-T recipients and 2 placebo recipients; bronchitis: 5 CAIV-T recipients and 5 placebo recipients; bronchiolitis: 4 CAIV-T recipients and 2 placebo recipients; bronchospasm: 7 CAIV-T recipients and 11 placebo recipients) and second (pneumonia: 6 CAIV-T recipients and 4 placebo recipients; bronchitis: 13 CAIV-T recipients and 15 placebo recipients; bronchiolitis: 2 CAIV-T recipients and 4 placebo recipients; bronchospasm: 8 CAIV-T recipients and 7 placebo recipients; LRI: 1 CAIV-T recipient and 0 placebo recipients) vaccine doses.

Lower respiratory tract illnesses reported as serious AEs from receipt of the first dose of study medication through the end of the first influenza surveillance period were also similar between treatment groups (pneumonia: 11 CAIV-T recipients and 9 placebo recipients; bronchitis: 3 CAIV-T recipients and 1 placebo recipient; bronchospasm: 2 CAIV-T recipients and 2 placebo recipients; bronchiolitis: 1 CAIV-T recipient and 2 placebo recipients). In subjects 6 to <12 months of age, lower respiratory tract infections reported as serious AEs were pneumonia (2 CAIV-T recipients and 1 placebo recipient), bronchitis (2 CAIV-T recipients and 0 placebo recipients), and bronchospasm (1 CAIV-T recipient and 0 placebo recipients). Serious AEs judged to be possibly, probably, or definitely related to study vaccination were reported for 9 CAIV-T recipients (pneumonia and AOM, 2 recipients; bronchopneumonia, 2 recipients; pneumonia, 1 recipient; bronchiolitis, 1 recipient; bronchitis and AOM, 1 recipient; idiopathic thrombocytopenic purpura, 1 recipient; and fever, acute respiratory tract infection, dehydration, and AOM, 1 recipient) and 5 placebo recipients (1 each for pneumonia and constipation; cough, wheeze, and lung consolidation; pneumonia; idiopathic thrombocytopenic purpura; and hypersensitivity, erythema, and periorbital edema). There were no statistically significant differences in serious AEs between treatment groups during the second influenza surveillance period. Six lower respiratory tract illnesses were reported, all among CAIV-T recipients (5 cases of pneumonia and 1 of bronchospasm). Two cases of pneumonia were judged to be possibly, probably, or definitely related to study vaccination. A total of 4 subjects (2 CAIV-T recipients and 2 placebo recipients) were withdrawn from the study because of AEs. No deaths occurred during the study period.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the current trial, vaccination of children 6 to <36 months of age (mean age: 23 months) with CAIV-T over 2 consecutive influenza seasons was safe, well tolerated, and highly efficacious against culture-confirmed influenza illness. The frozen formulation of LAIV was studied previously over 2 seasons by using similar nasal swab criteria and was shown to be highly effective in year 1 against vaccine-matched A/H3N2 virus (95%; 95% CI: 88%–97%) and B virus (91%; 95% CI: 79%–96%) and in year 2 against a mismatched A/H3N2 virus (86%; 95% CI: 75%–92%).30,37 Children in that study had a mean age of >40 months, and few children <2 years of age were enrolled. Data from the current trial demonstrated high efficacy rates in children with a mean age of 23 months.

This study demonstrated the efficacy of CAIV-T against all 3 A/H1, A/H3, and B strains circulating in the same season. Because Centers for Disease Control and Prevention subtyping and full antigenic characterization of isolates were unsuccessful for 22% of isolates in year 1, influenza viruses that could not be matched to vaccine antigen in that year might have been a mixture of vaccine-like and unmatched viruses. PCR assays in year 2 allowed subtyping and antigenic characterization of 99% of isolates and therefore dramatically improved the ability to distinguish isolates as vaccine-like or unmatched. The efficacy against a related but drifted influenza B virus in the second season was not surprising, given previous observations with the frozen formulation of CAIV-T among older children,30 which demonstrated protection between strains of considerably less antigenic similarity. In the current trial, the point estimates of efficacy against antigenically similar influenza B strains in years 1 and 2 were lower than those for influenza A strains. However, because the CIs for these point estimates overlapped, conclusions regarding relative efficacy against matched A or B strains could not be drawn. In the current trial, 36% of influenza B isolates in year 2 were not antigenically similar to the vaccine strain; although the point estimate of efficacy against these unmatched B viruses was 50.8%, this did not achieve statistical significance.

In previous trials, the 2-dose primary series of LAIV was administered at intervals of 60 ± 14 days.37 In the current study, doses were planned to be given at a reduced interval of 35 ± 7 days. Despite an actual mean dosing interval of 33 days in a much younger population, vaccine efficacy was high and comparable to that reported among older children.

In this trial, CAIV-T demonstrated a high level of efficacy against episodes of AOM that were associated with a positive influenza nasal swab. This was not surprising, given the high efficacy against culture-confirmed influenza. For this trial, a case definition for AOM that had been published previously and was used in previous trials involving other pediatric vaccines in this age range35,36 was used. As also seen in clinical trials with pneumococcal conjugate vaccine35 and TIV,26 CAIV-T was not able to reduce significantly all episodes of AOM from any cause during the influenza season. TIV was shown to reduce AOM rates for children attending day care,24,38 but a study conducted in younger children did not support those findings.26 Influenza viruses might represent a smaller fraction of the pathogens associated with AOM in younger children, limiting the impact of influenza vaccine in preventing this illness.

The impact of CAIV-T vaccination on effectiveness outcomes was most apparent when influenza attack rates for children were high. Vaccine effectiveness was statistically significant for all parameters measured in the second year of the trial. In that year, CAIV-T reduced significantly the proportion of households with a parent taking time off from work to care for a child, the number of days lost from day care, the number of days of parental work loss, the number of antibiotic prescriptions written, the number of days of antibiotic use, the use of outpatient clinics and emergency departments, and the use of nonprescription medications for respiratory illness. Vaccinating children had effects on equivalent parameters that were comparable to those of directly immunizing healthy adults with CAIV-T.39 Although this study was not designed to address the community impact of vaccinating children, other studies showed that vaccinating school-aged children decreases significantly health care utilization and school and work days missed.40–43 In addition, an economic analysis of LAIV vaccination of children 15 to 71 months of age demonstrated that vaccination is cost-effective from societal and third-party payer perspectives and that the greatest benefits occur when children are vaccinated in a group setting and when only 1 dose is required for protection.44

With respect to safety and tolerability events reported by parents or legal guardians that occurred in the first 11 days after each dose, CAIV-T, when administered to this much-younger pediatric population, had fewer significant reactogenicity and tolerability findings than reported for older children.30,37 Although previous reports indicated statistically significant increases of fever, runny nose or nasal congestion, abdominal pain, and vomiting among CAIV-T recipients, only runny nose or nasal congestion achieved statistical significance in this trial of younger children and only in the first year, after the first dose. No statistically significant increases in rates of fever were observed for placebo or CAIV-T recipients after any dose in either year.

Furthermore, no significant safety events were observed in the 2 study groups during the influenza season. A large-scale clinical trial showed an increase in asthma episodes in children 18 to 35 months of age who were given the frozen formulation of CAIV-T.45 No such observations were found in this clinical trial; however, this trial was not powered to detect small differences in such events among CAIV-T versus placebo recipients. In a large study of children 6 to 59 months of age who were assigned randomly to receive CAIV-T or TIV, there was a small but significant increase in medically significant wheezing in previously unvaccinated children 6 to 23 months of age who received CAIV-T.46 However, in a similar study in children 6 to 71 months of age with a history of recurrent respiratory tract infections, there was no difference between treatment groups in the incidence of wheezing.47 Similar findings were seen in a trial comparing TIV and CAIV-T in children and adolescents 6 to 17 years of age with asthma; there was no difference between treatment groups in pulmonary outcomes, including asthma exacerbations.48

This clinical trial of an intranasally delivered liquid formulation of LAIV in children 6 to <36 months of age demonstrated conclusively efficacy against culture-confirmed influenza illness over 2 consecutive seasons, including efficacy against all 3 vaccine-like influenza viruses. Significant vaccine effectiveness was also observed. Other than a previously observed increase in runny nose or nasal congestion, no significant tolerability or safety findings were observed. CAIV-T represents a valuable public health intervention for reducing influenza illness in young children.


   ACKNOWLEDGMENTS
 
This work was supported by MedImmune and Wyeth Vaccine Research.

The CAIV-T Pediatric Day Care Clinical Trial Network was as follows: United Kingdom: I. Jones, S. Ahmed, Scottish Centre for Infection and Environmental Health, Glasgow; E. R. Moxon, John Radcliffe Hospital, Oxford; A. Finn, Sheffield Children’s Hospital, Sheffield; C. P. Fletcher, Woolwell Medical Centre, Woolwell; J. Rudge, Bridgehouse Medical Centre, Stratford-on-Avon; B. Bodalia, Gables Medical Centre, Coventry; B. Crichton, Hobs Moat Medical Centre, Solihull; A. M. George, Staploe Medical Centre, Soham; S. Barnard, Newnham Walk Surgery, Cambridge; K. Young, St Mary’s Surgery, Ely; A. Graham, Yaxley Group Practice, Yaxley; A. D. Bremner, Rutherglen Health Centre, Glasgow; M. D. Blagden, Avondale Surgery, Chesterfield; M. R. Newby, Eaton Socon Health Centre, Eaton Socon; A. T. S. Wright, Hathaway Surgery, Chippenham; D. M. Fleming, Northfield Health Center, Birmingham; M. Saville, H. Smith, Wyeth Vaccines Research, Taplow; Spain: F. Moraga, Hospital Vall d’Hebron, Barcelona; I. Hidalgo Vicario, C. S. Barrio del Pilar, Madrid; J. Ruiz Contreras, Hospital 12 Octubre Materno-Infantil, Madrid; J. F. Aristegui, Hospital de Basurto, Bilbao; Belgium: C. Abrassart, J.-P. Wackenier, Huy; P. Aerssens, Hasselt; G. Hendrickx, Marie Ziekenhuis N. Limburg, Lommel; S. Bastaits, Bruxelles; P. Bauche, Liege; M. Van de Weyer, Braine L’Alleud; M.-T. Van Damme, Kinderdagverblif "de Sijsjes," Houthalen; K. Mathe, Bruxelles; B. Orban Dejong, Jodoigne; B. Delwart, Plancemont; R. Jadoul, Dinant; O. Bauraind, M. Michel, Clinique Saint Pierre, Ottignies; P. Dacier, Libramont; M. T. Deurinck, Leuven; H. Geussens, Sint Jozefkliniek Vilvoorde, Vilvroorde; M. Goor, Tournai; B. Haufroid, Aywaille; T. Hecquet, B. Lambelin, Bruxelles; C. Macours-Verelst, Hasselt; A. Krygier, Jette; L. Reginster, Seraing; J. P. Van Biervliet, Algemeen Ziekenhuis St Jan, Brugge; J. Hoyoux, Herstal; A. Vertruyen, St Vincentius Hospitaal, Antwerp; Israel: A. Rachmel, C. Mintzer-Ophir, Petach Tikva; I. Levy, Tel Aviv; G. Livni, Shaari-Tikva; D. Inbar, G. Diamond, H.-C. Yishai, Bnei-Beraq; Y. Senecky, Natanyia; R. Weis, Clalit Sick Fund, Kubbutz Gazit; D. Steinmetz, Timrat Clinic, Timrat; B. Chazan, Kibbutz Beit-Zera, Emak Hayarden; Y. Schlesinger, Sharai Zedek Medical Centre, Jerusalem; A. Yarom, T. Itai, D. Paz, Jerusalem; C. Goodman, Clalit Sick Fund, Jerusalem; J. Urbach, Maccabi Sick Fund, Effrat; J. Armon, Clalit Sick Fund, Effrat; Y. Shaag, Ramot Medical Centre, Jerusalem; H. Tabenkin, Hemek Medical Center, Afula; S. Ivry, Clalit Sick Fund, Kibbutz Ein-Harod Meuhad; S. Eilat-Tsanani, Givat Ela; S. Ashkenazi, Schneider Children’s Hospital, Petah Tikva; Finland: T. Vesikari, A. Karvonen, University of Tampere Medical School, Vaccine Research Center; T. Korhonen, Tampere Clinic, Tampere; K. Edelman, Turku Clinic; M. Espo, H. Khary, K. Isoherranen, A. Sarajuuri, Espoo Clinic; J. Majuri, T. Karppa, Lahti Clinic; P. Riikonen, L. Panula, Pori Clinic; S. Parry, Jyväskylä Clinic; United States: G. Palladino, S. M. Cheng, R. Rappaport, J. Skinner, W. C. Gruber, B. D. Forrest, Wyeth Vaccines Research, Pearl River, NY.

We thank the participating children and their parents, the study nurses and coordinators, the clinical testing laboratory staff members, the clinical research associates, and the scientists at Wyeth and MedImmune. We thank Raija Vainionpäa, PhD, and her staff at the University of Turku (Turku, Finland) for performing influenza culture confirmation and subtyping of several thousands of clinical specimens obtained during the course of the trial and Alexander Klimov, PhD, and his staff at the Centers for Disease Control and Prevention (Atlanta, GA) for donating their time and effort to serotype numerous influenza isolates. We also thank Iksung Cho, MS, Robert Walker, MD, and Edward M. Connor, MD, for their critical review of the manuscript and Catherine Grillo, MS, and Janet Stead, BM, BS, for providing medical writing and editorial assistance.


   FOOTNOTES
 
Accepted Aug 24, 2006.

Address correspondence to Timo Vesikari, MD, Tampere University Medical School/FM3, Biokatu 10, 33520 Tampere, Finland. E-mail: timo.vesikari{at}uta.fi

Financial Disclosure: Drs Vesikari and Fleming have received consultancy fees from pharmaceutical manufacturers and have been supported to attend meetings all in relation to influenza vaccination, treatment, and surveillance. Dr Skinner was employed by Wyeth as a statistician during the reporting of this trial and the development of this manuscript. Dr Gruber is an employee of Wyeth Vaccines Research, which has a commercial interest in the development of FluMist (CAIV-T) in partnership with MedImmune. Dr Forrest was a paid employee of Wyeth Pharmaceuticals at the time this work was performed.


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 RESULTS
 DISCUSSION
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