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Influenza

PEDIATRICS Vol. 110 No. 4 October 2002, pp. 662-672

Safety of the Trivalent, Cold-Adapted Influenza Vaccine in Preschool-Aged Children

Pedro A. Piedra, MD*,Dagger;, Lihan Yan, MS§, Karen Kotloff, MD||, Ken Zangwill, MD, David I. Bernstein, MD#, James King, MD||, John Treanor, MD**, Flor Munoz, MD*,{ddagger}, Mark Wolff, PhD§, Iksung Cho, MS{ddagger}{ddagger}, Paul M. Mendelman, MD{ddagger}{ddagger}, Julie Cordova, BS{ddagger}{ddagger} and Robert B. Belshe, MD§§

* Department of Molecular Virology and Microbiology
{ddagger} Pediatrics, Baylor College of Medicine, Houston, Texas
§ EMMES Corporation, Potomac, Maryland
|| Center for Vaccine Development, University of Maryland, Baltimore, Maryland
Kaiser-UCLA Vaccine Program and Department of Pediatrics, Harbor-University of California Los Angeles Medical Center, Los Angeles, California
# Department of Medicine, Department of Pediatrics, Children’s Hospital Medical Center, Cincinnati, Ohio
** University of Rochester, Rochester, New York
{ddagger}{ddagger} Aviron, Mountain View, California
§§ Department of Medicine, Saint Louis University, St Louis, Missouri

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   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Objective. To provide additional information on the safety of trivalent, cold-adapted influenza vaccine (CAIV-T) in children.

Methods. Children 15 to 71 months of age were enrolled in a multicenter, prospective, randomized, double-blind, and placebo-controlled trial to receive by nasal spray CAIV-T or placebo. In year 1 (1996–1997), 1314 were enrolled in the 2-dose cohort and 288 were enrolled in the 1-dose cohort. In year 2 (1997–1998), 1358 of the original participants received 1 dose of vaccine or placebo according to their original treatment group assignment. In year 3 (1998–1999) and year 4, the trial continued as an open-label safety trial of CAIV-T. A total of 642 and 549 children enrolled in years 3 and 4, respectively, received their third and fourth sequential annual doses of CAIV-T. Measured were 1) the occurrence of specific respiratory, gastrointestinal and systemic symptoms, unexpected symptoms (not specified in the diary card), and use of medications within the first 10 days after vaccination; 2) the occurrence of an acute illness and use of medication within 11 to 42 days after vaccination; and 3) the occurrence of serious adverse events within 42 days after vaccination.

Results. The adjusted odd ratios of specific respiratory and gastrointestinal symptoms during the 10 days after vaccination were determined in years 1 and 2. Runny nose or nasal congestion, vomiting, muscle aches, and fever were significantly associated with the first dose of CAIV-T. With the second dose, runny nose was the only symptom that was associated with CAIV-T. In year 2, CAIV-T did not cause excess in any of the specific respiratory and gastrointestinal symptoms. In years 3 and 4, specific respiratory and gastrointestinal symptoms were comparable to that observed in year 2. A CAIV-T–associated symptom was most likely to occur on day 2 with the first dose of vaccine. The occurrence of unexpected symptoms was primarily of the gastrointestinal system. Approximately 6% of CAIV-T and 3.6% of placebo recipients had a gastrointestinal symptom. CAIV-T seemed to be associated with a mild excess in abdominal pain and vomiting only with the first vaccine dose. A statistically significant increase in the use of analgesics/antipyretics was detected only with the first dose in CAIV-T vaccinees compared with placebo recipients (23.5% vs 16.6%). Between days 11 and 42, CAIV-T use was not associated with an excess of illness, otitis media, or use of medication. None of the 6 serious adverse events in CAIV-T recipients in years 1 to 4 was attributed to the vaccine.

Conclusions. CAIV-T was safe in children. Mild respiratory, gastrointestinal, and systemic symptoms of short duration were observed in a minority of children and primarily with the first vaccine dose. Sequential annual doses of CAIV-T were well tolerated.

Key Words: trivalent • cold-adapted influenza vaccine • safety • preschool-aged children

Abbreviations: IIV-T, trivalent inactivated influenza vaccine • CAIV-T, trivalent, cold-adapted influenza vaccine • PD-OM, physician-diagnosed otitis media • PD-FOM, physician-diagnosed febrile otitis media • PD-LRTI, physician-diagnosed lower respiratory tract illness • SAE, serious adverse event • COSTART, Coding Symbols for Thesaurus of Adverse Reaction Terms


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Influenza is a vaccine-preventable disease that causes widespread infection and morbidity in all age groups. The attack rate and morbidity are greatest among individuals with minimal previous exposure to influenza, particularly children.1–4 Vaccination of healthy children is being considered because they have high rates of infection and are important in the spread of influenza.5–10 The licensed trivalent inactivated influenza vaccine (IIV-T) administered by an injection intramuscularly is recommended for people who have conditions that put them at risk for severe influenza disease, for residents of chronic care facilities, and for healthy individuals 50 years of age or older.11

The trivalent, cold-adapted influenza vaccine (CAIV-T), administered by nasal spray, has recently been demonstrated to be highly efficacious against influenza infection in preschool-aged children. In a prelicensure phase III efficacy trial in children 15 to 71 months of age, CAIV-T given by a nasal spray was well tolerated, safe, and efficacious.12 CAIV-T was 93% efficacious against culture-confirmed influenza. During the second year of the trial, CAIV-T was 100% efficacious against culture-confirmed influenza of circulating strains represented in the vaccine and 86% efficacious against A/Sydney/05/97, a significantly drifted variant strain not contained in the vaccine.13 CAIV-T offers an alternative approach in the prevention of influenza infection in healthy children. CAIV-T is easy to administer and well tolerated. It is generally not associated with fear and perceived discomfort often expressed by children to vaccines that are delivered by injection (personal experience of the authors).

Vaccination of individuals who are at risk before the onset of the influenza season is currently the most effective measure for ameliorating the impact of influenza. Influenza-associated mortality remains high in the elderly population, ranging from 20 000 to >40 000 deaths annually.14,15 For reducing excess mortality, the main strategy in the United States has been the yearly vaccination of high-risk individuals. An emerging vaccination strategy that is being considered is universal immunization of children for the control of influenza epidemics.10,16 In Japan, vaccinating school-aged children with IIV-T was obligatory from 1977 to 1987. During this period, vaccination of the majority of school-aged children with IIV-T provided indirect protection against influenza among elderly adults.17 It is postulated that vaccination of children in the United States would decrease the introduction and spread of influenza within the household and community. Such a strategy could reduce health care utilization and have substantial economic benefit to society.18 An influenza vaccine that is safe, well tolerated, cost saving, easy to administer, child acceptable, and efficacious could be regarded as a vaccine candidate for universal vaccination of healthy children. CAIV-T has been submitted for licensure in the United States. If licensed for use in children, this vaccine may be considered for universal immunization of preschool- and school-aged children.

Vaccine safety is an important issue for considering universal immunization in children against influenza. In the phase III efficacy trial, CAIV-T was demonstrated to be safe and well tolerated in children.12 The purpose of this report is to provide additional information on the safety of the CAIV-T that was prospectively ascertained in the phase III efficacy trial conducted in children and on subsequent annual revaccination of this cohort.12,13 Also reported for the first time is the safety of sequential annual doses of CAIV-T during a 4-year period in this cohort.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Study Children
The study was approved by the local Institutional Review Boards of each participating center, and signed informed consent was obtained from legal guardians before the children entered the study. In year 1 (1996–1997), healthy children 15 to 71 months of age were enrolled in the study. Children were excluded if they had a history of significant hypersensitivity to eggs or an underlying chronic illness for which IIV-T would be recommended. In year 2 (1997–1998), only children who had participated in year 1 were eligible for revaccination. In year 3 (1998–1999) and year 4 (1999–2000), children who had previously participated in years 1 and 2 were eligible for revaccination.

Vaccine
CAIV-T was provided by Aviron (Mountain View, CA) frozen in single-dose intranasal applicators. Each year, the composition of the vaccine strains matched the antigens of the licensed IIV-T as recommended by the US Food and Drug Administration. The median tissue culture infectious dose of CAIV-T for each of the attenuated, cold-adapted strains was approximately 107. In year 2, the H1N1 component of the vaccine was changed to A/Shenzhen/227/95; otherwise, the vaccine formulations were comparable in years 1 and 2 (Table 1). In year 3, the H1N1 and H3N2 strains were changed to A/Beijing/262/95 (H1N1) and A/Sydney/5/97 (H3N2). Year 4 CAIV-T was identical to that in year 3. CAIV-T also contained egg allantoic fluid with sucrose-phosphate-glutamate. The placebo, which was indistinguishable from the vaccine, contained egg allantoic fluid with sucrose-phosphate-glutamate. Storage of the vaccine was at -20°C or colder.


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  		TABLE 1. Composition of CAIV-T

 
Study Design
As previously described, this multicenter study was prospective, randomized, double-blind, and placebo-controlled.12 Children were randomized in a 2:1 ratio to receive vaccine or placebo. Children received by nasal spray a 0.5-mL dose (0.25 mL in each nostril) of CAIV-T or placebo. In year 1, 1602 children were enrolled in the study: 1314 in the 2-dose cohort and 288 in the 1-dose cohort. Children in the 2-dose cohort received the second dose approximately 60 days (±14 days) after the first dose. Illustrated in Table 2 are the demographic data at enrollment between the CAIV-T and placebo groups. Statistically significant differences were not observed in age, race, gender, child care attendance, household composition, and primary caregiver working at home between the vaccine and placebo groups.12 In year 2, 1358 of the original participants received 1 dose of vaccine or placebo according to their year 1 randomized treatment group assignment. Statistical differences between the groups were not observed for the demographic characteristics (Table 2). 13 In years 3 and 4, all children who participated in years 1 and 2 were given CAIV-T (open-label trial); 642 and 549 children received their third and fourth sequential annual doses of CAIV-T, respectively. Excluded from the sequential annual dose analysis in years 3 and 4 were the 299 placebo recipients who received their first dose of CAIV-T in year 3.


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  		TABLE 2. Demographic Characteristics by Treatment Group

 
Safety
Years 1 to 4
The parents of enrolled children were given a digital thermometer. After each intranasal dose, the parents were asked to record daily for 10 days in a diary card the temperature of the child, the occurrence of specific symptoms (symptoms delineated in the diary card: cough, runny nose or nasal congestion, sore throat, irritability, chills, vomiting, muscle aches, decrease activity, fever), the occurrence of unexpected symptoms (any symptom not specified in the diary card), over-the-counter medication, and prescription drugs.

Years 1 and 2
In addition, parents were contacted by telephone for illness evaluation (efficacy measure) every 1 to 3 weeks to inquire whether children developed acute respiratory symptoms and to remind the parents to notify study personnel if they did. Fever, lower respiratory tract illness (wheezing, shortness of breath, pneumonia), ear infection (diagnosed or suspected), or other symptoms (cough, headache, runny nose or nasal congestion, sore throat, muscle ache, chills, vomiting, irritability, decreased activity) triggered an assessment of the child’s illness by study personnel. In general, fever, lower respiratory tract illness, or ear infection with any other symptom triggered a visit. Active surveillance also captured the illness if a child was evaluated by his or her primary care provider. An assignment to an illness category was made on the basis of the diagnosis by the study personnel or health care provider. The categories used to define the outcome within day 11 to day 42 after vaccination were afebrile illness, febrile illness (by history or documented on the basis of axillary temperature >37.6°C, oral temperature >37.7°C, or rectal temperature >38.1°C), physician-diagnosed otitis media (PD-OM), physician-diagnosed febrile otitis media (PD-FOM), or physician-diagnosed lower respiratory tract illness (PD-LRTI; croup, bronchitis, pneumonia, or wheeze).

Years 1 to 4
Serious adverse events (SAEs) occurring within 42 days of vaccination and vaccine-related SAEs occurring at any time during the study were recorded by study personnel. An SAE was an event that satisfied 1 of the following conditions: fatal (resulted in death from any cause); immediately life-threatening (child was at immediate risk of death from the event); resulted in or prolonged hospitalization; resulted in permanent or substantial disability; or may not have resulted in death, been life-threatening, or required hospitalization but may have been considered an SAE on the basis of appropriate medical judgment. All SAEs were reported in a timely manner to the appropriate regulatory boards.

Statistical Analysis
Statistical analyses were performed using SAS 8.0 software (SAS Inc, Cary, NC). Logistic regressions were used to obtain odds ratios (and their 95% Wald confidence intervals) of having symptoms while controlling for age at vaccination, month of vaccination, and school/child care attendance. Odds ratios derived from the logistic regressions were used to compare CAIV-T versus placebo. Poisson regressions controlling for age at vaccination, month of vaccination, and school/child care attendance were used to examine treatment effect on the duration of symptoms and number of illness events (afebrile illness, febrile illness, PD-OM, PD-FOM, and PD-LRTI) per child. Concomitant medications between day 0 and day 10 after vaccination and medications used during illness visits between day 11 and day 42 after vaccination were compared between the 2 treatment groups using a {chi}2 test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
We previously reported that some vaccinated children had transient findings of a minor upper respiratory tract illness associated with CAIV-T.12,13 The incidence of these symptoms (fever, runny nose or nasal congestion, and decreased activity) was significantly associated with the first dose of CAIV-T. Minor respiratory findings, however, were not significantly increased after the second vaccine dose in year 1 or with revaccination in year 2.12,13 In the current report, adverse reactions potentially associated with CAIV-T were reassessed using multivariate techniques by determining the odds ratios of the specific symptoms after adjusting for age, child care attendance, and month of vaccination, factors that can affect the risk of an acute respiratory illness (Table 3). In year 1, runny nose or nasal congestion, vomiting, muscle aches, fever (oral >100.0°F, rectal/aural >100.6°F, or axillary >99.6°F) and "any symptoms" were significantly associated with the first dose of CAIV-T. With the second dose, runny nose or nasal congestion and "any symptoms" were the only significant findings associated with CAIV-T. In year 2, reactogenicity associated with the CAIV-T was not significantly different from that observed in the placebo cohort.


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  		TABLE 3. Symptoms Associated With CAIV-T Between Day 0 and Day 10 After Vaccination After Adjusting for Age of Child, Month of Vaccination, and Child Care Attendance

 
Previously, we had observed that the incidence of runny nose or nasal congestion was increased on days 2, 3, 8, and 9 after the first dose of CAIV-T.12 Vaccine reactogenicity was reassessed for days 2, 3, 8, and 9 after adjusting for age, month of vaccination, and child care attendance (Table 4). Presented are the symptoms that were significantly associated with CAIV-T. In year 1 dose 1, there was an increase (1.56- to 1.82-fold) in the incidence of runny nose or nasal congestion on days 2, 3, 8, and 9 after dose 1 but not after dose 2. An excess of runny nose or nasal congestion, however, was observed in year 2 on day 2 after vaccination. An increased incidence of irritability, decreased activity, and fever was detected on day 2 after vaccination with year 1 dose 1. An increased incidence of fever was also observed in year 2 on day 3 after vaccination. CAIV-T, however, was associated with a significantly lower incidence of irritability and decreased activity on days 8 and/or 9 after vaccination in year 1 dose 2 and year 2.


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  		TABLE 4. Symptoms Associated With CAIV-T on Days 2, 3, 8, and 9 After Vaccination After Adjusting for Age of Child, Month of Vaccination, and Child Care Attendance

 
Duration of symptoms by vaccine assignment was compared for each of the symptoms measured during the first 10 days after vaccination (Fig 1). This analysis was restricted to children with symptom(s). Runny nose or nasal congestion, a CAIV-T-associated symptom, was of comparable duration in the CAIV-T year 1 dose 1 group compared with the placebo cohort (Fig 1A). For the other CAIV-T-associated symptoms (fever 1, vomiting, and muscle ache), the duration was comparable between the CAIV-T and placebo groups (Fig 1A). Comparable duration of symptoms was observed between the CAIV-T and placebo groups in year 1 dose 2 (Fig 1B) and year 2 (Fig 1C).



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  		Fig 1. Mean duration of symptoms by vaccine assignment was compared for each of the symptoms measured during the first 10 days after vaccination in year 1 dose 1 (A), year 1 dose 2 (B), and year 2 (C). This analysis was restricted to children with symptom(s). As noted in the Methods section, runny nose includes runny nose or nasal congestion. Poisson regression controlling for age at vaccination, month of vaccination, and school/child care attendance was used to examine the duration of symptoms per child.

 
Vomiting was reported in more children who received CAIV-T than in the placebo recipients at some time on days 1 through 10 after the first dose.12 We explored the potential association of CAIV-T with gastrointestinal adverse reactions. Reports of the occurrence of unexpected symptoms (any symptom not specified in the diary card) were coded with Coding Symbols for Thesaurus of Adverse Reaction Terms12 (COSTART; Phoenix International, Irvine, CA). The COSTART terms for the digestive systems were diarrhea, nausea, abdominal pain, and gastroenteritis. Also included in the analysis were the specific symptoms captured in the diary card that may be associated with the digestive system (vomiting and muscle ache). Fewer than 2% of the CAIV-T and placebo recipients had the first occurrence of a gastrointestinal symptom at any day during the first 10 days after vaccination in years 1 and 2. Gastroenteritis and nausea were rarely documented symptoms. The percentage of children with the first occurrence of vomiting, abdominal pain, muscle ache, or diarrhea in year 1 dose 1 is summarized in Fig 2. The numbers of children with symptoms between day 0 and day 10 were compared between the CAIV-T and placebo recipients using Fisher’s exact test. CAIV-T was associated with mild excess in vomiting (64/1070 vs 19/532; P = .04), abdominal pain (19/1070 vs 1/532; P = .01), and muscle aches (55/1070 vs 14/532; P = .02) but not diarrhea (38/1070 vs 17/532; P = .77) in year 1 dose 1. No excess in gastrointestinal symptoms was observed in year 1 dose 2 and year 2 (data not shown). Two or more gastrointestinal symptoms, although uncommon, occurred more frequently in the CAIV-T group in dose 1 (25/1070 vs 4/532; P = .03) and dose 2 (17/854 vs 3/418; P = .06) of year 1 (Fig 3). Muscle ache and vomiting were the most frequently reported combination of symptoms.



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  		Fig 2. Percentage of children who had the first occurrence of vomiting (A), abdominal pain (B), diarrhea (C), and muscle ache (D) during the first 10 days after vaccination in year 1 dose 1. CAIV-T compared with placebo was associated with mild excess in vomiting (64/1070 vs 19/532; P = .04), abdominal pain (19/1070 vs 1/532; P = .01), and muscle aches (55/1070 vs 14/532; P = .02) but not diarrhea (38/1070 vs 17/532; P = .77) in year 1 dose 1.

 


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  		Fig 3. Percentage of children who had 2 or more gastrointestinal symptoms during the first 10 days after vaccination in year 1 dose 1 (A), year 1 dose 2 (B), and year 2 (C). Two or more gastrointestinal symptoms occurred more frequently in the CAIV-T group in dose 1 (25/1070 vs 4/532; P = .03), and there was a trend to increase frequency with dose 2 (17/854 vs 3/418; P = .06) of year 1.

 
Mild adverse reactions associated with CAIV-T may result in an increase in use of over-the-counter medications. More severe respiratory illnesses may result in use of prescription medications such as antibiotics that frequently are prescribed inappropriately for treatment of a respiratory illness. An analysis on the use of medications (antibiotics, analgesics/antipyretics, and antihistamines/decongestants/antitussives) during the first 10 days after vaccination was performed in years 1 and 2. A statistically significant increase in the use of analgesics/antipyretics was detected in the CAIV-T recipients only with the first dose in year 1 (Table 5). An increase in use of over-the-counter medications and oral antibiotics was not observed in the CAIV-T recipients compared with placebo recipients with the second dose in year 1 and year 2.


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  		TABLE 5. Medication Use Within the First 10 Days After Vaccination in Year 1 and Year 2

 
CAIV-T occasionally has been associated with mild abbreviated symptoms of the upper respiratory tract.12,13 Theoretically, this mild CAIV-T-associated respiratory illness could alter the mucosal epithelial integrity, predisposing to colonization and even disease by pathogenic bacteria. An analysis of illness events was performed to determine whether CAIV-T was associated with an increased risk of acute illnesses between days 11 and 42 after vaccination. The analysis was restricted to events in which a nasal wash specimen was obtained for isolation of respiratory viruses. Each illness was assigned to 1 of 3 mutually exclusive categories: afebrile illness, febrile illness, and PD-LRTI. PD-OM and PD-FOM were comorbid outcomes. Use of medication (antibiotics, analgesics/antipyretics, and antihistamines/decongestants/antitussives) during an illness was also evaluated. The time period day 11 to day 42 after the second dose in year 1 was omitted from the analysis because it overlapped with the influenza season. CAIV-T use was not associated with an excess of illness or otitis media or use of medication in years 1 and 2 (Table 6). In year 2, the CAIV-T group used significantly less antihistamines/decongestants compared with the placebo group.


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  		TABLE 6. Number of Illness Events That Were Cultured for Respiratory Viruses and Medication Use Within 11 to 42 Days After Vaccination in Year 1 and Year 2

 
SAEs within 42 days of vaccination were detected in 5 children in year 1: 4 in the CAIV-T group and 1 in the placebo cohort. All were deemed either definitely not or probably not associated with the study vaccine. The diagnoses were abdominal trauma secondary to an automobile accident, dehydration, staphylococcus foot infection, abdominal pain (9 days after dose 1, the child was observed 1 day in the hospital to rule out appendicitis), and revision of ventricular peritoneal shunt (placebo). In year 2, 1 placebo and 1 CAIV-T vaccine recipient experienced an SAE. The SAEs were asthma and bacterial infection (placebo) and were considered to be definitely not and probably not related to the study vaccine, respectively. In years 3 and 4, no SAE and 1 SAE occurred, respectively. The SAE in year 4 was a head injury in a CAIV-T recipient. No CAIV-T-attributable SAE was observed in years 1 to 4. All children had a complete recovery and continued in the study.

The safety of sequential annual doses of CAIV-T in children is illustrated in Table 7. The occurrence of symptoms during the first 10 days after vaccination was collected similarly in all 4 years. In the first 2 years, the study was double-blind and placebo-controlled; in the last 2 years, the study was open-label. The cohort aged with each subsequent year. Given those limitations, the percentage of CAIV-T recipients with symptoms in years 3 or year 4 were comparable to CAIV-T recipients in year 2 and seemed lower compared with year 1 dose 1 CAIV-T recipients. Similar results were observed when the analysis was restricted to the 549 CAIV-T recipients who participated in all 4 years (data not shown).


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  		TABLE 7. Sequential Annual Doses of CAIV-T: Percentage of CAIV-T Recipients Who Experienced Symptoms Between Day 0 and Day 10 After Vaccination

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
We previously demonstrated the safety and efficacy of CAIV-T in children in this phase III randomized, multicenter, placebo-controlled trial.12,13 In year 1 of this trial, CAIV-T was demonstrated to cause minor transient respiratory symptoms in some children during the first 10 days after vaccination. This article provides additional safety information on CAIV-T in children who participated in the pivotal phase III trial and in the 3 subsequent study years.

Age, month of vaccination, and child care attendance may have an impact on respiratory symptoms observed with CAIV-T. Younger children may demonstrate a higher incidence of respiratory symptoms after CAIV-T because they are more likely not to have been infected previously with at least 1 of the influenza types (H1N1, H3N2, or B) as compared with older children. Also young age, month of vaccination, and child care attendance are factors known to have an impact on the incidence of acute respiratory tract illness. A concurrent respiratory viral infection during the active replication of CAIV-T may increase the number of symptoms associated with the vaccine or result in a higher incidence of symptoms temporally associated with CAIV-T. To address this issue, we evaluated the safety of CAIV-T in the first 10 days after adjusting for age, month of vaccination, and child care attendance. Runny nose or nasal congestion, vomiting, muscle ache, and fever were significantly associated with the first vaccine dose of CAIV-T. The increased incidence of these symptoms in the CAIV-T group was approximately 1.5- to 2-fold that in the placebo group. With the second dose in year 1, runny nose or nasal congestion was the only symptom that was associated with CAIV-T. An excess of symptoms was not observed in year 2. These findings are in agreement with our previous observations using unadjusted data12,13 and with the published data on the safety of monovalent, bivalent, and trivalent preparations of the live-attenuated, cold-adapted intranasal influenza vaccine in children.19–25

As in our previous publications, CAIV-T-associated symptoms were more likely to occur on day 2 after the first vaccine dose, although an excess of runny nose or nasal congestion was also detected on days 3, 8, and 9 (Table 4). In this analysis, a higher incidence of runny nose or nasal congestion and fever were observed on days 2 and 3, respectively, after CAIV-T in year 2. The peak days in CAIV-T-associated symptoms may be a reflection of the viral shedding patterns of the vaccine strains in the nasal passages of children.24 The severity of these symptoms could also be ascertained indirectly by the medications that were provided by the parents or prescribed by the physician. During the first 10 days after vaccination, analgesics/antipyretics were used more frequently by the CAIV-T recipients compared with the placebo group (Table 5) but only with the first vaccine dose in year 1. This observation supports the increased incidence of mild fever observed primarily with the first vaccine dose in year 1. It is doubtful that the occurrence of these mild symptoms in some children will result in an increase in health care utilization after CAIV-T. In a community trial being conducted in Temple, TX, we have provided CAIV-T to >7400 children, at least 2100 of whom have received 2 sequential annual doses of vaccine. In both years of the community trial, an excess of medically attended acute respiratory illnesses was not detected during the 14-day interval after vaccination.26

In the years of this trial, the composition of the vaccine strains matched the antigens of the licensed IIV-T as recommended by the US Food and Drug Administration. In year 2, the H1N1 vaccine component of CAIV-T differed from that in year 1 (Table 1). It is of interest that the mild vaccine-associated symptoms observed in year 1 were either not detected in year 2 or significantly milder. The study design did not permit us to determine whether the CAIV-T used in year 2 was more attenuated compared with CAIV-T given in year 1. If we assume that both vaccines were comparable in reactogenicity, then it is likely that previous homotypic immunity induced by H3N2 and B vaccine strains in year 1 reduced the reactogenicity induced by the same vaccine strains in year 2. Similarly, we can speculate that the H1N1 vaccine strain in year 1 induced sufficient heterotypic immunity to reduce the reactogenicity associated with the new H1N1 vaccine strain in year 2. This hypothesis is supported by studies that have demonstrated that CAIV-T vaccine-induced protection can extend beyond that influenza season, that challenge with an H1N1 monovalent CAIV-T vaccine in CAIV-T-vaccinated children results in minimal reactogenicity, and that heterotypic protective immunity can occur with CAIV-T.13,27,28 It is also supported by our year 3 reactogenicity data. In year 3, new H1N1 and H3N2 strains were incorporated into CAIV-T. The reactogenicity observed in year 3 was similar to that in year 2 (Table 7).

Vomiting within 10 days after the first vaccine dose was observed in 6% of vaccine and 3.6% of placebo recipients, and abdominal pain occurred in 1.8% of vaccine and 0.2% of placebo recipients. This mild excess in vomiting and abdominal pain was observed only with the first vaccine dose. One of the children who experienced abdominal pain required observation in the hospital to rule out appendicitis. The child had a prompt recovery. The pathophysiology of gastrointestinal symptoms associated with CAIV-T or natural infection remains unanswered. Active replication of influenza viruses in the gastrointestinal tract of humans has not been reported. Gastrointestinal symptoms may be related to an increased production and release of proinflammatory cytokines during infection. Alternatively, the CAIV-T-associated runny nose or nasal congestion may be sufficient to cause gagging and vomiting in a small number of children. With greater experience with use of CAIV-T in children, we may be able to address the significance of this uncommon and mild event.

Adverse reactions beyond day 10 after vaccination were not statistically different in the vaccinated compared with control children in either year 1 or year 2 of this trial. Importantly, the mild respiratory events associated with the live-attenuated, cold-adapted influenza vaccine strains were not of sufficient magnitude to predispose the vaccinated children to a secondary bacterial complication. Natural influenza infection is widely known to predispose the host to bacterial infections that can result in otitis media and pneumonia.29–32 An increase in the incidence of otitis media with or without fever or lower respiratory tract illness was not observed during the interval from day 11 to day 42 after vaccination. This is supported by the absence of an increase in the use of oral antibiotics during this same period in CAIV-T recipients compared with placebo recipients in years 1 and 2. Our data are consistent with the data recently reported from a large, randomized, double-blind, placebo-controlled trial that evaluated medically attended events in the 42 days after vaccination in healthy children 1 to 17 years of age and concluded that CAIV-T seemed to be well tolerated.33,34 In regard to medically attended lower respiratory events, pneumonia, bronchiolitis, and croup were not significantly increased in vaccine recipients compared with placebo recipients. Asthma events were increased in children 18 to 35 months of age, although these were not temporally clustered after vaccination. In a separate placebo-controlled study, CAIV-T was shown to be well tolerated in 48 children with moderate to severe asthma; 2 of 24 vaccine recipients compared with 0 of 24 placebo recipients experienced an asthma exacerbation, but the difference was not statistically different.35

Sequential annual doses of CAIV-T were shown to be safe in children. An increase in symptoms was not observed in children who received 2, 3, or 4 sequential annual doses of CAIV-T. Our data support the safety of annual vaccination with CAIV-T. A number of other studies have also shown the safety of sequential annual vaccination with bivalent and trivalent preparations of CAIV-T.27,28,36


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
CAIV-T administered by nasal spray is a safe and well-tolerated influenza vaccine in children. Mild respiratory symptoms were observed in a minority of children and primarily with the first CAIV-T dose. Vomiting occurred in 6% and abdominal pain occurred in <2% of CAIV-T recipients. Similar to the respiratory symptoms, the gastrointestinal symptoms were mild and of short duration in the few children who experienced them. An excess of illness or use of medication was not observed from day 11 to day 42 after vaccination. Sequential annual doses of CAIV-T were well tolerated and not associated with increased reactogenicity. We predict that the use of CAIV-T in children will not be associated with an increase in health care utilization for the infrequent and minor respiratory and gastrointestinal symptoms associated with CAIV-T.26


   ACKNOWLEDGMENTS
 
Supported by a collaborative research agreement between the National Institutes of Health (Bethesda, MD) and Aviron (Mountain View, CA) and by grants (N01-AI-45248, N01-AI-45249, N01-AI-45250, N01-AI-45251, N01-AI-45252, and N01-AI-25135) from the National Institutes of Health. Aviron was acquired by MedImmune, Inc on January 15, 2002.

We thank Drs Keith Reisinger and Stan L. Block as principal investigators from Pittsburgh Pediatric Research (Pittsburgh, PA) and Kentucky Pediatric Research, Inc (Bardstown, KY). We are also indebted to the clinical coordinators, study personnel, and referring pediatricians who assisted in this study, and a very special thanks to the parents and children who gave their time to this study.


   FOOTNOTES
 
Received for publication Jul 18, 2002; Accepted Apr 12, 2002.

Reprint requests to (P.A.P.) Baylor College of Medicine, Department of Molecular Virology and Microbiology, Rm 248E, One Baylor Plaza, Houston, TX 77030. E-mail: ppiedra{at}bcm.tmc.edu


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 DISCUSSION
 CONCLUSION
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PEDIATRICS (ISSN 1098-4275). ©2002 by the American Academy of Pediatrics



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