ARTICLE
Safety and Tolerability of Cold-Adapted Influenza
Vaccine, Trivalent, in Infants Younger Than 6 Months
of Age
Timo Vesikari, MDa, Aino Karvonen, MDa, Helen M. Smith, BScb, Andrew Dunning, PhDc, Ahmad Razmpour, PhDc, Melanie K. Saville, MB, BSb,
William C. Gruber, MDc, Bruce D. Forrest, MDc
aVaccine Research Center, University of Tampere Medical School, Tampere, Finland;bWyeth Vaccines Research, Taplow, United Kingdom;cWyeth Vaccines Research,
Pearl River, New York
Financial Disclosure: Drs Smith, Dunning, Saville, Gruber, and Forrest are current or former employees of Wyeth Vaccines Research, codevelopment partner for FluMist with Aviron (now MedImmune).
ABSTRACT
OBJECTIVE.Young children are at high risk for influenza-related complications. Vacci-nation of close household contacts is recommended to provide indirect protection to children ⬍6 months of age. Studies have shown that live, cold-adapted influenza vaccine, trivalent, is efficacious in children. To assess the risks associated with inadvertent exposure of infants to vaccine viruses from vaccinated contacts, this study was designed to evaluate the safety and tolerability of cold-adapted influenza vaccine, trivalent, administered intranasally to healthy children 6 to⬍24 weeks of age.
METHODS.Healthy infants aged 6 to ⬍16 weeks and 16 to ⬍24 weeks, respectively, were randomly assigned to receive 2 doses of influenza vaccine, or placebo intrana-sally 35⫾7 days apart. Reactogenicity events were monitored for 11 days after each dose. Other adverse events were monitored through 28 to 35 days after dose 2.
RESULTS.Of the infants aged 6 to ⬍16 weeks, 31 received influenza vaccine and 28 received placebo, and of those aged 16 to⬍24 weeks, 30 received influenza vaccine and 31 received placebo. In the 6- to ⬍16-week cohort, more influenza vaccine, recipients experienced irritability (66.7% vs 35.7%) and runny nose or nasal con-gestion (63.3% vs 33.3%) after dose 1 but not dose 2. There were no significant increases in any other reactogenicity events or adverse events in the vaccine recip-ients compared with the placebo group.
CONCLUSIONS.Although there was an increase in mild reactogenicity events in children 6 to⬍16 weeks of age, cold-adapted influenza vaccine, trivalent, was generally well tolerated in infants 6 to⬍24 weeks of age. These findings support further evaluation of cold-adapted influenza vaccine, trivalent, in infants⬍6 months of age.
I
NFLUENZA INFECTION ISassociated with a significant excess of outpatient visits and hospitalizations in young children.1–5 The majority of children hospitalized for influenza or influenza-related complications are previously healthy children.6TheAdvisory Committee on Immunization Practices and the American Academy of Pediatrics currently recommend influenza immunization for all children between 6 and 59 months of age,7,8 and vaccination of close household contacts is recommended to provide indirect protection to children⬍6 months of age.7
Live attenuated influenza vaccine (LAIV) (FluMist, cold-adapted influenza vaccine, trivalent [CAIV-T]; Med-Immune, Gaithersburg, MD) is currently approved in the United States for use in healthy children and adolescents aged 2 to 17 years and adults aged 18 to 49 years and is not licensed outside the United States. Recently published data from clinical trials suggest that LAIV has a higher relative efficacy compared with TIV in children⬍5 years of age.9–11Additional data are needed for children⬍12 months of age however, in light of an unexplained observation in 1 study of higher hospitalization rates in this population.11
www.pediatrics.org/cgi/doi/10.1542/ peds.2007-1405
doi:10.1542/peds.2007-1405
Data from this study were presented at the International Conference on Options for the Control of Influenza; October 7–11, 2003; Okinawa, Japan; and the annual meeting of the Pediatric Academic Societies; April 29 to May 2, 2006; San Francisco, CA.
This trial has been registered at www.clinicaltrials.gov (identifier NCT00192348).
Key Words
live attenuated influenza vaccine, immunogenicity, infants, clinical trial
Abbreviations
TIV—trivalent inactivated influenza vaccine
LAIV—live attenuated influenza vaccine CAIV-T— cold-adapted influenza vaccine, trivalent
RE—reactogenicity event AE—adverse event SAE—serious adverse event
Accepted for publication Aug 3, 2007 Address correspondence to Timo Vesikari, MD, University of Tampere Medical School/FM3, Biokatu 10, 33520 Tampere, Finland. E-mail: timo.vesikari@uta.fi
Because LAIV replicates in the nose of a vaccinated individual, the potential for transmission of vaccine vi-ruses from vaccinated contacts to unvaccinated infants has been raised as a concern. Children infected with wild-type influenza virus can shed virus in nasal secre-tions for ⱕ14 days after onset of symptoms.12–15 Simi-larly, vaccine virus can be detected in nasal secretions from children after immunization with CAIV-T.16 In a recent study of children aged between 9 and 36 months attending day care, 80% of vaccinated children shed vaccine virus for a mean of 8 days postvaccination, whereas transmission of shed vaccine virus to an unvac-cinated contact was documented in only 1 instance, and the estimated transmission rate was low (0.58%).16 Be-cause of the theoretical possibility that vaccine virus could be transmitted by household contacts to unvacci-nated infants, this study was designed to evaluate the safety and tolerability of CAIV-T in healthy young in-fants 6 to⬍24 weeks of age.
METHODS
Participants
Eligible subjects were infants 6 to⬍24 weeks of age who were ⱖ37 weeks’ gestational age with a birth weight
ⱖ2500 g and in good health as assessed by medical history, physical examination, and clinical judgment. Exclusion cri-teria included serious chronic disease including progressive neurologic disease; Down syndrome or other known cyto-genetic disorders; known or suspected disease of the im-mune system, receipt of immunosuppressive therapy, or the presence of an immunosuppressed or immunocompro-mised individual in the same household; receipt of blood products from birth through the conclusion of the study; documented history of hypersensitivity to egg or egg pro-tein or any other component of study vaccine or placebo; receipt of any live virus vaccine within 1 month before enrollment or intent to receive another live vaccine within 1 month of vaccination in the study; intent to administer any other investigational vaccine or agent from 1 month before enrollment through the conclusion of the study; receipt of any influenza treatment within 2 weeks before enrollment, including prophylactic use of antiviral medica-tion, or any influenza vaccine at any time before entry into the study; any respiratory illness with wheezing within 2 weeks of each dose of study vaccine; receipt of aspirin or aspirin-containing products in the 2 weeks before vaccina-tion or anticipated use during the study; and any medical condition that, in the opinion of the investigator, might interfere with interpretation of the study results. Concom-itant routine childhood vaccination with inactivated vac-cines was permitted during this study.
Study Design
This randomized, double-blind, placebo-controlled study was conducted between May and December 2002 at the University of Tampere Vaccine Research Center, which has clinics in Tampere, Turku, Espoo, Pori, Lahti, and Jyva¨skyla¨, Finland. The study was conducted in accor-dance with the Declaration of Helsinki and in compli-ance with the ethical principles of the International
Con-ference on Harmonization Guideline for Good Clinical Practice. The study was approved by the independent ethics committee of Tampere University Hospital Dis-trict. For each subject, parents provided written, in-formed consent.
Subjects were prospectively randomly assigned in a 1:1 ratio to receive 2 doses of CAIV-T or placebo 35 (⫾7) days apart. Subjects were stratified by age at first vaccination into 2 age groups: 6 to⬍16 weeks and 16 to⬍24 weeks. Both vaccine doses were administered after the 2001 in-fluenza season and before the start of the 2002 season.
Vaccine and Placebo
CAIV-T (manufactured by Wyeth Vaccines Research, Marietta, PA) contained 3 cold-adapted reassortant influ-enza virus strains representing the 3 strains recommended by the World Health Organization for the 2001–2002 in-fluenza season (A/New Caledonia/20/99 [H1N1], A/Pana-ma/2007/99 [H3N2], and B/Victoria/504/2000)17grown in specific pathogen-free chicken eggs. Each 0.2-mL dose contained⬃107⫾0.5fluorescent focus units of each of the vaccine strains. The vaccine was shipped to the study sites at 2 to 8°C, where it was stored at that temperature until just before administration. CAIV-T was administered intra-nasally with a spray applicator (⬃0.1 mL into each nostril). Placebo consisted of 0.2 mL of the physiologic saline ad-ministered intranasally with a spray applicator (⬃0.1 mL into each nostril).
Study Evaluations
The primary study end point was the tolerability of CAIV-T based on reactogenicity events (REs) reported within 11 days of the first or second dose of study vaccine. REs were predefined events that included fever (ⱖ38°C rectal temperature), runny nose, nasal conges-tion, cough, vomiting, activity level, appetite, and irrita-bility. The subjects’ parents or guardians were instructed to assess the presence or absence of each event and to record the assessment on diary cards.
Secondary study end points included the occurrence of adverse events (AEs), unscheduled physician visits, and use of prescription and nonprescription medica-tions. An AE was defined as any clinically significant event, including those that required any prescription or nonprescription medication, required an unscheduled physician visit, resulted in withdrawal from the study, or resulted in any other medically significant event. AEs were monitored through days 28 to 35 after the second dose of vaccine. REs that also met the definition of an AE were recorded as both. A serious AE (SAE) was any event that resulted in death, was life-threatening, re-quired or prolonged hospitalization, resulted in a persis-tent or significant disability, or resulted in cancer.
Statistical Analyses
study was designed to have 80% power to detect abso-lute differences in event probabilities ranging from .305 to .380. The occurrence of systemic reactions was com-pared between groups by a 2-sided Fisher’s exact test.P values were not adjusted for multiple comparisons. The dose 1 and 2 safety analysis populations consisted of all of the subjects who received the first or second dose of study vaccine, respectively, as actually administered.
RESULTS
Subject Characteristics
The study population was composed of 120 subjects who were randomly assigned to receive CAIV-T (n⫽61) or placebo (n ⫽ 59). There were 59 infants in the 6- to ⬍16-week cohort (31 CAIV-T and 28 placebo) and 61 in the 16- to ⬍24-week cohort (30 CAIV-T and 31
pla-cebo). Treatment groups were well matched with regard to age at first vaccination, gender, and ethnicity (Table 1). A total of 114 subjects (95%) completed the study (Fig 1). Of the 6 subjects withdrawn from the study, 1 subject in the CAIV-T group withdrew because of paren-tal request, and 1 CAIV-T recipient was withdrawn after experiencing a convulsion without fever possibly related to study vaccine 2 days after vaccination. The next day the child was fully recovered and was discharged from the hospital. Four placebo recipients were withdrawn because they did not receive the second dose within the 28- to 42-day window for vaccination. The mean age⫾ SD at first vaccination was 12.0⫾2.2 weeks for the 6- to ⬍16-week cohort and 20.0⫾2.5 weeks for the 16- to ⬍24-week cohort. The mean interval between vaccine doses was the same for CAIV-T and placebo recipients
FIGURE 1
Patient flow through the trial.
TABLE 1 Demographic Characteristics
Characteristic 6- to⬍16-wk Cohort 16- to⬍24-wk Cohort
CAIV-T (n⫽31)
Placebo (n⫽28)
Total (n⫽59)
CAIV-T (n⫽30)
Placebo (n⫽31)
Total (n⫽61)
Gender,n(%)
(30.9⫾3.7 days). Concomitant routine childhood vac-cination with inactivated vaccines was permitted during this study, and the numbers of patients receiving the diphtheria-tetanus-pertussis, Haemophilus b conjugate, and inactivated polio vaccines were similar among CAIV-T and placebo recipients (data not shown).
Safety Analysis
More CAIV-T than placebo recipients experienced any RE during the 11 days after dose 1 (80.3% vs 72.7%;P⫽ .383). Conversely, after dose 2, REs were reported less frequently in CAIV-T than in placebo recipients (69.5% vs 72.2%; P ⫽ .837). In the 6- to ⬍16-week cohort, runny nose or nasal congestion and irritability occurred significantly more frequently in CAIV-T than in placebo recipients (63.3% vs 33.3%, P ⫽ .034; and 67.7% vs 35.7%, P ⫽.035, respectively), and there was a trend toward decreased appetite in the CAIV-T group (23.3% vs 3.7%;P⫽.054) after the first dose but not after the second dose (Table 2). There were no statistically signif-icant differences in any REs between treatment groups after dose 2 in the 6- to⬍16-week cohort. Similarly, in the 16- to⬍24-week cohort, runny nose or nasal con-gestion and irritability were the most frequently re-ported REs among CAIV-T and placebo recipients, but the incidence was similar in both treatment groups (Ta-ble 2). In the 16- to ⬍24-week cohort, cough was sig-nificantly more common in placebo than CAIV-T recip-ients after dose 2 (39.3% vs 10.7%;P⫽.029).
The most frequently reported AEs in both age cohorts and after each dose were bodily discomfort, fever, and rhinitis (Table 3). There was no significant difference in the incidence of any AE between treatment groups in either age cohort, although there was a trend for bodily discomfort to be more common among CAIV-T
recipi-ents in the 6- to ⬍16-week cohort after dose 1 (P ⫽ .055).
A single SAE was reported in the 6- to ⬍16-week cohort: a case of pyelonephritis with fever 18 days after the second dose of CAIV-T that was considered by the investigator to be unrelated to study vaccine. Three SAEs were reported in the 16- to ⬍24-week cohort: (1) the subject described above who experienced a convulsion (manifesting as lethargy) 2 days after receiving the first dose of CAIV-T that was considered possibly related to vaccine and led to withdrawal of the subject from the study; (2) severe vomiting 16 days after receiving the second dose of CAIV-T that was considered by the in-vestigator to be unrelated to study treatment; and (3) an upper respiratory tract infection with fever and otitis media beginning 3 days after receiving the first dose of placebo. All of these subjects recovered fully.
DISCUSSION
This study assessed the safety and tolerability of intra-nasal CAIV-T (a refrigerated formulation of LAIV) com-pared with placebo in infants 6 to ⬍24 weeks of age at the time of vaccination. Young children are at high risk for influenza-related complications, and vaccination of household contacts is recommended to provide indirect protection to children⬍6 months of age for whom vac-cination is not currently recommended.7 Despite the very low risk of transmission of live influenza vaccine viruses to nonvaccinated individuals, it is possible that children in this age group may be exposed to vaccine viruses through close contact with vaccinated playmates, caregivers, and other household members.
The findings from this study suggest that transmission of CAIV-T vaccine virus to a young infant is not likely to pose a significant health risk. Doses of CAIV-T
contain-TABLE 2 Reactogenicity Events After Dose 1 or 2
Event 6- to⬍16-wk Cohort 16- to⬍24-wk Cohort
CAIV-T Placebo P CAIV-T Placebo P
Dose 1, range of the No of subjects with known values 28–31 26–28 29–30 27–31
Feverⱖ38°C,n(%) 2 (6.9) 1 (3.8) ⬎.99 9 (30.0) 6 (22.2) .559
ⱖ39.1°C,n(%) 0 (0.0) 0 (0.0) NA 1 (3.3) 1 (3.7) ⬎.99
ⱖ40°C,n(%) 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NA
Decreased appetite,n(%) 7 (23.3) 1 (3.7) .054 7 (23.3) 7 (22.6) ⬎.99
Cough,n(%) 9 (31.0) 5 (18.5) .361 7 (23.3) 8 (25.8) ⬎.99
Runny nose or nasal congestion,n(%) 19 (63.3) 9 (33.3) .034 14 (46.7) 17 (54.8) .612 Irritability,n(%) 20 (66.7) 10 (35.7) .035 16 (53.3) 17 (54.8) ⬎.99 Decreased activity,n(%) 7 (23.3) 5 (17.9) .749 7 (23.3) 8 (25.8) ⬎.99
Vomiting,n(%) 4 (13.8) 0 (0.0) .112 1 (3.4) 4 (12.9) .355
Dose 2, range of the No of subjects with known values 31 24–26 27–28 26–28
Feverⱖ38°C,n(%) 4 (12.9) 3 (12.0) ⬎.99 3 (11.1) 8 (30.8) .099
ⱖ39.1°C,n(%) 0 (0.0) 0 (0.0) NA 0 (0.0) 1 (3.8) .491
ⱖ40°C,n(%) 0 (0.0) 0 (0.0) NA 0 (0.0) 0 (0.0) NA
Decreased appetite,n(%) 5 (16.1) 3 (11.5) .715 5 (17.9) 9 (32.1) .355
Cough,n(%) 11 (35.5) 4 (15.4) .132 3 (10.7) 11 (39.3) .029
Runny nose or nasal congestion,n(%) 12 (38.7) 9 (34.6) .789 10 (35.7) 10 (35.7) ⬎.99 Irritability,n(%) 19 (61.3) 11 (42.3) .189 11 (39.3) 17 (60.7) .181 Decreased activity,n(%) 6 (19.4) 4 (15.4) .741 2 (7.1) 6 (21.4) .252
Vomiting,n(%) 4 (12.9) 1 (3.8) .362 2 (7.1) 3 (11.1) .669
ing 107 infectious viruses of each vaccine strain were well tolerated in infants 16 to ⬍24 weeks of age. The incidence and profile of REs were similar to those re-ported in larger studies in older children 6 to 71 months of age in which the safety of CAIV-T viruses has been clearly established.10,16,18–20 In contrast, this study sug-gests that some REs may be increased in infants 6 to⬍16 weeks of age who receive CAIV-T.
Despite a possible increase in reactogenicity, addi-tional safety, efficacy, and immunogenicity trials in in-fants⬍6 months of age may be warranted in view of the significant burden of influenza in this age group. To date, efficacy of CAIV-T has been demonstrated in children as young as 6 months of age.9–11In a study of 1616 children 6 to⬍36 months of age attending day care, efficacy of CAIV-T in preventing culture-confirmed influenza was 85% and 89% in the first and second years of the study, respectively.10 CAIV-T has also demonstrated superior efficacy compared with TIV in children as young as 6 months of age. In a study of 2187 subjects aged 6 to 71 months, there were 53% fewer cases of influenza caused by circulating influenza viruses among CAIV-T than TIV recipients, and there were fewer medically attended vis-its for respiratory tract infections and fewer days of school or day care missed by CAIV-T recipients.9These findings have been confirmed recently in a larger study of 8475 children 6 to 59 months of age in which there were 55% fewer cases of culture-confirmed influenza in CAIV-T compared with TIV recipients.11
In addition, CAIV-T has been shown to protect against circulating influenza strains that are not anti-genically matched to the vaccine strains. During a period of antigenic drift in circulating influenza H3N2 viruses, the vaccine viruses in CAIV-T were ⱕ86% effective in
protecting children and adults against antigenically drifted influenza strains.21,22More recently, in a study in children 6 to 59 months of age, there were 58% fewer episodes of influenza caused by antigenically drifted in-fluenza strains among CAIV-T than TIV recipients.11
Despite a relatively small sample size, this study has demonstrated that CAIV-T was well tolerated when ad-ministered to infants 6 to 24 weeks of age. The symp-toms that were observed in infants 6 to ⬍16 weeks of age were mild and transient. These findings suggest that there should not be adverse clinical consequences in the unlikely event of transmission of CAIV-T vaccine virus from a vaccinated contact to a young infant. Immuno-genicity and efficacy of CAIV-T in this young population has not been evaluated to date. The results presented here support further evaluation of CAIV-T in young infants. However, such studies should be performed with caution, because recent studies have suggested that vaccination with CAIV-T may be associated with an increased risk of wheezing in children ⬍24 months of age and with increased risk of hospitalization in children 6 to 11 months of age.11In our study, no such adverse experiences were observed, but the number of subjects in this study was too small to detect these rare events.
ACKNOWLEDGMENTS
This work was supported by MedImmune and Wyeth Vaccines Research.
We thank the participating subjects and the parents of the children; Pa¨ivi Salonen, RN, the nurse coordinator; the investigators and study nurses of the vaccine study clinics of Tampere, Turku, Espoo, Pori, Lahti, and Jyva¨s-kyla¨; the clinical testing laboratory staff; and the clinical
TABLE 3 Adverse Events Reported in>5% of Subjects After Dose 1 or 2
Event 6- to⬍16-wk Cohort 16- to⬍24-wk Cohort
CAIV-T Placebo P CAIV-T Placebo P
Dose 1,n 31 28 30 31
Any event,n(%) 12 (38.7) 10 (35.7) ⬎.99 19 (63.3) 16 (51.6) .44 Bodily discomfort,n(%) 7 (22.6) 1 (3.6) .055 3 (10.0) 4 (12.9) ⬎.99
Rhinitis,n(%) 2 (6.5) 5 (17.9) .24 5 (16.7) 5 (16.1) ⬎.99
Fever,n(%) 3 (9.7) 3 (10.7) ⬎.99 5 (16.7) 5 (16.1) ⬎.99
Otitis media,n(%) 0 (0.0) 1 (3.6) .475 2 (6.7) 4 (12.9) .671 Conjunctivitis,n(%) 2 (6.5) 3 (10.7) .661 2 (6.7) 1 (3.2) .612
Pain,n(%) — — — 3 (10.0) 2 (6.5) .671
Cough,n(%) 0 (0.0) 2 (7.1) .221 1 (3.3) 1 (3.2) ⬎.99
Upper respiratory tract infection,n(%) — — — 1 (3.3) 2 (6.5) ⬎.99
Tooth disorder,n(%) — — — 1 (3.3) 3 (9.7) .612
Diarrhea,n(%) 0 (0.0) 1 (3.6) .475 1 (3.3) 2 (6.5) ⬎.99
Dose 2,n 31 27 28 28
Any event,n(%) 16 (51.6) 14 (51.9) ⬎.99 11 (39.3) 15 (53.6) .422 Bodily discomfort,n(%) 7 (22.6) 5 (18.5) .756 5 (17.9) 10 (35.7) .227
Rhinitis,n(%) 4 (12.9) 4 (14.8) ⬎.99 1 (3.6) 7 (25.0) .051
Fever,n(%) 7 (22.6) 2 (7.4) .154 2 (7.1) 5 (17.9) .422
Tooth disorder,n(%) 0 1 (3.7) .466 3 (10.7) 4 (14.3) ⬎.99
Otitis media,n(%) 1 (3.2) 1 (3.7) ⬎.99 0 (0.0) 3 (10.7) .236
Bronchitis,n(%) — — — 0 (0.0) 2 (7.1) .491
Bronchospasm,n(%) — — — 0 (0.0) 2 (7.1) .491
Conjunctivitis,n(%) 2 (6.5) 0 (0.0) .494 — — —
research associates and scientists at Wyeth and Med-Immune. We also thank Gerard P. Johnson, PhD, and Janet Stead, BM, BS, who provided medical writing and editorial assistance.
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DOI: 10.1542/peds.2007-1405 originally published online February 25, 2008;
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