Published online September 1, 2006
PEDIATRICS Vol. 118 No. 3 September 2006, pp. e579-e585 (doi:10.1542/peds.2006-0201)
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ARTICLE

Immunization With Trivalent Inactivated Influenza Vaccine in Partially Immunized Toddlers

Janet A. Englund, MDa, Emmanuel B. Walter, MD, MPHb, Adepeju Gbadebo, MSb, Arnold S. Monto, MDc, Yuwei Zhu, MD, MSd and Kathleen M. Neuzil, MD, MPHe

a Division of Pediatric Infectious Diseases, Allergy, and Rheumatology, University of Washington and Children's Hospital and Regional Medical Center, Seattle, Washington
b Department of Pediatrics, Duke University Medical Center, Durham, North Carolina
c School of Public Health, University of Michigan, Ann Arbor, Michigan
d Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee
e Program for Appropriate Technology in Health and Department of Medicine, University of Washington School of Medicine, Seattle, Washington


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE. Children ≥6 months of age who have previously received 1 dose of trivalent inactivated influenza vaccine are recommended to be given an additional single trivalent inactivated influenza vaccine dose the following fall. Limited data exist documenting the immunogenicity of 2 doses of influenza vaccine given in separate years to young children, and it is not known if the antigen content of each of the 2 doses of vaccine must be identical or similar to optimally immunize children in this age group. In 2004, the A/H3N2 and B antigens contained in trivalent inactivated influenza vaccine were changed from those in the 2003–2004 influenza vaccine, providing the opportunity to assess the effect of such a change on the single-dose recommendation in trivalent inactivated influenza vaccine-experienced toddlers.

PATIENTS AND METHODS. We conducted an observational, nonrandomized, open-label study comparing immunogenicity and reactogenicity of 2 doses of trivalent inactivated influenza vaccine in 2 groups of healthy children aged 6 to 23 months. Children who had received 1 dose of 2003 trivalent inactivated influenza vaccine the previous season received 1 dose of 2004 trivalent inactivated influenza vaccine according to current guidelines (group 1). Trivalent inactivated influenza vaccine-naïve toddlers received the standard 2 doses of 2004 trivalent inactivated influenza vaccine 1 month apart (group 2). Blood was obtained 4 weeks after the second dose of trivalent inactivated influenza vaccine. The primary outcome measure was antibody response to the 3 vaccine antigens in the 2004 trivalent inactivated influenza vaccine after 2 doses of vaccine, as determined by hemagglutination-inhibition antibody titers. Noninferiority of the antibody response was based on the proportion of subjects in each group achieving a titer of ≥1:32 postvaccination to antigens (H1N1, H3N2, and B) contained in the 2004–2005 vaccine. For each antigen, the antibody response was proposed to be noninferior if the upper bound of the 95% confidence interval of the difference between the proportion of children in the 2 groups with postvaccination titers ≥1:32 was <15%. Reactogenicity was a secondary outcome and was assessed by parental diaries or telephone follow-up.

RESULTS. Fifty six of 58 previously immunized children (group 1) and 63 of 64 vaccine-naïve children (group 2) completed the study. The groups were similar, except group 1 was older at receipt of the second trivalent inactivated influenza vaccine. Reactogenicity did not differ by age or time between doses. Antibody responses to the unchanged influenza A/H1N1 antigen at 4 weeks after the second trivalent inactivated influenza vaccine dose were similar in both groups, with good responses as measured by geometric mean titer (75.2 vs 69.1) and percentage with antibody titers ≥1:32 (82.1% group 1 vs 85.7% group 2). For the A/H3N2 antigen, which changed between 2003 and 2004, there was a significantly higher geometric mean titer in group 1 compared with group 2 (156 vs 53.7), but both groups had very high rates of seroconversion that were not statistically different (91% vs 84%). The antibody response to influenza B was significantly lower in group 1 recipients, who received only a single dose of 2005 vaccine, as measured by both geometric mean titer and percentage with antibody ≥1:32. The group 1 geometric mean titer was 13.8, and the group 2 geometric mean titer was 49.1. Only 27% of children in group 1 achieved antibody levels ≥1:32 to influenza B compared with 86% in group 2. Using logistic regression, we also determined that older children had less potentially seroprotective levels to influenza B. Overall, noninferiority of the antibody response for group 1 compared with group 2 was confirmed for influenza A/H3N2, was marginally significant for A/H1N1, and was not confirmed for influenza B.

CONCLUSIONS. The assessment of immune responses in children after changes in vaccine composition is important, because influenza vaccines change frequently, affecting not only antibody responses in partially immunized toddlers, but potentially immune responses in more fully immunized individuals. In this study, a change in 2 different vaccine antigens enabled us to assess and compare the impact of the original priming antigens after relatively minor changes in 1 antigen (A/H3N2) or after considerable antigenic changes in another vaccine antigen (B). Our subjects demonstrated relatively good responses to the vaccine antigen change characterized by relatively minor changes (A/H3N2). Circulating virus may have primed infants in both groups to antigen more closely related to the 2004 influenza A/H3N2 strain. The high A/H3N2 antibody response to the second dose of trivalent inactivated influenza vaccine in children who were immunized the previous fall with a different vaccine is consistent with the fact that more children in group 1 were alive during this epidemic and, therefore, were more likely to have experienced priming with natural infection. In contrast, a decreased antibody response to the influenza B antigen was seen in children primed with the earlier 2003 vaccine, suggesting that the major change in B virus lineage in the 2004 vaccine reduced the priming benefit of previous vaccination. Our findings are reminiscent of antibody responses in children seen after immunization with different but novel influenza antigens, such as swine flu vaccine (influenza A/swine/1976/37-like virus). Our results should be taken into account when evaluating new vaccines in young children for novel viruses, such as new pandemic strains of influenza. The need for multiple doses of vaccine to produce potentially protective antibody levels in children needs to be considered, even when vaccine is in short supply.

Key Words: trivalent inactivated influenza vaccine • children • immunogenicity • reactogenicity

Abbreviations: ACIP—Advisory Committee on Immunization Practices • TIV—trivalent inactivated influenza vaccine • CI—confidence interval • HAI— hemagglutination inhibition • GMT—geometric mean titer

In 2004, the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices (ACIP) recommended routine immunization with influenza vaccine for all children 6 to 23 months of age, as well as their close contacts,1 based on the recognition of the safety and effectiveness of influenza vaccine and the high burden of disease in this age group.1–6 Recommendations included 2 fall doses of trivalent inactivated influenza vaccine (TIV) for children <9 years of age not previously immunized with TIV, and 1 fall dose of TIV for children previously primed with ≥1 dose. The 2004–2005 influenza season was the first full season after the ACIP recommendation to vaccinate all children 6 to 23 months of age. This season was complicated by vaccine shortages, changes in vaccine prioritization, and practical issues associated with the incorporation of routine TIV administration into clinical practice. Nonetheless, ~48% of toddlers received ≥1 dose of TIV during this time period.7

Current recommendations to immunize toddlers who have previously received TIV with another single TIV dose the following fall are practical, particularly during times of vaccine shortages or early onset of influenza season. However, limited data exist in young children documenting immunogenicity of 2 doses of influenza vaccine given in separate years, and it is not known whether the antigen content of each of the 2 doses of influenza vaccine must be identical or similar to optimally immunize children in this age group. Our previous study demonstrated that the timing of the second TIV dose in young children does not significantly affect vaccine immunogenicity when influenza antigens remain the same,8 but, because the vaccine did not change during our study period, we were unable to assess the impact of a change in vaccine antigens during that study.

The 2004–2005 TIV differed in both the A/H3N2 and B components (A/Wyoming/03/2003 [H3N2] and B/Jiangsu/10/2003) compared with the 2003–2004 TIV.9 Of note, the changes in the A/H3N2 vaccine components reflected relatively minor changes, whereas the antigenic changes in the B component were more considerable. The influenza B virus included in the 2003–2004 vaccine was derived from the B/Victoria lineage, whereas the B virus included in the 2004–2005 vaccine was derived from the B/Yamagata lineage. The objective of this study was to determine immunogenicity and reactogenicity of 2 doses of TIV in healthy toddlers when the identical vaccine was administered 1 month apart compared with that when TIV vaccine with different antigens was administered 1 year apart.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Design
This study was a nonrandomized open-label clinical trial conducted at 3 clinics near Seattle, WA, (Skagit Valley Pediatrics, Children's Hospital and Regional Medical Center; Madigan Army Medical Center; and Virginia Mason Medical Center) and 2 pediatric practices in Durham, NC (Duke Children's Primary Care and Durham Pediatrics). Children were enrolled between September 1 and October 15, 2004. The study protocol was approved by each institutional review board, and informed consent was obtained from a parent or guardian of each study participant. Children 10 to 24 months of age who were documented to have been vaccinated with 1 dose of 2003–2004 TIV during the fall of 2003 were recruited to receive a single dose of licensed TIV in fall 2004, as recommended (group 1). Children 6 to 24 months of age who had never received influenza vaccine were also enrolled (group 2) and received 2 doses of 2004–2005 TIV in the fall (Table 1). Thus, all of the children received 2004–2005 TIV in accordance with ACIP guidelines.1 Blood samples were obtained 4 weeks after the second dose of influenza vaccine in children in both groups. Blood was also drawn 4 weeks after the first dose of vaccine in children assigned to group 2.


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  		TABLE 1 Study Design and Enrollment

 
The primary objective of this study was to demonstrate noninferiority of the antibody response after administration of a different vaccine given 1 year earlier (group 1) compared with the standard dosing schedule (group 2). This noninferiority was based on the proportion of subjects in each group achieving a titer of ≥1:32 postvaccination to 2 of the 3 antigens (H1N1, H3N2, and B) contained in the 2004–2005 vaccine. For each antigen, the antibody response was proposed to be noninferior if the upper bound of the 95% confidence interval (CI) of the difference between the proportion of children in 2 groups with postvaccination titers ≥1:32 was <15%. We assumed a 1-sided {alpha} of .05, expected seroprotection rates in the standard group of 80%, and expected <5% lower rates in group 1 for each included antigen, with a 15% maximum margin. Secondary study objectives included comparisons of reactogenicity in the 2 groups.

Population
Healthy children <24 months of age were recruited for enrollment if they had received a previous dose of TIV the previous year (ie, they must have been ≥6 months of age the previous fall) or if they had not received any TIV vaccine and were between 6 and 24 months of age. Children were enrolled after parental informed consent. Subjects with acute febrile illnesses were eligible for enrollment, but immunization was deferred for 24 hours after the last axillary temperature of >38°C. Children were excluded from the study for birth before 36 weeks' gestation, allergy to eggs or egg products, history of Guillain-Barré syndrome, immunosuppression as a result of underlying illness or treatment, any acute or chronic condition that, in the opinion of the investigator or primary physician, would render vaccination unsafe or ineffective, history of receiving immunoglobulin or other blood product within 3 months before enrollment, receipt of a live virus vaccine (eg, measles-mumps-rubella vaccine or varicella) within the preceding 4 weeks, or need to obtain a live virus vaccine within the consecutive 4 weeks. Simultaneous administration of a live virus vaccine was permitted.1

Vaccine
Single lots of licensed 2004–2005 trivalent inactivated preservative-free influenza vaccine provided by Aventis-Pasteur (A/New Caledonia/20/99 [H1N1], H3N2, and B/Jiangsu/10/2003) were used throughout the trial. Before the study, children in group 1 had received commercially available 2003–2004 TIV containing H1N1, A/Panama/2007/99 (H3N2), and B/Hong Kong/1434/2002. All of the study vaccine was prepackaged in 0.25-mL syringes and administered intramuscularly in the thigh with a 25-gauge needle by use of a standard sterile technique.

Immunogenicity
Sera were stored frozen at –20°C or less until analyzed at the University of Michigan. Hemagglutination-inhibition (HAI) antibody titers were determined in duplicate, with all of the paired specimens run in the same test. Antigens were provided by the Centers for Disease Control and Prevention. Sera were treated with receptor-destroying enzyme (Denke Seiken Co Ltd, Tokyo, Japan) and then heated to 56°C for 30 minutes to inactivate the receptor-destroying enzyme. Sera were diluted 1:8 and subsequently underwent serial twofold dilutions. Twenty-five microliters of the diluted sera were incubated with an equal volume of antigen diluted to contain 4–8 hemagglutinin units, and 50 µL of a 0.5% suspension of chicken red blood cells were then added to the mixture. A potentially protective antibody titer was defined as an HAI titer ≥1:32.10,11

Reactogenicity
Prospective evaluation of reactogenicity was obtained either by parental diary or telephone follow-up by study personnel. Parents were requested to record daily axillary temperatures, any local reactions (pain, tenderness, redness, and swelling at the site of TIV), and systemic reactions (irritability, alteration in sleep behavior, emesis, and change in appetite) for 5 days after vaccination. In addition, parents were contacted by telephone between 3 and 5 days after vaccination to confirm temperatures and document any adverse reactions. Parents were contacted 6 months after the last dose of vaccine to inquire about any serious adverse reactions.

Statistics
Descriptive and exploratory analyses were used to evaluate demographic characteristics stratified by different vaccine regimen groups. Univariate analyses were performed to assess the associations among reactogenicity, concomitant vaccines, and groups. Antibody titers were expressed as log2, and geometric mean titers (GMTs) were reported. Any titer <1:8 was assigned a minimum value of 4, and values ≥1:2048 were coded as 2048. Antibody titers ≥1:32 were considered positive. All of the comparisons were made using {chi}2 test or Fisher's exact test when appropriate for contingency tables and t test for continuous variables. Logistic regression was used to evaluate the relationship between age and seroprotection while controlling for race and gender. The predefined 15% difference was considered to be the threshold of noninferiority. Tests for noninferiority were done by StatXact 6.0 (Cytel Corporation, Cambridge, MA), and the remaining calculations and analyses were performed using SPSS version 13.0 (SAS Institute, Cary, NC).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Subjects
All 122 study participants were enrolled between September and October 2004. Overall, 58 previously immunized children 11 to 24 months of age were enrolled in group 1, and 64 vaccine-naïve children 6 to 22 months of age were enrolled in group 2 (Table 1). Overall, 122 children received 186 doses of TIV. No serious adverse events were recorded after any dose of vaccine.

All 58 children in group 1, who had received a single dose of TIV ~1 year earlier, received a single dose of TIV at study enrollment. Two children in this group withdrew from the study or became lost to follow-up after immunization. Serologic and reactogenicity data were available from 56 (96%) and 36 (62%) children in this group. All 64 influenza vaccine-naïve children (group 2) received 2 doses of TIV 1 month apart (mean interval between vaccinations: 34.2 days; range: 28–49 days). One child in this group withdrew from the study after the second inoculation but before the blood draw, and blood samples were not successfully obtained on 2 additional children. Serologic and reactogenicity data in group 2 were available from 61 (95%) and 63 (98%) children, respectively.

Children in group 1 were significantly older than those in group 2 at the time of enrollment (median age: 18.5 months vs 8.5 months; P < .001) and at the age of second dose of TIV (median age: 18.5 months and 10.0 months; P < .001). Both groups were similar in terms of gender (47% girls in group 1 vs 50% in group 2) and race/ethnicity, with the majority of children self-reporting as white (81% in group 1 vs 75% in group 2). The Seattle-affiliated sites enrolled more children (55%) in group 1 than did the Duke-affiliated sites (45%), whereas the Duke-affiliated sites enrolled more children in group 2 (39% vs 61%).

Immunogenicity
Antibody responses were assessed both by geometric mean antibody titer and the percentage of subjects reaching a titer of ≥1:32 (Figs 1 and 2). Responses to the unchanged influenza A/H1N1 antigen at 4 weeks after the second TIV dose were similar in both groups, with good responses as measured by geometric mean titer ([GMT] 75.2 vs 69.1) and by percentage with antibody titers >1:32 (82.1% group 1 vs 85.7% group 2). For the A/H3N2 antigen, which changed between 2003 and 2004, there was a significantly higher GMT in group 1 compared with group 2 (156; 95% CI: 105–231, vs 53.7; 95% CI: 41–70), but both groups had very high rates of seroconversion that were not statistically different (91% vs 84%).


Figure 1
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  		FIGURE 1 Percentage with potentially protective antibody responses and 95% CIs 1 month after the first dose of 2004–2005 TIV in vaccine-naïve toddlers (group 2 after first dose, {square}), 1 month after a single dose of 2004–2005 TIV vaccine in toddlers primed the previous year with 2003–2004 TIV (group 1, {square}), and 1 month after the second of 2 doses of identical 2004–2005 TIV (group 2 after second dose, {blacksquare}).

 

Figure 2
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  		FIGURE 2 Geometric mean HAI antibody titers and 95% CIs to the 3 influenza antigens in the 2004–2005 vaccine 1 month after the first dose of 2004–2005 TIV in vaccine-naïve toddlers (group 2 after first dose, {square}), 1 month after a single dose of 2004–2005 TIV vaccine in toddlers primed the previous year with 2003–2004 TIV (group 1, {square}), and 1 month after the second of 2 doses of identical 2004–2005 TIV (group 2 after second dose, {blacksquare}).

 
The antibody response to influenza B was significantly lower in group 1 recipients, who received only a single dose of 2005 vaccine, as measured by both GMT and percentage with antibody ≥1:32. The group 1 GMT was 13.8 (95% CI: 11–17), and the group 2 GMT was 49.1 (95% CI: 41–59). Only 27% of children in group 1 achieved seroprotection to influenza B compared with 86% in group 2 (P < .001). Using logistic regression, we also determined that older children had less seroprotection to influenza B (P < .001). Because of this, we are unable to confirm the noninferiority of response to influenza B in group 1 compared with group 2. Overall, noninferiority of the antibody response for group 1 compared with group 2 was confirmed for influenza A/H3N2 (P < .001), was marginally significant for A/H1N1 (P = .054), and was not confirmed for influenza B.

Reactogenicity
Complete reactogenicity data were available from 96 of 122 evaluable children, with partial reactogenicity data available in an additional 4 children (3%). Overall, reactogenicity rates were low and similar between groups. Specifically, temperatures >37.8°C axillary during the first 3 days after vaccination were reported in 5% of children overall, with no significant differences between groups. No child reported a fever >39.5°C; only 1 child in group 1 and 7 in group 2 had a temperature >37.8°C axillary during the first 5 days after TIV. Rates of overall moderate-to-severe pain, redness, or swelling during the first 3 days after the first study dose of vaccine were 0%, 3%, and 0%, respectively, in group 1 and 0%, 2%, and 0% in group 2; rates after the second dose in the second group who received 2 TIV doses were similar (1.6%, 0%, and 0%; Table 2). These rates did not differ by age. Reactogenicity did not differ by dose of TIV, except that fever >37.8°C after the first dose was significantly higher than after the second dose in group 2 recipients (P < .01). Rates of fever >37.8°C axillary were 10.5% when TIV was given concomitantly with pneumococcal conjugate vaccine (Prevnar; n = 38), 11.1% or with any diphtheria-tetanus toxoid-acellular pertussis combination vaccine (n = 27), and 2.7% when given alone (n = 113). Although there was no statistically significant association between fever and any concomitant vaccines, we noted a marginally significant relationship of fever when TIV was given concomitantly with pneumococcal conjugate vaccine (P = .06) or with any concomitant vaccine (P = .07).


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  		TABLE 2 Reactogenicity During the First 3 Days After TIV in Children 6 to 23 Months of Age

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The role that specific influenza vaccine antigens play in priming young children to produce "potentially protective" antibody responses to TIV is not well characterized, and the impact of changes in vaccine antigen(s) between seasons in young children has not been evaluated prospectively. With new guidelines in place for universal immunization of toddlers with inactivated influenza vaccine, evaluation of immunogenicity after standard immunization with TIV given 1 year apart with different vaccine preparations is an increasingly important issue. Although prospective studies evaluating efficacy and immunogenicity of influenza vaccine in children have been published,2,3,12–14 relatively limited immunogenicity data are available in children <2 years of age.15–21 We have demonstrated previously that the time interval between administration of TIV containing identical antigens does not affect antibody response in toddlers8 and have also studied the use of springtime priming of toddlers with an inactivated influenza vaccine changed in both the H3N2 and B components.22 In this study, the immune response in children who received only 1 dose of influenza vaccine the previous year and were reimmunized with 1 dose of a different vaccine was used to evaluate the importance of "priming" young children to various influenza antigens.

The assessment of immune responses in children after changes in vaccine composition is important, because influenza vaccines change frequently, affecting not only antibody responses in partially immunized toddlers, but potentially immune responses in more fully immunized individuals. In this study, a change in 2 different vaccine antigens enabled us to assess and compare the impact of the original priming antigens after relatively minor changes in 1 antigen (A/H3N2) or after substantial antigenic changes in another vaccine antigen (B). Our subjects demonstrated relatively good responses to the vaccine antigen change characterized by relatively minor changes (H3N2). Importantly, all of the children in group 1 but only 56% of children in group 2 were alive during the previous influenza season when H3N2 was widely circulating (November 2003 to February 2004). Circulating virus may have primed infants in both groups to antigen more closely related to the 2004 influenza A/H3N2 strain. The high antibody response to the second dose of TIV in group 1 is consistent with the fact that more children in group 1 were alive during this epidemic and, therefore, more likely to have experienced priming with natural infection.

We demonstrated a relatively good response to the influenza B antigen after 2 doses of identical TIV in the TIV-naïve group (group 2), with antibody seroprotection rates superior to those from children in the same population 1 year previously8 and in other published studies conducted in young children.3,23–25 However, relatively low rates of protective antibody responses were seen in group 1 children who had been primed the previous year with a TIV containing B antigen, which was relatively different antigenically. Low rates of antibody response to influenza B and GMT were seen in children receiving a spring dose of 2003–2004 TIV followed by a fall dose of the 2004–2005 TIV22 and in children 5 to 9 years of age receiving 1 dose of TIV.26 Thus, children primed with a different B antigen or naïve-to-influenza vaccine seem to respond equally poorly. Such findings are reminiscent of antibody responses in children seen after immunization with swine flu vaccine (influenza A/swine/1976/37-like virus), a different but novel influenza antigen.27 Our results should also be taken into account when evaluating new vaccines in young children for viruses such as novel pandemic strains. The need for multiple doses of vaccine to produce potentially protective antibody levels needs to be considered, even when vaccine is in short supply.

Our study is limited in part because it was not prospectively randomized and controlled. Furthermore, the ages of the children in the different groups also differed significantly, in large part because of compliance with ACIP vaccine recommendations during the previous 2003–2004 influenza season. The age difference between groups is biologically significant in terms of exposure to other circulating viruses, as well as in the immunologic maturity of the individual children. However, the standard guidelines and recommendations for immunization with TIV in children in the United States make prospective blinded studies on this subject problematic; vaccine uptake in pediatric practices has been amazingly successful, and intentional delay of the second dose of vaccine in toddlers would not be allowed under current guidelines. Similar responses in both groups to the unchanging A/H1N1 antigen demonstrate that immunologic immaturity did not play a major role in our immunogenicity analysis, but rather the vaccine antigens themselves were a more significant factor in the immunogenicity of the vaccine.

We have demonstrated that giving 2 doses of TIV to toddlers who have not been vaccinated previously is better than a single dose, regardless of the time between doses or antigen content of the vaccine. This reinforces our earlier studies, as well as other studies of novel influenza vaccines, and may be of importance in proposed studies of avian influenza vaccine virus in children. In young patients, the antigen content of the influenza vaccine is substantially more important than the time interval between doses in this patient population, even when the time interval is as long as 1 year. We again confirmed that influenza vaccine is remarkably well tolerated in this age group, with low rates of fever, pain, redness, or swelling after each dose and no significant change in reactogenicity after increased exposure to the vaccine. Influenza vaccine was also well accepted by parents and well integrated into the routine of the pediatric clinics in our study.

Although better immune responses were found after the second dose of vaccine when the antigens were identical (H1N1) or relatively closely related (H3N2), our data reveal the benefits of 2 doses of influenza vaccine in the toddler age group. Results of this study reinforce the benefits of the second dose, whether this dose is identical or not identical to the original priming vaccine. Importantly, our study results support the current recommendations for immunization of TIV in unimmunized and partially immunized young children.


   ACKNOWLEDGMENTS
 
We gratefully acknowledge the assistance of the physicians and staff at Skagit Valley Pediatrics (Dr Frances Chalmers and colleagues), Virginia Mason Pediatrics/Federal Way (Dr Jon Almquist and colleagues), Well Child Clinic at Madigan Army Medical Center (Dr Elizabeth Hasert and colleagues), Duke Children's Primary Care (Dr Elizabeth Landolfo and colleagues), and Durham Pediatrics (Dr Martha Gagliano and colleagues). We also thank our research nurses in this study (Susan Chambers, Lynn Harrington, Diane Kinnunen, Laurel Laux, Beth Patterson, Lisa Pulley, and Leslie Walker) and the participating families and their children.


   FOOTNOTES
 
Accepted Apr 11, 2006.

Address correspondence to Janet Englund, MD, Pediatric ID, Children's Hospital and Regional Medical Center, 4800 Sand Point Way, NE #W8851, Seattle, WA 98105. E-mail: janet.englund{at}seattlechildrens.org

Financial Disclosure: This study was funded by an unrestricted grant from Sanofi Pasteur, the vaccine division of the Sanofi-Aventis Group, Swiftwater, PA. Dr Englund received research support from Sanofi Pasteur and MedImmune; is a consultant for Sanofi Pasteur, Solvay Pharmaceuticals, and Arrow, Inc; and is a paid speaker for Sanofi Pasteur and MedImmune. Dr Walter is a member of the speaker's bureau of Sanofi Pasteur. Dr Monto has received research support from Sanofi-Aventis. Dr Neuzil has received research support from Sanofi Pasteur and MedImmune, makers of influenza vaccines, and Merck, Inc.

This work was presented in part at the 43rd Annual Meeting of the Infectious Diseases Society of America; October 6-9, 2005; San Francisco, CA.


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 METHODS
 RESULTS
 DISCUSSION
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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics




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