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Influenza Vaccine Immunogenicity in 6- to 23-Month-Old Children: Are Identical Antigens Necessary for Priming?

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

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
OBJECTIVES. Immunoprophylaxis with influenza vaccine is the primary method for reducing the effect of influenza on children, and inactivated influenza vaccine has been shown to be safe and effective in children. The Advisory Committee on Immunization Practices recommends that children 6 to 23 months of age who are receiving trivalent inactivated influenza vaccine for the first time be given 2 doses; however, delivering 2 doses of trivalent inactivated influenza vaccine 4 weeks apart each fall can be logistically challenging. We evaluated an alternate spring dosing schedule to assess whether a spring dose of trivalent inactivated influenza vaccine was capable of "priming" the immune response to a fall dose of trivalent inactivated influenza vaccine containing 2 different antigens.

PATIENTS AND METHODS. Healthy children born between November 1, 2002, and December 31, 2003, were recruited in the spring and randomly assigned to either the alternate spring schedule or standard fall schedule. The 2003–2004 licensed trivalent inactivated influenza vaccine was administered in the spring; the fall 2004–2005 vaccine had the same A/H1N1 antigen but contained drifted A/H3N2 antigen and B antigen with a major change in strain lineage. Reactogenicity was assessed by parental diaries and telephone surveillance. Blood was obtained after the second dose of trivalent inactivated influenza vaccine for all of the children and after the first dose of trivalent inactivated influenza vaccine in the fall group. The primary outcome of this study was to demonstrate noninferiority of the antibody response after a spring-fall dosing schedule compared with the standard fall dosing schedule. Noninferiority was based on the proportion of subjects in each group achieving a hemagglutination-inhibition antibody titer of 1:32 after vaccination to 2 of the 3 antigens (H1N2, H3N2, and B) contained in the 2004–2005 vaccine. For each antigen, the antibody response was proposed to be noninferior if, within the upper bound of 95% confidence interval, there was <15% difference between the proportion of children in the fall and spring groups with postvaccination titers 1:32.

RESULTS. A total of 468 children were randomly assigned to either the spring (n = 233) or fall (n = 235) trivalent inactivated influenza vaccine schedule. Excellent response rates to A/H1N1, as measured by antibody levels 1:32, were noted in both the spring (86%) and fall groups (93%). The A/H1N1 response rate of the spring group was noninferior to that of the fall group. Noninferiority of the spring schedule was not met with respect to the other 2 influenza antigens: for A/H3N2 the response was 70% in the spring group versus 83% for the fall group, and the response to B was 39% in the spring group versus 88% for the fall group. After 2 doses of vaccine, the geometric mean antibody titers also were less robust in the spring group for both A/H3N2 and B antigens. For each of the 3 vaccine antigens, the respective geometric mean antibody titers for the spring group versus the fall group were: A/H1N1, 79.5 ± 3.3 and 91.9 ± 2.6; A/H3N2, 57.1 ± 4.1 and 77.8 ± 3.7; and B, 18.0 ± 2.4 and 61.6 ± 2.5. However, a significantly higher proportion of children in the spring group achieved potentially protective levels of antibody to all 3 antigens after their first fall dose of trivalent inactivated influenza vaccine than children in the fall group after receiving their first fall dose. For influenza A/H1N1, there was an antibody level 1:32 in 86% of children in the spring group versus 55% of children in the fall group. Likewise, for influenza A/H3N2, 70% of children in the spring group and 47% of children in the fall group had antibody levels >1:32; for influenza B, the proportions were 39% of children in the spring group and 16% of children in the fall group. Reactogenicity after trivalent inactivated influenza vaccine in both groups of children was minimal and did not differ by dose.

CONCLUSIONS. Although the immune response to the identical A/H1N1 vaccine antigen was similar in both groups, priming with different A/H3N2 antigens and B antigens in the spring produced a lower immune response to both antigens than that shown in children who received 2 doses of the same vaccine in the fall. However, 70% of children in the spring group had a protective response to the H3N2 antigen after 2 doses. Initiating influenza immunization in the spring was superior to 1 dose of trivalent inactivated influenza vaccine in the fall. The goal of delivering 2 doses of influenza vaccine a month apart to vaccine-naive children within the narrow flu vaccination season is a challenge not yet met; thus far, only about half of children aged 6 to 23 months of age are receiving influenza vaccine. By using the spring schedule, we were able to administer 2 doses of trivalent inactivated influenza vaccine to a higher proportion of children earlier in the influenza vaccination season. In years when there is an ample supply of trivalent inactivated influenza vaccine, and vaccine remains at the end of the season, priming influenza vaccine-naive infants with a spring dose will lead to the earlier protection of a higher proportion of infants in the fall. This strategy may be particularly advantageous when there is an early start to an influenza season as occurred in the fall of 2003. A priming dose of influenza vaccine in the spring may also offer other advantages. Many vaccine-naive children may miss the second dose of fall trivalent inactivated influenza vaccine because of vaccine shortages or for other reasons, such as the potential implementation of new antigens at a late date. Even with seasonal changes in influenza vaccine antigens, by giving a springtime dose of trivalent inactivated influenza vaccine, such children would be more protected against influenza than would children who were only able to receive 1 dose in the fall. In summary, our data suggest that identical influenza antigens are not necessary for priming vaccine-naive children and that innovative uses of influenza vaccine, such as a springtime dose of vaccine, could assist in earlier and more complete immunization of young children.

Key Words: inactivated influenza vaccine • children • immunogenicity

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

Healthy children <2 years of age are at a substantially increased risk for influenza-related hospitalization.^1–5 Immunoprophylaxis with influenza vaccine is the primary method for reducing the effect of influenza on children, and inactivated influenza vaccine has been shown to be safe and effective in children.^6–11 Consequently, the Advisory Committee on Immunization Practices (ACIP) recommended that, beginning in fall 2004, children aged 6 to 23 months receive trivalent inactivated influenza vaccine (TIV).^11,12 For influenza vaccine-naive children in this age group, 2 doses of vaccine are necessary to achieve a protective response.^11–13 However, delivering 2 doses of vaccine to all previously unvaccinated 6- to 23-month-old children between September and November is logistically challenging. For example, in the fall of 2003, the proportion of children aged 6 to 23 months who received 1 dose of vaccine was nearly twice that of children receiving 2 doses of vaccine by December 7 (27% vs 15%).¹⁴ Partial immunization with influenza vaccine frequently occurs in vaccine-naive high-risk children as well.¹⁵ As an alternative to delivering 2 doses of TIV in the fall, we sought to learn whether a springtime dose of the TIV from the previous year could prime infants sufficiently so that only a single dose of TIV would be required in the fall.

We reported previously that antibody responses and the rates of reactogenicity were similar in 6- to 23-month-old children receiving the standard 2-dose regimen of TIV 1 month apart in the fall versus an alternative regimen in which a spring dose of TIV was followed in 6 months by a fall dose of TIV containing identical influenza antigens.¹³ In the current study, we examined whether the administration of the influenza vaccine from the previous year for the first dose in the spring would adequately prime for the second fall dose when 2 of the 3 TIV vaccine antigens had changed. Thus, the primary goal of our study was to compare the immunogenicity of 2 doses of TIV with different A/H3N2 and B vaccine antigens administered in a spring-fall schedule with the immunogenicity of 2 doses of TIV containing the same vaccine antigens administered in a standard fall schedule.

	METHODS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Study Design
This study was a prospective, randomized, open-label clinical trial conducted at 3 clinics near Seattle, WA (Skagit Valley Pediatrics, Madigan Army Medical Center, and Virginia Mason Medical Center), 3 pediatric practices in Durham, NC (Duke Children's Primary Care, Durham Pediatrics, and Regional Pediatrics), and 1 pediatric practice in Chapel Hill, NC (Chapel Hill Pediatrics). All of the children were enrolled between April 1, 2004, and June 30, 2004. The study protocol was approved by each institutional review board, and informed consent was obtained from a parent or guardian. Site-specific randomization was allocated by an investigator not involved in patient recruitment or patient care and performed in blocks of 10 by using random-number tables. In this open-label trial, children were randomly assigned to either the "spring" or "fall" group. Those randomly assigned to the spring group received their first dose of 2003–2004 TIV in the spring and 2 doses of 2004–2005 TIV in the fall (a total of 3 doses), whereas children in the fall group received no vaccine in the spring and 2 doses of 2004–2005 TIV in the fall (Table 1). Thus, all of the children received 2 doses of 2004–2005 TIV in the fall. To evaluate the primary outcome, blood samples were obtained 4 weeks after the second dose of influenza vaccine in both groups. Blood samples were also taken before the first dose of vaccine in the spring group and 4 weeks after the first dose of vaccine in the fall group.

Secondary study objectives included the following: determining the children's immune status against antigens contained in the 2004–2005 TIV before any dose of TIV was given (spring group only), characterizing the seroconversion rate in children receiving 2 doses of vaccine separated by 6 months (spring group only), comparing the proportion of seroresponders after 1 injection (fall group) versus 2 injections (fall group and spring group), and comparing reactogenicity between the 2 groups.

Population
Healthy children born between November 1, 2002, and December 31, 2003, were eligible for enrollment. Inclusion criteria included parental informed consent, availability for all of the study visits, and telephone access. Subjects with acute febrile illnesses were eligible for enrollment, but immunization was deferred for 24 hours after the last temperature of >38°C axillary. Exclusion criteria included birth before 36 weeks' gestation, previous receipt of influenza vaccine of any kind, 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, 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, and rubella vaccine or varicella vaccine) 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.¹²

Children were referred for inclusion in the study by their health care practitioners. Documented medical reasons for exclusion from the study were noted for 8 children, including children with the following conditions: cleft lip and palate with impending surgical procedure, sleep apnea, Down syndrome, perinatal stroke and esophageal atresia, pulmonary hypertension, biliary atresia, lymphatic malformation and severe gastroesophageal reflux with gastrostomy and tracheostomy, and a complicated hemangioma. Children were not excluded from participation in the study on the basis of their prevaccination titer.

Vaccine
Single lots of licensed 2003–2004 and 2004–2005 trivalent inactivated preservative-free influenza vaccine (TIV) provided by Aventis-Pasteur (Swiftwater, PA) were used throughout the trial. The 2003–2004 TIV contained A/New Caledonia/20/99 (H1N1), A/Panama/2007/99 (H3N2), and B/ HongKong/1434/2002 antigens, whereas the 2004–2005 TIV contained the H1N1, A/Wyoming/03/2003 (H3N2), and B/Jiangsu/10/2003 strains. Vaccine was prepackaged in 0.25-mL syringes and administered intramuscularly in the thigh with a 25-gauge needle using standard sterile technique. Each 0.25-mL dose of vaccine contained a total of 22.5 µg of hemagglutinin (HA), representing 7.5 µg of HA per strain of influenza antigen.

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 (H1N1, H3N2, and B/Jiangsu/10/2003, ether extracted). Sera were treated with receptor-destroying enzyme (Denke Seiken Co Ltd, Tokyo, Japan). To inactivate the receptor-destroying enzyme, sera were heated to 56°C for 30 minutes. Twenty-five microliters of diluted sera were incubated with an equal volume of antigen diluted to contain 4-8 HA units, and 50 µL of a 0.5% suspension of chicken red blood cells were then added to the mixture. Antibody response was defined as an HAI titer 1:32, which has been correlated with protection against influenza.^16,17

Reactogenicity
Prospective evaluation of reactogenicity was obtained by using a parental diary. 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 any adverse reactions. Reactogenicity data were obtained by using both parental diaries and nurse telephone interviews after all of the study visits, including the enrollment visit. At the enrollment visit, children in the spring group received TIV and may have received concomitant routine childhood immunizations, but children in the fall group received whatever vaccinations were scheduled at that visit. Children in both the spring and fall groups were followed for 5 days after the enrollment visit. By capturing reactogenicity data from children in the fall group who received other pediatric vaccines, reactogenicity from a comparison group not receiving TIV was available for analysis. Parents were again contacted 6 months after the last dose of vaccine to elicit information 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. Vaccination titers 1:32 were considered positive. Seroconversion rate was defined as the number of subjects with a fourfold rise divided by the number of paired preimmunization and post–second-dose subjects. All of the comparisons were done by using a ² test for contingency tables and a t test for continuous variables. There was no adjustment for multiple comparisons. Noninferior tests were done by using StatXact 6.0 (Cytel Corporation, Cambridge, MA), and the remaining analyses were performed by using SAS 9.1 (SAS Institute, Inc, Cary, NC).

	RESULTS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Subjects
Children aged 6 to 23 months were enrolled between April and June 2004. Overall, 468 children were enrolled: 233 in the spring group and 235 in the fall group. We excluded 6 subjects (2 spring and 4 fall) from data analysis, because they either did not receive any study vaccines or did not provide any information about vaccine reactogenicity. Thus, 462 children were included in the final analysis, with 231 in each group (Fig 1). Children in the spring and fall groups were similar with respect to gender and race/ethnicity: female, 53% vs 48%; white, 65% vs 62%; black, 14% vs 16%; and other race/ethnicity, 21% in both groups.

View larger version (20K): [in this window] [in a new window]   FIGURE 1 Follow-up and procedures for children enrolled.

Altogether, 432 children received 2 immunizations (220 spring and 212 fall), and 212 children in the spring group received 3 doses of TIV. Because of the slight variation in the number of subjects with adequate blood samples or returned diaries after each dose of vaccine, the number of subjects analyzed for immunogenicity or reactogenicity at each time point is not identical (Fig 1). An adequate blood sample was obtained from 417 children (214 spring and 203 fall) after the second dose of TIV, and paired blood sample results were available for 404 subjects (205 spring and 199 fall). Reactogenicity data were recorded and analyzed on 1079 immunizations from a total of 1089 doses of TIV.

Based on influenza surveillance in both North Carolina and Washington, influenza disease activity was initially detected in late January 2005, well after the period when study participants were vaccinated. In the spring group, 95% of children received their second dose of vaccine by October 21, 2004, whereas 95% of children in the fall group received their first dose of vaccine by October 13, 2004, and their second dose of vaccine by November 18, 2004.

Immunogenicity
Primary Outcome
For the influenza A/H1N1 antigen, the antibody responses after 2 doses of vaccine were comparable between the spring and fall groups; however, for the A/H3N2 and B antigens, the responses in the spring group were less robust than those in the fall group (Fig 2). Excellent response rates to A/H1N1, as measured by antibody levels 1:32, were noted in both the spring (86%) and fall groups (93%). The A/H1N1 response rate of the spring group was noninferior to that of the fall group (P < .001). Noninferiority of the spring schedule was not met with respect to the other 2 influenza antigens: for A/H3N2, the response was 70% in the spring group versus 83% for the fall group (P = .336), and the response to B was 39% in the spring group versus 88% for the fall group (P = 1.0). After 2 doses of vaccine, the GMTs for antibodies were also less robust in the spring group for both A/H3N2 and B antigens (Fig 3). For each of the 3 vaccine antigens, the respective GMTs for the spring group versus the fall group were: A/H1N1, 79.5 ± 3.3 and 91.9 ± 2.6 (P = .174); A/H3N2, 57.1 ± 4.1 and 77.8 ± 3.7 (P = .022); and B, 18.0 ± 2.4 and 61.6 ± 2.5 (P < .001).

View larger version (20K): [in this window] [in a new window]   FIGURE 2 Seroresponse rate before vaccine (spring group only), after 1 dose of TIV (fall group only), or after 2 doses of TIV in young children receiving the spring or fall regimen.

View larger version (18K): [in this window] [in a new window]   FIGURE 3 HAI antibody titers before administration of vaccine (spring group only), after 1 dose of TIV (fall group only), or after 2 doses of TIV in young children receiving either the spring or standard fall regimen.

In contrast to children at baseline, antibody titers 1:32 to both A/H1N1 and A/H3N2 were noted in approximately half of the children in the fall group after receipt of a single dose of vaccine, whereas antibody titers to influenza B were noted in only 16% of the children (Fig 2). A significant increase in antibody between the first and second dose of TIV was noted for each of the 3 vaccine antigens in the fall group (P < .001 for each antigen). After receiving 2 doses of vaccine, >80% of the children in the fall group had titers 1:32 for each of the 3 vaccine antigens, demonstrating a need for a second dose of vaccine to achieve adequate protections.

A significantly higher proportion of children in the spring group achieved potentially protective levels of antibody to all 3 of the antigens after their first fall dose of TIV than children in the fall group after receiving their first fall dose (Fig 2). For influenza A/H1N1, there was an antibody level 1:32 in 86% of children in the spring group versus 55% of children in the fall group. Likewise, for influenza A/H3N2, 70% of children in the spring group and 47% of children in the fall group had antibody levels >1:32; for influenza B, the proportions were 39% of children in the spring group and 16% of children in the fall group (P < .001 for each antigen).

Reactogenicity
Overall, TIV was well tolerated with relatively low rates of reactions. Moderate-to-severe fever (ie, temperature >38°C axillary) was reported during the first 3 days after 3.8% of the doses of TIV were received. There were 6 episodes (0.6%) of fever >39.5°C noted after receipt of any dose of TIV. Local reactions were also minimal after receipt of TIV. Moderate-to-severe pain and tenderness at the injection site were noted after 4% of doses. Redness was noted after 0.6% of doses and swelling after 0.3% of doses. Other moderate-to-severe symptoms reported after receipt of TIV included: irritability (16%), changes in sleep patterns (11%), vomiting (3%), and change in appetite (4%). Moderate-to-severe fever was twice as common in children who received routine immunizations but no influenza vaccine (fall group at enrollment, 8%) than in children who received TIV either alone or with other concomitant immunizations (4%; P = .021). Reports of irritability after any TIV were comparable to the rates seen in the fall group receiving routine immunizations other than TIV. No serious adverse events were recorded after any dose of vaccine.

There were no significant differences in the rate of moderate and severe reactions reported between the spring and fall groups, with the exception of vomiting after the second dose of TIV. Moderate-to-severe vomiting after a second dose of TIV was reported in 6 children in the fall group and no children in the spring group (P < .04). Rates of moderate-to-severe reactions were comparable after dose 1, dose 2, or dose 3 of vaccine and did not increase after subsequent doses of TIV (Fig 4). In general, rates of moderate-to-severe reactions also did not vary when stratified according to the age of the child (<12 months of age versus 12 months of age). Irritability after receipt of TIV was reported more frequently in children <12 months of age (18.2% vs 12.4%; P = .01).

View larger version (16K): [in this window] [in a new window]   FIGURE 4 Reactogenicity as shown by dose of TIV compared with that of subjects in the fall group not receiving TIV at the enrollment visit. Reactogenicity was assessed for 3 days only and was based on moderate-to-severe symptoms.

	DISCUSSION

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

Our study confirmed that the immune response to the unchanging A/H1N1 antigen was similar between the spring and fall groups. The response verified data from our previous study, which revealed that the time interval between influenza vaccine doses in toddlers receiving the vaccine for the first time does not affect immunogenicity when antigens remain the same.¹³ This finding has been noted with other vaccines, such as hepatitis B, where the timing of antigen administration is not as important as the delivery of sequential doses.^19–21

Although the HAI antibody responses to drifted A/H3N2 after 2 different TIV preparations were less robust in children in the spring group than those of children who received 2 doses of identical A/H3N2 antigen in the fall group, 70% of children in the spring group developed protective levels of antibody to this antigen after receipt of 2 doses of vaccine. The proportion of children in the spring group with serologic protection against A/H3N2 was markedly better than that of the fall group after just a single dose of TIV in the fall. This suggests that the spring A/H3N2 antigen "primed" the immune response to the drifted fall A/H3N2 antigen.

The antibody responses to B antigen were remarkably lower in those children in the spring group, who were primed with a B antigen from a different major lineage, suggesting that priming with a significantly different influenza antigen is not as successful as priming with a closely related antigen. Although previous studies have suggested that, in young children, antibody responses to B antigens after vaccination are lower than responses to A antigens,^10,13 we observed an excellent response to the B antigen in the fall group after 2 doses of the 2004 vaccine. In fact, the B response in children in the spring group who were immunized with different B antigens was actually more similar to the response that we observed in children after 2 doses of antigenically identical 2003 vaccine.¹³ In addition, alternate measures of protection, including determining levels of neutralizing antibody, may provide more sensitive measures of immunity to influenza when compared with measures of HAI antibodies as determined in the current study.²²

Despite the noted increase in antibody over baseline, there was a relatively low proportion of children in the fall group who, after a single dose of vaccine, had an antibody level 1:32 for any of the 3 TIV antigens. These results support previous findings and affirm the ACIP recommendation that 2 doses of TIV are needed in vaccine-naive recipients.^12,13 Furthermore, clinical experience from the 2003–2004 influenza season suggested that TIV was more effective in young children receiving 2 doses of vaccine than in those receiving a single dose of vaccine.¹⁴

Although the immune response was not as robust for the spring regimen as for the fall regimen in our study, the spring approach to vaccination seems to prime well for minor changes in influenza A antigens. If there are minor changes or no changes in vaccine antigens from one season to the next, the spring approach offers a clear advantage for administering influenza vaccine along with routine well-child care visits, obviating the need for additional office visits for influenza immunization. Our results are also consistent with the current ACIP recommendation for administering only a single dose of TIV to children who have received a single dose of TIV in the preceding season.¹²

We believe that our study has some important lessons for the development of vaccines against novel influenza antigens, such as new pandemic strains or even avian influenza. We observed that young vaccine-naive patients require 2 doses of influenza antigen to develop an ideal protective response; likewise, multiple doses of avian influenza vaccine have been required to produce adequate immune responses in adults who have been infected with unrelated, previously circulating influenza strains.²³ As in our vaccine-naive children, immunization with a novel influenza antigen in both adults and children will probably require 2 doses of vaccine. Furthermore, the priming that we observed with a drifted A/H3N2 antigen suggests that vaccination with a prototype avian influenza vaccine might "prime" people who may be subsequently exposed to a slightly different avian influenza virus.

The goal of delivering 2 doses of influenza vaccine a month apart to vaccine-naive children within the narrow flu vaccination season is a challenge not yet met; thus far, only about half of children aged 6 to 23 months of age are receiving influenza vaccine.²⁴ By using the spring schedule, we were able to administer 2 doses of TIV to a higher proportion of children earlier in the influenza vaccination season during 2 successive clinical trials.¹³ In years when there is an ample supply of TIV and vaccine remains at the end of the season, priming influenza vaccine-naive infants with a spring dose will lead to the earlier protection of a higher proportion of infants in the fall. This strategy may be particularly advantageous when there is an early start to an influenza season as occurred in the fall of 2003. A priming dose of influenza vaccine in the spring may also offer other advantages. Many vaccine-naive children may miss the second dose of fall TIV because of vaccine shortages or other reasons, such as the potential implementation of new antigens at a late date. Even with seasonal changes in influenza vaccine antigens, by giving a springtime dose of TIV, such children would be more protected against influenza than would children who were only able to receive 1 dose in the fall.

	CONCLUSIONS

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 
Our data suggest that identical influenza antigens are not necessary for priming vaccine-naive children and that innovative uses of influenza vaccine, such as a springtime dose of vaccine, could assist in earlier and more complete immunization of 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), Durham Pediatrics (Dr James Rouse and colleagues), Regional Pediatrics (Dr Clarence Bailey and colleagues), and Chapel Hill Pediatrics (Dr Kathy Merritt 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), research assistants (Leigh Ellen Floyd and Kathy Chmielewski), and the participating families and their children.

	FOOTNOTES

 
Accepted May 11, 2006.

Address correspondence to Emmanuel B. Walter, MD, MPH, Duke Children's Primary Care, 4020 N Roxboro Rd, Durham, NC 27704. E-mail: walte002{at}mc.duke.edu

Financial Disclosure: This study was funded by an unrestricted grant from Sanofi Pasteur, the vaccine division of the Sanofi-Aventis Group (Swiftwater, PA). Dr Walter is a speaker for; Drs Neuzil, Fairchok, and Monto have received research support from; and Dr Englund has received research support, consulting fees, and honoraria from Sanofi-Aventis Group.

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 (abstracts 63 and 1007).

The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of Defense.

	REFERENCES

TOP ABSTRACT METHODS RESULTS DISCUSSION CONCLUSIONS REFERENCES

 

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