Compliance With the Recommendations for 2 Doses of Trivalent Inactivated Influenza Vaccine in Children Less Than 9 Years of Age Receiving Influenza Vaccine for the First Time: A Vaccine Safety Datalink Study
OBJECTIVES. Children <9 years of age do not respond optimally to a first dose of trivalent inactivated influenza vaccine, and so 2 doses of trivalent inactivated influenza vaccine are recommended for children <9 years of age who are being vaccinated for the first time. We conducted a population-based retrospective cohort study to evaluate compliance with the 2-dose trivalent inactivated influenza vaccine recommendations.
POPULATION AND SETTING. We evaluated 125928 children 6 months through 8 years of age who were enrolled in health maintenance organizations in the United States participating in the Vaccine Safety Datalink project and who received their first dose of trivalent inactivated influenza vaccine in the 2001–2002, 2002–2003, or 2003–2004 influenza seasons.
RESULTS. Compliance with the 2 dose recommendations varied by age group and influenza season. Among children 6 to 23 months of age, the proportion of first-vaccinated children who received a second vaccination was 44% in 2001–2002, 54% in 2002–2003, and 29% in 2003–2004. Among children 2 to 8 years of age, the corresponding proportions were 15%, 24%, and 12%, respectively. In all seasons, compliance with the second vaccination was highest in children first vaccinated by mid-November.
CONCLUSIONS. The majority of children who received their first dose of trivalent inactivated influenza vaccine did not complete the 2-dose series. The recently expanded recommendation for universal vaccination of children 6 to 59 months of age and their household contacts will substantially increase the number of children targeted for a first influenza vaccination. Noncompliance with the 2-dose trivalent inactivated influenza vaccine series may be associated with suboptimal protection against infection, which may impact the magnitude of the direct and indirect benefits achieved by the vaccination program.
Children <2 years of age and older children with asthma or other chronic medical conditions are at increased risk of hospitalization during influenza season compared with healthy older children and young adults.1,2 Since 2004, influenza vaccination has been recommended for all children 6 to 23 months of age and for older children with high-risk medical conditions or who are household contacts of children <2 years of age.3 Those recommendations have been expanded recently to include children 6 to 59 months of age and their household contacts.4
Children who have not been exposed previously to influenza viruses, either as a consequence of vaccination or natural infection, do not respond optimally to a single dose of trivalent inactivated influenza vaccine (TIV).5–7 In children 6 months through 8 years of age, a second influenza vaccination is associated with a significant increase in the proportion of children achieving a hemagglutination-inhibition (HAI) antibody titer of ≥32, a level that is generally correlated with protection.5,7 In addition, the results of an observational study suggest that, among young children receiving TIV for the first time, a higher level of protection against influenza-like illness may be achieved with administration of the second vaccination.8 These data support the longstanding recommendation that all children <9 years of age who are receiving TIV vaccine for the first time should be given 2 doses of vaccine administered ≥4 weeks apart.3
To estimate compliance with the 2-dose influenza vaccine recommendations, we conducted a population-based assessment of children 6 months through 8 years of age receiving their first influenza vaccination for the 2001–2002, 2002–2003, and 2003–2004 influenza seasons. The study population included children in the 8 health maintenance organizations (HMOs) participating in the Centers for Disease Control and Prevention-sponsored Vaccine Safety Datalink project,9 a population that represents ∼3% of all children in the United States.
The study cohorts of influenza vaccine naïve children 6 through 8 years of age were identified from the Vaccine Safety Datalink population. The Vaccine Safety Datalink is a Centers for Disease Control and Prevention-sponsored project that includes 8 HMOs in the United States with administrative data systems recording information on demographics, enrollment, vaccinations, and International Classification of Diseases, Ninth Revision, Clinical Modification, codes assigned to medical encounters.9
Each study cohort included children who were 6 months through 8 years of age as of October 1 of the study season and who had no previous record of influenza vaccination. To ensure complete identification of previous influenza vaccinations, children ≥14 months of age as of October 1 were required to have been continuously enrolled in the HMO since ≥5 months of age. Five months of age was chosen as the lower cut point to capture children who received an influenza vaccine before the recommended 6 months of age. Each study cohort was further restricted to children who remained enrolled in the HMO from October 1 through March 31 to allow ascertainment of all of the influenza vaccines administered during the study season.
Each participating HMO has a computerized immunization registry, but for 3 of the 8 HMOs, vaccination information did not extend back far enough to allow assessment of lifetime vaccination history for older children. For those HMOs, the study cohorts for each study season were restricted to children who were young enough to have lifetime vaccination history recorded. The other 5 HMOs had vaccination information available for a sufficient duration to allow assessment of previous vaccinations for children through 8 age years of age. Of those 5, one HMO could not contribute data for the last study season.
Analyses of the proportion of cohort members receiving a first influenza vaccine and the proportion completing the 2-dose series were based on data from all 8 of the HMOs. Analyses of absolute counts of influenza vaccines given by week and by study season were restricted to the 4 HMOs that provided data for all of the age groups and for all 3 study seasons.
In the Vaccine Safety Datalink, study data sets that include information from the HMO administrative data systems are created at each HMO and stored locally at each site. The data sets are formatted to common specifications to ensure that data extraction programs can be generalized across HMOs. For this study, a uniform data extraction program was submitted over a secure system and run against the data sets at each HMO. The program generated summary data tables that included aggregate information, such as vaccine coverage by age group and year. Individual-level data were not collected.
Human subjects review committee approval for creation of the Vaccine Safety Datalink project data sets, and participation in the overall project was obtained by each HMO. Because individual level data were not collected, additional approval specifically for this study not required by all of the HMO institutional review committees. When required, institutional review board approval for this study was obtained.
The number of previously influenza vaccine-naïve children 6 months through 8 years of age included the study cohort was 325929 in 2001–2002, 328452 in 2002–2003, and 293312 in 2003–2004 (a season that did not include 1 of the 8 HMOs). Children 6 to 23 months of age accounted for ∼32% of the study population in each of the 3 study years. Across the study period, 125928 children received a first TIV, and the proportion of previously vaccine-naïve children who received their first TIV increased from 5% in 2001–2002 to 12% in 2002–2003 to 23% in 2003–2004. In evaluating trends by age group over time, the largest increases in the proportion of children receiving a first influenza vaccine were among those <24 months of age; however, vaccination rates increased in all of the age groups (Fig 1). In children 6 to 23 months of age, there was a ninefold increase (3%–29%) in first vaccination coverage from 2001–2002 through 2003–2004, and in children 2 through 8 years of age there was a threefold increase (6%–20%) over that period.
Among children who received a first TIV, the proportion who completed the 2-dose series was highest for children 6 to 11 months of age and then decreased with age (Fig 2). Compliance with the second dose recommendation improved from 2001–2002 to 2002–2003 but then decreased in 2003–2004. Among children 6 to 23 months of age, the proportion of first-vaccinated children who received a second vaccination was 44% in 2001–2002, 54% in 2002–2003, and 29% in 2003–2004. Among children 2 through 8 years of age, the corresponding proportions were 15%, 24%, and 12%, respectively.
In the analysis restricted to the 4 HMOs that provided data for all of the age groups and for all 3 study seasons, the number and temporal pattern of administration of first influenza vaccinations varied by study season (Fig 3). In 2003–2004, there was a bimodal pattern, with a second, large peak of vaccinations in week 49 of the year for both children 6 to 23 months of age and for older children (data not shown).
Among all of the participating HMOs in every season, compliance with the second influenza vaccination was correlated with the timing of administration of the first dose, and compliance with the second dose was highest for children who received their first vaccination before week 46 (approximately mid-November; Fig 4). In the 3 influenza seasons evaluated, very few vaccinations were given before week 40 (approximately the last week in September), and so compliance with the second dose among children vaccinated before that time could not be assessed. Among children 6 to 23 months of age, compliance with the second dose was lowest in 2003–2004, regardless of the week of administration of the first vaccination. Similar findings were documented for older children (data not shown). Ideally, second vaccinations would be given before the onset of the influenza season, which can begin in late November or early December. Among children 6 months through 8 years of age, the cumulative proportion of second influenza vaccinations administered by week 48 and by week 52 was 2% and 31% for 2001–2002, 16% and 63% for 2002–2003, and 24% and 74% for 2003–2004.
Influenza vaccination has long been recommended for children ≥6 months with certain chronic medical conditions, such as asthma. Beginning in 2002, influenza vaccination of healthy children 6 to 23 months of age was encouraged when feasible,10 and in 2004, influenza vaccination was formally recommended for all children 6 to 23 months of age.3 The recommendations for the 2006–2007 season are further expanded to include vaccination of all children 6 to 59 months of age and their household contacts.4 Implementation of these recommendations will substantially increase the number of children <9 years of age receiving influenza vaccine for the first time.
In this assessment of 125928 children <9 years of age receiving a first TIV, we found a suboptimal level of compliance with the recommendations for 2 doses of influenza vaccine. In 2001–2002 and 2002–2003, only ∼50% of children 6 to 23 months of age who received a first vaccination were given the recommended second dose, and compliance decreased to 29% in 2003–2004. Compliance with the second dose was lower in older children, and, for 2 of the 3 seasons studied, only ∼1 in 6 children 2 to 8 years of age who received a first vaccination completed the 2-dose series. Many of the children who received a second dose were not fully vaccinated until January or later.
Coincident with the initiation of the permissive recommendations for infant vaccination for the 2002–2003 season, we observed a substantial increase in influenza vaccination coverage of the targeted age group of children 6 through 23 months of age, which increased further in 2003–2004. In 2003–2004, there was also a considerable increase in vaccination coverage of previously unvaccinated children 2 through 8 years of age. This may, to some extent, represent compliance with the recommendation to vaccinate children who are household contacts of infants <2 years of age or possibly a spillover effect from the increased emphasis on prevention of influenza infection in children. However, the 2003–2004 influenza season was unusual in that influenza activity began earlier than in most seasons, and publicity in mid-November surrounding reports of influenza-associated deaths in children led to a greatly increased demand for influenza vaccine.11,12 This phenomenon likely accounted for the large second peak of first vaccinations given on week 49, and the subsequent vaccine shortage may have decreased compliance with administration of second vaccinations in that year.
Our study population was restricted to children enrolled in HMOs, and so it is possible that our results are not generalizable to other populations, such as medically underserved groups. Our season-specific estimates of influenza vaccination coverage are, however, consistent with those obtained from the National Immunization Survey11,13 for children 6 through 23 months of age and with coverage estimates reported from other clinical settings.12,14 The National Immunization Survey data indicate that 7% of children 6 through 23 months of age received ≥1 influenza vaccination in 2002–2003 and that 59% of those children were fully vaccinated. As with our data, in 2003–2004 the vaccine coverage estimate for 6- to 23-month-olds was higher, 17%, but the proportion fully vaccinated was lower, 42%. Published information from one of the Vaccine Safety Datalink HMOs15 and unpublished data from another (L.A.J., unpublished data, 2006) indicate that vaccination coverage of 6- to 23-month-old children continued to increase from 2003-2004 to 2004-2005, but coverage in older children decreased over that period.
In infants, the antibody response to a first TIV is poor, and the proportion achieving antibody titers generally correlated with clinical protection increases substantially with a second vaccination. In a prospective assessment of the immunogenicity of 1 vs 2 doses of TIV in children 6 through 23 months of age, the proportion achieving an HAI titer of ≥32 increased from 16% after the first vaccination to 78% after the second vaccination for the A/H1N1 antigen, from 46% to 89% for the A/H3N2 antigen, and from 8% to 52% for the B antigen.5 Similar benefits of a second dose of TIV have also been documented in older children. In a recent Vaccine Safety Datalink study of previously unvaccinated children 5 through 8 years of age, the proportion of children achieving an HAI titer of ≥40 increased from 67% after 1 dose to 93% after 2 doses for the A/H1N1 antigen, from 92% to 97% for the H3N2 antigen, and from 42% to 64% for the B antigen.7
Delivery of 2 doses of influenza vaccine to previously vaccine-naïve children is, therefore, associated with higher antibody levels but is logistically challenging, especially for toddlers and school-aged children who encounter the health care system less frequently than infants. Alternate strategies to improve compliance could potentially include the use of live attenuated influenza vaccine, which is currently approved only for healthy persons 5 to 49 years of age but has been evaluated in younger children. In a randomized, placebo-controlled trial, a single dose of trivalent live attenuate vaccine was ∼90% effective against culture-proven H3N2 and B influenza infection in children 15 to 71 months of age, most of whom were seronegative before vaccination.16 It is, therefore, possible that a single dose of live attenuated vaccine may offer advantages over a single dose of TIV in vaccine-naïve children <9 years of age.
Another strategy that has been evaluated involves administration of a first dose of TIV in the spring (using vaccine remaining from the previous season) followed by delivery of a single dose (of the new vaccine formulation) in the fall. Two studies evaluating this strategy in 6- to 23-month-old children have found that antibody levels in infants who received a dose in the spring followed by a dose in the fall were comparable to levels after administration of 2 doses in the fall if the vaccine antigens did not change between the spring and fall vaccines.5,17 If the vaccine antigens changed, as is usually the case, then the immune response to the new antigens in the fall vaccine was lower in the spring/fall group than in the fall/fall group.17 However, it is possible that the less optimal immunogenicity in the spring vaccination strategy would be balanced by a larger proportion of children achieving compliance with the 2-dose schedule before the onset of influenza season. In other words, a dose in the spring followed by a dose in the fall may be preferable to receipt of a single dose in the fall, but the relative advantage of this strategy would depend on the magnitude of the difference in compliance with a second dose between the 2 strategies.
Because children <9 years of age receiving TIV for the first time require 2 doses for an optimal HAI response to the 3 influenza vaccine strains, poor compliance with the 2-dose TIV recommendations could potentially influence the magnitude of the public health benefit of the vaccination program. Children who receive only a first vaccination may not be adequately protected from influenza infection and associated complications, and vaccinated children with breakthrough infection serve as sources of viral transmission to their household contacts and the broader community. We found that the highest compliance with the 2-dose series was among children given a first vaccination before mid-November. This reinforces the recommendations to target previously unvaccinated children <9 years of age for early vaccination, in September if possible.18 There were delays in influenza vaccine availability for the 2001-2002 season, which may have influenced vaccination coverage.19 Compliance with the 2-dose vaccination series may be better in years in which an adequate supply of vaccine is available early, and compliance may be further improved by education of parents and health care providers regarding the importance of the second dose of influenza vaccine in children <9 years of age receiving influenza vaccine for the first time.
This study was supported by the Vaccine Safety Datalink contract with America's Health Insurance Plans, funded by the Centers for Disease Control and Prevention.
- Accepted July 11, 2006.
- Address correspondence to Lisa Jackson, MD, MPH, 1730 Minor Ave, Suite 1600, Seattle, WA 98101. E-mail:
Financial Disclosure: Dr Jackson has received research funding from GlaxoSmithKline and Novartis Vaccines. Dr Black has received research funding from MedImmune and Sanofi Pasteur. Dr Marcy is a consultant to Merck, GlaxoSmithKline, MedImmune, Sanof-Pasteur, and Abbott. Dr Nordin has received research funding from Sanofi-Pasteur.
- ↵Neuzil KM, Zhu Y, Griffin MR, Edwards KM, et al. Burden of interpandemic influenza in children younger than 5 years: a 25-year prospective study. J Infect Dis.2002;185 :147– 152
- ↵Englund JA, Walter EB, Fairchok MP, Monto AS, Neuzil KM. A comparison of 2 influenza vaccine schedules in 6- to 23-month-old children. Pediatrics.2005;115 :1039– 1047
- ↵Neuzil KM, Jackson LA, Nelson JC, et al. Immunogenicity and reactogenicity of one vs two doses of trivalent inactivated influenza vaccine in vaccine-naive 5–8-year-old children. J Infect Dis.2006; In press.
- ↵Ritzwoller DP, Bridges CB, Shetterly S, Yamasaki K, Kolczak M, France EK. Effectiveness of the 2003–2004 influenza vaccine among children 6 months to 8 years of age, with 1 vs 2 doses. Pediatrics.2005;116 :153– 159
- ↵Ma KK, Schaffner W, Colmenares C, Howser J, Jones J, Poehling KA. Influenza vaccinations of young children increased with media coverage in 2003. Pediatrics.2006;117 (2). Available at: www.pediatrics.org/cgi/content/full/117/2/e157
- ↵Santibanez TA, Santoli JM, Bridges CB, Euler GL. Influenza vaccination coverage of children aged 6 to 23 months: the 2002–2003 and 2003–2004 influenza seasons. Pediatrics2006;118 :1167– 1175
- ↵Hemingway CO, Poehling KA. Change in recommendation affects influenza vaccinations among children 6 to 59 months of age. Pediatrics.2004;114 :948– 952
- ↵Walter EB, Neuzil KM, Zhu Y, et al. Influenza vaccine immunogenicity in 6- to 23-month-old children: Are identical antigens necessary for priming? Pediatrics. 2006;118(3). Available at: www.pediatrics.org/cgi/content/full/118/3/e570
- Copyright © 2006 by the American Academy of Pediatrics