Influenza vaccine for young children: Two doses are better than one
Article Outline
Clinical vaccine trials are generally conducted under ideal conditions, with rigorous monitoring, to test whether a particular vaccine will prevent a target infection. Although randomized, controlled clinical trials are the “gold standard” methodology for assessing vaccine efficacy, they have limited ability to accurately predict the performance of a vaccine in clinical practice.1 For example, extending the use of a vaccine from a highly selected clinical trial population to the more general population may lead to lower efficacy than would be predicted from the clinical trial data. In contrast, using the vaccine on a broader level may lead to public health benefits that exceed clinical trial expectations. As an example of this effect, the universal immunization of all young children in the United States with the −7-valent pneumococcal conjugate vaccine has led to significant indirect effects, with declines in invasive pneumococcal disease observed in all age groups.2
See related article, p 755
“Effectiveness” studies are usually conducted after the introduction of vaccine into a population and aim to measure the net balance of benefits and adverse effects observed when a vaccine is applied routinely in practice.1 Such studies are particularly important for a disease like influenza, for which attack rates, vaccine match with circulating strain, and timing of vaccination in relationship to disease exposure can vary considerably from year to year. The challenge of conducting effectiveness studies for influenza is that a laboratory diagnosis of the disease is rarely made in clinical practice, and the disease syndrome is nonspecific.3 Therefore, effectiveness studies generally measure the impact of the vaccine against a nonspecific outcome, such as pneumonia, for which influenza would be expected to cause only a portion of cases.
Influenza vaccine was “encouraged” for 6- to 23-month-old children in 2002 and 2003, and recommended in 2004. At the time of that recommendation, clinical trials in children under age 5 years reported efficacies of trivalent inactivated influenza vaccine (TIV) against laboratory-confirmed illness ranging from 0 to 83%.4, 5, 6, 7, 8 In many of these studies, children received only 1 dose of TIV, not the 2-dose schedule recommended in vaccine-naive children under age 9 years.4 In the only randomized controlled trial to date targeting children age 6 to 23 months, a 2-dose regimen of TIV proved 66% efficacious against culture-positive influenza in the first year but demonstrated no efficacy in the second year, when influenza attack rates were low (< 5%) in both the placebo and vaccine groups.8 The efficacy estimates in young children during the first year of the trial were similar to those from the single published randomized controlled trial of TIV in elderly adults. In that trial, TIV was associated with a 50% reduction in laboratory-proven influenza and a 53% reduction in clinical influenza in vaccinated persons.9
Effectiveness studies are now being published that describe how TIV is performing in children under age 2 years in the “real world.” A retrospective study conducted during the 2003–2004 season in more than 5000 children age 6 to 23 months enrolled in a Colorado Health Maintenance Organization demonstrated an effectiveness of 49% for fully vaccinated children against clinically defined pneumonia and influenza seen in the outpatient and emergency room settings. As expected, the effectiveness was lower (25%) for the less-specific clinical outcome of influenza-like illness. Importantly, this study demonstrated no effectiveness for either outcome in 6- to 23-month-old children who received only 1 dose of TIV.10
The study by Allison et al11 reported in this issue of The Journal, also conducted during the 2003-2004 season in Colorado, included healthy children age 6 to 21 months enrolled in 5 private pediatric practices in Denver. Similar to the earlier study, the primary outcomes were ICD-9–defined outpatient visits for influenza-like illness and for pneumonia and influenza during the influenza season. In contrast to the earlier study, this study included only healthy children, emergency room visits were not included in the primary outcome, and the influenza season was longer. The overall effectiveness for fully vaccinated children was higher in the current study than in the earlier study: 69% for influenza-like illness and 87% for pneumonia and influenza. Similar to the earlier study, a single vaccination conferred no clinical protection against either outcome. Immunogenicity data support that a second dose of TIV significantly improves the antibody response in this age group, regardless of when it is given.12, 13, 14, 15
Currently, children who receive 1 dose of TIV in a previous season are recommended to receive only 1 dose in the current season. Allison and colleagues were able to divide the fully vaccinated children into 2 groups, based on timing of vaccination. Somewhat surprisingly, effectiveness for influenza-like illness was significantly higher in the group that received 2 doses in the same season than in the group that received 2 doses in consecutive seasons (82% vs 62%). This finding is in contrast to randomized controlled trial data indicating a similar antibody response between 2 doses of identical TIV given in different seasons and 2 doses given in the same season.13, 14, 15 However, the impact of a vaccine in a population depends on both individual protection and vaccine coverage levels. In 2003-2004, children who received 1 dose of TIV in the previous season were fully vaccinated sooner than children who required 2 doses at the start of the season.13 The benefit of fewer children entering the season with only 1 dose of TIV, and its demonstrated lack of effectiveness, may outweigh the relatively small effectiveness benefit of delivering both doses in the same season.
Both recent effectiveness studies were done in a single season, 2003-2004, in which an H3N2 strain predominated and in which the vaccine strains from the previous year were identical to the vaccine strains from the current year. Further effectiveness studies are needed to determine the relative benefits and optimal timing of TIV delivery during years in which influenza B and H1N1 are prevalent, and to evaluate the performance of the 2 dosage schedules in consecutive seasons in years when TIV antigens change.
The live-attenuated nasal spray influenza vaccine (LAIV) has demonstrated high efficacy in young children even after a single dose.16 However, LAIV is not yet licensed for children under age 5 years, and the final decision on whether to license or recommend this vaccine for young children will depend on the cumulative assessment of benefit and risk.
The current effectiveness study adds to a growing body of evidence demonstrating clear benefits of a 2-dose TIV regimen in 6- to 23-month-old children. Pediatric health care providers should strive to deliver 2 doses of TIV to all young children receiving the vaccine for the first time. The best approach for young children who received 1 dose in the previous influenza season is uncertain. Given the limited evidence and the challenges in communicating and implementing vaccine schedule changes, the Centers for Disease Control’s Advisory Committee on Immunization Practices decided to maintain the current recommendation to administer only 1 dose of TIV to those children who received a dose in the previous season.4 Practitioners should also remind family members and other close contacts to receive TIV, to help reduce transmission of influenza to vulnerable infants and young children.4
References
- . Evaluating new vaccines for the developing world: efficacy or effectiveness?. JAMA. 1996;275:390–397
- . Direct and indirect effects of routine vaccination of children with 7-valent pneumococcal conjugate vaccine on incidence of invasive pneumococcal disease. MMWR Morb Mortal Weekly Rep. 2005;54:893–897
- The underrecognized burden of influenza in young children. N Engl J Med. 2006;355:31–40
- . Prevention and control of influenza. MMWR Morb Mortal Weekly Rep. 2006;55(RR10):1–42
- . Efficacy of inactivated and cold-adapted vaccines against influenza A infection, 1985 to 1990: the pediatric experience. Pediatr Infect Dis J. 2001;20:733–740
- . Influenza A vaccine decreases the incidence of otitis media in 6- to 30-month-old children in day care. Arch Pediatr Adolesc Med. 1995;149:1113–1117
- . Influenza vaccination in the prevention of acute otitis media in children. Am J Dis Child. 1991;145:445–448
- Efficacy of inactivated influenza vaccine in preventing acute otitis media in young children. JAMA. 2003;290:1608–1616
- . The efficacy of influenza vaccination in elderly individuals: a randomized double-blind placebo-controlled trial. JAMA. 1994;272:1661–1665
- . 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
- Influenza vaccine effectiveness in healthy 6- to 21-month-old children during the 2003-2004 season. J Pediatr. 2006;149:755
- . Trials of A/New Jersey/76 virus vaccine in normal children: an overview of age-related antigenicity and reactogenicity. J Infect Dis. 1977;136(suppl):S731–S741
- . A comparison of two influenza vaccine schedules in 6- to 23-month-old children. Pediatrics. 2005;115:1039–1047
- . Immunization with trivalent inactivated influenza vaccine in partially immunized toddlers. Pediatrics. 2006;3:e579–e585
- Influenza vaccine immunogenicity in 6- to −23-month-old children: are identical antigens necessary for priming?. Pediatrics. 2006;3:e570–e578
- The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine in children. N Engl J Med. 1998;338:1405–1412
PII: S0022-3476(06)00880-8
doi:10.1016/j.jpeds.2006.09.002
© 2006 Mosby, Inc. All rights reserved.
