Influenza virus is a major cause of illness among infants and children. Several ecological and population-based surveillance studies have described the excessive burden of influenzal disease in children in the United States and worldwide.1–6 This article discusses the effects of influenza immunization in infants and children..
The Burden of Influenza
Poehling et al. conducted a prospective, population-based surveillance study in children younger than 5 years in three United States counties. Children were enrolled during hospitalizations or outpatient or emergency department visits for acute respiratory tract infections or fever. Influenza was confirmed by culture or polymerase chain reaction assay on nasal and throat swabs, and epidemiological data were collected.4 This study determined that the average annual hospitalization rate associated with influenza during four consecutive seasons was 0.9 per 1000 children. The age-specific rates were 4.5 per 1000 children younger than 6 months, 0.9 per 1000 children 6 to 23 months, and 0.3 per 1000 children 24 to 59 months (see Table 1, page 492).
The burden of influenza disease was also evaluated in the outpatient and emergency department settings during a 2-year surveillance period. There were between 50 and 95 clinic visits and between 6 and 27 emergency department visits for laboratoryconfirmed influenza per 1000 children per year (see Table 2, page 493).
Influenza-associated deaths in children are also reported to the Centers for Disease Control and Prevention (CDC). During the 2003 to 2004 influenza season, 153 children (median age 3 years) died from influenza; 63% were younger than 5 years; and only 33% of the children had underlying conditions. The mortality rate was highest among children younger than 6 months (0.88 per 100,000 children).7 Since that report, influenza death rates have continued to be assessed. The annual number of deaths among children during the last four influenza seasons ranged from 39 during the 2004 to 2005 season to 83 during the 2007 to 2008 season.8
Children are also important disseminators of disease in the community. A study conducted in a U.S. elementary school evaluated the effect of influenza in children. For every 100 school children enrolled during the 37 school days of the influenza season, there were 28 illness episodes and 63 missed school days attributable to influenza. In addition, for every 100 children followed, influenza accounted for an estimated 20 days of work missed by their parents and 22 secondary illness episodes among other family members.9 These data support the substantial role children have in spreading influenza virus to their families and to the community.
Ultimately, immunization is the most effective preventive measure to reduce influenza virus infection and its related morbidity and mortality. Despite a clear call for universal immunization, however, influenza vaccine coverage rates remain suboptimal. Surveys conducted after the 2008 to 2009 influenza season reported influenza vaccine coverage with one dose in children 6 to 23 months was 47.8% (range 34.3% to 60.1%) and with two doses was 28.9% (range 19.8% to 39.7%). Among children 2 to 4 years, coverage with one dose was 27.8% (range 17.3 to 38.1%), and with two doses was 21.8% (range 12.6% to 32.3%). Coverage rates for one and two doses for children 5 to 10 years were 16.3% (range 9.4% to 23.7%), and 12% (range 6.2% to 19.7%), respectively. For children to 11 to 12 years who require only one dose of vaccine, only 12.7% were vaccinated (range 6.6% to 18%), and among children aged 13 to 18 years, only 9.1 % (range 4.8% to 14.5%) were vaccinated.10
Numbers Are Combined Rates for Three Sites in the NVSN. CI Denotes Confidence Interval. Counts Were Weighted for Days of Surveillance and Proportion of Eligible Children Enrolled.4 Copyright © 2006 Massachusetts Medical Society. All Rights Reserved.
Two seasonal influenza vaccines are licensed in the United States for use in children: the trivalent inactivated vaccine (TIV) and the trivalent live attenuated influenza vaccine (LAIV). Both contain a combination of influenza strains predicted to be prevalent in the upcoming influenza season, including strains of type A H1N1 and H3N2 and type B. TIV is administered by intramuscular injection and is approved for use in all children 6 months of age and older, while LAIV is given intranasally and is approved for administration to previously healthy children 2 years and older with no history of asthma. TIV and LAIV vaccines have been demonstrated to be efficacious for the prevention of clinical and laboratory-confirmed seasonal influenza.
Efficacy and Safety of TIV
Several studies have described the efficacy of TIV in children. A randomized, placebo-controlled, comparative efficacy trial of TIV and LAIV for prevention of laboratory-confirmed influenza was conducted at Vanderbilt University between 1985 and 1990 in people 1 to 65 years.11 During the study period, 791 children younger than 16 years received TIV, LAIV, or placebo. TIV had 91.4% and 77.3% vaccine efficacy in preventing culture-positive A H1N1 and H3N2 disease, respectively. Using seroconversion over the influenza season as the study outcome, TIV had an efficacy of 67.1% and 65.5% for H1N1 and H3N2, respectively.12 No statistically significant differences in vaccine efficacy were found between the TIV and LAIV in this study.
A meta-analysis conducted by Manzoli et al.13 reviewed all published randomized clinical studies of TIV for the prevention of influenza-like illness (ILI) and laboratory-confirmed influenza in healthy children. Nineteen randomized clinical studies of TIV, using ILI as the study endpoint, described overall vaccine efficacy to be 36% (95% confidence interval: 31–40%).. Data from 18 trials of TIV using laboratory-confirmed influenza as the study endpoint, determined overall vaccine efficacy to be 67% (51–78%).
Another review14 assessed the efficacy of TIV in younger children, and reported that after two doses of TIV in children younger than 9 years, the efficacy was 63% when laboratory-confirmed influenza was used as the endpoint. Vaccine efficacy increased with age and efficacy data in younger children were limited because of the small sample size of the studies.
Although children younger than 6 months of age are at highest risk for influenza-associated hospitalization, no influenza vaccines are approved for this population. Several studies have been conducted to evaluate the safety and immunogenicity of TIV in young infants. One prospective, open-label study administered two doses of TIV to 42 healthy infants 10 to 22 weeks and followed the infants over two influenza seasons.15
During the first season, they reported postvaccination seroprotective hemagglutination inhibition (HAI) titers > 1:32 in 31.6%, 47.4%, and 21.1% of children for H1N1, H3N2, and B strains, respectively.
During the second season, postvaccination HAI titers > 1:32 were seen in 45.5%, 59.1%, and 0% of subjects for H1N1, H3N2, and B strains, respectively. A more recently published study compared the immunogenicity and safety of TIV in children 2 months of age with those who were 6 months of age.16 Postvaccination HAI titers ≥1:40 were seen in 46% of the younger children when compared with 69% in older children for H1N1; 59% and 79% for H3N2; and 5% and 22% for influenza B, respectively. All comparisons of HAI titers between the two age groups demonstrated statistically significant differences (P < .001), with the antibody titers always higher in the older infants. In the younger infants whose mothers had not received TIV during pregnancy, postvaccination HAI titers ≥ 1:40 were achieved in 70% to H1N1 and in 68% to H3N2. The authors concluded that lower antibody responses were seen in the younger children, likely related to suppression from passively acquired maternal antibody. Safety studies indicated that fewer children in the younger age group had fever within 7 days of vaccine administration when compared with the older children.16 Further studies are needed in young infants to evaluate the efficacy of TIV in this population.
A number of TIV safety studies have been conducted in children. France et al.17 evaluated the risk of hospitalization and outpatient or emergency department visits after 251,600 TIV vaccinations in children up to 18 years. No major adverse events were reported, and the vaccines were well tolerated. In another study, adverse events after administration of TIV alone or TIV plus other vaccines were assessed using the Vaccine Adverse Event Reporting System (VAERS) in children younger than 2 years.18 Of the 166 events reported to the VAERS, 37% occurred after administration of TIV alone and 63% after administration of TIV with one or more concurrent vaccines. The most common adverse events reported were fever (36%); seizures (17%); injection site reactions (17%); unspecified rashes (15%); and urticarial rashes (10%). Eighty-eight percent of the seizure episodes occurred within 2 days of vaccine administration and were accompanied by fever.
The conclusions of this study were that TIV was safe, although limited data were available in the youngest children.18 To address this limitation, a recent retrospective study assessed serious adverse events (SAE) reported to the VAERS between 2003 and 2006 after TIV administration in children 6 to 23 months of age.19 Fever and seizures were the most frequent SAE reported. Therefore, overall TIV appears to be safe and well tolerated in children of all ages.
Copyright © 2006 Massachusetts Medical Society. All Rights Reserved.
Efficacy and Safety of LAIV
Several studies have been published assessing the immunogenicity, efficacy, and safety of LAIV in children. A large, multicenter, double-blind, placebo-controlled trial was conducted among 1,314 children 15 to 71 months in 1998.20 Fourfold serologic rises were noted after LAIV in 61% to 96% of initially seronegative children. Episodes of influenza were significantly less common in vaccine recipients than in placebo recipients, with a vaccine efficacy of 93% (95% CI: 88% to 96%) against culture-confirmed influenza.
A comparative safety and efficacy study of LAIV and TIV was conducted during the 2004 to 2005 influenza season in children 6 to 59 months.21 Children were randomized to receive either LAIV or TIV in a double-blind manner. There were 54.9% fewer cases of cultured-confirmed influenza in the LAIV group than in the TIV recipients (153 vs. 338 cases, P < .001). Wheezing during the first 42 days after immunization was significantly more common after LAIV than TIV among previously unvaccinated children. Also, hospitalization rates within the first 180 days after vaccination for any cause were significantly higher in recipients of LAIV who were 6 to 11 months of age than in the recipients of TIV (P = .002). Because of these findings, LAIV was licensed for administration in children older than 2 years of age without a previous history of wheezing or asthma.
Another placebo-controlled trial of LAIV, evaluating vaccine efficacy and safety during two influenza seasons, was conducted in Asia.22 During the first season, 3,174 children between the ages of 12 and 36 months were randomized to receive either two doses of LAIV or placebo, and during the second year, 2,947 children were re-randomized to receive either one dose of LAIV or placebo. Vaccine efficacy against laboratory-confirmed influenza was 72.9% (95% CI: 62.8% to 80.5%) for antigenically matched influenza subtypes and 70.1% (95% CI: 60.9% to 77.3%) for any influenza strain. During the second year, vaccine efficacy of LAIV against antigenically matched strains was 84.3%; (95% CI: 70.1% to 92.4%) and against any influenza strain was 64.2% (95% CI: 44.2% to 77.3%). In contrast to findings in earlier studies, there was no increase in wheezing episodes reported among LAIV recipients.
An additional recent review analyzed data from three different studies of LAIV conducted in children 2 to 7 years and reported an overall vaccine efficacy of LAIV against matched influenza strains of between 69.2% (95% CI: 52.7, 80.4) to 94.6% (95% CI: 88.6, 97.5). LAIV recipients experienced 52.5% (95% CI: 26.7, 68.7) fewer cases of influenza illness caused by matched strains and 54.4% (95% CI: 41.8, 64.5) fewer cases caused by mismatched strains when compared with TIV recipients.23
Given the concern about the safety of LAIV in patients with asthma, an open-label study was conducted among 2,229 asthmatic children aged 6 to 17 years.24 No significant differences were reported between the LAIV and TIV vaccine groups in the incidence of asthma exacerbations, mean peak expiratory flow rates, asthma symptom scores, or nighttime awakening scores. Rhinorrhea and nasal congestion were more common in the recipients of LAIV, and injection site reactions were reported more often after TIV.
During a 4-year open-label, nonrandomized, community-based trial conducted in Texas, medical records of all children who received LAIV were evaluated for SAEs and healthcare use 6 weeks after vaccination. In the study period, 18,780 doses of LAIV were administered to 11,096 children; only 42 SAEs were reported, and none were attributed to LAIV.25
During one of the study years, a relative risk of 2.85 (95% CI: 1.01–8.03) was noted for wheezing events 15 to 42 days after vaccination in children aged 18 months to 4 years. This higher risk of wheezing was not found during the other study years. Therefore, LAIV is currently licensed for use in children older than 2 years with no underlying health problems. Children with asthma are recommended to receive TIV, not LAIV.
Influenza vaccine recommendations in the United States have changed considerably over the past decade. In 2004, a universal recommendation was issued for all children 6 to 23 months to receive influenza vaccine. In 2006, these universal recommendations were extended to children 24 to 59 months, and in 2008, universal influenza vaccination recommendations were extended to all children between 6 months and 18 years.10 Two doses separated by 1 month were recommended for the first vaccination in previously unvaccinated children 6 months to 9 years of age followed by one dose annually thereafter. Only one annual dose was recommended for children 9 to 18 years.
A New Virus Demands New Action
During the past several years, the fear of an influenza pandemic has grown, and many countries have developed pandemic preparedness plans. In April 2009, two children were infected with a novel swine-origin influenza A (H1N1) virus characterized by a unique new combination of gene segments that had not been previously reported.26 This new influenza virus rapidly spread around the world, and an influenza pandemic was declared by the World Health Organization (WHO). The disease was particularly severe in the Southern Hemisphere, where the pandemic H1N1 strain (2009 H1N1) was the primary infecting strain from May through July 2009. The effect of the epidemic on children in Argentina was recently reported.27 Two hundred fifty-one children younger than 18 years of age with laboratory-confirmed 2009 H1N1 infection were hospitalized in six hospitals in Buenos Aires.
When compared with seasonal influenza in the previous year, hospitalization rates associated with 2009 H1N1 were twice as high. Nineteen percent of hospitalized children were admitted to the intensive care unit, 17% required mechanical ventilation, and 5% died. Eighty-five percent of the children who died were younger than 4 years, and 69% had underlying high-risk conditions (OR 4.87, 95% CI 1.30–22.23, P = .005). Underlying medical conditions of asthma and neurologic disease were associated with markedly higher mortality (OR 3.69, P = .02 and OR 5.62, P = .003) respectively.
Overall, the pediatric mortality rate in Buenos Aires was 1.1 per 100,000 children, 10 times higher than the mortality rates reported in the previous influenza season; the highest rates were in children younger than 1 year (7.6 per 100,000 children) (see Figure, see page 495).
Figure. Distribution of Hospitalizations and Rates of Disease Severity Among Children with 2009 H1N1 Influenza in Buenos Aires. The Left Panel Shows the Number of Children Who Were Hospitalized per 100,000 Children, According to Age, for an Overall Rate of 20.9 per 100,000 Children (as Represented by the Dashed Line). The Right Panel Shows the Number of Deaths from 2009 H1N1 Influenza, According to Age, for an Overall Rate of 1.1 per 100,000 Children (dashed Line).27 Copyright © 2010, Massachusetts Medical Society. All Rights Reserved.
Additional reports of the effect of the 2009 H1N1 influenza virus in the United States have also summarized the characteristics of hospitalized patients.28 From April to June 2009, 272 patients were hospitalized, with a median age of 26 years (range 1.3 to 57 years); 45% were children younger than 18 years; 38% were between 18 and 49 years; and only 5% were 65 years or older — the group with the greatest burden of hospitalization during usual seasonal influenza outbreaks. Twenty-five percent of these hospitalized individuals were admitted to an intensive care unit, and 7% died. Seventy-three percent of the patients had at least one underlying medical condition, including asthma, diabetes, heart, lung, or neurologic diseases, or pregnancy.28
In September 2009, monovalent inactivated and live attenuated 2009 pandemic influenza A California/H1N1 vaccines were approved by the Food and Drug Administration (FDA) to be used in the prevention of influenza caused by the 2009 pandemic H1N1 virus. None of the vaccines approved in the United States included adjuvants.
Two doses of the monovalent vaccine were recommended for children 6 months to 9 years, and only one dose was recommended for individuals 10 years and older.29 The priority groups to receive the 2009 H1N1 vaccine included pregnant women, household contacts of infants younger than 6 months, healthcare and emergency services personnel, individuals between 6 months and 24 years, and those 25 years or older with underlying high-risk conditions.30
A randomized, observer-blinded, age-stratified trial assessed the immunogenicity and safety of two doses of either 15 μg or 30 μg of the 2009 H1N1 vaccine in 370 healthy children 6 months to 9 years.31 Antibody titers ≥ 1:40 were achieved in 92.5% of the 15 μg group and 97.7% of the children in the 30 μg group. When measured 21 days after the first vaccine dose, the seroconversion rates after either 15 or 30 μg were 86.8% and 94.2%, respectively. Antibody titers of 1:40 were achieved by all children after the second dose. Regarding safety, most of the reported adverse events were of mild to moderate intensity. Results of the study indicated that a 15-μg dose of the H1N1 monovalent vaccine was safe and immunogenic in children 6 months to 9 years.31
Overall, the safety of the 2009 H1N1 vaccine has been reassuring. As of mid-December, 3,783 reports of adverse events associated with 2009 H1N1 vaccine had been reported to VAERS. This represents 82 adverse events per 1 million 2009 H1N1 vaccine doses distributed, compared with 47 adverse events per 1 million seasonal influenza vaccine doses distributed. In the Vaccine Safety Datalink (VSD), which incorporates data from eight large managed care organizations, 438,376 children were vaccinated with H1N1 vaccine, with no increase in the rates of adverse events reported when compared with rates after seasonal influenza vaccine.32 Ongoing surveillance in VAERS and VSD continues.
As a result of the effectiveness and safety of the monovalent 2009 H1N1 vaccine, the 2010 to 2011 trivalent seasonal influenza vaccines will contain A/California/7/2009 (H1N1)-like, A/Perth/16/2009 (H3N2)-like, and B/Brisbane/60/2008-like antigens. The A/California/7/2009 (H1N1)-like strain is the same strain that was included in the pandemic influenza 2009 monovalent vaccines.