Volume 13, Issue 4 , Pages 469-475, July 2009
The safety and immunogenicity of influenza vaccine in children with asthma in Mexico
Article Outline
Summary
Background
The morbidity and mortality associated with influenza is substantial in children with asthma. There are no available data on the safety and immunogenicity of influenza vaccine in children with asthma in Latin America. Furthermore, it is unclear if influenza vaccination may cause asthma exacerbations.
Methods
We conducted a placebo-controlled trial to investigate the safety and immunogenicity of an inactivated trivalent split virus influenza vaccine in children with asthma in Mexico. We also measured the impact of influenza vaccination on pulmonary function tests in this population.
Results
The inactivated influenza vaccine was immunogenic and safe in terms of local and systemic side effects compared to placebo. We observed no significant impact on pulmonary function tests among vaccine recipients.
Conclusions
Given the significant morbidity associated with influenza in children, strategies to promote increased influenza vaccination coverage in this high-risk group in Latin America and elsewhere are urgently needed.
Keywords: Asthma, Influenza, Vaccine, Safety, Immunogenicity, Forced expiratory volume (FEV)
Introduction
Infections due to influenza virus are considered an important cause of morbidity and mortality. On average, there are 36
000 influenza-associated deaths and approximately 114000 hospitalizations related to influenza each year in the USA.1, 2 The effects of influenza are felt most at both ends of the age spectrum, but individuals of any age with chronic medical illnesses such as asthma or chronic obstructive pulmonary disease are also subject to a considerable burden of disease.1, 2, 3 In this regard, in Mexico4, 5 and in other countries, influenza is considered a leading cause of acute respiratory tract infections that lead to health visits, hospitalizations, and mortality, particularly among those with chronic pulmonary and cardiac diseases.1, 2, 3, 4, 5, 6, 7, 8, 9
Children typically have the highest attack rate, but the elderly have the highest rate of complications.7, 8, 9 In Mexico, community-acquired pneumonias and influenza were identified as the ninth cause of death in all age groups in 1998.8 However, the burden of influenza disease in children in Mexico has not been determined. A recent report from the New Vaccine Surveillance Network (NSVN) sponsored by the Centers for Disease Control and Prevention, Atlanta, GA, USA, identified that the rates of influenza virus infection in children less than 5 years of age admitted to the hospital due to fever or respiratory tract infections are substantial.10, 11 These rates were estimated at 4.5 per 1000 for children up to 5 months of age and almost 1 per 1000 for the total number of children younger than 5 years of age. This study confirms the vulnerability of children to influenza infection and thus the importance of targeting this population for vaccination.7, 10, 11
The negative attitudes that parents and healthcare workers have towards the effectiveness of influenza vaccine act to reduce vaccine uptake in children.7, 12, 13, 14, 15, 16 Some of these attitudes are related to the lack of protection of the vaccine due to occasional poor match between vaccine and the circulating influenza virus strains.14, 15, 16 In addition, it is believed that influenza vaccination in children with asthma is associated with disease exacerbation.17, 18, 19, 20 In this regard, although limited evidence of decrease in pulmonary function associated with the administration of influenza vaccine has been identified in some earlier studies,21, 22 more recent trials have not observed these negative effects. Indeed, in a large controlled trial conducted in adults and children with asthma, influenza vaccination was demonstrated to be safe in various ethnic groups living in the USA and in other settings as well.22
The safety and immunogenicity of influenza vaccines has not been previously assessed in children with asthma in Latin America. Thus, we were interested in evaluating safety in terms of the occurrence of systemic and local adverse events and the impact on pulmonary function tests, and in determining the immunogenicity of a trivalent inactivated influenza vaccine in children with asthma in Mexico.
Methods
We conducted a randomized, placebo-controlled, double-blind clinical trial in 163 subjects (31 in the placebo group and 132 in the influenza vaccine group). Written informed consent was obtained from parents or guardians of potential subjects. The study was approved by the Institutional Review Board of the Instituto Nacional de Pediatria, Mexico. Children between 5 and 9 years of age with a diagnosis of mild intermittent and moderate persistent asthma without a history of allergy to egg protein or thimerosal were randomized to receive either placebo or a trivalent inactivated influenza vaccine. The diagnosis of asthma and its staging was made according to the following criteria: symptoms of daily life consistent with asthma (dyspnea on exertion, wheezing), nocturnal awakenings (number per week), lung function (forced expiratory volume at 1 second (FEV1) and peak flow measurements), and medication use to relieve symptoms (frequency of beta-antagonist use). All individuals were recruited from the outpatient clinics at the Instituto Nacional de Pediatria, one of the leading pediatric institutions in Mexico City and part of the National Institutes of Health. At the end of the study, children in the placebo group were also immunized.
Eligible subjects were randomly assigned to receive two doses of trivalent influenza vaccine at a dose of 15μg of hemagglutinin (per strain) or placebo. The trial was conducted during the influenza season in Mexico in 2001–2002, starting September 1, 2001, and with a follow-up of each individual for 56 days after the administration of the first dose of influenza vaccine. Each dose was administered intramuscularly in the deltoid muscle; the second dose was administered 28 days after the first dose. The influenza vaccine used was the trivalent inactivated influenza vaccine Fluzone® (Sanofi Pasteur) with the following purified, fractionated, and inactivated strains (2001–2002 strains): A/New Caledonia/20/99 (H1N1), A/Panama/2007/99 (H3N2), and B/Victoria/504/2000. The vaccine product was generated according to standard techniques. All vaccinations were administered by a clinician who was not involved in the assessment of adverse events or the laboratory follow-up, and the contents of the syringe were shielded from the subject's view.
The primary immunological end-point of the trial was the proportion of subjects in each group according to vaccine or receipt of placebo in whom a neutralizing antibody titer of 1:40 or greater developed against the strains contained in the vaccine at day 28 after the administration of the first dose of the vaccine and at day 28 (day 56 of the study) after the administration of the second dose of the vaccine.
Laboratory analysis was conducted by hemagglutination inhibition assays according to established procedures with the use of horse erythrocytes. After treatment with receptor-destroying enzyme to remove non-specific inhibitors of agglutination, the serum samples were tested at an initial dilution of 1:20. Serum samples were tested separately and in duplicate. These assays were performed at the viral laboratory of the National Institute of Diagnosis and Reference of the Ministry of Health, Mexico (INDRE) with the use of inactivated influenza vaccine 2001–2002 strains to measure the titers of protective antibodies. A titer of 1:40 was considered as evidence of adequate levels of protection. This viral laboratory is part of the FLUNET surveillance system of the World Health Organization, and viral detection methodologies have been standardized and have quality certifications on influenza diagnostics.
The primary safety end-points included the occurrence of local adverse events at the inoculation site (pain, erythema, induration) and systemic adverse events (malaise, fever, headache). Evaluation of adverse events was assessed on days 3–5 (visit 2), and days 3–5 after the administration of the second dose (visit 4). In addition, measurement of pulmonary function tests with measurement of the forced expiratory volumes at 1, 2, and 3seconds (FEV1, FEV2, and FEV3, respectively) were obtained at baseline (visit 1), at day 5 (visit 2), and at day 5 after the administration of the second dose (visit 4). The objective was to identify the proportion of subjects who developed local and systemic side effects after the first and second dose of the administered vaccine and also the effects of the vaccine on lung function as measured by FEV1, FEV2, and FEV3 determinations. Pulmonary function tests were carried out by standardized and approved spirometric protocols at the pulmonary laboratory of the institution. All the above data were recorded by research nurses and physicians who were not aware of the product administered to the individuals in the study. The safety analysis was carried out according to the rates of symptoms reported during the first 5 days after administration of each vaccine dose.
Statistical analysis was performed to measure the primary immunologic end-point of the trial through the analysis of the proportion of subjects in each group in whom a neutralizing titer of 1:40 or greater developed against the three vaccine strains contained in Fluzone, A/New Caledonia/20/99 (H1N1), A/Panama/2007/99 (H3N2), and B/Victoria/504/2000, at day 28 after the administration of the second dose of the vaccine. In addition, reactogenicity was assessed after each vaccination based on local and systemic reaction rates. In order to help the interpretation, p-values were calculated using the Chi-square test to compare the rates between each group. All were conducted with SAS software, version 8.2.
Results
There were no significant differences in gender, age, weight, height, and severity of asthma between the two groups (Table 1, Table 2). The primary immunogenicity end-point chosen for this study was the development of hemagglutination titers of 1:40 or greater after two doses of vaccine. The results of immunogenicity testing with the use of hemagglutination inhibition are shown in (Table 3). As expected, the majority of subjects who received the vaccine had antibody titer production after the first and second doses of the vaccine at a titer of >1:40 dilutions for H1N1 (p<0.01 compared to placebo recipients), H3N2 (p<0.01 compared to placebo recipients), and influenza B vaccine strains (p<0.01 compared to placebo recipients).
Table 1. General data.
| Placebo n=31 | Influenza vaccine n=132 | |
|---|---|---|
| Females | 10 (32.3%) | 50 (37.9%) |
| Males | 21 (67.7%) | 82 (62.1%) |
| Age, years; median (min, max) | 7.71 (5.04, 9.98) | 7.87 (5.0, 9.99) |
| Weight, kg; median (min, max) | 30.3 (17, 56) | 28.3 (12.6, 59) |
| Height, m; median (min, max) | 1.25 (1.03, 1.44) | 1.24 (0.91, 1.47) |
Table 2. Description of FEV evolution between visits.
| Placebo (n=31) | Influenza vaccine (n=132) | p-Value (t-test) | |
|---|---|---|---|
| Change in FEV1 between visit 1 and visit 2 | |||
| Increase or stagnation (>0%) | 22 (71.0%) | 75 (56.8%) | |
| Decrease by less than 15% (>−15%) | 7 (22.6%) | 46 (34.8%) | |
| Decrease by more than 15% (<−15%) | 2 (6.4%) | 11 (8.3%) | 0.73 |
| Change in FEV1 between visit 1 and visit 4 | |||
| Increase or stagnation (>0%) | 19 (61.3%) | 65 (49.2%) | |
| Decrease by less than 15% (>−15%) | 7 (22.6%) | 42 (31.8%) | |
| Decrease by more than 15% (<−15%) | 5 (16.1%) | 25 (18.9%) | 0.72 |
| Change in FEV2 between visit 1 and visit 2 | |||
| Increase or stagnation (>0%) | 24 (80%) | 79 (63.7%) | |
| Decrease by less than 15% (>−15%) | 4 (13.3%) | 36 (29.0%) | |
| Decrease by more than 15% (<−15%) | 2 (6.7%) | 9 (7.3%) | 0.94 |
| Change in FEV2 between visit 1 and visit 4 | |||
| Increase or stagnation (>0%) | 17 (54.8%) | 70 (53.4%) | |
| Decrease by less than 15% (>−15%) | 10 (32.3%) | 41 (31.3%) | |
| Decrease by more than 15% (<−15%) | 4 (12.9%) | 20 (15.3%) | 0.75 |
| Change in FEV3 between visit 1 and visit 2 | |||
| Increase or stagnation (>0%) | 15 (48.4%) | 78 (59.1%) | |
| Decrease by less than 15% (>−15%) | 9 (29.0%) | 26 (19.7%) | |
| Decrease by more than 15% (<−15%) | 7 (22.6%) | 28 (21.2%) | 0.87 |
| Change in FEV3 between visit 1 and visit 4 | |||
| Increase or stagnation (>0%) | 21 (67.7%) | 73 (55.3%) | |
| Decrease by less than 15% (>−15%) | 3 (9.7%) | 25 (18.9%) | |
| Decrease by more than 15% (<−15%) | 7 (22.6%) | 34 (25.8%) | 0.71 |
Table 3. Immunogenicity of influenza vaccine by virus strain in children with asthma after receiving placebo or influenza vaccine.
| Placebo (n=31) | Influenza vaccine (n=132) | p-Value | |
|---|---|---|---|
| Titers >1:40 H1N1 | |||
| Pre-vaccination | 7 (22.6%) | 23 (17.4%) | 0.50 |
| Post first dose | 8 (25.8%) | 108 (81.8%) | <0.01 |
| Post second dose | 10 (32.3%) | 124 (93.9%) | <0.01 |
| Titers >1:40 H3N2 | |||
| Pre-vaccination | 8 (25.8%) | 57 (43.2%) | 0.07 |
| Post first dose | 11 (35.5%) | 121 (91.7%) | <0.01 |
| Post second dose | 12 (38.7%) | 127 (96.2%) | <0.01 |
| Titers >1:40 B | |||
| Pre-vaccination | 12 (38.7%) | 59 (44.7%) | 0.54 |
| Post first dose | 14 (45.2%) | 122 (92.4%) | <0.01 |
| Post second dose | 18 (58.1%) | 129 (97.7%) | <0.01 |
The frequencies of local reactions at the injection site after each dose were similar between vaccine recipients and placebo recipients and there were no severe local reactions reported (Table 4). Reports of local pain were not necessarily accompanied by objective findings of erythema or induration at the injection site. Systemic symptoms were present in both groups after the first and the second dose, but there were no statistical differences between them. It is important to note that fever was only observed in the vaccine group, but was judged not clinically relevant (Table 5).
Table 4. Local adverse reactions after the first dose and the second dose of placebo or influenza vaccine.
| Adverse events | Placebo (n=31) | Influenza vaccine (n=132) | p-Value |
|---|---|---|---|
| First dose | |||
| Pain | 8 (25.8%) | 44 (33.3%) | 0.41 |
| Erythemaa | 2 (6.5%) | 6 (4.5%) | 0.66 |
| Indurationa | 3 (9.7%) | 20 (15.2%) | 0.43 |
| Total No. | 12 (38.7%) | 55 (41.7%) | 0.76 |
| Second dose | |||
| Pain | 7 (22.6%) | 40 (30.3%) | 0.39 |
| Erythemaa | 1 (3.2%) | 7 (5.3%) | 0.63 |
| Indurationa | 4 (12.9%) | 18 (13.6%) | 0.91 |
| Total No. | 9 (29.0%) | 46 (34.8%) | 0.54 |
aAny measurable reaction >0 |
Table 5. Systemic adverse reactions after the first dose and the second dose of placebo or influenza vaccine.
| Adverse events | Placebo (n=31) | Influenza vaccine (n=132) | p-Value |
|---|---|---|---|
| First dose | |||
| Fevera | 0 (0%) | 3 (2.3%) | 0.40 |
| Malaise | 5 (16.1%) | 8 (6.1%) | 0.06 |
| Headache | 1 (3.2%) | 1 (0.8%) | 0.26 |
| Others | 6 (19.4%) | 16 (12.1%) | 0.29 |
| Total No. | 9 (29.0%) | 21 (15.9%) | 0.09 |
| Second dose | |||
| Fevera | 0 (0%) | 1 (0.8%) | 0.63 |
| Malaise | 1 (3.2%) | 4 (3.0%) | 0.95 |
| Headache | 1 (3.2%) | 0 (0.0%) | 0.04 |
| Others | 6 (19.4%) | 27 (20.5%) | 0.89 |
| Total No. | 8 (25.8%) | 25 (18.9%) | 0.39 |
aAxillary temperature ≥38.0 |
We observed no statistically significant differences in FEV1, FEV2, and FEV3 determinations at baseline (visit 1) and determinations on subsequent visits (visit 2 and visit 4), between those who received the vaccine compared to the placebo group (Table 2). There were no significant differences in change in FEV1 between visits 1 and 2 (p=0.73) or between visits 1 and 4 (p=0.72), or in FEV2 between visits 1 and 2 (p=0.94) or between visits 1 and 4 (0.75), or in FEV3 between visits 1 and 2 (p=0.87) or between visits 1 and 4 (p=0.71). Table 6, Table 7, Table 8 show the FEV1, FEV2, and FEV3 measured at each visit and demonstrate that there were no differences between visits for all determinations (p>0.05), and only a slight difference between the vaccine and placebo groups for visit 2.
Table 6. Description of FEV1 by vaccine group and by visit.
| Placebo (n=31) | Influenza vaccine (n=132) | p-Value (t-test) | |
|---|---|---|---|
| Visit 1 | |||
| Mean | 99.1 | 94.2 | 0.16 |
| Median | 97 | 95 | |
| (Min, max) | (60, 147) | (49, 136) | |
| Q1:Q3 | 88:112 | 84.5:103.5 | |
| Visit 2 | |||
| Mean | 104.5 | 96.2 | 0.02 |
| Median | 105 | 96 | |
| (Min, max) | (73, 150) | (48, 140) | |
| Q1:Q3 | 95:114 | 83.5:109 | |
| Visit 4 | |||
| Mean | 99.9 | 93.6 | 0.11 |
| Median | 103 | 94 | |
| (Min, max) | (32, 150) | (42, 147) | |
| Q1:Q3 | 91:114 | 81:107 | |
| Test of time effect (p-value) | 0.463 | 0.505 | |
Table 7. Description of FEV2 by vaccine group and by visit.
| Placebo (n=31) | Influenza vaccine (n=132) | p-Value (t-test) | |
|---|---|---|---|
| Visit 1 | |||
| Mean | 97.1 | 99.1 | 0.86 |
| Median | 98 | 94 | |
| (Min, max) | (61, 144) | (49, 782) | |
| Q1:Q3 | 86:106 | 84.5:106 | |
| Visit 2 | |||
| Mean | 104.8 | 96.1 | 0.02 |
| Median | 104 | 97.5 | |
| (Min, max) | (79, 165) | (44, 146) | |
| Q1:Q3 | 93:113 | 85:106.5 | |
| Visit 4 | |||
| Mean | 100 | 93.9 | 0.12 |
| Median | 100 | 94 | |
| (Min, max) | (64, 162) | (39, 144) | |
| Q1:Q3 | 92:108 | 81.5:107 | |
| Test of time effect (p-value) | 0.218 | 0.540 | |
Table 8. Description of FEV3 by vaccine group and by visit.
| Placebo (n=31) | Influenza vaccine (n=132) | p-Value (t-test) | |
|---|---|---|---|
| Visit 1 | |||
| Mean | 98.7 | 90.3 | 0.12 |
| Median | 92 | 90 | |
| (Min, max) | (52, 162) | (32, 174) | |
| Q1:Q3 | 70:121 | 71.5:104.5 | |
| Visit 2 | |||
| Mean | 95.8 | 89.8 | 0.23 |
| Median | 94 | 98.5 | |
| (Min, max) | (41, 131) | (17, 150) | |
| Q1:Q3 | 85:112 | 72.5:110 | |
| Visit 4 | |||
| Mean | 98.1 | 88.5 | 0.07 |
| Median | 90 | 85.5 | |
| (Min, max) | (59, 145) | (27, 168) | |
| Q1:Q3 | 76:114 | 73:105 | |
| Test of time effect (p-value) | 0.907 | 0.838 | |
Discussion
Yearly seasonal influenza vaccination is targeted toward the prevention of the serious consequences of influenza, which include severe disease, risk of hospitalization, and death.7 Among children, the administration of influenza vaccine is associated with fewer outpatient visits, decreased morbidity, and decreased hospitalizations.8, 23, 24, 25, 26 In addition, influenza vaccination in children may decrease viral shedding and therefore may impact the transmission dynamics in the community.27
Infection with influenza is a common reason for hospitalization in children with asthma since this virus makes children and adults with asthma prone to bronchoconstriction and decreased pulmonary function.28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38 The role of influenza virus as an inducer of asthma exacerbations has been suggested by the fact that antiviral therapy against influenza leads to fewer asthma exacerbations.21, 30, 39 Influenza immunization is considered the most important method to prevent influenza and its severe complications in this and other high-risk groups.31, 32, 33, 34, 35, 36, 37 Given the worldwide prevalence of asthma, estimated to be at least 10–15% in the pediatric population, the impact of influenza infection on patients with asthma is high.17, 22 Despite this important association, only a very small proportion of patients with asthma receive the influenza vaccine each year.17, 24 Some of the obstacles associated with the low influenza vaccine coverage in individuals with asthma include concerns about the efficacy and safety of the vaccine.17 In particular, there has been some concern about the possibility of asthma exacerbations due to the administration of the vaccine.17, 18, 19, 20, 21, 22
Most of the studies on the safety of influenza vaccine in individuals with asthma have been retrospective analyses or systematic reviews that used different methodologies for evaluating lung function in patients with asthma. Nevertheless, these studies demonstrate a trend towards a significant reduction in the risk of asthma exacerbations with the use of influenza vaccine with no evidence of worsening of asthma after vaccine administration.22 While some early studies suggested a possible worsening of lung function associated with the vaccine, more recent large placebo-controlled trials have demonstrated that the administration of influenza vaccine in individuals of all ages with asthma is safe.21, 22 The largest prospective study on the safety of influenza vaccine demonstrated that while patients with severe asthma were more likely to have an exacerbation than those with fewer asthma symptoms, there were no differences in the frequency of exacerbations of asthma after influenza vaccine in the vaccinees versus placebo.22 Our study also confirms that vaccination of children with asthma living in Mexico City with a trivalent inactivated influenza vaccine is not associated with a significant deterioration in pulmonary function tests. In Mexico and elsewhere there is an ongoing need to increase influenza vaccination uptake in patients with asthma to prevent exacerbation of symptoms and hospitalizations associated with influenza infection.
While the efficacy of influenza vaccine in populations with asthma continues to demonstrate variable results, most international authorities agree that influenza vaccination is an important preventive component of asthma care.27, 28, 29, 30, 31, 32, 33, 34 Furthermore, health-related quality of life is improved during virus-positive influenza-related illness in vaccine recipients.35
Although vaccination against influenza is recommended for all patients with asthma, the efficacy of this vaccine in preventing asthma exacerbations secondary to influenza is still a matter of debate. It has been suggested that the absence of a clear efficacy benefit in clinical trials may be due to the fact that placebo-controlled trials are difficult to perform in a disease state in which vaccination is widely recommended and requires a large cohort of patients and should control for several confounding factors that may interfere in the data analysis.27, 28, 29, 30, 31, 32, 33, 34 Another possible explanation may be due to the concomitant administration of high-dose inhaled corticosteroids in patients with asthma. However, despite the use of inhaled steroids, in our findings the vaccine was demonstrated to be highly immunogenic.40, 41
Despite the above limitations, it is widely recommended in official guidelines that influenza vaccine be administered to patients with asthma.7, 17 In addition, better communication strategies are needed to resolve confusion surrounding influenza vaccine to improve rates of coverage in high-risk groups such as children with asthma in subspecialty settings.35 The benefit of influenza vaccine clearly outweighs any potential concern about reactogenicity and impact on lung function as shown by our results.7, 17
The low overall rates of influenza vaccination among children with asthma highlight the need for improvement of coverage rates as a component of asthma care for all children with asthma. Interventions directed toward parents and healthcare providers, such as informing them of the relevance of preventing influenza through vaccination and also about the safety profile of the vaccine, may help improve influenza vaccination rates in this high-risk group in Latin America and elsewhere.
Conflict of interest: Christele Deroche and Cesar Mascareñas are part of the scientific panel of Sanofi Pasteur.
Funding: The study was financed by Sanofi Pasteur.
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PII: S1201-9712(08)01534-8
doi:10.1016/j.ijid.2008.08.015
© 2008 International Society for Infectious Diseases. Published by Elsevier Inc. All rights reserved.
Volume 13, Issue 4 , Pages 469-475, July 2009
