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Immunogenicity, safety and tolerability of inactivated trivalent influenza vaccine in overweight and obese children
Vaccine 34 (2016) 56–60
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Immunogenicity, safety and tolerability of inactivated trivalent influenza vaccine in overweight and obese children Susanna Esposito a,∗ , Claudia Giavoli b , Claudia Trombetta c , Sonia Bianchini a , Valentina Montinaro a , Anna Spada b , Emanuele Montomoli c,d , Nicola Principi a a Paediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy b Endocrinology and Diabetology Unit, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy c Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy d VisMederi srl, Enterprise in Life Science, Italy
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Article history: Received 31 July 2015 Received in revised form 15 October 2015 Accepted 6 November 2015 Available online 19 November 2015 Keywords: Influenza Influenza vaccination Obesity Overweight Prevention Vaccination
a b s t r a c t Obesity may be a risk factor for increased hospitalization and deaths from infections due to respiratory pathogens. Additionally, obese patients appear to have impaired immunity after some vaccinations. To evaluate the immunogenicity, safety and tolerability of an inactivated trivalent influenza vaccine (TIV) in overweight and obese children, 28 overweight/obese pediatric patients and 23 healthy normal weight controls aged 3–14 years received a dose of TIV. Four weeks after vaccine administration, significantly higher seroprotection rates against the A/H1N1 strain were observed among overweight/obese children compared with normal weight controls (p < 0.05). Four months after vaccination, similar or slightly higher seroconversion and seroprotection rates against the A/H1N1 and A/H3N2 strains were detected in overweight/obese than in normal weight children, whereas significantly higher rates of seroconversion and seroprotection against the B strain were found in overweight/obese patients than in normal weight controls (p < 0.05 for seroconversion and seroprotection). Geometric mean titers (GMTs) and fold increase against B strains were significantly higher in overweight/obese patients than in normal weight controls 4 months after vaccine administration (p < 0.01 for GMT values and p < 0.05 for fold increase). The frequency of local and systemic reactions was similar between the groups, and there were no serious adverse events. The results of this study indicate that in overweight and obese children, antibody response to TIV administration is similar or slightly higher than that evidenced in normal weight subjects of similar age and this situation persists for at least 4 months after vaccine administration in the presence of a favorable safety profile. © 2015 Elsevier Ltd. All rights reserved.
1. Introduction The incidence of overweight and obese children has increased at an alarming rate worldwide. The World Health Organization (WHO) has estimated that in 2013 the total number of overweight children under the age of 5 years was over 42 million [1]. This causes relevant clinical problems. A reduction in life expectancy of obese subjects due to comorbidities such as cardiovascular diseases, insulin
∗ Corresponding author at: Paediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Commenda 9, 20122 Milano, Italy. Tel.: +39 02 55032498; fax: +39 02 50320206. E-mail address: [email protected] (S. Esposito). http://dx.doi.org/10.1016/j.vaccine.2015.11.019 0264-410X/© 2015 Elsevier Ltd. All rights reserved.
resistance with development of type 2 diabetes, and increased susceptibility to infection has been repeatedly reported [2]. Epidemiological evidence suggests that obesity alone, independent of the comorbidities, is a relevant risk factor for increased hospitalization and death from infections due to respiratory pathogens, mainly influenza viruses. This has been clearly evidenced in recent years in both experimental animal models and in humans [3,4]. Kim et al. reported that in diet-induced obese mice infected with pandemic 2009 A/H1N1 (pA/H1N1) influenza virus, virus titers, tissue pathology and expression of mRNAs for proinflammatory cytokines and chemokines in the lungs of these animals were significantly higher than in lean controls [3]. Moreover, it has been reported that in both children and adults, obesity emerged as an important risk factor for morbidity and mortality during the 2009 influenza pandemic [4]. This explains why, in 2010,
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the Advisory Committee on Immunization Practice (ACIP) in the United States of America added obesity to the list of clinical conditions for which influenza vaccination is strongly recommended, at least in the case of morbid obesity (body mass index [BMI] ≥40 in adults) [5]. Unfortunately, the protection offered by influenza vaccines to obese and overweight subjects has not been established. Usually, although with some limitations, seroconversion, seroprotection, geometric mean titers (GMT), and fold increase evaluated through the haemagglutination-inhibiting (HI) antibodies are considered correlates of protection against influenza [5]. The evidence that obesity is a risk factor for reduced immune responses to vaccines for hepatitis A and B [6,7] and rabies in adults [8], as well as to the tetanus vaccine in children [9], seems to suggest a potential risk for a poor immune response to influenza vaccination. Moreover, some studies have shown that influenza immunity is impaired in obese animals, and that obese mice vaccinated with commercial monovalent pA/H1N1 influenza vaccine were not protected from pandemic influenza [3]. However, the results of most of the studies carried out in humans conflict with these experimental evaluations and with the results of studies carried out with non-influenza vaccines. Sperling et al. examined pregnant and postpartum obese women and reported that they had immune responses similar to that of normal subjects, with only slightly lower odds of seroconversion [10]. Talbot et al. reported that immunogenicity of a seasonal trivalent inactivated influenza vaccine (TIV) was similar in obese and lean older adults, with a slight increase in seroconversion for the A/H3N2 virus but not for the other viruses [11]. Sheridan et al. evidenced that obese adults had a higher initial fold increase in IgG antibodies after TIV administration, although 12 months after vaccination, a higher BMI was associated with a greater decline in influenza antibody titers [12]. Callahan et al. studied adults and a small number of children and adolescents and found that age could significantly condition the immune response to monovalent pA/H1N1 influenza vaccine in overweight and obese subjects [13]. In adults, they found that the amount of antibody production 21 days after a single vaccine administration was significantly higher in obese patients than in lean subjects. By contrast, they evidenced no significant differences in immune response among children and adolescents of various BMI that had received two doses of the vaccine, after either vaccine dose 1 or 2 [13]. However, because the study by Callahan et al. is the only one involving children and adolescents [13], further data are needed to know whether obese and overweight pediatric subjects can be protected by influenza vaccines. This study was therefore planned to increase our knowledge in this regard.
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trivalent influenza vaccine (Fluarix, GlaxoSmithKline Biologicals, Rixensart, Belgium) in already primed children aged 3–14 years with documented overweight or obesity and in healthy controls. Children with any serious chronic disease (i.e., chronic pulmonary diseases including asthma, signs of cardiac or renal failure, severe malnutrition, or progressive neurological diseases), Down syndrome or other known cytogenetic disorder, or a known or suspected disease of the immune system were excluded, as were those who had received immunosuppressive therapy, including systemic corticosteroids at a prednisone-equivalent dosage of 2 mg/kg per day (or a total of 20 mg per day) for more than 14 days, and those with a documented history of hypersensitivity to egg, egg protein, or any other component of the vaccine. Vaccine components for the 2014–2015 Northern hemisphere influenza season included an A/California/7/2009 (H1N1) pdm09-like virus, an A/Texas/50/2012 (H3N2)-like virus, and a B/Massachusetts/2/2012-like virus. Overweight/obese children were selected from those attending the endocrinology outpatient clinic for diet-induced overweight and obesity, whereas children of similar age and gender with normal weight for height were randomly selected from those attending the hospital’s outpatient clinic for a follow-up visit following a previous minor surgical intervention carried out 3 months before enrolment in Day-Surgery without general anesthesia. In all of the enrolled children, height and weight were measured by research staff, and BMI was calculated as weight (kg)/height (m)2 . Age- and gender-specific z-scores for BMI were calculated using software available from the Centers for Disease Control and Prevention (CDC), based on the 2000 CDC growth charts to define BMI categories of normal weight (5–84th percentile), overweight (85–94th percentile) and obese (≥95th percentile). Patients and controls were vaccinated between 1 October and 15 November 2014 by means of an injection in the deltoid region of the left arm. Serum samples for the immunogenicity assessments were collected before the first vaccination dose on days 1 (baseline), 28 ± 3, and 120 ± 7 after vaccine administration. Safety was assessed by collecting data concerning any local and systemic reactions (from the investigators at baseline in the 30 min following vaccine’s administration, thereafter reported from the children’s parents/legal guardians for the 14 days after vaccination using a diary card), as previously described [14,15]. The children were evaluated for the occurrence of local adverse events (i.e., erythema, swelling/induration, and pain) (AEs) and questioned about systemic AEs (i.e., body temperature ≥38 ◦ C, rhinitis, irritability, sleepiness, changed eating habits, vomiting, and diarrhea). 2.2. Assessment of humoral immune response
2. Materials and methods 2.1. Study design This prospective study was carried out at the Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy, between 1 October 2014 and 31 March 2015. The study protocol was approved by the Ethics Committee of the Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, and the study was conducted in accordance with the standards of Good Clinical Practice for trials of medicinal products in humans. Written informed consent was obtained from the parents/legal guardians of each enrolled child and written consent was obtained from children aged ≥8 years. The study compared the immunogenicity, safety, and tolerability of a standard intramuscular (i.m.) dose of a split-virion
The titers of HI antibodies against each of the three influenza strains contained in the 2014–2015 influenza vaccine formulation were determined in all of the children on days 1, 28 ± 3 and 120 ± 7 as previously described [16,17]. The results were expressed as the reciprocal of the highest dilution inhibiting agglutination. To calculate GMTs, a titer of 1:5 was arbitrarily assigned to nonresponders [16,17]. The immunogenicity end-points were based on the HI licensure criteria established by the guideline of the European Medicines Agency (EMA) [18]. As there are no EMA-defined criteria for children, immunogenicity was evaluated using the criteria for adults aged 18–60 years, which require at least one of the following for each strain: (1) seroconversion, a ≥4-fold increase in HI antibody titer with a titer of ≥1:40 being reached in >40% of the subjects; (2) seroprotection, an HI antibody titer of ≥1:40 in >70% of the subjects; or (3) GMT, a >2.5-fold increase in the GMT of HI antibodies.
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2.3. Statistical analysis The continuous variables are presented as the mean ± standard deviation (SD), and the categorical variables are presented as numbers and percentages. The continuous data were analyzed using a two-sided Student’s test whether they were normally distributed (on the basis of the Shapiro–Wilk statistic) or a two-sided Wilcoxon rank-sum test if they were not. The categorical data were analyzed using a contingency table analysis and the 2 or Fisher’s test, as appropriate. All of the analyses were two-tailed, and p values of 0.05 or less were considered significant. The analyses were conducted using SAS version 9.2 (Cary, NC, USA).
Table 1 Baseline characteristics of children vaccinated with trivalent inactivated influenza vaccine, according to their weight status.a Overweight/ obese (n = 28)
Normal weight (n = 23)
p-Value
BMI Mean ± SD
24.1 ± 3.9
16.4 ± 2.3
<0.001
Age (years) Mean ± SD
10.9 ± 3.2
10.7 ± 3.7
0.99
Sex Male Female
14 (50.0) 14 (50.0)
13 (56.5) 10 (43.5)
0.64
14 (51.8) 13 (48.2)
14 (60.9) 9 (39.1)
0.52
11 (39.3)
7 (31.8)
17 (60.7)
15 (68.2)
0.59
10 (35.7) 7 (25.0)
2 (8.7) 0 (0.0)
0.02 0.01
4 (14.3) 16 (57.1) 8 (28.6) 14 (50.0) 3/27 (11.1) 25/28 (89.3)
2 (8.7) 13 (56.5) 8 (34.8) 8 (34.8) 3/23 (13.0) 14/22 (63.6)
0.78 0.27 0.99 0.04
15 (53.6)
10 (43.5)
0.47
2 (7.1)
3 (13.0)
0.65
2 (7.1)
2 (8.7)
0.99
2 (7.1)
5 (21.7)
0.22
Characteristic
b
3. Results
Ethnicity Caucasian Non-Caucasian b
3.1. Population A total of 28 overweight/obese children were enrolled. Of these, 14 (50.0%) children were overweight, and 14 (50.0%) children were obese. All of the children completed all the study visits. A total of 28 children with normal weight for their height were initially enrolled. Unfortunately, 5 of these subjects did not return for control visits after vaccine administration and were withdrawn from the study. Moreover, one overweight/obese child could not be tested after 28 ± 3 days for difficulties in obtaining an adequate volume of blood, whereas three overweight/obese children and two healthy weight children could not be tested after 120 ± 7 days for the same reason. Consequently, analysis of the immune response to TIV administration was carried out in 28 overweight/obese and 23 normal weight children. Because a preliminary analysis did not show any difference in general characteristics, immune response, or adverse events incidence between overweight and obese children, the two subgroups of patients were considered together. Table 1 lists the general characteristics of the children who entered the study. As shown, overweight/obese children had a significantly higher BMI (p < 0.001), were more likely to have obese relatives (p = 0.02) and obese parents (p = 0.01), and were more often breastfed in the first months of life (p = 0.04) than normal weight controls. No significant differences in any other studied variable (age, sex, ethnicity, education of parents, number of siblings, parental allergies, preterm birth status, respiratory infections and hospitalization rates in the previous 6 months, and use of steroids and antibiotics in the previous 3 months) were evidenced between the groups. 3.2. Immune response to TIV administration Table 2 shows the immune responses of the two groups after the administration of the vaccine. Less than 20% of the overweight/obese patients and normal weight controls had baseline-specific antibody titers ≥40 upon HI assay against the A/H1N1 and B influenza viruses, whereas more than 40% of the overweight/obese patients and approximately 30% of the normal weight controls had baseline-specific antibody titers of ≥40 upon HI assay against the A/H3N2 strain. Four weeks after vaccine administration, the overweight/obese patients and normal weight controls had seroconversion rates of 81.5% and 60.9% against A/H1N1, 63.0% and 65.2% against A/H3N2, and 74.1% and 60.9% against the B strain, respectively, with no significant betweengroup difference. The seroprotection rates were 96.3% and 73.9% against A/H1N1, 96.3% and 87.0% against A/H3N2, and 81.5% and 69.6% against the B strain for overweight/obese patients and normal weight controls, respectively, with significantly higher seroprotection rates against A/H1N1 strain among patients than among controls (p < 0.05). Four months after vaccination, most of the overweight/obese patients and normal weight subjects remained
Education of parents No high school (or higher) degree ≥1 with high school (or higher) degree Obese relatives (at least one) Obese parents (at least one) No. of siblings 0 1 ≥2 Parental allergies Preterm birthb Breastfed (for at least 3 months)b Respiratory infections (last 6 months) Hospitalization (last 6 months) Systemic steroid use (last 3 months) Antibiotic use (last 3 months)
BMI, body mass index; SD, standard deviation. Percentages in parentheses. a Information from five children with normal weight lost to follow-up was not included in the table. b The sums do not add up to the total because of missing values.
seroconverted and were still seroprotected, with similar or slightly higher seroconversion and seroprotection rates in patients than in controls against the A/H1N1 and A/H3N2 strains. Furthermore, significantly higher rates of seroconversion and seroprotection against the B strain were found among overweight/obese patients than among normal weight controls (p < 0.05 for both seroconversion and seroprotection rates). GMTs and fold increase against A/H1N1 and A/H3N2 strains were not different between the groups, but they were significantly higher among overweight/obese patients than among normal weight controls 4 months after vaccine administration against the B strain (p < 0.01 for GMT values and p < 0.05 for fold increase). 3.3. Safety and tolerability of TIV Table 3 summarizes the incidence of local and systemic reactions in overweight/obese patients and in normal weight controls during the 14 days after vaccination. The frequency of local and systemic reactions was similar between the groups without any statistically significant difference although for some local reactions, such as pain, a trend toward a greater prevalence in obese children was evidenced. No serious adverse events occurred. 4. Discussion The results of this study indicate that the antibody response to TIV administration is similar or slightly higher in overweight/obese
S. Esposito et al. / Vaccine 34 (2016) 56–60 Table 2 Haemagglutination inhibition (HI) antibody responses against seasonal influenza strains after vaccination with trivalent inactivated influenza vaccine in overweight/obese and normal weight children.a Immune response A/H1N1 Seroconversionb , no. (%) After 28 ± 3 days After 120 ± 7 days Seroprotectionc , no. (%) Baseline After 28 ± 3 days After 120 ± 7 days GMT Baseline After 28 ± 3 days (fold increase) After 120 ± 7 days (fold increase) A/H3N2 Seroconversionb , no. (%) After 28 ± 3 days After 120 ± 7 days Seroprotectionc , no. (%) Baseline After 28 ± 3 days After 120 ± 7 days GMT Baseline After 28 ± 3 days (fold increase) After 120 ± 7 days (fold increase)
Overweight/ obese (n = 28)
Normal weight (n = 23)
14/23 (60.9) 15/21 (71.4)
0.11 0.73
6/28 (21.4) 26/27 (96.3) 24/25 (96.0)
4/23 (17.4) 17/23 (73.9) 19/21 (90.5)
0.99 0.04 0.59
11.0 354.6 (31.2)
9.7 146.2 (15.1)
0.76 0.08 (0.19)
263.5 (21.7)
230.0 (22.6)
0.70 (0.96)
17/27 (63.0) 16/25 (64.0)
15/23 (65.2) 12/21 (57.1)
0.87 0.64
12/28 (42.9) 26/27 (96.3) 22/25 (88.0)
7/23 (30.4) 20/23 (87.0) 18/21 (85.7)
0.36 0.32 0.99
25.3 359.2 (13.4)
16.7 275.3 (16.5)
0.44 0.53 (0.71)
235.9 (12.3)
241.7 (15.2)
0.96 (0.73)
20/27 (74.1) 18/25 (72.0)
14/23 (60.9) 8/21 (38.1)
0.32 0.02
5/28 (17.9) 22/27 (81.5) 20/25 (80.0)
3/23 (13.0) 16/23 (69.6) 10/21 (47.6)
0.72 0.33 0.02
8.7 119.1 (13.4)
7.0 59.2 (8.5)
0.46 0.19 (0.38)
93.2 (10.0)
21.7 (3.4)
0.006 (0.03)
B Seroconversionb , no. (%) After 28 ± 3 days After 120 ± 7 days Seroprotectionc , no. (%) Baseline After 28 ± 3 days After 120 ± 7 days GMT Baseline After 28 ± 3 days (fold increase) After 120 ± 7 days (fold increase)
Table 3 Comparison of local and systemic adverse events in overweight/obese and normal weight children.a Type of event
p-Valued
22/27 (81.5) 19/25 (76.0)
GMT, geometric mean titers. a One overweight/obese child could not be tested after 28 ± 3 days, whereas three overweight/obese children and two healthy weight children could not be tested after 120 ± 7 days. b ≥4-fold increase in haemagglutination inhibition (HI) titer. c HI titer ≥40. d p-Values from 2 or Fisher’s exact test (as appropriate, for categorical variables) or from Student’s t-test (for continuous variables).
children than that evidenced in normal weight subjects of similar age and that this situation persists for at least 4 months after vaccine administration. In comparison with normal weight controls, the greatest difference in favor of overweight/obese patients was found regarding influenza B virus, the TIV component against which the immune response in normal subjects is frequently the lowest [14,15,19]. This study enrolled a relatively low number of patients and for this the evaluation of the relationships between BMI and response to TIV was not possible. Moreover, it was likely underpowered to detect all the effects of TIV administration also comparing overweight with obese children, particularly for immunogenicity and incidence of minor adverse events. However, a trend toward a greater seroconversion rate and a higher GMT against A/H1N1 at 28 days after administration together with an increase in the incidence of some local adverse events was evidenced in overweight/obese children. These findings deserve
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Local adverse event Pain Erythemab Induration Swelling Any local adverse event Systemic adverse event Fever Changes in eating habits Sleepiness Vomiting/diarrhea Irritability Rash/any other Any systemic adverse event
Overweight/ obese (n = 28)
Normal weight (n = 23)
p-Valuec
8 (29.6) 7 (28.0) 4 (14.8) 6 (22.2) 10 (37.0) 1 (3.7)
2 (8.7) 2 (8.7) 2 (8.7) 1 (4.3) 3 (13.0) 2 (8.7)
0.09 0.14 0.67 0.11 0.10 0.59
2 (7.4) 4 (14.8) 4 (14.8) 2 (7.4) 0 (0.0) 7 (25.9)
0 (0.0) 1 (4.3) 1 (4.3) 0 (0.0) 0 (0.0) 3 (13.0)
0.49 0.36 0.36 0.49 – 0.31
Percentages in parentheses. a Safety data are not available for one child from the overweight/obese group. b Two additional children are missing data. c p-Values from 2 or Fisher’s exact test, as appropriate.
attention and further studies enrolling a greater number of overweight (obese subjects are needed to detail the response of these patients to TIV administration. However, data collected with this study seem to suggest that overweight and obese children might be adequately protected against influenza by TIV without any risk of severe adverse events. Although a normal or elevated immune response in obese subjects to at least some TIV components has been previously reported [10–13], the findings of this study remain surprising. Studies in experimental animals and humans have suggested that obesity is associated with an impairment of several immune system functions that should lead to poor antibody response to vaccination [6–9]. Elevation of leukocyte and lymphocyte subset counts, reduction of T- and B-cell function, an increase in monocyte and granulocyte phagocytosis and an increase in oxidative burst activity were common findings in obese subjects [20–22]. Certain data collected from influenza-vaccinated obese individuals are consistent with immune system impairment in obesity. Sheridan et al. reported that 12 months after TIV administration, peripheral blood mononuclear cells (PBMCs) of obese subjects had a significantly lower increase in the percentage of CD8+ T cell surface marker CD69 (p = 0.015), a marker of activation, than did PBMCs from healthy weight controls, despite the total number of CD8+ cells being similar between groups [12]. Moreover, CD8+ T cells from obese subjects expressed lower levels of interferon-␥ (IFN-␥) (p = 0.006) and granzyme B (p = 0.026), which are both cytokines essential for adequate CD8+ activity. Paich et al. [23] reported that CD4+ and CD8+ T cells from overweight and obese individuals expressed lower levels of CD69, CD28, and CD40 ligand, as well as interleukin (IL)-12 receptor, and produced lower levels of IFN-␥ and granzyme B, compared with healthy weight individuals. Moreover, these authors found that obese individuals had higher concentrations of IL-5, a cytokine responsible for CD4+ T cell differentiation into type 2 helper T cells (Th2), leading to an imbalance between Th1 and Th2 cells. Because obesity has been shown to dampen the potency of the immune response [24], it should be associated with a reduced immune response to TIV and an increased susceptibility to severe influenza disease. Despite these negative assumptions, in this study, it was found that overweight/obese children had a satisfactory response to TIV; in some cases, the response was even greater than that found in healthy weight controls. This phenomenon is difficult to explain. Adipokines, mainly leptin, might exert a role at this regard. These factors regulate immune system function, are significantly increased in obese individuals and might modulate response to
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TIV [25–29]. Moreover, a role could be played by diet because it has been demonstrated that diets containing n-3 polyunsaturated fatty acids (PUFAs) can impact B cell activation and antibody production [30]. In conclusion, this study suggests that TIV could adequately protect overweight/obese pediatric patients from influenza in the presence of an acceptable safety profile. Further studies are needed to evaluate whether, when and why TIV can cause in obese/overweight children an immune response greater than in healthy controls. Moreover, further researches should evaluate the differences between overweight and obese children with a 12-month-follow-up. In addition, because in children frequently the live attenuated influenza vaccine is used, further studies with this nasal vaccine can permit to complete our knowledge on the immune response of obese/overweight children to influenza vaccination. However, data collected with this study should be a stimulus to vaccinate children of excessive weight in those countries that currently recommend the influenza vaccine be given only to high-risk children. Acknowledgements This study was supported by a grant from the Italian Ministry of Health (Bando Giovani Ricercatori 2009). References [1] World Health Organization. Childhood overweight and obesity; 2015. Available from: http://www.who.int/dietphysicalactivity/childhood/en [accessed 19.11.15]. [2] Martin-Rodriguez E, Guillen-Grima F, Martí A, Brugos-Larumbe A. Comorbidity associated with obesity in a large population: the APNA study. Obes Res Clin Pract 2015 [Epub May 12]. [3] Kim YH, Kim JK, Kim DJ, Nam JH, Shim SM, Choi YK, et al. Diet-induced obesity dramatically reduces the efficacy of a 2009 pandemic H1N1 vaccine in a mouse model. J Infect Dis 2012;205:244–51. [4] Fezeu L, Julia C, Henegar A, Bitu J, Hu FB, Grobbee DE, et al. Obesity is associated with higher risk of intensive care unit admission and death in influenza A (H1N1) patients: a systematic review and meta-analysis. Obes Rev 2011;12:653–9. [5] Fiore AE, Uyeki TM, Broder K, Finelli L, Euler GL, Singleton JA, et al. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Recomm Rep 2010;59(RR-8):1–62. [6] Weber DJ, Rutala WA, Samsa GP, Santimaw JE, Lemon SM. Obesity as a predictor of poor antibody response to hepatitis B plasma vaccine. J Am Med Assoc 1985;254:3187–9. [7] Weber DJ, Rutala WA, Samsa GP, Bradshaw SE, Lemon SM. Impaired immunogenicity of hepatitis B vaccine in obese persons. N Engl J Med 1986;314:1393. [8] Banga N, Guss P, Banga A, Rosenman KD. Incidence and variables associated with inadequate antibody titers after pre-exposure rabies vaccination among veterinary medical students. Vaccine 2014;32:979–83. [9] Eliakim A, Schwindt C, Zaldivar F, Casali P, Cooper DM. Reduced tetanus antibody titers in overweight children. Autoimmunity 2006;39:137–41. [10] Sperling RS, Engel SM, Wallenstein S, Kraus TA, Garrido J, Singh T, et al. Immunogenicity of trivalent inactivated influenza vaccination received during pregnancy or postpartum. Obstet Gynecol 2012;119:631–9.
[11] Talbot HK, Coleman LA, Crimin K, Zhu Y, Rock MT, Meece J, et al. Association between obesity and vulnerability and serologic response to influenza vaccination in older adults. Vaccine 2012;30:3937–43. [12] Sheridan PA, Paich HA, Handy J, Karlsson EA, Hudgens MG, Sammon AB, et al. Obesity is associated with impaired immune response to influenza vaccination in humans. Int J Obes (Lond) 2012;36:1072–7. [13] Callahan ST, Wolff M, Hill HR, Edwards KM. Impact of body mass index on immunogenicity of pandemic H1N1 vaccine in children and adults. J Infect Dis 2014;210:1270–4. [14] Tanzi E, Esposito S, Bojanin J, Amendola A, Trabattoni D, Pariani E, et al. Immunogenicity and effect of a virosomal influenza vaccine on viral replication and T cell activation in HIV-infected children receiving highly active antiretroviral therapy. J Med Virol 2006;78:440–5. [15] Principi N, Marchisio P, Terranova L, Zampiero A, Baggi E, Daleno C, et al. Impact of vitamin D administration on immunogenicity of trivalent inactivated influenza vaccine in previously unvaccinated children. Hum Vaccin Immunother 2013;9:969–74. [16] Ansaldi F, Bacilieri S, Durando P, Sticchi L, Valle L, Montomoli E, et al. Cross-protection by MF59-adjuvanted influenza vaccine: neutralizing and haemagglutination-inhibiting antibody activity against A(H3N2) drifted influenza viruses. Vaccine 2008;26:1525–9. [17] Setti M, Fenoglio D, Ansaldi F, Filaci G, Bacilieri S, Sticchi L, et al. Flu vaccination with a virosomal vaccine does not affect clinical course and immunological parameters in scleroderma patients. Vaccine 2009;27:3367–72. [18] European Agency for the Evaluation of Medicinal Products (EMEA) – Committee for Proprietary Medicinal Products (CPMP). Note for guidance on harmonization of requirements for influenza vaccines (CPMP/BWP/214/96). London; March 1997. [19] Esposito S, Marchisio P, Prada E, Daleno C, Porretti L, Carsetti R, et al. Impact of a mixed bacterial lysate (OM-85 BV) on the immunogenicity, safety and tolerability of inactivated influenza vaccine in children with recurrent respiratory tract infection. Vaccine 2014;32:2546–52. [20] Nieman DC, Henson DA, Nehlsen-Cannarella SL, Ekkens M, Utter AC, Butterworth DE, et al. Influence of obesity on immune function. J Am Diet Assoc 1999;99:294–9. [21] Huttunen R, Syrjänen J. Obesity and the risk and outcome of infection. Int J Obes (Lond) 2013;37:333–40. [22] Costanzo AE, Taylor KR, Dutt S, Han PP, Fujioka K, Jameson JM. Obesity impairs ␥␦ T cell homeostasis and antiviral function in humans. PLOS ONE 2015;10:e0120918. [23] Paich HA, Sheridan PA, Handy J, Karlsson EA, Schultz-Cherry S, Hudgens MG, et al. Overweight and obese adult humans have a defective cellular immune response to pandemic H1N1 influenza A virus. Obesity (Silver Spring) 2013;21:2377–86. [24] van der Weerd K, Dik WA, Schrijver B, Schweitzer DH, Langerak AW, Drexhage HA, et al. Morbidly obese human subjects have increased peripheral blood CD4+ T cells with skewing toward a Treg- and Th2-dominated phenotype. Diabetes 2012;61:401–8. [25] Milner JJ, Beck MA. The impact of obesity on the immune response to infection. Proc Nutr Soc 2012;71:298–306. [26] Matarese G, Moschos S, Mantzoros CS. Leptin in immunology. J Immunol 2005;174:3137–42. [27] Nave H, Mueller G, Siegmund B, Jacobs R, Stroh T, Schueler U, et al. Resistance of Janus kinase-2 dependent leptin signaling in natural killer (NK) cells: a novel mechanism of NK cell dysfunction in diet-induced obesity. Endocrinology 2008;149:3370–8. [28] De Rosa V, Procaccini C, Calì G, Pirozzi G, Fontana S, Zappacosta S, et al. A key role of leptin in the control of regulatory T cell proliferation. Immunity 2007;26:241–55. [29] Ovsyannikova IG, White SJ, Larrabee BR, Grill DE, Jacobson RM, Poland GA. Leptin and leptin-related gene polymorphisms, obesity, and influenza A/H1N1 vaccine-induced immune responses in older individuals. Vaccine 2014;37:881–7. [30] Shaikh SR, Haas KM, Beck MA, Teague H. The effects of diet-induced obesity on B cell function. Clin Exp Immunol 2015;179:90–9.
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Immunogenicity, safety and tolerability of inactivated trivalent influenza vaccine in overweight and obese children Susanna Esposito a,∗ , Claudia Giavoli b , Claudia Trombetta c , Sonia Bianchini a , Valentina Montinaro a , Anna Spada b , Emanuele Montomoli c,d , Nicola Principi a a Paediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy b Endocrinology and Diabetology Unit, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy c Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy d VisMederi srl, Enterprise in Life Science, Italy
a r t i c l e
i n f o
Article history: Received 31 July 2015 Received in revised form 15 October 2015 Accepted 6 November 2015 Available online 19 November 2015 Keywords: Influenza Influenza vaccination Obesity Overweight Prevention Vaccination
a b s t r a c t Obesity may be a risk factor for increased hospitalization and deaths from infections due to respiratory pathogens. Additionally, obese patients appear to have impaired immunity after some vaccinations. To evaluate the immunogenicity, safety and tolerability of an inactivated trivalent influenza vaccine (TIV) in overweight and obese children, 28 overweight/obese pediatric patients and 23 healthy normal weight controls aged 3–14 years received a dose of TIV. Four weeks after vaccine administration, significantly higher seroprotection rates against the A/H1N1 strain were observed among overweight/obese children compared with normal weight controls (p < 0.05). Four months after vaccination, similar or slightly higher seroconversion and seroprotection rates against the A/H1N1 and A/H3N2 strains were detected in overweight/obese than in normal weight children, whereas significantly higher rates of seroconversion and seroprotection against the B strain were found in overweight/obese patients than in normal weight controls (p < 0.05 for seroconversion and seroprotection). Geometric mean titers (GMTs) and fold increase against B strains were significantly higher in overweight/obese patients than in normal weight controls 4 months after vaccine administration (p < 0.01 for GMT values and p < 0.05 for fold increase). The frequency of local and systemic reactions was similar between the groups, and there were no serious adverse events. The results of this study indicate that in overweight and obese children, antibody response to TIV administration is similar or slightly higher than that evidenced in normal weight subjects of similar age and this situation persists for at least 4 months after vaccine administration in the presence of a favorable safety profile. © 2015 Elsevier Ltd. All rights reserved.
1. Introduction The incidence of overweight and obese children has increased at an alarming rate worldwide. The World Health Organization (WHO) has estimated that in 2013 the total number of overweight children under the age of 5 years was over 42 million [1]. This causes relevant clinical problems. A reduction in life expectancy of obese subjects due to comorbidities such as cardiovascular diseases, insulin
∗ Corresponding author at: Paediatric Highly Intensive Care Unit, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Via Commenda 9, 20122 Milano, Italy. Tel.: +39 02 55032498; fax: +39 02 50320206. E-mail address: [email protected] (S. Esposito). http://dx.doi.org/10.1016/j.vaccine.2015.11.019 0264-410X/© 2015 Elsevier Ltd. All rights reserved.
resistance with development of type 2 diabetes, and increased susceptibility to infection has been repeatedly reported [2]. Epidemiological evidence suggests that obesity alone, independent of the comorbidities, is a relevant risk factor for increased hospitalization and death from infections due to respiratory pathogens, mainly influenza viruses. This has been clearly evidenced in recent years in both experimental animal models and in humans [3,4]. Kim et al. reported that in diet-induced obese mice infected with pandemic 2009 A/H1N1 (pA/H1N1) influenza virus, virus titers, tissue pathology and expression of mRNAs for proinflammatory cytokines and chemokines in the lungs of these animals were significantly higher than in lean controls [3]. Moreover, it has been reported that in both children and adults, obesity emerged as an important risk factor for morbidity and mortality during the 2009 influenza pandemic [4]. This explains why, in 2010,
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the Advisory Committee on Immunization Practice (ACIP) in the United States of America added obesity to the list of clinical conditions for which influenza vaccination is strongly recommended, at least in the case of morbid obesity (body mass index [BMI] ≥40 in adults) [5]. Unfortunately, the protection offered by influenza vaccines to obese and overweight subjects has not been established. Usually, although with some limitations, seroconversion, seroprotection, geometric mean titers (GMT), and fold increase evaluated through the haemagglutination-inhibiting (HI) antibodies are considered correlates of protection against influenza [5]. The evidence that obesity is a risk factor for reduced immune responses to vaccines for hepatitis A and B [6,7] and rabies in adults [8], as well as to the tetanus vaccine in children [9], seems to suggest a potential risk for a poor immune response to influenza vaccination. Moreover, some studies have shown that influenza immunity is impaired in obese animals, and that obese mice vaccinated with commercial monovalent pA/H1N1 influenza vaccine were not protected from pandemic influenza [3]. However, the results of most of the studies carried out in humans conflict with these experimental evaluations and with the results of studies carried out with non-influenza vaccines. Sperling et al. examined pregnant and postpartum obese women and reported that they had immune responses similar to that of normal subjects, with only slightly lower odds of seroconversion [10]. Talbot et al. reported that immunogenicity of a seasonal trivalent inactivated influenza vaccine (TIV) was similar in obese and lean older adults, with a slight increase in seroconversion for the A/H3N2 virus but not for the other viruses [11]. Sheridan et al. evidenced that obese adults had a higher initial fold increase in IgG antibodies after TIV administration, although 12 months after vaccination, a higher BMI was associated with a greater decline in influenza antibody titers [12]. Callahan et al. studied adults and a small number of children and adolescents and found that age could significantly condition the immune response to monovalent pA/H1N1 influenza vaccine in overweight and obese subjects [13]. In adults, they found that the amount of antibody production 21 days after a single vaccine administration was significantly higher in obese patients than in lean subjects. By contrast, they evidenced no significant differences in immune response among children and adolescents of various BMI that had received two doses of the vaccine, after either vaccine dose 1 or 2 [13]. However, because the study by Callahan et al. is the only one involving children and adolescents [13], further data are needed to know whether obese and overweight pediatric subjects can be protected by influenza vaccines. This study was therefore planned to increase our knowledge in this regard.
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trivalent influenza vaccine (Fluarix, GlaxoSmithKline Biologicals, Rixensart, Belgium) in already primed children aged 3–14 years with documented overweight or obesity and in healthy controls. Children with any serious chronic disease (i.e., chronic pulmonary diseases including asthma, signs of cardiac or renal failure, severe malnutrition, or progressive neurological diseases), Down syndrome or other known cytogenetic disorder, or a known or suspected disease of the immune system were excluded, as were those who had received immunosuppressive therapy, including systemic corticosteroids at a prednisone-equivalent dosage of 2 mg/kg per day (or a total of 20 mg per day) for more than 14 days, and those with a documented history of hypersensitivity to egg, egg protein, or any other component of the vaccine. Vaccine components for the 2014–2015 Northern hemisphere influenza season included an A/California/7/2009 (H1N1) pdm09-like virus, an A/Texas/50/2012 (H3N2)-like virus, and a B/Massachusetts/2/2012-like virus. Overweight/obese children were selected from those attending the endocrinology outpatient clinic for diet-induced overweight and obesity, whereas children of similar age and gender with normal weight for height were randomly selected from those attending the hospital’s outpatient clinic for a follow-up visit following a previous minor surgical intervention carried out 3 months before enrolment in Day-Surgery without general anesthesia. In all of the enrolled children, height and weight were measured by research staff, and BMI was calculated as weight (kg)/height (m)2 . Age- and gender-specific z-scores for BMI were calculated using software available from the Centers for Disease Control and Prevention (CDC), based on the 2000 CDC growth charts to define BMI categories of normal weight (5–84th percentile), overweight (85–94th percentile) and obese (≥95th percentile). Patients and controls were vaccinated between 1 October and 15 November 2014 by means of an injection in the deltoid region of the left arm. Serum samples for the immunogenicity assessments were collected before the first vaccination dose on days 1 (baseline), 28 ± 3, and 120 ± 7 after vaccine administration. Safety was assessed by collecting data concerning any local and systemic reactions (from the investigators at baseline in the 30 min following vaccine’s administration, thereafter reported from the children’s parents/legal guardians for the 14 days after vaccination using a diary card), as previously described [14,15]. The children were evaluated for the occurrence of local adverse events (i.e., erythema, swelling/induration, and pain) (AEs) and questioned about systemic AEs (i.e., body temperature ≥38 ◦ C, rhinitis, irritability, sleepiness, changed eating habits, vomiting, and diarrhea). 2.2. Assessment of humoral immune response
2. Materials and methods 2.1. Study design This prospective study was carried out at the Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy, between 1 October 2014 and 31 March 2015. The study protocol was approved by the Ethics Committee of the Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, and the study was conducted in accordance with the standards of Good Clinical Practice for trials of medicinal products in humans. Written informed consent was obtained from the parents/legal guardians of each enrolled child and written consent was obtained from children aged ≥8 years. The study compared the immunogenicity, safety, and tolerability of a standard intramuscular (i.m.) dose of a split-virion
The titers of HI antibodies against each of the three influenza strains contained in the 2014–2015 influenza vaccine formulation were determined in all of the children on days 1, 28 ± 3 and 120 ± 7 as previously described [16,17]. The results were expressed as the reciprocal of the highest dilution inhibiting agglutination. To calculate GMTs, a titer of 1:5 was arbitrarily assigned to nonresponders [16,17]. The immunogenicity end-points were based on the HI licensure criteria established by the guideline of the European Medicines Agency (EMA) [18]. As there are no EMA-defined criteria for children, immunogenicity was evaluated using the criteria for adults aged 18–60 years, which require at least one of the following for each strain: (1) seroconversion, a ≥4-fold increase in HI antibody titer with a titer of ≥1:40 being reached in >40% of the subjects; (2) seroprotection, an HI antibody titer of ≥1:40 in >70% of the subjects; or (3) GMT, a >2.5-fold increase in the GMT of HI antibodies.
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2.3. Statistical analysis The continuous variables are presented as the mean ± standard deviation (SD), and the categorical variables are presented as numbers and percentages. The continuous data were analyzed using a two-sided Student’s test whether they were normally distributed (on the basis of the Shapiro–Wilk statistic) or a two-sided Wilcoxon rank-sum test if they were not. The categorical data were analyzed using a contingency table analysis and the 2 or Fisher’s test, as appropriate. All of the analyses were two-tailed, and p values of 0.05 or less were considered significant. The analyses were conducted using SAS version 9.2 (Cary, NC, USA).
Table 1 Baseline characteristics of children vaccinated with trivalent inactivated influenza vaccine, according to their weight status.a Overweight/ obese (n = 28)
Normal weight (n = 23)
p-Value
BMI Mean ± SD
24.1 ± 3.9
16.4 ± 2.3
<0.001
Age (years) Mean ± SD
10.9 ± 3.2
10.7 ± 3.7
0.99
Sex Male Female
14 (50.0) 14 (50.0)
13 (56.5) 10 (43.5)
0.64
14 (51.8) 13 (48.2)
14 (60.9) 9 (39.1)
0.52
11 (39.3)
7 (31.8)
17 (60.7)
15 (68.2)
0.59
10 (35.7) 7 (25.0)
2 (8.7) 0 (0.0)
0.02 0.01
4 (14.3) 16 (57.1) 8 (28.6) 14 (50.0) 3/27 (11.1) 25/28 (89.3)
2 (8.7) 13 (56.5) 8 (34.8) 8 (34.8) 3/23 (13.0) 14/22 (63.6)
0.78 0.27 0.99 0.04
15 (53.6)
10 (43.5)
0.47
2 (7.1)
3 (13.0)
0.65
2 (7.1)
2 (8.7)
0.99
2 (7.1)
5 (21.7)
0.22
Characteristic
b
3. Results
Ethnicity Caucasian Non-Caucasian b
3.1. Population A total of 28 overweight/obese children were enrolled. Of these, 14 (50.0%) children were overweight, and 14 (50.0%) children were obese. All of the children completed all the study visits. A total of 28 children with normal weight for their height were initially enrolled. Unfortunately, 5 of these subjects did not return for control visits after vaccine administration and were withdrawn from the study. Moreover, one overweight/obese child could not be tested after 28 ± 3 days for difficulties in obtaining an adequate volume of blood, whereas three overweight/obese children and two healthy weight children could not be tested after 120 ± 7 days for the same reason. Consequently, analysis of the immune response to TIV administration was carried out in 28 overweight/obese and 23 normal weight children. Because a preliminary analysis did not show any difference in general characteristics, immune response, or adverse events incidence between overweight and obese children, the two subgroups of patients were considered together. Table 1 lists the general characteristics of the children who entered the study. As shown, overweight/obese children had a significantly higher BMI (p < 0.001), were more likely to have obese relatives (p = 0.02) and obese parents (p = 0.01), and were more often breastfed in the first months of life (p = 0.04) than normal weight controls. No significant differences in any other studied variable (age, sex, ethnicity, education of parents, number of siblings, parental allergies, preterm birth status, respiratory infections and hospitalization rates in the previous 6 months, and use of steroids and antibiotics in the previous 3 months) were evidenced between the groups. 3.2. Immune response to TIV administration Table 2 shows the immune responses of the two groups after the administration of the vaccine. Less than 20% of the overweight/obese patients and normal weight controls had baseline-specific antibody titers ≥40 upon HI assay against the A/H1N1 and B influenza viruses, whereas more than 40% of the overweight/obese patients and approximately 30% of the normal weight controls had baseline-specific antibody titers of ≥40 upon HI assay against the A/H3N2 strain. Four weeks after vaccine administration, the overweight/obese patients and normal weight controls had seroconversion rates of 81.5% and 60.9% against A/H1N1, 63.0% and 65.2% against A/H3N2, and 74.1% and 60.9% against the B strain, respectively, with no significant betweengroup difference. The seroprotection rates were 96.3% and 73.9% against A/H1N1, 96.3% and 87.0% against A/H3N2, and 81.5% and 69.6% against the B strain for overweight/obese patients and normal weight controls, respectively, with significantly higher seroprotection rates against A/H1N1 strain among patients than among controls (p < 0.05). Four months after vaccination, most of the overweight/obese patients and normal weight subjects remained
Education of parents No high school (or higher) degree ≥1 with high school (or higher) degree Obese relatives (at least one) Obese parents (at least one) No. of siblings 0 1 ≥2 Parental allergies Preterm birthb Breastfed (for at least 3 months)b Respiratory infections (last 6 months) Hospitalization (last 6 months) Systemic steroid use (last 3 months) Antibiotic use (last 3 months)
BMI, body mass index; SD, standard deviation. Percentages in parentheses. a Information from five children with normal weight lost to follow-up was not included in the table. b The sums do not add up to the total because of missing values.
seroconverted and were still seroprotected, with similar or slightly higher seroconversion and seroprotection rates in patients than in controls against the A/H1N1 and A/H3N2 strains. Furthermore, significantly higher rates of seroconversion and seroprotection against the B strain were found among overweight/obese patients than among normal weight controls (p < 0.05 for both seroconversion and seroprotection rates). GMTs and fold increase against A/H1N1 and A/H3N2 strains were not different between the groups, but they were significantly higher among overweight/obese patients than among normal weight controls 4 months after vaccine administration against the B strain (p < 0.01 for GMT values and p < 0.05 for fold increase). 3.3. Safety and tolerability of TIV Table 3 summarizes the incidence of local and systemic reactions in overweight/obese patients and in normal weight controls during the 14 days after vaccination. The frequency of local and systemic reactions was similar between the groups without any statistically significant difference although for some local reactions, such as pain, a trend toward a greater prevalence in obese children was evidenced. No serious adverse events occurred. 4. Discussion The results of this study indicate that the antibody response to TIV administration is similar or slightly higher in overweight/obese
S. Esposito et al. / Vaccine 34 (2016) 56–60 Table 2 Haemagglutination inhibition (HI) antibody responses against seasonal influenza strains after vaccination with trivalent inactivated influenza vaccine in overweight/obese and normal weight children.a Immune response A/H1N1 Seroconversionb , no. (%) After 28 ± 3 days After 120 ± 7 days Seroprotectionc , no. (%) Baseline After 28 ± 3 days After 120 ± 7 days GMT Baseline After 28 ± 3 days (fold increase) After 120 ± 7 days (fold increase) A/H3N2 Seroconversionb , no. (%) After 28 ± 3 days After 120 ± 7 days Seroprotectionc , no. (%) Baseline After 28 ± 3 days After 120 ± 7 days GMT Baseline After 28 ± 3 days (fold increase) After 120 ± 7 days (fold increase)
Overweight/ obese (n = 28)
Normal weight (n = 23)
14/23 (60.9) 15/21 (71.4)
0.11 0.73
6/28 (21.4) 26/27 (96.3) 24/25 (96.0)
4/23 (17.4) 17/23 (73.9) 19/21 (90.5)
0.99 0.04 0.59
11.0 354.6 (31.2)
9.7 146.2 (15.1)
0.76 0.08 (0.19)
263.5 (21.7)
230.0 (22.6)
0.70 (0.96)
17/27 (63.0) 16/25 (64.0)
15/23 (65.2) 12/21 (57.1)
0.87 0.64
12/28 (42.9) 26/27 (96.3) 22/25 (88.0)
7/23 (30.4) 20/23 (87.0) 18/21 (85.7)
0.36 0.32 0.99
25.3 359.2 (13.4)
16.7 275.3 (16.5)
0.44 0.53 (0.71)
235.9 (12.3)
241.7 (15.2)
0.96 (0.73)
20/27 (74.1) 18/25 (72.0)
14/23 (60.9) 8/21 (38.1)
0.32 0.02
5/28 (17.9) 22/27 (81.5) 20/25 (80.0)
3/23 (13.0) 16/23 (69.6) 10/21 (47.6)
0.72 0.33 0.02
8.7 119.1 (13.4)
7.0 59.2 (8.5)
0.46 0.19 (0.38)
93.2 (10.0)
21.7 (3.4)
0.006 (0.03)
B Seroconversionb , no. (%) After 28 ± 3 days After 120 ± 7 days Seroprotectionc , no. (%) Baseline After 28 ± 3 days After 120 ± 7 days GMT Baseline After 28 ± 3 days (fold increase) After 120 ± 7 days (fold increase)
Table 3 Comparison of local and systemic adverse events in overweight/obese and normal weight children.a Type of event
p-Valued
22/27 (81.5) 19/25 (76.0)
GMT, geometric mean titers. a One overweight/obese child could not be tested after 28 ± 3 days, whereas three overweight/obese children and two healthy weight children could not be tested after 120 ± 7 days. b ≥4-fold increase in haemagglutination inhibition (HI) titer. c HI titer ≥40. d p-Values from 2 or Fisher’s exact test (as appropriate, for categorical variables) or from Student’s t-test (for continuous variables).
children than that evidenced in normal weight subjects of similar age and that this situation persists for at least 4 months after vaccine administration. In comparison with normal weight controls, the greatest difference in favor of overweight/obese patients was found regarding influenza B virus, the TIV component against which the immune response in normal subjects is frequently the lowest [14,15,19]. This study enrolled a relatively low number of patients and for this the evaluation of the relationships between BMI and response to TIV was not possible. Moreover, it was likely underpowered to detect all the effects of TIV administration also comparing overweight with obese children, particularly for immunogenicity and incidence of minor adverse events. However, a trend toward a greater seroconversion rate and a higher GMT against A/H1N1 at 28 days after administration together with an increase in the incidence of some local adverse events was evidenced in overweight/obese children. These findings deserve
59
Local adverse event Pain Erythemab Induration Swelling Any local adverse event Systemic adverse event Fever Changes in eating habits Sleepiness Vomiting/diarrhea Irritability Rash/any other Any systemic adverse event
Overweight/ obese (n = 28)
Normal weight (n = 23)
p-Valuec
8 (29.6) 7 (28.0) 4 (14.8) 6 (22.2) 10 (37.0) 1 (3.7)
2 (8.7) 2 (8.7) 2 (8.7) 1 (4.3) 3 (13.0) 2 (8.7)
0.09 0.14 0.67 0.11 0.10 0.59
2 (7.4) 4 (14.8) 4 (14.8) 2 (7.4) 0 (0.0) 7 (25.9)
0 (0.0) 1 (4.3) 1 (4.3) 0 (0.0) 0 (0.0) 3 (13.0)
0.49 0.36 0.36 0.49 – 0.31
Percentages in parentheses. a Safety data are not available for one child from the overweight/obese group. b Two additional children are missing data. c p-Values from 2 or Fisher’s exact test, as appropriate.
attention and further studies enrolling a greater number of overweight (obese subjects are needed to detail the response of these patients to TIV administration. However, data collected with this study seem to suggest that overweight and obese children might be adequately protected against influenza by TIV without any risk of severe adverse events. Although a normal or elevated immune response in obese subjects to at least some TIV components has been previously reported [10–13], the findings of this study remain surprising. Studies in experimental animals and humans have suggested that obesity is associated with an impairment of several immune system functions that should lead to poor antibody response to vaccination [6–9]. Elevation of leukocyte and lymphocyte subset counts, reduction of T- and B-cell function, an increase in monocyte and granulocyte phagocytosis and an increase in oxidative burst activity were common findings in obese subjects [20–22]. Certain data collected from influenza-vaccinated obese individuals are consistent with immune system impairment in obesity. Sheridan et al. reported that 12 months after TIV administration, peripheral blood mononuclear cells (PBMCs) of obese subjects had a significantly lower increase in the percentage of CD8+ T cell surface marker CD69 (p = 0.015), a marker of activation, than did PBMCs from healthy weight controls, despite the total number of CD8+ cells being similar between groups [12]. Moreover, CD8+ T cells from obese subjects expressed lower levels of interferon-␥ (IFN-␥) (p = 0.006) and granzyme B (p = 0.026), which are both cytokines essential for adequate CD8+ activity. Paich et al. [23] reported that CD4+ and CD8+ T cells from overweight and obese individuals expressed lower levels of CD69, CD28, and CD40 ligand, as well as interleukin (IL)-12 receptor, and produced lower levels of IFN-␥ and granzyme B, compared with healthy weight individuals. Moreover, these authors found that obese individuals had higher concentrations of IL-5, a cytokine responsible for CD4+ T cell differentiation into type 2 helper T cells (Th2), leading to an imbalance between Th1 and Th2 cells. Because obesity has been shown to dampen the potency of the immune response [24], it should be associated with a reduced immune response to TIV and an increased susceptibility to severe influenza disease. Despite these negative assumptions, in this study, it was found that overweight/obese children had a satisfactory response to TIV; in some cases, the response was even greater than that found in healthy weight controls. This phenomenon is difficult to explain. Adipokines, mainly leptin, might exert a role at this regard. These factors regulate immune system function, are significantly increased in obese individuals and might modulate response to
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TIV [25–29]. Moreover, a role could be played by diet because it has been demonstrated that diets containing n-3 polyunsaturated fatty acids (PUFAs) can impact B cell activation and antibody production [30]. In conclusion, this study suggests that TIV could adequately protect overweight/obese pediatric patients from influenza in the presence of an acceptable safety profile. Further studies are needed to evaluate whether, when and why TIV can cause in obese/overweight children an immune response greater than in healthy controls. Moreover, further researches should evaluate the differences between overweight and obese children with a 12-month-follow-up. In addition, because in children frequently the live attenuated influenza vaccine is used, further studies with this nasal vaccine can permit to complete our knowledge on the immune response of obese/overweight children to influenza vaccination. However, data collected with this study should be a stimulus to vaccinate children of excessive weight in those countries that currently recommend the influenza vaccine be given only to high-risk children. Acknowledgements This study was supported by a grant from the Italian Ministry of Health (Bando Giovani Ricercatori 2009). References [1] World Health Organization. Childhood overweight and obesity; 2015. Available from: http://www.who.int/dietphysicalactivity/childhood/en [accessed 19.11.15]. [2] Martin-Rodriguez E, Guillen-Grima F, Martí A, Brugos-Larumbe A. Comorbidity associated with obesity in a large population: the APNA study. Obes Res Clin Pract 2015 [Epub May 12]. [3] Kim YH, Kim JK, Kim DJ, Nam JH, Shim SM, Choi YK, et al. Diet-induced obesity dramatically reduces the efficacy of a 2009 pandemic H1N1 vaccine in a mouse model. J Infect Dis 2012;205:244–51. [4] Fezeu L, Julia C, Henegar A, Bitu J, Hu FB, Grobbee DE, et al. Obesity is associated with higher risk of intensive care unit admission and death in influenza A (H1N1) patients: a systematic review and meta-analysis. Obes Rev 2011;12:653–9. [5] Fiore AE, Uyeki TM, Broder K, Finelli L, Euler GL, Singleton JA, et al. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Recomm Rep 2010;59(RR-8):1–62. [6] Weber DJ, Rutala WA, Samsa GP, Santimaw JE, Lemon SM. Obesity as a predictor of poor antibody response to hepatitis B plasma vaccine. J Am Med Assoc 1985;254:3187–9. [7] Weber DJ, Rutala WA, Samsa GP, Bradshaw SE, Lemon SM. Impaired immunogenicity of hepatitis B vaccine in obese persons. N Engl J Med 1986;314:1393. [8] Banga N, Guss P, Banga A, Rosenman KD. Incidence and variables associated with inadequate antibody titers after pre-exposure rabies vaccination among veterinary medical students. Vaccine 2014;32:979–83. [9] Eliakim A, Schwindt C, Zaldivar F, Casali P, Cooper DM. Reduced tetanus antibody titers in overweight children. Autoimmunity 2006;39:137–41. [10] Sperling RS, Engel SM, Wallenstein S, Kraus TA, Garrido J, Singh T, et al. Immunogenicity of trivalent inactivated influenza vaccination received during pregnancy or postpartum. Obstet Gynecol 2012;119:631–9.
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