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Immunogenicity and safety of a monovalent vaccine for the 2009 pandemic influenza virus A (H1N1) in children and adolescents
Vaccine 28 (2010) 5864–5870
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Immunogenicity and safety of a monovalent vaccine for the 2009 pandemic influenza virus A (H1N1) in children and adolescents Chun-Yi Lu a , Pei-Lan Shao a , Luan-Yin Chang a , Yhu-Chering Huang b , Cheng-Hsun Chiu b , Yu-Chia Hsieh b , Tzou-Yien Lin b,∗∗ , Li-Min Huang a,∗ a b
Department of Pediatrics, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan
a r t i c l e
i n f o
Article history: Received 4 February 2010 Received in revised form 4 June 2010 Accepted 18 June 2010 Available online 13 July 2010 Keywords: H1N1 Vaccine Children
a b s t r a c t The 2009 pandemic influenza A (H1N1) has caused significant morbidity and mortality around the world. Safety and immunogenicity studies of 2009 pandemic influenza A (H1N1) virus in children and adolescents are limited. In this prospective, open-label study, 2 doses of a monovalent, unadjuvanted, inactivated, split-virus 2009 pandemic influenza virus A (H1N1) vaccine (AdimFlu-S) were administered to 183 healthy children and adolescents aged 1–17 years. Adverse reactions were assessed, and hemagglutination inhibition antibody titers were determined. Three weeks after the first dose, 36.2% of children aged 1–2 years, 52.5% of children aged 3–5 years, 56.7% of children aged 6–9 years, and 90.3% of adolescents aged 10–17 years generated protective antibodies. A second vaccination given 3 weeks later induced protective antibodies in 89.4% of all age groups. No severe adverse effects were found 6 weeks after vaccination. © 2010 Elsevier Ltd. All rights reserved.
1. Introduction A newly emerged novel influenza A (H1N1) virus that was first identified in Mexico in spring 2009 has continued to spread rapidly throughout the world. On June 11, 2009, the World Health Organization (WHO) declared a worldwide pandemic of the novel influenza A (H1N1) virus [1,2]. The 2009 pandemic influenza A (H1N1) virus contains a novel constellation of gene segments, which most likely stemmed from triple re-assortment of two or more viruses of swine, human, and avian origin [3]. Serological studies have shown that seasonal influenza vaccines conferred no protection against this new pandemic H1N1 virus [4]. A safe and effective vaccine for the 2009 pandemic influenza A (H1N1) virus is urgently needed. Many governments and vaccine makers have begun producing vaccines for the 2009 pandemic influenza A (H1N1) virus. However, reports of clinical trials on the safety and immunogenicity of vaccines for this virus are limited. A trial performed in Australia showed a single dose of a monovalent, unadjuvanted, inactivated,
∗ Corresponding author at: Department of Pediatrics, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100, Taiwan. Tel.: +886 931034642; fax: +886 2 23147450. ∗∗ Corresponding author at: Department of Pediatrics, Chang Gung Children’s Hospital, Chang Gung University, No. 5, Fu-Hsing Street, Kweishan, Taoyuan 333, Taiwan. E-mail addresses: [email protected] (T.-Y. Lin), [email protected] (L.-M. Huang). 0264-410X/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2010.06.059
split-virus 2009 pandemic influenza A (H1N1) vaccine (CSL Biotherapies, Australia) was safe and capable of inducing seroconversions in 70.8% of subjects receiving 15 g of hemagglutinin antigen and 77.5% subjects receiving 30 g [5]. Another trial using a MF59adjuvanted monovalent pandemic influenza A (H1N1) 2009 vaccine (Novartis, Germany) demonstrated a good safety profile and seroconversion in up to 96% of subjects [6]. Unfortunately, children aged 18 years or under were not included in both trials. A large-scale trial performed in China revealed that subjects aged 3–11 years receiving a single 15-g dose of 2009 pandemic influenza vaccine (Hualan Biological Bacterin Company, China) showed less robust immune responses compared to subjects between 12 and 60 years of age [7]. No children aged less than 3 years were included in the study. In a phase 2 trials done in USA, 45% (45/101) and 50% (47/94) of children aged 6–35 months showed seroprotection after a single dose of a 2009 pandemic H1N1 vaccine (Fluzone; Sanofi-Pasteur, USA) containing 7.5 or 15 g hemagglutinin, respectively [8]. We undertook a clinical trial in healthy children and adolescents to investigate the immunogenicity and safety of a monovalent, split-virus pandemic influenza A (H1N1) vaccine (AdimFlu-S) produced in Taiwan. 2. Subjects and methods 2.1. Study design This was a prospective, open-label, laboratory-blinded study in healthy children and adolescents designed to investigate the
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safety and immunogenicity of an inactivated influenza H1N1 vaccine (AdimFlu-S, A/H1N1). There were 4 age strata: 1–2 years old, 3–5 years, 6–9 years, and 10–17 years. In each age strata, all subjects received one of two designated doses (7.5 g for the 1–2 years group, and 15 g for the other age groups) of AdimFlu-S at an interval of 3 weeks (±3 days). Following immunization, safety was measured by assessment of the reactogenicity to the vaccines for 7 days following each vaccination, adverse events for 6 weeks following the first vaccination, and serious adverse events and new-onset chronic medical conditions through 7 months post first vaccination. Immunogenicity testing included hemagglutination inhibition (HAI) testing on serum obtained before the first vaccination and three weeks after the first and second vaccinations.
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2.5. Laboratory assays The HAI assay was used to determine the anti-influenza antibody titers for all study subjects at enrollment and 21 days after each vaccination. The specimens were tested in duplicate. The immunogenicity profiles including the seroprotection rate (the proportion of subjects with antibody levels of 1:40 or more as determined by HAI assay), seroconversion rate (the proportion of subjects with a pre-vaccination HAI antibody titer <1:10 and a post-vaccination titer ≥1:40 or a pre-vaccination titer ≥1:10 and an increase in the titer by a factor of four or more) and GMT fold rises were summarized. The exact (Clopper–Pearson) method was applied to calculate the 95% confidence interval on seroprotection and seroconversion rate. 2.6. Ethics
2.2. Vaccine The 2009 pandemic influenza A (H1N1) virus vaccine (AdimFluS, A/H1N1) used in this study was produced by Adimmune (Taichung, Taiwan) in embryonated chicken eggs using standard techniques for the production of seasonal inactivated influenza vaccines. It is a monovalent, unadjuvanted, inactivated, split-virus vaccine. The seed virus was supplied by the US Centers for Diseases Control and Prevention and prepared from the reassortant vaccine virus NYMC-179A, derived from the A/California/7/2009 (H1N1) virus. The vaccine contained 30 g of hemagglutinin (HA) per milliliter, 0.01% (w/v) thimerosal as a preservative, <0.01% (w/v) formaldehyde and <0.01% (v/v) polysorbate 80 as stabilizers.
2.3. Study population Healthy children aged 1–17 years were eligible for enrollment. To be included in the study, subjects and/or their parent(s)/legal guardian(s) needed to be willing to comply with the planned study procedures. Subjects who had received influenza vaccines (seasonal or investigational) within the previous 6 months were excluded from the study. Subjects should not have had influenza like illness as defined by the presence of fever (temperature ≥38.5 ◦ C) and at least two of the following four symptoms: headache, myalgia/arthralgia, sore throat and cough. Subjects with the following conditions were also excluded: a history of hypersensitivity to eggs or egg protein, a personal or family history of Guillain–Barré syndrome, an acute febrile illness within the last 72 h prior to vaccination, female subjects who were pregnant, lactating or likely to become pregnant during the study, and subjects who were receiving any other investigational medicine or device within the 3 months before consent.
2.4. Assessment of safety A 7-day diary card was used to record pre-specified adverse events during the immediate post-vaccination period by all participants. The events included fever (≥38 ◦ C), nasal congestion, cough, sore throat, muscle aches, headache, vomiting, nausea and malaise. Furthermore, the local (injection site) reactions including soreness/pain, swelling, redness, ecchymosis and limitation of arm motion were also evaluated. In order to monitor the occurrence of rare neurological complications, e.g., optic neuritis, cranial neuropathy, brachial neuropathy, and Guillain–Barré syndrome, after vaccination, all reactogenicity/adverse events would be monitored up to 7 months after the last vaccination.
The protocol, amendments, informed consent form, and all other forms of patient’s information related to the study were reviewed and approved by the Institutional Review Board. A voluntary written informed consent form was signed by each subject or guardian. 3. Results A total of 183 subjects from the National Taiwan University Hospital and Chang Gung Memorial Hospital were enrolled into this study. The first subject received the first dose of the study vaccine on October 2, 2009. Demographic data including gender, age, body weight, and pre-vaccination antibody positivity are summarized in Table 1. All subjects receiving at least one dose of the study vaccine were included in the safety population. Two subjects in the 1–2 years and one subject in the 3–5 years age groups were not assigned to the correct group and were excluded from the immunogenicity analysis. One subject withdrew before receiving the second dose and was excluded from the analysis of immunogenicity at week 6. 3.1. Immunogenicity Prior to the vaccination, 13 of 180 subjects (7.2%) had antibody titers of 1:40 or more. Table 2 shows the percentage of subjects with seroprotection by age group; no significant difference in seroprotection rates was found between age groups prior to the vaccination. Three weeks after the first vaccination, seroprotective response was observed in 36.2% of children aged 1–2 years; 52.5% aged 3–5 years; 56.7% aged 6–9 years; and 90.3% aged 10–17 years (Table 2). A second dose of the study vaccine, given 3 weeks later, successfully increased the proportion of subjects with HAI titers of 1:40 or more in all age groups. Overall, protective anti-HA antibodies were detected in 89.4% of study subjects after the second dose (Table 2). Subjects aged 10–18 years showed the highest response rate, 96.8%. In addition to the proportion of study subjects having HAI titers higher than 1:40, we also looked at the seroconversion rates. Again, subjects in the younger age groups showed lower seroconversion rates after the first dose of the study vaccine. Only 27.6%, 44.3%, and 46.7% of subjects showed seroconversion in subjects aged 1–2 years, 3–5 years, and 6–9 years, respectively. Age-related differences were found among subjects receiving 15 g HA, with significantly higher seroconversion rates in subjects who were 10 years old or above, 83.9% (Table 2). The seroconversion rates increased after the second dose in all age groups, with 75.4% of subjects aged 1–2 years, 80.3% aged 3–5 years of age, 80.0% aged 6–9 years of age and 87.1% aged 10–17 years of age showing seroconversion. Before the first vaccine dose, the mean antibody GMTs were within the same range (8.2–12.0) in all age groups (Table 2). After
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Table 1 Demographics of all vaccinated children and adolescents in the different age groups. Age group Sex (no. (%)) Boy Girl Age (years) Mean ± SD Median Range Body weight (kg) Mean ± SD Median Range Pre-vaccination antibody titera (no. (%)) HAI < 1:10 HAI ≥ 1:10 HAI ≥ 1:40 a
1–2 years (N = 60)
3–5 years (N = 62)
6–9 years (N = 30)
10–17 years (N = 31)
All (N = 183)
31 (51.7%) 29 (48.3%)
27 (43.5%) 35 (56.5%)
8 (26.7%) 22 (73.3%)
19 (61.3%) 12 (38.7%)
85 (46.4%) 98 (53.6%)
2.1 ± 0.4 2.0 1.0–2.9
4.3 ± 0.9 4.0 3.0–5.99
7.7 ± 1.1 7.6 6.1–9.98
13.6 ± 1.9 13.1 10.5–17.5
5.7 ± 4.2 4.2 1.0–17.5
12.4 ± 2.1 12.0 7.5–19.5
16.9 ± 3.2 17.0 12–27
27.4 ± 8.0 24.7 18.0–50.2
53.0 ± 13.4 52.0 32.0–90.0
23.3 ± 15.9 17.0 7.5–90.0
37 (61.7%) 23 (38.3%) 4 (6.6%)
36 (58.1%) 26 (41.9%) 2 (3.2%)
17 (56.7%) 13 (43.3%) 2 (6.7%)
14 (45.2%) 17 (54.8%) 5 (16.1%)
104 (56.8%) 79 (43.2%) 13 (7.1%)
Antibody titer was determined by the hemagglutination inhibition (HAI) assay.
the first dose, the fold increase in GMT was significantly higher among adolescents aged 10–17 years than children aged less than 10 years. Three weeks after the first vaccination, the GMTs from pre-vaccination levels increased 2.4-fold, 3.3-fold, 5.3-fold, and 25.3-fold for children aged 1–2, 3–5, 6–9 and 10–17 years respectively. Second dose of vaccine further boosted the antibody titers in subjects less than 10 years old. Three weeks after the second vaccination, the GMTs from pre-vaccination levels increased 7.1-fold,
8.5-fold, 9.6-fold, and 20.5-fold for children aged 1–2, 3–5, 6–9 and 10 to <18 years, respectively (Table 2). Fig. 1 shows the accumulating percentage of subjects having different levels of HAI titers against the 2009 pandemic influenza A (H1N1) virus before and after vaccinations in the different age groups. Again, a single vaccination results in strong antibody responses in the adolescent group. A second vaccination induced a booster response and resulted in satisfying antibody production
Table 2 Immune responses to one and two doses of an inactivated 2009 novel influenza A (H1N1) vaccine in children aged 1–18 years. Age group Pre-vaccination (N)
1–2 years 58
3–5 years 61
6–9 years 30
10–17 years 31
All 180
HAIa titer ≥ 1:40 N % (95% CI) Geometric mean titer Value (95% CI)
4 6.9 (1.9–16.7)
2 3.3 (0.4–11.3)
2 6.7 (0.8–22.1)
5 16.1 (5.5–33.7)
13 7.2 (3.9–12.0)
8.7 ± 2.31 (6.9–10.8)
8.2 ± 1.98 (6.9–9.8)
8.5 ± 2.01 (6.6–11.0)
12.0 ± 2.79 (8.2–17.4)
9.0 ± 2.25 (8.0–10.1)
Age group Post first vaccination (N)
1–2 years 58
3–5 years 61
6–9 years 30
10–17 years 31
All 180
21 36.2 (24.0–49.9)
32 52.5 (39.3–65.4)
17 56.7 (37.4–74.5)
28 90.3 (74.2–98.0)
98 54.4 (46.9–61.9)
16 27.6 (16.6–40.9)
27 44.3 (31.5–57.6)
14 46.7 (28.3–65.7)
26 83.9 (66.3–94.5)
83 46.1 (38.7–53.7)
HAI titer ≥ 1:40 N % (95% CI) Subjects with seroconversion N % (95% CI) Geometric mean titers (GMT) Value (95% CI) Fold increase in GMT Mean ± SD (95% CI)
20.5 ± 3.43 (14.8–28.3)
27.3 ± 3.13 (20.4–36.6)
44.9 ± 4.20 (26.3–76.7)
302.6 ± 4.09 (180.4–507.5)
41.4 ± 4.83 (32.8–52.3)
2.4 ± 3.04 (1.8–3.2)
3.3 ± 3.04 (2.5–4.4)
5.3 ± 4.82 (2.9–9.5)
25.3 ± 6.03 (13.1–48.9)
4.6 ± 4.77 (3.7–5.8)
Age group Post second vaccination (N)
1–2 years 57
3–5 years 61
6–9 years 30
10–17 years 31
All 179
50 87.7 (76.3–94.9)
53 86.9 (75.8–94.2)
27 90.0 (73.5–97.9)
30 96.8 (83.3–99.9)
160 89.4 (83.9–93.5)
43 75.4 (62.2–85.9)
49 80.3 (68.2–89.4)
24 80.0 (61.4–92.3)
27 87.1 (70.2–96.4)
143 79.9 (73.3–85.5)
62.0 ± 2.89 (46.8–82.1)
69.8 ± 2.90 (53.1–91.7)
81.9 ± 3.00 (54.3–123.4)
244.7 ± 3.13 (161.0–371.9)
85.8 ± 3.26 (72.1–102.1)
7.1 ± 2.90 (5.3–9.4)
8.5 ± 3.06 (6.4–11.3)
9.6 ± 3.53 (6.0–15.4)
20.5 ± 5.03 (11.3–37.0)
95 ± 3.56 (7.9–11.5)
Subjects with HAI titer ≥ 1:40 N % (95% CI) Subjects with seroconversion N % (95% CI) Geometric mean titer Value (95% CI) Fold increase in GMT Mean ± SD (95% CI) a
HAI denotes hemagglutination inhibition.
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Fig. 1. Reverse cumulative distribution curve of hemagglutination inhibition (HAI) antibody titers before, 3 and 6 weeks after vaccinations with Adimmune 2009 pandemic influenza A (H1N1) vaccine in children of different age groups.
in all age groups. Interestingly, in the teenagers group, the mean antibody levels did not rise after the second dose. 3.2. Safety All eligible subjects were included in the analysis of postvaccination adverse events. Overall, 31.1% and 43.3% of subjects reported local and systemic adverse events after the first dose, respectively; 35.6% and 37.5% of subjects reported local and systemic adverse events after the second dose, respectively (Tables 3 and 4). The frequency and severity of local or systemic reactions did not increase after the second dose when compared with the first dose. After the first vaccination, 16 (27.6%) subjects who received 7.5 g HA and 40 (32.8%) subjects who received 15 g HA had at least one solicited local event. The most commonly reported solicited local adverse event was injection-site pain (24.4% of all subjects). It showed that subjects who received the 15 g HA dose
had a higher incidence of pain than those who received the 7.5 g HA dose (27.9% vs. 17.2%). Other more commonly reported local events were redness (13.3% of all subjects) and swelling (11.7% of all subjects) over the injection site. The incidence of solicited local events appeared to be slightly higher in children who were 6 years old or above. Injection-site pain was still the most commonly reported solicited local event (28.5% of all recipients) after the second vaccination. The most commonly reported solicited systemic adverse event was nasal congestion (28.7%), cough (21.7%), and malaise (15.1%). Fever with a body temperature over 38.0 ◦ C was noted in only 5.0% of subjects after the first dose and 4.5% after the second dose. Subjects or their legal guardians used a subjective scale to grade adverse events. Symptoms were considered mild, if they did not interfere with daily activities; moderate, if they caused some impairment; and severe, if they affected daily activities and required medical attention. No subject reported a severe solicited local event in any age group (Tables 3 and 4). All of the solicited
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Table 3 Solicited local adverse events within 7 days after receipt of the first and second doses of Adimmune 2009 pandemic influenza A (H1N1) vaccine in the different age groups. Age group First dose (N)
1–2 years 58 (100%)
3–5 years 61 (100%)
6–9 years 30 (100%)
10–17 years 31 (100%)
All 180 (100%)
Any Pain Mild Moderate Redness Mild Moderate Swelling Mild Moderate Ecchymosis Mild Moderate Decreased limb mobility Mild
16 (27.6%) 10 (17.2%) 10 (17.2%) 0 9 (15.5%) 9 (15.5%) 0 8 (13.8%) 8 (13.8%) 0 5 (8.6%) 5 (8.6%) 0 3 (5.2%) 3 (5.2%)
16 (26.2%) 12 (19.7%) 10 (16.4%) 2 (3.3%) 8 (13.1%) 7 (11.5%) 1 (1.6%) 5 (8.2%) 4 (6.6%) 1 (1.6%) 4 (6.6%) 4 (6.6%) 0 3 (4.9%) 3 (4.9%)
13 (43.3%) 12 (40.0%) 10 (33.3%) 2 (6.7%) 4 (13.3%) 3 (10.0%) 1 (3.3%) 5 (16.7%) 4 (13.3%) 1 (3.3%) 3 (10.0%) 3 (10.0%) 0 3 (10.0%) 3 (10.0%)
11 (35.5%) 10 (32.3%) 9 (29.0%) 1 (3.2%) 3 (9.7%) 3 (9.7%) 0 3 (9.7%) 2 (6.5%) 1 (3.2%) 1 (3.2%) 0 1 (3.2%) 3 (9.7%) 3 (9.7%)
56 (31.1%) 44 (24.4%) 39 (21.6%) 5 (2.8%) 24 (13.3%) 22 (12.2%) 2 (1.1%) 21 (11.7%) 18 (10.0%) 3 (1.7%) 13 (7.2%) 12 (6.7%) 1 (0.6%) 12 (6.7%) 12 (6.7%)
Age group Second dose (N)
1–2 years 57 (100%)
3–5 years 61 (100%)
6–9 years 30 (100%)
10–17 years 31 (100%)
All 179 (100%)
Any Pain Mild Moderate Redness Mild Moderate Swelling Mild Ecchymosis Mild Decreased limb mobility Mild
13 (22.8%) 7 (12.3%) 7 (12.3%) 0 7 (12.3%) 7 (12.3%) 0 6 (10.5%) 6 (10.5%) 2 (3.5%) 2 (3.5%) 0 0
22 (36.1%) 17 (27.9%) 17 (27.9%) 0 11 (18.0%) 10 (16.4%) 1 (1.6%) 9 (14.8%) 9 (14.8%) 4 (6.6%) 4 (6.6%) 2 (3.3%) 2 (3.3%)
14 (46.7%) 13 (43.3%) 12 (40.0%) 1 (3.3%) 5 (16.7%) 5 (16.7%) 0 7 (23.3%) 7 (23.3%) 2 (6.7%) 2 (6.7%) 1 (3.3%) 1 (3.3%)
15 (48.4%) 14 (45.2%) 13 (41.9%) 1 (3.2%) 2 (6.5%) 2 (6.5%) 0 3 (9.7%) 3 (9.7%) 0 (0.0%) 0 4 (12.9%) 4 (12.9%)
64 (35.6%) 51 (28.5%) 49 (27.3%) 2 (1.1%) 25 (14.0%) 24 (13.4%) 1 (0.6%) 25 (14.0%) 25 (14.0%) 8 (4.5%) 8 (4.5%) 7 (3.9%) 7 (3.9%)
Items were presented in a sequence according to their frequency after the first dose, starting with the most frequently reported. Severity grading items with zero cases were omitted.
local events were mild in children receiving 7.5 g HA. Only a few solicited local events were graded as moderate among subjects receiving 15 g HA. Roughly half (48.3%) of the subjects reported unsolicited adverse events within 6 weeks after the first vaccination (55.2% in the 1–2 years old group receiving two doses of 7.5 g HA and 45.1% in other age groups receiving two doses of 15 g HA). The most commonly reported unsolicited adverse events were upper respiratory tract infection (27.6% in toddlers and 20.5% in children/teenagers) and nasopharyngitis (13.8% in the 1–2 years old group and 5.7% in the other age groups). No deaths, vaccine-related serious adverse events, or adverse events of special interest, such as the optic neuritis, cranial neuropathy, brachial neuropathy, and Guillain–Barré syndrome, have been reported in the trial to date. Adverse event monitoring will continue for six months after the second vaccination. 4. Discussion It has been well known that children play a major role as the principal disseminators in the spread of influenza. Studies have shown that vaccinating school-age children may prevent elderly deaths from flu more effectively than increasing elderly vaccination rates [9]. Beginning with the 2008/2009 influenza season, annual vaccination of all children aged 5–18 years is recommended [10]. Right from the early stage of the 2009 influenza A (H1N1) pandemic, children have been reported to have the highest attack rate and hospitalization rates [11]. Recent reports from Australia, where the 2009 influenza A (H1N1) epidemic has ended, further confirmed children are at a disproportionate risk for 2009 pandemic influenza A (H1N1) infection and hospitalization. The highest rate of hospitalization occurred among children under 5 years of age [12].
These findings support prevention strategies that target children and young adults. This report confirmed that Adimmune 2009 pandemic influenza A (H1N1) vaccine is immunogenic and safe (up to 3 weeks after the second dose) in children and teenagers aged 1–18 years. However, a single dose of the vaccine was immunogenic in only about half of the vaccinees in children aged 3–9 years and about a third of children aged 1–2 years. The positive correlation between immunogenicity and age was also reflected in all measures of immunogenicity including seroconversion and GMT increase. Two doses of the vaccine, given 3 weeks apart, are necessary for children aged less than 10 years to ensure the development of a protective antibody response. This is expected as younger children usually have a relatively immature immune system and are naïve to influenza infection as well. In studies of trivalent seasonal influenza vaccines, two vaccine doses were needed to induce adequate antibody responses in children aged 9 years or less [13–16]. Based on this, 2 doses of seasonal influenza vaccines are recommended for children aged 6 months to 8 years if they have not been previously vaccinated [10]. In the setting of pandemic influenza, basically all infants and children are naïve to the virus and unlikely to mount adequate immune response to a single dose of vaccine for the pandemic influenza. As we mentioned earlier, clinical trials of 2009 pandemic influenza A (H1N1) vaccines in children are limited. Some of studies showed results in line with that of seasonal influenza vaccines, that is, lower immune responses were observed in infants and children. For example, a dose of monovalent pandemic influenza vaccine (Fluzone; Sanofi-Pasteur, USA) with 7.5 g hemagglutinin induced seroprotection in 45% (45/101) of subjects aged 6–35 months, 69% (75/109) in 3–9 years, 95% (134/141) in 18–64 years, and 94% (90/96) in 65 years or older [8]. A second dose is needed for children
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Table 4 Solicited systemic adverse events within 7 days after receipt of the first and second doses of Adimmune 2009 pandemic influenza A (H1N1) vaccine in the different age groups. Age group First dose (N)
1–2 years 58 (100%)
3–5 years 61 (100%)
6–9 years 30 (100%)
10–17 years 31 (100%)
Any Nasal congestion Mild Moderate Cough Mild Moderate Malaise Mild Moderate Sore throat Mild Moderate Muscle aches Mild Moderate Fever (≥38.0 ◦ C) Mild Moderate Severe Headache Mild Moderate Eye redness Vomiting Mild Moderate Nausea Chest tightness Respiratory distress
22 (37.9%) 13 (22.4%) 9 (15.5%) 4 (6.9%) 13 (22.4%) 9 (15.5%) 4 (6.9%) 8 (13.8%) 6 (10.3%) 2 (3.4%) 4 (6.9%) 3 (5.2%) 1 (1.7%) 1 (1.7%) 1 (1.7%) 0 3 (5.2%) 2 (3.4%) 1 (1.7%) 0 0 0 0 3 (5.2%) 5 (8.6%) 5 (8.6%) 0 1 (1.7%) 0 0
26 (42.6%) 21 (34.4%) 15 (24.6%) 6 (9.8%) 11 (18.0%) 8 (13.1%) 3 (4.9%) 8 (13.1%) 8 (13.1%) 0 6 (9.8%) 4 (6.6%) 1 (1.6%) 0 0 0 3 (4.9%) 2 (3.3%) 1 (1.6%) 0 2 (3.3%) 2 (3.3%) 0 2 (3.3%) 0 0 0 0 0 0
12 (40.0%) 9 (30.0%) 8 (26.7%) 1 (3.3%) 9 (30.0%) 9 (30.0%) 0 3 (10.0%) 3 (10.0%) 0 2 (6.7%) 2 (6.7%) 0 2 (6.7%) 2 (6.7%) 0 1 (3.3%) 0 0 1 (3.3%) 4 (13.3%) 3 (10.0%) 1 (3.3%) 0 0 0 0 1 (3.3%) 1 (3.3%) 0
18 (58.1%) 9 (29.0%) 8 (25.8%) 1 (3.2%) 6 (19.4%) 5 (16.1%) 1 (3.25) 8 (25.8%) 7 (22.6%) 1 (3.2%) 4 (12.9%) 2 (6.5%) 2 (6.5%) 10 (32.3%) 9 (29.0%) 1 (3.2%) 2 (6.5%) 0 2 (6.5%) 0 3 (9.7%) 2 (6.5%) 1 (3.2%) 3 (9.7%) 2 (6.5%) 1 (3.2%) 1 (3.2%) 3 (9.7%) 3 (9.7%) 3 (9.7%)
Age group Second dose (N)
1–2 years 57 (100%)
3–5 years 61 (100%)
6–9 years 30 (100%)
10–17 years 31 (100%)
Any Nasal congestion Mild Moderate Cough Mild Moderate Malaise Mild Moderate Sore throat Mild Moderate Muscle aches Mild Moderate Fever (≥38.0 ◦ C) Mild Moderate Severe Headache Eye redness Vomiting Mild Moderate Nausea Chest tightness Respiratory distress
19 (33.3%) 13 (22.8%) 12 (21.1%) 1 (1.8%) 11 (19.3%) 9 (15.8%) 2 (3.5%) 8 (14.0%) 8 (14.0%) 0 4 (7.0%) 3 (5.3%) 1 (1.8%) 1 (1.8%) 1 (1.8%) 0 4 (7.0%) 4 (7.0%) 0 0 0 0 3 (5.3%) 2 (3.5%) 1 (1.8%) 1 (1.8%) 0 0
20 (32.8%) 10 (16.4%) 10 (16.4%) 0 15 (24.6%) 13 (21.3%) 2 (3.3%) 3 (4.9%) 3 (4.9%) 0 5 (8.2%) 5 (8.2%) 0 1 (1.6%) 1 (1.6%) 0 3 (4.9%) 1 (1.6%) 1 (1.6%) 1 (1.6%) 1 (1.6%) 0 2 (3.3%) 2 (3.3%) 0 0 0 0
13 (43.3%) 5 (16.7%) 5 (16.7%) 0 6 (20.0%) 6 (20.0%) 0 3 (10.0%) 2 (6.7%) 1 (3.3%) 0 0 0 2 (6.7%) 2 (6.7%) 0 1 (3.3%) 1 (3.3%) 0 0 2 (6.7%) 0 0 0 0 1 (3.3%) 0 0
11 (35.5%) 5 (16.1%) 5 (16.1%) 0 4 (12.9%) 4 (12.9%) 0 6 (19.4%) 5 (16.1%) 1 (3.2%) 2 (6.5%) 2 (6.5%) 0 7 (22.6%) 6 (19.4%) 1 (3.2%) 0 0 0 0 1 (3.2%) 1 (3.2%) 1 (3.2%) 1 (3.2%) 0 0 1 (3.2%) 0
All 180 (100%) 78 (43.3%) 52 (28.8%) 40 (22.2%) 12 (6.7%) 39 (21.7%) 31 (17.2%) 8 (4.4%) 27 (15.1%) 24 (13.3%) 3 (1.7%) 16 (8.9%) 11 (6.1%) 4 (2.2%) 13 (7.2%) 12 (6.7%) 1 (0.6%) 9 (5.0%) 4 (2.2%) 4 (2.2%) 1 (0.6%) 9 (5%) 7 (3.9%) 2 (1.1%) 8 (4.4%) 7 (3.9%) 6 (3.3%) 1 (0.6%) 5 (2.8%) 4 (2.2%) 3 (1.7%) All 179 (100%) 63 (37.5%) 33 (18.4%) 32 (17.9%) 1 (0.6%) 36 (20.1%) 32 (17.9%) 4 (22%) 20 (11.2%) 18 (10.1%) 2 (1.1%) 11 (6.1%) 10 (5.6%) 1 (0.6%) 11 (6.1%) 10 (5.6%) 0 8 (4.5%) 6 (3.4%) 1 (0.6%) 1 (0.6%) 4 (2.2%) 1 (0.6%) 6 (3.4%) 5 (2.8%) 1 (0.6%) 2 (1.1%) 1 (0.6%) 0
Items were presented in a sequence according to their frequency after the first dose, starting with the most frequently reported. Severity grading items with zero cases were omitted.
aged less than 9 years. Based on early reports from several vaccine manufacturers, the US CDC recommended two doses of 2009 pandemic influenza A (H1N1) vaccine for children aged 6 months to 9 years [17]. Our results showed comparable results and provided further evidence supporting the idea that eight to nine years of age is an appropriate age cut-off for a second dose of influenza vaccines, either seasonal or pandemic.
However, a large-scale trial in China revealed different results. The trial recruited 12,691 study subjects including 2629 children aged 3–11 years, using eight different formulations (7.5, 15, and 30 g of hemagglutinin, whole- or split-virus, with and without aluminium hydroxide adjuvant) of Chinese made 2009 pandemic influenza A (H1N1) vaccine. The trial showed robust immune responses to a single dose of influenza vaccine in children. Vac-
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cination with one 15 or 30 g hemagglutinin dose of the vaccine resulted in seroprotection in 76.7% in children aged 3–11 years and 84.4–98.1% of study subjects aged 12 years or older [18]. A second dose induced seroprotection in 97.7% of children. Another trial in Australia showed that a 15-g dose of pandemic influenza vaccine (CSL Biotherapies, Australia) induced seroconversion in 86.8% (151/174) of children, including those as young as 6 months [19]. A second dose induced seroconversion in 97.5% (155/159). These figures are extraordinarily high, even higher than those observed in adults. Using the same vaccine, seroconversion of HAI antibodies was observed in 70.8% of adult subjects [5]. The reason behind this is not clear. For those younger than 3 years of age, the doubled antigen dose (15 g) might be responsible. Usually, a half dose was used for children aged less than 3 years. According to the authors, subclinical infections during the trial were not totally excluded, but not likely to have significant influence on the study results [19]. The difference in immunogenicity might simply come from the poorly understood differences in the antigens used in the vaccines. The 2009 pandemic influenza A(H1N1) virus will very likely circulate around the world for many years. Co-administration of this vaccine with other seasonal influenza vaccines, either in separate or trivalent formulations, is inevitable. Regarding the feasibility of co-administration of 2009 pandemic influenza A (H1N1) vaccine with seasonal influenza vaccine, a prospective, randomized study done in Hungary showed a monovalent 2009 pandemic influenza A (H1N1) vaccine (Fluval P; Omninvest, Hungary) is safe and immunogenic in 76.8% of adults when co-administered with the 2009–2010 seasonal influenza vaccine [20]. An HAI titer of 1:40 or greater is generally assumed to be protective against influenza infection and used as a cut-off when evaluating the immunogenicity of influenza vaccines. There are no published criteria for assessing the immunogenicity of influenza vaccines in children aged 18 years or less. If the European Agency for the Evaluation of Medicinal Products/Committee for Proprietary Medicinal Products immunogenicity criteria for influenza vaccines used in healthy adults aged 18–60 years (seroconversion in >40% and/or seroprotection in >70% of vaccinated persons and/or mean factor increase of GMT of HAI ≥2.5 for each virus strain) [21] are applied, the current study vaccine has clearly fulfilled the criteria. The Department of Health of Taiwan has adopted the criteria and granted a license to this vaccine for use in children. Although such a simplified and sped-up licensure process is justified when facing a rapid and severe pandemic, the mid- or long-term adverse effect of the vaccine are still unknown and needs continued monitoring. In addition, several questions regarding the study vaccine also require answers. First, the persistence of the immunity induced by the vaccine remains unclear. Based on the experience gained from seasonal influenza vaccines, annual vaccination is probably needed. Second, our trial studied healthy subjects only. The immunogenicity and safety of this vaccine in immunocompromised or other special hosts needs further investigation. Conflict of interest: LMH and TYL have been principle investigators of clinical trials sponsored by GlaxoSmithKline, Wyeth, MSD, and Sanofi-Pasteur. All the other authors have been co-investigators of or involved in clinical trials sponsored by GlaxoSmithKline, Wyeth, MSD, and Sanofi-Pasteur. LMH has served as a consultant to Adimmune.
Funding: The study was funded by the Adimmune coorporation, Taichung, Taiwan. Adimmune manufactured and provided the study vaccine. They were also involved in study design, data collection, serology data interpretation and statistical analyses. They were not involved in manuscript writing or decision to submit the paper for publication. References [1] New influenza A (H1N1) virus: global epidemiological situation, June 2009. Wkly Epidemiol Rec 2009;84(June (25)):249–57. [2] Chang LY, Shih SR, Shao PL, Huang DT, Huang LM. Novel swine-origin influenza virus A (H1N1): the first pandemic of the 21st century. J Formos Med Assoc 2009;108(July (7)):526–32. [3] Dawood FS, Jain S, Finelli L, Shaw MW, Lindstrom S, Garten RJ, et al. Emergence of a novel swine-origin influenza A (H1N1) virus in humans. N Engl J Med 2009;360(June (25)):2605–15. [4] Serum cross-reactive antibody response to a novel influenza A (H1N1) virus after vaccination with seasonal influenza vaccine. MMWR Morb Mortal Wkly Rep 2009;58(May (19)):521–4. [5] Greenberg ME, Lai MH, Hartel GF, Wichems CH, Gittleson C, Bennet J, et al. Response to a monovalent 2009 influenza A (H1N1) vaccine. N Engl J Med 2009;361(December (25)):2405–13. [6] Clark TW, Pareek M, Hoschler K, Dillon H, Nicholson KG, Groth N, et al. Trial of 2009 influenza A (H1N1) monovalent MF59-adjuvanted vaccine. N Engl J Med 2009;361(December (25)):2424–35. [7] Zhu FC, Wang H, Fang HH, Yang JG, Lin XJ, Liang XF, et al. A novel influenza A (H1N1) vaccine in various age groups. N Engl J Med 2009;361(December (25)):2414–23. [8] Plennevaux E, Sheldon E, Blatter M, Reeves-Hoche MK, Denis M. Immune response after a single vaccination against 2009 influenza A H1N1 in USA: a preliminary report of two randomised controlled phase 2 trials. Lancet 2010;375(January (9708)):41–8. [9] Cohen J. Vaccine policy. Immunizing kids against flu may prevent deaths among the elderly. Science 2004;306(November (5699)):1123. [10] Fiore AE, Shay DK, Broder K, Iskander JK, Uyeki TM, Mootrey G, et al. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2008. MMWR Recomm Rep 2008;57(RR7):(August):1–60. [11] 2009 pandemic influenza A (H1N1) virus infections—Chicago, Illinois, April–July 2009. MMWR Morb Mortal Wkly Rep 2009;58(August (33)):913–8. [12] Bishop JF, Murnane MP, Owen R. Australia’s winter with the 2009 pandemic influenza A (H1N1) virus. N Engl J Med 2009;361(December (27)):2591–4. [13] Englund JA, Walter EB, Gbadebo A, Monto AS, Zhu Y, Neuzil KM. Immunization with trivalent inactivated influenza vaccine in partially immunized toddlers. Pediatrics 2006;118(September (3)):e579–85. [14] Neuzil KM, Jackson LA, Nelson J, Klimov A, Cox N, Bridges CB, et al. Immunogenicity and reactogenicity of 1 versus 2 doses of trivalent inactivated influenza vaccine in vaccine-naive 5–8-year-old children. J Infect Dis 2006;194(October (8)):1032–9. [15] Schmidt-Ott R, Schwarz T, Haase R, Sander H, Walther U, Fourneau M, et al. Immunogenicity and reactogenicity of a trivalent influenza split vaccine in previously unvaccinated children aged 6–9 and 10–13 years. Vaccine 2007;26(December (1)):32–40. [16] Walter EB, Neuzil KM, Zhu Y, Fairchok MP, Gagliano ME, Monto AS, et al. Influenza vaccine immunogenicity in 6- to 23-month-old children: are identical antigens necessary for priming? Pediatrics 2006;118(September (3)):e570–8. [17] Update on influenza A (H1N1) 2009 monovalent vaccines. MMWR Morb Mortal Wkly Rep 2009;58(October (39)):1100–1. [18] Liang XF, Wang HQ, Wang JZ, Fang HH, Wu J, Zhu FC, et al. Safety and immunogenicity of 2009 pandemic influenza A H1N1 vaccines in China: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet 2010;375(January (9708)):56–66. [19] Nolan T, McVernon J, Skeljo M, Richmond P, Wadia U, Lambert S, et al. Immunogenicity of a monovalent 2009 influenza A(H1N1) vaccine in infants and children: a randomized trial. JAMA 2010;303(January (1)):37–46. [20] Vajo Z, Tamas F, Sinka L, Jankovics I. Safety and immunogenicity of a 2009 pandemic influenza A H1N1 vaccine when administered alone or simultaneously with the seasonal influenza vaccine for the 2009–10 influenza season: a multicentre, randomised controlled trial. Lancet 2010;375(January (9708)):49–55. [21] Committee for Medicinal Products for Human Use. Note for guidance on harmonisation of requirements for influenza vaccines. CPMP/BWP/214/96;1997.
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Immunogenicity and safety of a monovalent vaccine for the 2009 pandemic influenza virus A (H1N1) in children and adolescents Chun-Yi Lu a , Pei-Lan Shao a , Luan-Yin Chang a , Yhu-Chering Huang b , Cheng-Hsun Chiu b , Yu-Chia Hsieh b , Tzou-Yien Lin b,∗∗ , Li-Min Huang a,∗ a b
Department of Pediatrics, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan
a r t i c l e
i n f o
Article history: Received 4 February 2010 Received in revised form 4 June 2010 Accepted 18 June 2010 Available online 13 July 2010 Keywords: H1N1 Vaccine Children
a b s t r a c t The 2009 pandemic influenza A (H1N1) has caused significant morbidity and mortality around the world. Safety and immunogenicity studies of 2009 pandemic influenza A (H1N1) virus in children and adolescents are limited. In this prospective, open-label study, 2 doses of a monovalent, unadjuvanted, inactivated, split-virus 2009 pandemic influenza virus A (H1N1) vaccine (AdimFlu-S) were administered to 183 healthy children and adolescents aged 1–17 years. Adverse reactions were assessed, and hemagglutination inhibition antibody titers were determined. Three weeks after the first dose, 36.2% of children aged 1–2 years, 52.5% of children aged 3–5 years, 56.7% of children aged 6–9 years, and 90.3% of adolescents aged 10–17 years generated protective antibodies. A second vaccination given 3 weeks later induced protective antibodies in 89.4% of all age groups. No severe adverse effects were found 6 weeks after vaccination. © 2010 Elsevier Ltd. All rights reserved.
1. Introduction A newly emerged novel influenza A (H1N1) virus that was first identified in Mexico in spring 2009 has continued to spread rapidly throughout the world. On June 11, 2009, the World Health Organization (WHO) declared a worldwide pandemic of the novel influenza A (H1N1) virus [1,2]. The 2009 pandemic influenza A (H1N1) virus contains a novel constellation of gene segments, which most likely stemmed from triple re-assortment of two or more viruses of swine, human, and avian origin [3]. Serological studies have shown that seasonal influenza vaccines conferred no protection against this new pandemic H1N1 virus [4]. A safe and effective vaccine for the 2009 pandemic influenza A (H1N1) virus is urgently needed. Many governments and vaccine makers have begun producing vaccines for the 2009 pandemic influenza A (H1N1) virus. However, reports of clinical trials on the safety and immunogenicity of vaccines for this virus are limited. A trial performed in Australia showed a single dose of a monovalent, unadjuvanted, inactivated,
∗ Corresponding author at: Department of Pediatrics, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100, Taiwan. Tel.: +886 931034642; fax: +886 2 23147450. ∗∗ Corresponding author at: Department of Pediatrics, Chang Gung Children’s Hospital, Chang Gung University, No. 5, Fu-Hsing Street, Kweishan, Taoyuan 333, Taiwan. E-mail addresses: [email protected] (T.-Y. Lin), [email protected] (L.-M. Huang). 0264-410X/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2010.06.059
split-virus 2009 pandemic influenza A (H1N1) vaccine (CSL Biotherapies, Australia) was safe and capable of inducing seroconversions in 70.8% of subjects receiving 15 g of hemagglutinin antigen and 77.5% subjects receiving 30 g [5]. Another trial using a MF59adjuvanted monovalent pandemic influenza A (H1N1) 2009 vaccine (Novartis, Germany) demonstrated a good safety profile and seroconversion in up to 96% of subjects [6]. Unfortunately, children aged 18 years or under were not included in both trials. A large-scale trial performed in China revealed that subjects aged 3–11 years receiving a single 15-g dose of 2009 pandemic influenza vaccine (Hualan Biological Bacterin Company, China) showed less robust immune responses compared to subjects between 12 and 60 years of age [7]. No children aged less than 3 years were included in the study. In a phase 2 trials done in USA, 45% (45/101) and 50% (47/94) of children aged 6–35 months showed seroprotection after a single dose of a 2009 pandemic H1N1 vaccine (Fluzone; Sanofi-Pasteur, USA) containing 7.5 or 15 g hemagglutinin, respectively [8]. We undertook a clinical trial in healthy children and adolescents to investigate the immunogenicity and safety of a monovalent, split-virus pandemic influenza A (H1N1) vaccine (AdimFlu-S) produced in Taiwan. 2. Subjects and methods 2.1. Study design This was a prospective, open-label, laboratory-blinded study in healthy children and adolescents designed to investigate the
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safety and immunogenicity of an inactivated influenza H1N1 vaccine (AdimFlu-S, A/H1N1). There were 4 age strata: 1–2 years old, 3–5 years, 6–9 years, and 10–17 years. In each age strata, all subjects received one of two designated doses (7.5 g for the 1–2 years group, and 15 g for the other age groups) of AdimFlu-S at an interval of 3 weeks (±3 days). Following immunization, safety was measured by assessment of the reactogenicity to the vaccines for 7 days following each vaccination, adverse events for 6 weeks following the first vaccination, and serious adverse events and new-onset chronic medical conditions through 7 months post first vaccination. Immunogenicity testing included hemagglutination inhibition (HAI) testing on serum obtained before the first vaccination and three weeks after the first and second vaccinations.
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2.5. Laboratory assays The HAI assay was used to determine the anti-influenza antibody titers for all study subjects at enrollment and 21 days after each vaccination. The specimens were tested in duplicate. The immunogenicity profiles including the seroprotection rate (the proportion of subjects with antibody levels of 1:40 or more as determined by HAI assay), seroconversion rate (the proportion of subjects with a pre-vaccination HAI antibody titer <1:10 and a post-vaccination titer ≥1:40 or a pre-vaccination titer ≥1:10 and an increase in the titer by a factor of four or more) and GMT fold rises were summarized. The exact (Clopper–Pearson) method was applied to calculate the 95% confidence interval on seroprotection and seroconversion rate. 2.6. Ethics
2.2. Vaccine The 2009 pandemic influenza A (H1N1) virus vaccine (AdimFluS, A/H1N1) used in this study was produced by Adimmune (Taichung, Taiwan) in embryonated chicken eggs using standard techniques for the production of seasonal inactivated influenza vaccines. It is a monovalent, unadjuvanted, inactivated, split-virus vaccine. The seed virus was supplied by the US Centers for Diseases Control and Prevention and prepared from the reassortant vaccine virus NYMC-179A, derived from the A/California/7/2009 (H1N1) virus. The vaccine contained 30 g of hemagglutinin (HA) per milliliter, 0.01% (w/v) thimerosal as a preservative, <0.01% (w/v) formaldehyde and <0.01% (v/v) polysorbate 80 as stabilizers.
2.3. Study population Healthy children aged 1–17 years were eligible for enrollment. To be included in the study, subjects and/or their parent(s)/legal guardian(s) needed to be willing to comply with the planned study procedures. Subjects who had received influenza vaccines (seasonal or investigational) within the previous 6 months were excluded from the study. Subjects should not have had influenza like illness as defined by the presence of fever (temperature ≥38.5 ◦ C) and at least two of the following four symptoms: headache, myalgia/arthralgia, sore throat and cough. Subjects with the following conditions were also excluded: a history of hypersensitivity to eggs or egg protein, a personal or family history of Guillain–Barré syndrome, an acute febrile illness within the last 72 h prior to vaccination, female subjects who were pregnant, lactating or likely to become pregnant during the study, and subjects who were receiving any other investigational medicine or device within the 3 months before consent.
2.4. Assessment of safety A 7-day diary card was used to record pre-specified adverse events during the immediate post-vaccination period by all participants. The events included fever (≥38 ◦ C), nasal congestion, cough, sore throat, muscle aches, headache, vomiting, nausea and malaise. Furthermore, the local (injection site) reactions including soreness/pain, swelling, redness, ecchymosis and limitation of arm motion were also evaluated. In order to monitor the occurrence of rare neurological complications, e.g., optic neuritis, cranial neuropathy, brachial neuropathy, and Guillain–Barré syndrome, after vaccination, all reactogenicity/adverse events would be monitored up to 7 months after the last vaccination.
The protocol, amendments, informed consent form, and all other forms of patient’s information related to the study were reviewed and approved by the Institutional Review Board. A voluntary written informed consent form was signed by each subject or guardian. 3. Results A total of 183 subjects from the National Taiwan University Hospital and Chang Gung Memorial Hospital were enrolled into this study. The first subject received the first dose of the study vaccine on October 2, 2009. Demographic data including gender, age, body weight, and pre-vaccination antibody positivity are summarized in Table 1. All subjects receiving at least one dose of the study vaccine were included in the safety population. Two subjects in the 1–2 years and one subject in the 3–5 years age groups were not assigned to the correct group and were excluded from the immunogenicity analysis. One subject withdrew before receiving the second dose and was excluded from the analysis of immunogenicity at week 6. 3.1. Immunogenicity Prior to the vaccination, 13 of 180 subjects (7.2%) had antibody titers of 1:40 or more. Table 2 shows the percentage of subjects with seroprotection by age group; no significant difference in seroprotection rates was found between age groups prior to the vaccination. Three weeks after the first vaccination, seroprotective response was observed in 36.2% of children aged 1–2 years; 52.5% aged 3–5 years; 56.7% aged 6–9 years; and 90.3% aged 10–17 years (Table 2). A second dose of the study vaccine, given 3 weeks later, successfully increased the proportion of subjects with HAI titers of 1:40 or more in all age groups. Overall, protective anti-HA antibodies were detected in 89.4% of study subjects after the second dose (Table 2). Subjects aged 10–18 years showed the highest response rate, 96.8%. In addition to the proportion of study subjects having HAI titers higher than 1:40, we also looked at the seroconversion rates. Again, subjects in the younger age groups showed lower seroconversion rates after the first dose of the study vaccine. Only 27.6%, 44.3%, and 46.7% of subjects showed seroconversion in subjects aged 1–2 years, 3–5 years, and 6–9 years, respectively. Age-related differences were found among subjects receiving 15 g HA, with significantly higher seroconversion rates in subjects who were 10 years old or above, 83.9% (Table 2). The seroconversion rates increased after the second dose in all age groups, with 75.4% of subjects aged 1–2 years, 80.3% aged 3–5 years of age, 80.0% aged 6–9 years of age and 87.1% aged 10–17 years of age showing seroconversion. Before the first vaccine dose, the mean antibody GMTs were within the same range (8.2–12.0) in all age groups (Table 2). After
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Table 1 Demographics of all vaccinated children and adolescents in the different age groups. Age group Sex (no. (%)) Boy Girl Age (years) Mean ± SD Median Range Body weight (kg) Mean ± SD Median Range Pre-vaccination antibody titera (no. (%)) HAI < 1:10 HAI ≥ 1:10 HAI ≥ 1:40 a
1–2 years (N = 60)
3–5 years (N = 62)
6–9 years (N = 30)
10–17 years (N = 31)
All (N = 183)
31 (51.7%) 29 (48.3%)
27 (43.5%) 35 (56.5%)
8 (26.7%) 22 (73.3%)
19 (61.3%) 12 (38.7%)
85 (46.4%) 98 (53.6%)
2.1 ± 0.4 2.0 1.0–2.9
4.3 ± 0.9 4.0 3.0–5.99
7.7 ± 1.1 7.6 6.1–9.98
13.6 ± 1.9 13.1 10.5–17.5
5.7 ± 4.2 4.2 1.0–17.5
12.4 ± 2.1 12.0 7.5–19.5
16.9 ± 3.2 17.0 12–27
27.4 ± 8.0 24.7 18.0–50.2
53.0 ± 13.4 52.0 32.0–90.0
23.3 ± 15.9 17.0 7.5–90.0
37 (61.7%) 23 (38.3%) 4 (6.6%)
36 (58.1%) 26 (41.9%) 2 (3.2%)
17 (56.7%) 13 (43.3%) 2 (6.7%)
14 (45.2%) 17 (54.8%) 5 (16.1%)
104 (56.8%) 79 (43.2%) 13 (7.1%)
Antibody titer was determined by the hemagglutination inhibition (HAI) assay.
the first dose, the fold increase in GMT was significantly higher among adolescents aged 10–17 years than children aged less than 10 years. Three weeks after the first vaccination, the GMTs from pre-vaccination levels increased 2.4-fold, 3.3-fold, 5.3-fold, and 25.3-fold for children aged 1–2, 3–5, 6–9 and 10–17 years respectively. Second dose of vaccine further boosted the antibody titers in subjects less than 10 years old. Three weeks after the second vaccination, the GMTs from pre-vaccination levels increased 7.1-fold,
8.5-fold, 9.6-fold, and 20.5-fold for children aged 1–2, 3–5, 6–9 and 10 to <18 years, respectively (Table 2). Fig. 1 shows the accumulating percentage of subjects having different levels of HAI titers against the 2009 pandemic influenza A (H1N1) virus before and after vaccinations in the different age groups. Again, a single vaccination results in strong antibody responses in the adolescent group. A second vaccination induced a booster response and resulted in satisfying antibody production
Table 2 Immune responses to one and two doses of an inactivated 2009 novel influenza A (H1N1) vaccine in children aged 1–18 years. Age group Pre-vaccination (N)
1–2 years 58
3–5 years 61
6–9 years 30
10–17 years 31
All 180
HAIa titer ≥ 1:40 N % (95% CI) Geometric mean titer Value (95% CI)
4 6.9 (1.9–16.7)
2 3.3 (0.4–11.3)
2 6.7 (0.8–22.1)
5 16.1 (5.5–33.7)
13 7.2 (3.9–12.0)
8.7 ± 2.31 (6.9–10.8)
8.2 ± 1.98 (6.9–9.8)
8.5 ± 2.01 (6.6–11.0)
12.0 ± 2.79 (8.2–17.4)
9.0 ± 2.25 (8.0–10.1)
Age group Post first vaccination (N)
1–2 years 58
3–5 years 61
6–9 years 30
10–17 years 31
All 180
21 36.2 (24.0–49.9)
32 52.5 (39.3–65.4)
17 56.7 (37.4–74.5)
28 90.3 (74.2–98.0)
98 54.4 (46.9–61.9)
16 27.6 (16.6–40.9)
27 44.3 (31.5–57.6)
14 46.7 (28.3–65.7)
26 83.9 (66.3–94.5)
83 46.1 (38.7–53.7)
HAI titer ≥ 1:40 N % (95% CI) Subjects with seroconversion N % (95% CI) Geometric mean titers (GMT) Value (95% CI) Fold increase in GMT Mean ± SD (95% CI)
20.5 ± 3.43 (14.8–28.3)
27.3 ± 3.13 (20.4–36.6)
44.9 ± 4.20 (26.3–76.7)
302.6 ± 4.09 (180.4–507.5)
41.4 ± 4.83 (32.8–52.3)
2.4 ± 3.04 (1.8–3.2)
3.3 ± 3.04 (2.5–4.4)
5.3 ± 4.82 (2.9–9.5)
25.3 ± 6.03 (13.1–48.9)
4.6 ± 4.77 (3.7–5.8)
Age group Post second vaccination (N)
1–2 years 57
3–5 years 61
6–9 years 30
10–17 years 31
All 179
50 87.7 (76.3–94.9)
53 86.9 (75.8–94.2)
27 90.0 (73.5–97.9)
30 96.8 (83.3–99.9)
160 89.4 (83.9–93.5)
43 75.4 (62.2–85.9)
49 80.3 (68.2–89.4)
24 80.0 (61.4–92.3)
27 87.1 (70.2–96.4)
143 79.9 (73.3–85.5)
62.0 ± 2.89 (46.8–82.1)
69.8 ± 2.90 (53.1–91.7)
81.9 ± 3.00 (54.3–123.4)
244.7 ± 3.13 (161.0–371.9)
85.8 ± 3.26 (72.1–102.1)
7.1 ± 2.90 (5.3–9.4)
8.5 ± 3.06 (6.4–11.3)
9.6 ± 3.53 (6.0–15.4)
20.5 ± 5.03 (11.3–37.0)
95 ± 3.56 (7.9–11.5)
Subjects with HAI titer ≥ 1:40 N % (95% CI) Subjects with seroconversion N % (95% CI) Geometric mean titer Value (95% CI) Fold increase in GMT Mean ± SD (95% CI) a
HAI denotes hemagglutination inhibition.
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Fig. 1. Reverse cumulative distribution curve of hemagglutination inhibition (HAI) antibody titers before, 3 and 6 weeks after vaccinations with Adimmune 2009 pandemic influenza A (H1N1) vaccine in children of different age groups.
in all age groups. Interestingly, in the teenagers group, the mean antibody levels did not rise after the second dose. 3.2. Safety All eligible subjects were included in the analysis of postvaccination adverse events. Overall, 31.1% and 43.3% of subjects reported local and systemic adverse events after the first dose, respectively; 35.6% and 37.5% of subjects reported local and systemic adverse events after the second dose, respectively (Tables 3 and 4). The frequency and severity of local or systemic reactions did not increase after the second dose when compared with the first dose. After the first vaccination, 16 (27.6%) subjects who received 7.5 g HA and 40 (32.8%) subjects who received 15 g HA had at least one solicited local event. The most commonly reported solicited local adverse event was injection-site pain (24.4% of all subjects). It showed that subjects who received the 15 g HA dose
had a higher incidence of pain than those who received the 7.5 g HA dose (27.9% vs. 17.2%). Other more commonly reported local events were redness (13.3% of all subjects) and swelling (11.7% of all subjects) over the injection site. The incidence of solicited local events appeared to be slightly higher in children who were 6 years old or above. Injection-site pain was still the most commonly reported solicited local event (28.5% of all recipients) after the second vaccination. The most commonly reported solicited systemic adverse event was nasal congestion (28.7%), cough (21.7%), and malaise (15.1%). Fever with a body temperature over 38.0 ◦ C was noted in only 5.0% of subjects after the first dose and 4.5% after the second dose. Subjects or their legal guardians used a subjective scale to grade adverse events. Symptoms were considered mild, if they did not interfere with daily activities; moderate, if they caused some impairment; and severe, if they affected daily activities and required medical attention. No subject reported a severe solicited local event in any age group (Tables 3 and 4). All of the solicited
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Table 3 Solicited local adverse events within 7 days after receipt of the first and second doses of Adimmune 2009 pandemic influenza A (H1N1) vaccine in the different age groups. Age group First dose (N)
1–2 years 58 (100%)
3–5 years 61 (100%)
6–9 years 30 (100%)
10–17 years 31 (100%)
All 180 (100%)
Any Pain Mild Moderate Redness Mild Moderate Swelling Mild Moderate Ecchymosis Mild Moderate Decreased limb mobility Mild
16 (27.6%) 10 (17.2%) 10 (17.2%) 0 9 (15.5%) 9 (15.5%) 0 8 (13.8%) 8 (13.8%) 0 5 (8.6%) 5 (8.6%) 0 3 (5.2%) 3 (5.2%)
16 (26.2%) 12 (19.7%) 10 (16.4%) 2 (3.3%) 8 (13.1%) 7 (11.5%) 1 (1.6%) 5 (8.2%) 4 (6.6%) 1 (1.6%) 4 (6.6%) 4 (6.6%) 0 3 (4.9%) 3 (4.9%)
13 (43.3%) 12 (40.0%) 10 (33.3%) 2 (6.7%) 4 (13.3%) 3 (10.0%) 1 (3.3%) 5 (16.7%) 4 (13.3%) 1 (3.3%) 3 (10.0%) 3 (10.0%) 0 3 (10.0%) 3 (10.0%)
11 (35.5%) 10 (32.3%) 9 (29.0%) 1 (3.2%) 3 (9.7%) 3 (9.7%) 0 3 (9.7%) 2 (6.5%) 1 (3.2%) 1 (3.2%) 0 1 (3.2%) 3 (9.7%) 3 (9.7%)
56 (31.1%) 44 (24.4%) 39 (21.6%) 5 (2.8%) 24 (13.3%) 22 (12.2%) 2 (1.1%) 21 (11.7%) 18 (10.0%) 3 (1.7%) 13 (7.2%) 12 (6.7%) 1 (0.6%) 12 (6.7%) 12 (6.7%)
Age group Second dose (N)
1–2 years 57 (100%)
3–5 years 61 (100%)
6–9 years 30 (100%)
10–17 years 31 (100%)
All 179 (100%)
Any Pain Mild Moderate Redness Mild Moderate Swelling Mild Ecchymosis Mild Decreased limb mobility Mild
13 (22.8%) 7 (12.3%) 7 (12.3%) 0 7 (12.3%) 7 (12.3%) 0 6 (10.5%) 6 (10.5%) 2 (3.5%) 2 (3.5%) 0 0
22 (36.1%) 17 (27.9%) 17 (27.9%) 0 11 (18.0%) 10 (16.4%) 1 (1.6%) 9 (14.8%) 9 (14.8%) 4 (6.6%) 4 (6.6%) 2 (3.3%) 2 (3.3%)
14 (46.7%) 13 (43.3%) 12 (40.0%) 1 (3.3%) 5 (16.7%) 5 (16.7%) 0 7 (23.3%) 7 (23.3%) 2 (6.7%) 2 (6.7%) 1 (3.3%) 1 (3.3%)
15 (48.4%) 14 (45.2%) 13 (41.9%) 1 (3.2%) 2 (6.5%) 2 (6.5%) 0 3 (9.7%) 3 (9.7%) 0 (0.0%) 0 4 (12.9%) 4 (12.9%)
64 (35.6%) 51 (28.5%) 49 (27.3%) 2 (1.1%) 25 (14.0%) 24 (13.4%) 1 (0.6%) 25 (14.0%) 25 (14.0%) 8 (4.5%) 8 (4.5%) 7 (3.9%) 7 (3.9%)
Items were presented in a sequence according to their frequency after the first dose, starting with the most frequently reported. Severity grading items with zero cases were omitted.
local events were mild in children receiving 7.5 g HA. Only a few solicited local events were graded as moderate among subjects receiving 15 g HA. Roughly half (48.3%) of the subjects reported unsolicited adverse events within 6 weeks after the first vaccination (55.2% in the 1–2 years old group receiving two doses of 7.5 g HA and 45.1% in other age groups receiving two doses of 15 g HA). The most commonly reported unsolicited adverse events were upper respiratory tract infection (27.6% in toddlers and 20.5% in children/teenagers) and nasopharyngitis (13.8% in the 1–2 years old group and 5.7% in the other age groups). No deaths, vaccine-related serious adverse events, or adverse events of special interest, such as the optic neuritis, cranial neuropathy, brachial neuropathy, and Guillain–Barré syndrome, have been reported in the trial to date. Adverse event monitoring will continue for six months after the second vaccination. 4. Discussion It has been well known that children play a major role as the principal disseminators in the spread of influenza. Studies have shown that vaccinating school-age children may prevent elderly deaths from flu more effectively than increasing elderly vaccination rates [9]. Beginning with the 2008/2009 influenza season, annual vaccination of all children aged 5–18 years is recommended [10]. Right from the early stage of the 2009 influenza A (H1N1) pandemic, children have been reported to have the highest attack rate and hospitalization rates [11]. Recent reports from Australia, where the 2009 influenza A (H1N1) epidemic has ended, further confirmed children are at a disproportionate risk for 2009 pandemic influenza A (H1N1) infection and hospitalization. The highest rate of hospitalization occurred among children under 5 years of age [12].
These findings support prevention strategies that target children and young adults. This report confirmed that Adimmune 2009 pandemic influenza A (H1N1) vaccine is immunogenic and safe (up to 3 weeks after the second dose) in children and teenagers aged 1–18 years. However, a single dose of the vaccine was immunogenic in only about half of the vaccinees in children aged 3–9 years and about a third of children aged 1–2 years. The positive correlation between immunogenicity and age was also reflected in all measures of immunogenicity including seroconversion and GMT increase. Two doses of the vaccine, given 3 weeks apart, are necessary for children aged less than 10 years to ensure the development of a protective antibody response. This is expected as younger children usually have a relatively immature immune system and are naïve to influenza infection as well. In studies of trivalent seasonal influenza vaccines, two vaccine doses were needed to induce adequate antibody responses in children aged 9 years or less [13–16]. Based on this, 2 doses of seasonal influenza vaccines are recommended for children aged 6 months to 8 years if they have not been previously vaccinated [10]. In the setting of pandemic influenza, basically all infants and children are naïve to the virus and unlikely to mount adequate immune response to a single dose of vaccine for the pandemic influenza. As we mentioned earlier, clinical trials of 2009 pandemic influenza A (H1N1) vaccines in children are limited. Some of studies showed results in line with that of seasonal influenza vaccines, that is, lower immune responses were observed in infants and children. For example, a dose of monovalent pandemic influenza vaccine (Fluzone; Sanofi-Pasteur, USA) with 7.5 g hemagglutinin induced seroprotection in 45% (45/101) of subjects aged 6–35 months, 69% (75/109) in 3–9 years, 95% (134/141) in 18–64 years, and 94% (90/96) in 65 years or older [8]. A second dose is needed for children
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Table 4 Solicited systemic adverse events within 7 days after receipt of the first and second doses of Adimmune 2009 pandemic influenza A (H1N1) vaccine in the different age groups. Age group First dose (N)
1–2 years 58 (100%)
3–5 years 61 (100%)
6–9 years 30 (100%)
10–17 years 31 (100%)
Any Nasal congestion Mild Moderate Cough Mild Moderate Malaise Mild Moderate Sore throat Mild Moderate Muscle aches Mild Moderate Fever (≥38.0 ◦ C) Mild Moderate Severe Headache Mild Moderate Eye redness Vomiting Mild Moderate Nausea Chest tightness Respiratory distress
22 (37.9%) 13 (22.4%) 9 (15.5%) 4 (6.9%) 13 (22.4%) 9 (15.5%) 4 (6.9%) 8 (13.8%) 6 (10.3%) 2 (3.4%) 4 (6.9%) 3 (5.2%) 1 (1.7%) 1 (1.7%) 1 (1.7%) 0 3 (5.2%) 2 (3.4%) 1 (1.7%) 0 0 0 0 3 (5.2%) 5 (8.6%) 5 (8.6%) 0 1 (1.7%) 0 0
26 (42.6%) 21 (34.4%) 15 (24.6%) 6 (9.8%) 11 (18.0%) 8 (13.1%) 3 (4.9%) 8 (13.1%) 8 (13.1%) 0 6 (9.8%) 4 (6.6%) 1 (1.6%) 0 0 0 3 (4.9%) 2 (3.3%) 1 (1.6%) 0 2 (3.3%) 2 (3.3%) 0 2 (3.3%) 0 0 0 0 0 0
12 (40.0%) 9 (30.0%) 8 (26.7%) 1 (3.3%) 9 (30.0%) 9 (30.0%) 0 3 (10.0%) 3 (10.0%) 0 2 (6.7%) 2 (6.7%) 0 2 (6.7%) 2 (6.7%) 0 1 (3.3%) 0 0 1 (3.3%) 4 (13.3%) 3 (10.0%) 1 (3.3%) 0 0 0 0 1 (3.3%) 1 (3.3%) 0
18 (58.1%) 9 (29.0%) 8 (25.8%) 1 (3.2%) 6 (19.4%) 5 (16.1%) 1 (3.25) 8 (25.8%) 7 (22.6%) 1 (3.2%) 4 (12.9%) 2 (6.5%) 2 (6.5%) 10 (32.3%) 9 (29.0%) 1 (3.2%) 2 (6.5%) 0 2 (6.5%) 0 3 (9.7%) 2 (6.5%) 1 (3.2%) 3 (9.7%) 2 (6.5%) 1 (3.2%) 1 (3.2%) 3 (9.7%) 3 (9.7%) 3 (9.7%)
Age group Second dose (N)
1–2 years 57 (100%)
3–5 years 61 (100%)
6–9 years 30 (100%)
10–17 years 31 (100%)
Any Nasal congestion Mild Moderate Cough Mild Moderate Malaise Mild Moderate Sore throat Mild Moderate Muscle aches Mild Moderate Fever (≥38.0 ◦ C) Mild Moderate Severe Headache Eye redness Vomiting Mild Moderate Nausea Chest tightness Respiratory distress
19 (33.3%) 13 (22.8%) 12 (21.1%) 1 (1.8%) 11 (19.3%) 9 (15.8%) 2 (3.5%) 8 (14.0%) 8 (14.0%) 0 4 (7.0%) 3 (5.3%) 1 (1.8%) 1 (1.8%) 1 (1.8%) 0 4 (7.0%) 4 (7.0%) 0 0 0 0 3 (5.3%) 2 (3.5%) 1 (1.8%) 1 (1.8%) 0 0
20 (32.8%) 10 (16.4%) 10 (16.4%) 0 15 (24.6%) 13 (21.3%) 2 (3.3%) 3 (4.9%) 3 (4.9%) 0 5 (8.2%) 5 (8.2%) 0 1 (1.6%) 1 (1.6%) 0 3 (4.9%) 1 (1.6%) 1 (1.6%) 1 (1.6%) 1 (1.6%) 0 2 (3.3%) 2 (3.3%) 0 0 0 0
13 (43.3%) 5 (16.7%) 5 (16.7%) 0 6 (20.0%) 6 (20.0%) 0 3 (10.0%) 2 (6.7%) 1 (3.3%) 0 0 0 2 (6.7%) 2 (6.7%) 0 1 (3.3%) 1 (3.3%) 0 0 2 (6.7%) 0 0 0 0 1 (3.3%) 0 0
11 (35.5%) 5 (16.1%) 5 (16.1%) 0 4 (12.9%) 4 (12.9%) 0 6 (19.4%) 5 (16.1%) 1 (3.2%) 2 (6.5%) 2 (6.5%) 0 7 (22.6%) 6 (19.4%) 1 (3.2%) 0 0 0 0 1 (3.2%) 1 (3.2%) 1 (3.2%) 1 (3.2%) 0 0 1 (3.2%) 0
All 180 (100%) 78 (43.3%) 52 (28.8%) 40 (22.2%) 12 (6.7%) 39 (21.7%) 31 (17.2%) 8 (4.4%) 27 (15.1%) 24 (13.3%) 3 (1.7%) 16 (8.9%) 11 (6.1%) 4 (2.2%) 13 (7.2%) 12 (6.7%) 1 (0.6%) 9 (5.0%) 4 (2.2%) 4 (2.2%) 1 (0.6%) 9 (5%) 7 (3.9%) 2 (1.1%) 8 (4.4%) 7 (3.9%) 6 (3.3%) 1 (0.6%) 5 (2.8%) 4 (2.2%) 3 (1.7%) All 179 (100%) 63 (37.5%) 33 (18.4%) 32 (17.9%) 1 (0.6%) 36 (20.1%) 32 (17.9%) 4 (22%) 20 (11.2%) 18 (10.1%) 2 (1.1%) 11 (6.1%) 10 (5.6%) 1 (0.6%) 11 (6.1%) 10 (5.6%) 0 8 (4.5%) 6 (3.4%) 1 (0.6%) 1 (0.6%) 4 (2.2%) 1 (0.6%) 6 (3.4%) 5 (2.8%) 1 (0.6%) 2 (1.1%) 1 (0.6%) 0
Items were presented in a sequence according to their frequency after the first dose, starting with the most frequently reported. Severity grading items with zero cases were omitted.
aged less than 9 years. Based on early reports from several vaccine manufacturers, the US CDC recommended two doses of 2009 pandemic influenza A (H1N1) vaccine for children aged 6 months to 9 years [17]. Our results showed comparable results and provided further evidence supporting the idea that eight to nine years of age is an appropriate age cut-off for a second dose of influenza vaccines, either seasonal or pandemic.
However, a large-scale trial in China revealed different results. The trial recruited 12,691 study subjects including 2629 children aged 3–11 years, using eight different formulations (7.5, 15, and 30 g of hemagglutinin, whole- or split-virus, with and without aluminium hydroxide adjuvant) of Chinese made 2009 pandemic influenza A (H1N1) vaccine. The trial showed robust immune responses to a single dose of influenza vaccine in children. Vac-
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cination with one 15 or 30 g hemagglutinin dose of the vaccine resulted in seroprotection in 76.7% in children aged 3–11 years and 84.4–98.1% of study subjects aged 12 years or older [18]. A second dose induced seroprotection in 97.7% of children. Another trial in Australia showed that a 15-g dose of pandemic influenza vaccine (CSL Biotherapies, Australia) induced seroconversion in 86.8% (151/174) of children, including those as young as 6 months [19]. A second dose induced seroconversion in 97.5% (155/159). These figures are extraordinarily high, even higher than those observed in adults. Using the same vaccine, seroconversion of HAI antibodies was observed in 70.8% of adult subjects [5]. The reason behind this is not clear. For those younger than 3 years of age, the doubled antigen dose (15 g) might be responsible. Usually, a half dose was used for children aged less than 3 years. According to the authors, subclinical infections during the trial were not totally excluded, but not likely to have significant influence on the study results [19]. The difference in immunogenicity might simply come from the poorly understood differences in the antigens used in the vaccines. The 2009 pandemic influenza A(H1N1) virus will very likely circulate around the world for many years. Co-administration of this vaccine with other seasonal influenza vaccines, either in separate or trivalent formulations, is inevitable. Regarding the feasibility of co-administration of 2009 pandemic influenza A (H1N1) vaccine with seasonal influenza vaccine, a prospective, randomized study done in Hungary showed a monovalent 2009 pandemic influenza A (H1N1) vaccine (Fluval P; Omninvest, Hungary) is safe and immunogenic in 76.8% of adults when co-administered with the 2009–2010 seasonal influenza vaccine [20]. An HAI titer of 1:40 or greater is generally assumed to be protective against influenza infection and used as a cut-off when evaluating the immunogenicity of influenza vaccines. There are no published criteria for assessing the immunogenicity of influenza vaccines in children aged 18 years or less. If the European Agency for the Evaluation of Medicinal Products/Committee for Proprietary Medicinal Products immunogenicity criteria for influenza vaccines used in healthy adults aged 18–60 years (seroconversion in >40% and/or seroprotection in >70% of vaccinated persons and/or mean factor increase of GMT of HAI ≥2.5 for each virus strain) [21] are applied, the current study vaccine has clearly fulfilled the criteria. The Department of Health of Taiwan has adopted the criteria and granted a license to this vaccine for use in children. Although such a simplified and sped-up licensure process is justified when facing a rapid and severe pandemic, the mid- or long-term adverse effect of the vaccine are still unknown and needs continued monitoring. In addition, several questions regarding the study vaccine also require answers. First, the persistence of the immunity induced by the vaccine remains unclear. Based on the experience gained from seasonal influenza vaccines, annual vaccination is probably needed. Second, our trial studied healthy subjects only. The immunogenicity and safety of this vaccine in immunocompromised or other special hosts needs further investigation. Conflict of interest: LMH and TYL have been principle investigators of clinical trials sponsored by GlaxoSmithKline, Wyeth, MSD, and Sanofi-Pasteur. All the other authors have been co-investigators of or involved in clinical trials sponsored by GlaxoSmithKline, Wyeth, MSD, and Sanofi-Pasteur. LMH has served as a consultant to Adimmune.
Funding: The study was funded by the Adimmune coorporation, Taichung, Taiwan. Adimmune manufactured and provided the study vaccine. They were also involved in study design, data collection, serology data interpretation and statistical analyses. They were not involved in manuscript writing or decision to submit the paper for publication. References [1] New influenza A (H1N1) virus: global epidemiological situation, June 2009. Wkly Epidemiol Rec 2009;84(June (25)):249–57. [2] Chang LY, Shih SR, Shao PL, Huang DT, Huang LM. Novel swine-origin influenza virus A (H1N1): the first pandemic of the 21st century. J Formos Med Assoc 2009;108(July (7)):526–32. [3] Dawood FS, Jain S, Finelli L, Shaw MW, Lindstrom S, Garten RJ, et al. Emergence of a novel swine-origin influenza A (H1N1) virus in humans. N Engl J Med 2009;360(June (25)):2605–15. [4] Serum cross-reactive antibody response to a novel influenza A (H1N1) virus after vaccination with seasonal influenza vaccine. MMWR Morb Mortal Wkly Rep 2009;58(May (19)):521–4. [5] Greenberg ME, Lai MH, Hartel GF, Wichems CH, Gittleson C, Bennet J, et al. Response to a monovalent 2009 influenza A (H1N1) vaccine. N Engl J Med 2009;361(December (25)):2405–13. [6] Clark TW, Pareek M, Hoschler K, Dillon H, Nicholson KG, Groth N, et al. Trial of 2009 influenza A (H1N1) monovalent MF59-adjuvanted vaccine. N Engl J Med 2009;361(December (25)):2424–35. [7] Zhu FC, Wang H, Fang HH, Yang JG, Lin XJ, Liang XF, et al. A novel influenza A (H1N1) vaccine in various age groups. N Engl J Med 2009;361(December (25)):2414–23. [8] Plennevaux E, Sheldon E, Blatter M, Reeves-Hoche MK, Denis M. Immune response after a single vaccination against 2009 influenza A H1N1 in USA: a preliminary report of two randomised controlled phase 2 trials. Lancet 2010;375(January (9708)):41–8. [9] Cohen J. Vaccine policy. Immunizing kids against flu may prevent deaths among the elderly. Science 2004;306(November (5699)):1123. [10] Fiore AE, Shay DK, Broder K, Iskander JK, Uyeki TM, Mootrey G, et al. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2008. MMWR Recomm Rep 2008;57(RR7):(August):1–60. [11] 2009 pandemic influenza A (H1N1) virus infections—Chicago, Illinois, April–July 2009. MMWR Morb Mortal Wkly Rep 2009;58(August (33)):913–8. [12] Bishop JF, Murnane MP, Owen R. Australia’s winter with the 2009 pandemic influenza A (H1N1) virus. N Engl J Med 2009;361(December (27)):2591–4. [13] Englund JA, Walter EB, Gbadebo A, Monto AS, Zhu Y, Neuzil KM. Immunization with trivalent inactivated influenza vaccine in partially immunized toddlers. Pediatrics 2006;118(September (3)):e579–85. [14] Neuzil KM, Jackson LA, Nelson J, Klimov A, Cox N, Bridges CB, et al. Immunogenicity and reactogenicity of 1 versus 2 doses of trivalent inactivated influenza vaccine in vaccine-naive 5–8-year-old children. J Infect Dis 2006;194(October (8)):1032–9. [15] Schmidt-Ott R, Schwarz T, Haase R, Sander H, Walther U, Fourneau M, et al. Immunogenicity and reactogenicity of a trivalent influenza split vaccine in previously unvaccinated children aged 6–9 and 10–13 years. Vaccine 2007;26(December (1)):32–40. [16] Walter EB, Neuzil KM, Zhu Y, Fairchok MP, Gagliano ME, Monto AS, et al. Influenza vaccine immunogenicity in 6- to 23-month-old children: are identical antigens necessary for priming? Pediatrics 2006;118(September (3)):e570–8. [17] Update on influenza A (H1N1) 2009 monovalent vaccines. MMWR Morb Mortal Wkly Rep 2009;58(October (39)):1100–1. [18] Liang XF, Wang HQ, Wang JZ, Fang HH, Wu J, Zhu FC, et al. Safety and immunogenicity of 2009 pandemic influenza A H1N1 vaccines in China: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet 2010;375(January (9708)):56–66. [19] Nolan T, McVernon J, Skeljo M, Richmond P, Wadia U, Lambert S, et al. Immunogenicity of a monovalent 2009 influenza A(H1N1) vaccine in infants and children: a randomized trial. JAMA 2010;303(January (1)):37–46. [20] Vajo Z, Tamas F, Sinka L, Jankovics I. Safety and immunogenicity of a 2009 pandemic influenza A H1N1 vaccine when administered alone or simultaneously with the seasonal influenza vaccine for the 2009–10 influenza season: a multicentre, randomised controlled trial. Lancet 2010;375(January (9708)):49–55. [21] Committee for Medicinal Products for Human Use. Note for guidance on harmonisation of requirements for influenza vaccines. CPMP/BWP/214/96;1997.