Reactogenicity and safety of AS03_B-adjuvanted H5N1 influenza vaccine in children: an open-label, one-way, crossover trial

The primary study was a Phase II–III randomized, placebocontrolled, observer-blind trial that assessed the immunogenicity, reactogenicity, and safety of a 2-dose primary series of AS03_B-H5N1 (A/Indonesia/5/2005) vaccine in children aged 6 months to <18 years. The study was conducted in Thailand, the US, and Canada (www.ClinicalTrials.gov, NCT01310413).

After the database lock and unbinding at the end of Year 1, an open, one-way, crossover safety phase was conducted, in which eligible children allocated to receive placebo in Year 1 were invited to receive AS03_B-H5N1 vaccine in Year 2. The randomized phase ended in October 2012, and the first child was enrolled in Year 2 on 1 November 2012. The most recent study visit/contact was on 26 January 2014, and the data lock point was 23 April 2014. The Year 2 outcomes were reactogenicity during the 7-day postvaccination period and safety from Day 0 to Day 385 after vaccination.

All protocols and study documents were approved by independent and local ethics committees including the institutional review board of Khon Kaen University (approval No. HE531398), Chesapeake Research Review (protocol no. 114464), and Comité central ďethique de la recherche du ministre de la Santé et des Services sociaux (approval no. CCER 10-11–10) in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice Guidelines, the contemporary revision of the Declaration of Helsinki, and regulatory requirements. Informed consent was obtained for study participants before the start of Year 1 and again in Year 2. Parents or legal guardians provided informed written consent; children aged from 9 to <18 years provided their assent according to local standards. Children aged ≤18 years in Year 2 provided informed written consent.

The inclusion and exclusion criteria for the crossover study were the same as those previously reported for Year 1 apart from age range (i.e. children were about 1 year older in Year 2) [9]. In Year 2, eligible children received 2 doses of vaccine 21 days apart, containing 1.9 μg HA of H5N1 A/Indonesia/5/2005 adjuvanted with AS03_B (lot number H5N1 vaccine, DFLPA606A; lot number AS03 adjuvant, AA03A209C).

Definitions and methods for assessing reactogenicity and safety were as previously described [14]. In brief, solicited injection site symptoms and solicited general symptoms were recorded during each 7-day postvaccination period and unsolicited adverse events (AEs) from Day 0 to Day 42 (21 days after each vaccination) were recorded on diary cards; medically attended adverse events (MAEs), serious adverse events (SAEs), and potential immune-mediated diseases (pIMDs) were recorded from Day 0 to Day 385.

For medically attended events, the investigator reviewed available documentation (e.g. hospital progress notes, laboratory reports, and diagnostics reports) relative to the event and recorded relevant information as applicable on the participant’s electronic case report form. The assessment of an SAE or plMD and its severity was based on the investigator’s clinical judgment. Pain at the injection site was assessed and scored as follows: 0 (no pain), 1 (minor reaction to touch in children aged <6 years and pain on touching the site in children aged ≥6 years), 2 (cries/protests on touch in children aged <6 years and pain on moving the limb, which interfered with normal activities in children aged ≥6 years), or 3 (cries when limb was moved/spontaneously painful in children aged <6 years and significant pain at rest in children aged ≥6 years). Unsolicited events were coded using the Medical Dictionary for Regulatory Activities, and investigators provided causality assessments.

The reactogenicity data are provided as the overall frequency of solicited events pooled for each postvaccination period with 95% confidence intervals (CI). Unsolicited AEs, SAEs, and MAEs were tabulated with 95% CIs. Safety was assessed in the total vaccinated cohort (TVC), which included all children who received at least one dose of vaccine in Year 2. Reactogenicity was assessed in the TVC participants with data available (i.e. those who returned the diary cards).

Of 231 children who received a placebo in Year 1, 155 participants accepted the invitation to participate in Year 2 and received at least one dose of AS03_B-H5N1 vaccine (Figure 1). Among them, 154 received 2 doses of the vaccine and 1 participant received one dose of the vaccine.

Figure 1

Of eligible children who did not participate in Year 2, the reasons were consent withdrawal or not willing to participate (n = 39), eligibility criteria not fulfilled (n = 4), lost to followup (n = 14), migrated or moved from the study area (n = 6), and reason not documented (n = 13). The age of children at baseline in Year 2 TVC varied between 19 and 226 months. In the TVC, 47.7% were of Southeast Asian ancestry, 38.7% were white of European ancestry, and 11.0% were African or African American. Three children were withdrawn because of consent withdrawal not related to safety (n = 1) and loss to follow-up (n = 2).

During the 7-day postvaccination period, the most commonly reported solicited injection site symptom was pain, which was reported in 111 (72.1%) children. Grade 3 injection site pain was reported in 8 (5.2%) children. Redness and swelling were reported by 6 (3.9%) and 5 (3.2%) children, respectively, with no Grade 3 redness or swelling (>100 mm) being reported. In children aged <6 years (n = 79), the most frequent solicited general symptom was irritability or fussiness (n = 28; 35.4%). The incidence of fever (temperature ≥38.0°C) was observed in 4 (5.1%) children, with Grade 3 fever (≥39.0°C) in 2 (2.5%) children.

In children aged ≥ 6 years (n = 75), the most common solicited general events were muscle aches (n = 34; 45.3%), headache (n = 24; 32.0%), and fatigue (n = 18; 24.0%). The incidence of fever (temperature ≥38.0°C) was observed in 1 (1.3%) child, and there were no reports of Grade 3 fever. Reactogenicity is given in Table 1.

Table 1

Solicited injection site and general AEs in the TVC

The rate of unsolicited AEs reported up to Day 42 was 26.5% (n = 41; 95% CI 19.7, 34.1), which were most frequently nasopharyngitis (n = 10; 6.5%; 95% CI 3.1, 11.5), cough (n = 9; 5.8%; 95% CI 2.7, 10.7), and vomiting and pyrexia (each: n = 4; 2.6%; 95% CI 0.7, 6.5). The frequency of Grade 3 unsolicited AEs was low. Unsolicited AEs are summarized in Table 2.

Table 2

Summary of unsolicited AEs in the TVC

The rate of MAEs up to Day 385 was 23.2% (n = 36; 95% CI 16.8, 30.7), which were most frequently pyrexia, upper respiratory tract infection, and cough, with each symptom reported at a rate of 2.6% (each n = 4; 95% CI 0.7, 6.5). There were 2 SAEs up to Day 385, which were scarlet fever and wound that were not considered by the investigator to be causally related to vaccination (each n = 1; 0.6%; 95% CI 0.2, 4.6). There were no pIMDs reported during Year 2.

In this open-label, one-way, crossover safety extension phase, children who had received placebo in the randomized phase of the study (Year 1) were invited to receive a 2-dose primary series of AS03_B-H5N1 vaccine in Year 2. The rationale for the crossover phase was to ensure that, according to ethical practice, children in the placebo group in Year 1 had the opportunity to receive active vaccine. A further objective was to increase the safety data for AS03_B-H5N1 vaccine. Our results showed that the most frequent solicited AE (local and general) was injection site pain with mostly mild or moderate intensity. Although the incidence of unsolicited AEs in Year 1 was consistent between the vaccine and placebo groups, the rate of unsolicited AEs in Year 2 was lower than that reported in vaccine recipients in Year 1.

Injection site pain was the most frequent solicited symptom during the 7-day postvaccination period reported across the development program for AS03-adjuvanted H5N1 vaccines in adults (Québec- and Dresden-manufactured vaccines) and in children (Dresden-manufactured vaccine) [12, 13]. In the previous open-label pediatric study of Dresden-manufactured H5N1 vaccine, 2 doses (1.9 μg HA) of AS03_B-H5N1 vaccine (n = 51) was associated with an overall rate of injection site pain of 60.8% in children aged 3–5 years and 86.3% in children aged 6–9 years [8]. Our study of Québec-manufactured AS03_B-H5N1 vaccine (1.9 μg HA) included children with a broader age range than that in the previous study and showed that the incidence of solicited injection site pain in vaccine recipients overall was 67.2% in Year 1 and 72.1% in Year 2 [14]. In both years, the incidence of Grade 3 pain was low (3.3% in Year 1 and 5.2% in Year 2), and the incidence of Grade 3 redness and swelling (>100 mm) was ≤0.5% in Year 1, with no reports in Year 2.

The profile of general solicited events overall showed that the vaccine was well tolerated by this pediatric population. Irritability or fussiness was reported in about one-third of younger children (aged <6 years) during the 7-day postvaccination period and was the most common solicited general event in this age group. A postvaccination temperature (≥38°C) was reported in 4 (5.1%) children, including reports of fever ≥39.0°C in 2 children who were aged <36 months. The most common solicited general AEs in older children (aged ≥6 years) were muscle aches, headache, and fatigue. These results are similar to those reported in the vaccine recipients group in Year 1 during the 7-day postvaccination period: irritability or fussiness was the most reported symptom in children aged <6 years with an incidence of 43.5%, and in children aged ≥6 years, muscle aches, headache, and fatigue were also included in the most commonly reported solicited general symptoms (incidence rates of these symptoms were 39.8%, 32.4%, and 28.8%, respectively, in Year 1) [14]. The AS03_B-H5N1 vaccine had a clinically acceptable safety profile up to 385 days post vaccination. Unsolicited AEs during the first 42 days of the safety follow-up and MAEs during the 385-day follow-up were most frequent symptoms associated with upper respiratory tract infection such as nasopharyngitis and cough, which are common conditions in children. During the 385-day follow-up, there were 2 SAEs (scarlet fever and wound), which were not considered to be vaccine related, and no pIMDs were reported.

These data increase the safety database for this vaccine from 607 to 762 children who received at least one dose of Québec-manufactured AS03_B-H5N1 (A/Indonesia) vaccine. Nevertheless, experience with this vaccine remains too limited to exclude uncommon AEs occurring at rates of <1 in 250.

In our study, the incidence of unsolicited AEs in children who received AS03_B-H5N1 vaccine was lower in Year 2 than in Year 1, including the rates of children with one or more AE at Day 42, which was 26.5% and 40.2% in Years 2 and 1, respectively [14]. However, the population samples are not directly comparable because of the differences in age and study environment, i.e. children in Year 2 were about a year older than those in Year 1, and the Year 2 crossover study included eligible children from Year 1 who opted to participate. Overall, the incidence of unsolicited AEs was consistent with that of the open-label pediatric study of Dresden-manufactured H5N1 (A/Vietnam) vaccine in children aged 3–9 years [11].

The main limitations of the Year 2 crossover phase were that it was an open-label phase and lacked a parallel control group. A further limitation was the potential for selection bias among families who accepted the invitation to receive the vaccine in Year 2. At the time of the study, human cases of avian-influenza infection were not widely reported and the threat of “bird flu” was not prominent in the media and in the public consciousness. As such, the perception of the likelihood of benefit from vaccination may not have outweighed the demands and discomfort of study participation. Despite this, participation in Year 2 was relatively high, suggesting that the experience in Year 1 was favorable and that the willingness to contribute to the understanding of influenza pandemic vaccines was good (of the 231 placebo recipients in Year 1, 155 [60%] enrolled in Year 2). Of note, the randomized-controlled part of this trial (Year 1) was the basis for the regulatory approval of the pediatric dose (1.9 μg HA with AS03_B) in the US and Canada for use according to official recommendations.

In summary, this open-label, one-way crossover extension phase (Year 2) included 155 children who were aged from 6 months to <18 years at study entry in the randomized blinded phase (Year 1). Eligible placebo recipients from Year 1 received a 2-dose primary series of AS03_B-H5N1 vaccine in Year 2. Safety in the crossover phase was acceptable and consistent with that observed in 607 vaccine recipients in the randomized, controlled, blinded study phase.