Clinical and immune responses to inactivated influenza A(H1N1)pdm09 vaccine in children

Abstract

Background: As the influenza A H1N1 pandemic emerged in 2009, children were found to experience high morbidity and mortality and were prioritized for vaccination. This multicenter, randomized, double-blind, age-stratified trial assessed the safety and immunogenicity of inactivated influenza A(H1N1)pdm09 vaccine in healthy children aged 6 months to 17 years.

Methods: Children received 2 doses of approximately 15 or 30 µg hemagglutin antigen 21 days apart. Reactogenicity was assessed for 8 days after each dose, adverse events through day 42, and serious adverse events or new-onset chronic illnesses through day 201. Serum hemagglutination inhibition titers were measured on days 0 (prevaccination), 8, 21, 29 and 42.

Results: A total of 583 children received the first dose and 571 received the second dose of vaccine. Vaccinations were generally well-tolerated and no related serious adverse events were observed. The 15 µg dosage elicited a seroprotective hemagglutination inhibition (≥ 1:40) in 20%, 47% and 93% of children in the 6-35 month, 3-9 year and 10-17 year age strata 21 days after dose 1 and in 78%, 82% and 98% of children 21 days after dose 2, respectively. The 30 µg vaccine dosage induced similar responses.

Conclusions: The inactivated influenza A(H1N1)pdm09 vaccine exhibited a favorable safety profile at both dosage levels. While a single 15 or 30 µg dose induced seroprotective antibody responses in most children 10-17 years of age, younger children required 2 doses, even when receiving dosages 4- to 6-fold higher than recommended. Well-tolerated vaccines are needed that induce immunity after a single dose for use in young children during influenza pandemics.

Trial registration: ClinicalTrials.gov NCT00943202.

Figures

Figure 1. Infants and children assessed for eligibility, randomized, vaccinated, and included in the analysis of safety and immunogenicity

All subjects receiving Dose 1 were followed for safety through day 42; however, safety assessments after day 21 for those not receiving Dose 2 were limited to SAEs and new onset chronic medical conditions. *Reasons for ineligibility included intercurrent illness and receipt of a prohibited medication. Note: the most common reason for a missed blood sample was a scheduling error in the two younger strata; many children were assigned to an alternate schedule and remained analyzable. Common reasons for exclusion from immunogenicity analyses post dose 2 were missed vaccination (n=11), vaccinated >7 days out of window (n=6), or incorrectly vaccinated (n=3). Additional reasons for missed samples included unsuccessful phlebotomy (n=2), missed visits (n=5), and laboratory error (n=2). One child who withdrew prior to having blood collected post-vaccination and one child whose post-vaccination blood was drawn greater than 7 days out of window were excluded entirely from the immunogenicity analysis. Immunogenicity 21 days after dose 2 was not analyzed for one child whose blood sample was collected > 7 days out of window and for two children who received prohibited off-study vaccinations prior to this day. The two dosage groups experienced a similar number of blood sampling deviations.

Figure 2. Proportion of children who developed a hemagglutination inhibition titer (HAI) ≥1:40 21 days after receiving one (A) or two (B) 15 μg doses of vaccine, by age in years

The dashed line indicates the age at which the lower bound of the two-sided 95% CI for the percent of subjects achieving an HAI antibody titer ≥1:40 reaches at least 70%, which is a guide recommended by the U.S. Food and Drug Administration in developing endpoints that would support accelerated approval of pandemic influenza vaccines for children.