A randomized controlled study to evaluate the immunogenicity of a trivalent inactivated seasonal influenza vaccine at two dosages in children 6 to 35 months of age

Abstract

The trivalent inactivated influenza vaccine Fluarix™ is licensed in the US for adults and children from 3 years old. This randomized observer-blind study (NCT00764790) evaluated Fluarix™ at two doses; 0.25 ml (Flu-25) and 0.5 ml (Flu-50) in children aged 6–35 months. The primary objective was to demonstrate immunogenic non-inferiority vs. a control vaccine (Fluzone®; 0.25 ml). Children received Flu-25 (n = 1107), Flu-50 (n = 1106) or control vaccine (n = 1104) at Day 0 and for un-primed children, also on Day 28. Serum hemagglutination-inhibition titers were determined pre-vaccination and at Day 28 (primed) or Day 56 (un-primed). Non-inferiority was assessed by post-vaccination geometric mean titer (GMT) ratio, (upper 95% confidence interval [CI] ≤ 1.5) and difference in seroconversion rate (upper 95% CI ≤ 10%). Reactogenicity/safety was monitored. The immune response to Flu-50 met all regulatory criteria. Indicated by adjusted GMT ratios [with 95% CI], the criteria for non-inferiority of Flu-50 vs. control vaccine were reached for the B/Florida strain (1.13 [1.01–1.25]) but not for the A/Brisbane/H1N1 (1.74 [1.54–1.98]) or A/Uruguay/H3N2 (1.72 [1.57–1.89]) strains. In children aged 18–35 months similar immune responses were observed for Flu-50 and the control vaccine. Flu-50 induced a higher response than Flu-25 for all strains. Temperature (≥ 37.5°C) was reported in 6.2%, 6.4%, and 6.6% of the Flu-25, Flu-50, and control group, respectively. Reactogenicity/safety endpoints were within the same range for all vaccines.

In children aged 6–35 months, immune responses with Flu-50 fulfilled regulatory criteria but did not meet the pre-defined criteria for non-inferiority vs. control. This appeared to be due to differences in immunogenicity in children aged < 18 months.

Keywords: :

• influenza
• vaccine
• children
• immunogenicity
• trivalent inactivated

Acknowledgments

• All authors participated in the implementation of the study including substantial contributions to conception and design and/or the gathering of the data, or analysis and interpretation of the data. All authors were involved in the drafting of the article or revising it critically for important intellectual content, and final approval of the manuscript. All authors had full access to the data and had final responsibility to submit for publication.

• We thank all the participating study volunteers and their parents, study doctors and trial nurses, and laboratory technicians at the study site. In particular we thank J Hedrick, B Essink, M Leonardi, M Schear, L Chu, L Harris-Ford, C Ashley, M Cox, W Daly, E Franklin, E Goldblatt, D Hurley, W Johnston, M Lauret, K Zollo, T Chotpitayasunondh, NC Chiu, C Ying-Hsiang and N Dominguez.

• We are grateful to all teams of GlaxoSmithKline Vaccines for their contribution to this study: L Ray (4 Clinics on behalf of GlaxoSmithKline Vaccines) for preparation of the study report; I Naeije for global study management; A. Bastidas, Clinical Safety Representative.

• We thank M. Hynes and A. Moon (Freelance writers on behalf of GlaxoSmithKline Vaccines) for providing medical writing services, and J. Dedessus le Moutier and B. Dumont (Business & Decision Life Sciences on behalf of GlaxoSmithKline Vaccines) for editorial assistance and manuscript coordination.

Financial disclosure

GlaxoSmithKline Biologicals SA was the funding source and was involved in all stages of the study conduct and analysis. GlaxoSmithKline Biologicals SA also took responsibility for all costs associated with the development and publishing of the present manuscript.

Conflict of interest

V. Jain, M. El Idrissi, Y. Feng, B. Innis, M. Peeters, J.M. Devaster are employee of GlaxoSmithKline group of companies. V. Jain, B. Innis, M. Peeters, J.M. Devaster report ownership of stock options. L.M. Huang reports payment for consulting fee or honorarium for Pneumococcus advisory board, lectures, other advisory board, consultancy for vaccine use in Taiwan, pneumonia etiology study from GlaxoSmithKline group of companies and grants to his institution for clinical trials from GlaxoSmithKline group of companies. Y.L. Lau reports grants received for travel support and for other clinical trials received from GlaxoSmithKline group of companies. E.A.S. Nelson reports grants to his institution for performing this study from GlaxoSmithKline group of companies, for participating in diarrheal and respiratory disease surveillance studies from Merck and Pfizer (Wyeth), and for vaccine clinical trials from Baxter, GlaxoSmithKline group of companies, MedImmune and Pfizer (Wyeth). E.A.S. Nelson reports having received payments for travel, accommodation and honorarium for a lecture on respiratory disease surveillance and pneumococcal vaccine. E.A.S. Nelson is a member of Hong Kong's Scientific Committee on Vaccine Preventable Diseases, a member of a data Safety Monitoring Board for a Japanese Encephalitis vaccine study and a member of the ROTA Council. E.A.S. Nelson has been a technical advisor to the SIVAC (Supporting Independent Vaccine Advisory Committees) Initiative (2008–2011) and a member of WHO Quantitative Immunization and Vaccines Related Research Expert Advisory Group (2007–2012). M. Blatter reports payment received for board membership, lectures including service on speakers bureau from GlaxoSmithKline group of companies, and money paid to his institution for grants/grants pending, support for travel to meetings from GlaxoSmithKline group of companies. R. Jeanfreau reports payment for travel/accommodations/meeting expenses from GlaxoSmithKline group of companies. N. Pavia-Ruz reports payment for board membership received from Tibotec and payment to his institution for grants from GlaxoSmithKline group of companies and Bristol Myers Squibb. M.A.R. Weber, P. Silas, P. Qaqundah, P. Lei and A. Kerdpanich report no conflict of interest.

Trademark

Fluarix™ is a trademark of the GlaxoSmithKline group of companies. Fluzone® is a registered trademark of Sanofi Pasteur. Inflexal^® V is a registered trademark of Crucell. Vaxigrip^® is a registered trademark of Sanofi Pasteur