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Open Access Research article

Selection of an adjuvant for seasonal influenza vaccine in elderly people: modelling immunogenicity from a randomized trial

Hans C Rümke1, Jan Hendrik Richardus2, Lars Rombo3, Karlis Pauksens4, Georg Plaßmann5, Christelle Durand6, Jeanne-Marie Devaster7, Walthère Dewé6 and Lidia Oostvogels7*

Author Affiliations

1 Medical Director, Vaxinostics, University Vaccine Center, Rotterdam, The Netherlands

2 Senior Investigator, Department of Infectious Disease Control, Municipal Public Health Service (GGD) Rotterdam-Rijnmond, Rotterdam, The Netherlands

3 Clinical research centre Sormland, Uppsala University, Uppsala, Sweden

4 Department of Medical Sciences, Section of Infectious Diseases, Uppsala University, Akademiska Sjukhuset, Uppsala, Sweden

5 Unterfrintroper Hausarztzentrum, Unterstraße 75, 45359, Essen, Germany

6 Vaccine Value & Health Science, GlaxoSmithKline Vaccines, Wavre, Belgium

7 Vaccine Discovery and Development, GlaxoSmithKline Vaccines, Wavre, Belgium

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BMC Infectious Diseases 2013, 13:348  doi:10.1186/1471-2334-13-348

Published: 26 July 2013

Abstract

Background

Improved influenza vaccines are needed to reduce influenza-associated complications in older adults. The aim of this study was to identify the optimal formulation of adjuvanted seasonal influenza vaccine for use in elderly people.

Methods

This observer-blind, randomized study assessed the optimal formulation of adjuvanted seasonal influenza vaccine based on immunogenicity and safety in participants aged ≥65 years. Participants were randomized (~200 per group) to receive one dose of non-adjuvanted vaccine or one of eight formulations of vaccine formulated with a squalene and tocopherol oil-in-water emulsion-based Adjuvant System (AS03C, AS03B or AS03A, with 2.97, 5.93 and 11.86 mg tocopherol, respectively) together with the immunostimulant monophosphoryl lipid A (MPL, doses of 0, 25 or 50 mg). Hemagglutination-inhibition (HI) antibody responses and T-cell responses were assessed on Day 0 and 21 days post-vaccination. The ratio of HI-based geometric mean titers in adjuvanted versus non-adjuvanted vaccine groups were calculated and the lower limit of the 90% confidence interval was transformed into a desirability index (a value between 0 and 1) in an experimental domain for each vaccine strain, and plotted in relation to the AS03 and MPL dose combination in the formulation. This model was used to assess the optimal formulation based on HI antibody titers. Reactogenicity and safety were also assessed. The immunogenicity and safety analyses were used to evaluate the optimal formulation of adjuvanted vaccine.

Results

In the HI antibody-based model, an AS03 dose–response was evident; responses against the A/H1N1 and A/H3N2 strains were higher for all adjuvanted formulations versus non-adjuvanted vaccine, and for the AS03A-MPL25, AS03B-MPL25 and AS03B-MPL50 formulations against the B strain. Modelling using more stringent criteria (post hoc) showed a clear dose-range effect for the AS03 component against all strains, whereas MPL showed a limited effect. Higher T-cell responses for adjuvanted versus non-adjuvanted vaccine were observed for all except two formulations (AS03C and AS03B-MPL25). Reactogenicity increased with increasing AS03 dosage, and with MPL. No safety concerns were raised.

Conclusions

Five formulations containing AS03A or AS03B were identified as potential candidates to improve immune responses to influenza vaccination; AS03B without MPL showed the best balance between improved immunogenicity and acceptable reactogenicity.

Trial registration

This trial is registered at ClinicalTrials.gov, NCT00540592

Keywords:
Influenza vaccination; Elderly; Adjuvant system; Dose comparison; Immunogenicity; Reactogenicity; Safety