Rapid Immunization Against H5N1: A Randomized Trial Evaluating Homologous and Cross-Reactive Immune Responses to AS03A-Adjuvanted Vaccination in Adults

Abstract

Background. Accelerated immunization schedules may help gain early control of influenza pandemics. We investigated different schedules of an AS03A-adjuvanted H5N1 vaccine.Methods. This phase II, open-label, 6-month study randomized participants (aged 18–64 years) to 2 vaccine doses administered 21 (standard schedule), 14, or 7 days apart, or on the same day. Coprimary end points were that the lower limit of the 98.75% confidence interval 14 days after the last dose must be (1) >40% for seroconversion rate (SCR) (Center for Biologics Evaluation and Research [CBER] criterion) and (2) >50% for seroprotection rate (SPR) (attainment rate for reciprocal hemagglutination inhibition titers ≥40, protocol-defined criterion) for the vaccine homologous strain (A/Indonesia/5/2005). European Committee for Human Medicinal Products (CHMP) immunogenicity criteria were also evaluated.Results. Coprimary end points were achieved (lower 98.75% confidence intervals exceeded defined values). Titers were highest with the standard schedule. Nevertheless, CBER SCR, protocol-defined SPR, and CHMP criteria were met with all schedules for the A/Indonesia/5/2005 strain. There were no significant differences between age groups (18–40 vs 41–64 years). Immune response was robust against drift variants A/turkey/Turkey/1/2005 and A/Vietnam/1194/2004.Conclusions. The AS03A-adjuvanted H5N1 vaccine in accelerated schedules offers a robust immune response against vaccine homologous and drift variant strains, allowing consideration of compressed vaccination intervals.Clinical Trials Registration. NCT00695669.

Immunogenicity and Safety of an EB66 Cell-Culture-Derived Influenza A/Indonesia/5/2005(H5N1) AS03-Adjuvanted Vaccine: A Phase 1 Randomized Trial

“…Both of AS03-adjuvanted CC-H5N1 formulations were immunogenic for the homologous and drift variant A/Vietnam/1194/2004 strains in terms of HI and NAbs and met CBER criteria for immunogenicity of pandemic vaccines for both strains. The potential for cross-clade immunogenicity is fundamental to priming a population in a prepandemic or early pandemic setting, providing priming or protection until a pandemic strain-matched vaccine becomes available [ 10 , 20 , 21 ].…”

Influenza symptoms and their impact on elderly adults: randomised trial of AS03‐adjuvanted or non‐adjuvanted inactivated trivalent seasonal influenza vaccines

“…Studies have shown that vaccines formulated with AS03 are highly immunogenic against H5N1 avian strains and the human pandemic influenza H1N1 strain in elderly and non-elderly adults. [6][7][8][9][10] A community-based casecontrol study of the MF59-adjuvanted trivalent seasonal vaccine has also shown benefit in the elderly versus a nonadjuvanted vaccine. 11 Thus, adjuvanted vaccines provide a potential approach to reduce the incidence and severity of influenza in the elderly.…”

Strategies for Early Vaccination During Novel Influenza Outbreaks

“…Previous studies have considered a longer time-lag (four weeks) 26 , which would lead to even lower impact on reducing attack rates. However, a recent randomized trial of H5N1 adjuvanted vaccine suggests that accelerated immunization schedules with a short time-lag (7 or 14 days) between the first and second doses may be effective in enhancing vaccine efficacy and help gain early control of influenza pandemics 27 . Our simulations corroborate these effects in the population, demonstrating that as the time-lag between vaccine doses reduces, the impact of vaccination becomes more pronounced on reducing attack rates.…”