AS03A-adjuvanted Vaccine Research Articles

Heterologous prime-boost with A(H5N1) pandemic influenza vaccines induces broader cross-clade antibody responses than homologous prime-boost

Highly pathogenic avian influenza (HPAI) A(H5Nx) viruses continue to pose a pandemic threat. US national vaccine stockpiles are a cornerstone of the influenza pandemic preparedness plans. However, continual genetic and antigenic divergence of A(H5Nx) viruses requires the development of effective vaccination strategies using stockpiled vaccines and adjuvants for pandemic preparedness. Human sera collected from healthy adults who received either homologous (2 doses of a AS03A-adjuvanted A/turkey/Turkey/1/2005, A/Turkey), or heterologous (primed with AS03A-adjuvanted A/Indonesia/5/2005, A/Indo, followed by A/Turkey boost) prime-boost vaccination regimens were analyzed by hemagglutination inhibition and microneutralization assays against 8 wild-type HPAI A(H5Nx) viruses from 6 genetic clades. Molecular, structural and antigenic features of the A(H5Nx) viruses that could influence the cross-clade antibody responses were also explored. Compared with homologous prime-boost vaccinations, priming with a clade 2.1.3.2 antigen (A/Indo) followed by one booster dose of a clade 2.2.1 antigen (A/Turkey) administered 18 months apart did not compromise the antibody responses to the booster vaccine (A/Turkey), it also broadened the cross-clade antibody responses to several antigenically drifted variants from 6 heterologous clades, including an antigenically distant A(H5N8) virus (A/gyrfalcon/Washington/410886/2014, clade 2.3.4.4) that caused recent outbreaks in US poultry. The magnitude and breadth of the cross-clade antibody responses against emerging HPAI A(H5Nx) viruses are associated with genetic, structural and antigenic differences from the vaccine viruses and enhanced by the inclusion of an adjuvant. Heterologous prime-boost vaccination with AS03A adjuvanted vaccine offers a vaccination strategy to use existing stockpiled vaccines for pandemic preparedness against new emerging HPAI A(H5Nx) viruses.

An observer-blind, randomized, multi-center trial assessing long-term safety and immunogenicity of AS03-adjuvanted or unadjuvanted H1N1/2009 influenza vaccines in children 10–17 years of age

BackgroundVaccination is an effective strategy to prevent influenza. This observer-blind, randomized study in children 10–17 years of age assessed whether the hemagglutination inhibition (HI) antibody responses elicited by H1N1/2009 vaccines adjuvanted with AS03 (an adjuvant system containing α-tocopherol and squalene in an oil-in-water emulsion) or without adjuvant, met the European regulatory immunogenicity criteria at Days 21 and 182. MethodsThree hundred and ten healthy children were randomized (3:3:3:5) to receive one dose of 3.75μg hemagglutinin (HA) AS03A-adjuvanted vaccine, one or two doses of 1.9μg HA AS03B-adjuvanted vaccine, or one dose of 15μg HA pandemic vaccine. All children received a booster dose of the allocated vaccine at Day 182. Serum samples were tested for HI antibody response at Days 21, 42, 182 and 189. ResultsAll vaccination regimens elicited HI antibody responses that met the European regulatory criteria at Days 21 and 42. HI antibody responses fulfilling European regulatory criteria were still observed six months after the first vaccine dose in all study vaccines groups. Two doses of 1.9μg HA AS03B-adjuvanted vaccine elicited the strongest HI antibody response throughout the study. The non-adjuvanted 15μg HA vaccine elicited a lower HI antibody response than the AS03-adjuvanted vaccines. At Day 189, the European regulatory criteria were met for all vaccines with baseline HI antibody titers as reference. An anamnestic response for all vaccines was suggested at Day 189, based on the rapid increase in HI antibody geometric mean titers (1.5–2.5-fold increase). Injection site reactogenicity was higher following the AS03-adjuvanted vaccines compared with the non-adjuvanted vaccine. No safety concerns were identified for any study vaccine. ConclusionAll study vaccines elicited HI antibody responses that persisted at purported protective levels through six months after vaccination and fulfilled the European regulatory criteria.

Flexibility of interval between vaccinations with AS03A-adjuvanted influenza A (H1N1) 2009 vaccine in adults aged 18–60 and >60 years: a randomized trial

BackgroundFlexibility of vaccination schedule and lower antigen content can facilitate pandemic vaccine coverage. We assessed the immune response and safety of AS03-adjuvanted A/California/7/2009 H1N1 pandemic vaccine containing half of the registered adult haemagglutinin (HA) antigen content, administered as a two-dose schedule at intervals of 21 days or 6 months in both young and elderly adults.MethodsIn this open-label randomized trial, healthy adults aged 18–60 years (N = 163) and >60 years (N = 143) received AS03A-adjuvanted A/California/7/2009 H1N1 vaccine containing 1.9 μg HA on Day 0. A second dose was given on Day 21 (n = 177) or Day 182 (n = 106). Haemagglutination-inhibition (HI) antibody responses were analyzed on Days 0, 21, 42, 182, 364 and additionally on Day 203 for subjects vaccinated on Day 182. Solicited and unsolicited adverse events were recorded.ResultsThe HI antibody response in both age strata 21 days after the first dose met and exceeded all regulatory acceptance criteria although the results suggested a lower response in the older age stratum (geometric mean titres [GMTs] for HI antibodies of 420.5 for subjects aged 18–60 years and 174.4 for those >60 years). A second dose of AS03A adjuvanted A/H1N1/2009 vaccine induced a further increase in antibody titres and the response was similar whether the second dose was administered at 21 days (GMTs of 771.8 for 18–60 years and 400.9 for >60 years) or 6 months (GMTs of 708.3 for 18–60 years and 512.1 for >60 years) following the first dose. Seroprotection rates remained high at 6 months after one dose or two doses while at 12 months rates tended to be higher for the 6 month interval schedule (93.3% for 18–60 years and 80.4% for >60 years) than the 21 day schedule (82.3% for 18–60 years and 50.0% for >60 years). Reactogenicity/safety profiles were similar for both schedules, there was no evidence of an increase in reactogenicity following the second dose.ConclusionsThe results indicate that flexibility in the dosing interval for AS03A adjuvanted vaccine may be possible. Such flexibility could help to reduce the logistic stress on delivery of pandemic vaccination programmes.Trial registrationClinicalTrials.gov, NCT00975884

Effect on Cellular and Humoral Immune Responses of the AS03 Adjuvant System in an A/H1N1/2009 Influenza Virus Vaccine Administered to Adults during Two Randomized Controlled Trials

The influence of AS03(A), a tocopherol oil-in-water emulsion-based adjuvant system, on humoral and cell-mediated responses to A/California/7/2009 H1N1 pandemic vaccine was investigated. In two observer-blind studies, a total of 261 healthy adults aged 18 to 60 years were randomized to receive either AS03(A)-adjuvanted H1N1 vaccine containing 3.75 μg hemagglutinin (HA) or nonadjuvanted H1N1 vaccine containing 15 or 3.75 μg HA on days 0 and 21. Hemagglutination inhibition (HI) antibody and T-cell responses were analyzed up to day 42. A first dose of AS03(A)-adjuvanted vaccine (3.75 μg HA) or nonadjuvanted vaccine (15 μg HA) induced HI responses of similar magnitudes that exceeded licensure criteria (e.g., 94 to 100% with titers of ≥ 40). A lower response following 3.75 μg HA without adjuvant was observed (73% with titers of ≥ 40). Following a second dose, geometric mean HI titers at day 42 were higher for AS03(A)-adjuvanted vaccine (636 and 637) relative to nonadjuvanted vaccine (341 for 15 μg HA and 150 for 3.75 μg HA). Over the 42-day period, the increase in frequency of A/H1N1/2009-specific CD4⁺ T cells was significantly higher in the adjuvanted group than in the nonadjuvanted group. There was no evidence of correlation between baseline CD4⁺ T-cell frequencies and day 21 HI antibody titers, while there was some correlation (R = 0.35) between day 21 CD4⁺ T-cell frequencies and day 42 HI titers. AS03(A) adjuvant enhanced the humoral and CD4⁺ T-cell-mediated responses to A/H1N1/2009 vaccine. Baseline A/H1N1/2009-specific CD4⁺ T-cell frequencies did not predict post-dose 1 antibody responses, but there was some correlation between post-dose 1 CD4⁺ T-cell frequencies and post-dose 2 antibody responses.

Immunogenicity and Efficacy in Hemodialysis Patients of an AS03 A-Adjuvanted Vaccine for 2009 Pandemic Influenza A(H1N1): A Nonrandomized Trial

Hemodialysis patients have a reduced response to vaccinations because of uremia-related immune dysfunction. To increase the immunogenicity of vaccines, antigens can be formulated with adjuvants. The new tocopherol-containing adjuvant system AS03(A) has not been tested yet in patients with end-stage renal disease. Nonrandomized trial. 291 hemodialysis patients from 3 dialysis units co-operating with the Department of Nephrology at the University Hospital Heidelberg, Germany: 169 patients were vaccinated using either 1 (64 patients) or 2 doses (105 patients); 123 patients refused the vaccination and served as controls. Intramuscular immunization with 3.75 μg of an inactivated split-virion A/California/7/2009 H1N1v pandemic vaccine adjuvanted with AS03(A) in a single- or double-dose regimen. A pandemic influenza A immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA) response >11 AU (arbitrary units) was defined as a positive response. Quantitative antibody testing using the pandemic influenza A IgG ELISA. Antibody titers were tested 3 months after vaccination and compared with nonimmunized dialysis patients. After vaccination against 2009 pandemic influenza A(H1N1), 41 of 64 (64.1%) patients with 1 vaccination and 93 of 105 (88.6%) with 2 vaccinations showed a protective immune response compared with 43 of 123 (34.9%) unvaccinated patients (P < 0.001). Logistic regression analysis confirmed vaccination dose as an independent factor for response to pandemic H1N1 vaccination. No episode of pandemic H1N1 illness occurred in any group within the study period of 6 months after vaccination. No serious adverse events occurred, and local symptoms ranged from mild to moderate in 143 of 169 (84.6%) patients. Nonrandomized assignment; use of nontreated patients as controls; no comparison to nonadjuvanted vaccines; dose variation in the intervention group. Pandemic H1N1 vaccine adjuvanted with AS03(A) is immunogenic, effective, and safe in hemodialysis patients.

A randomised, partially observer blind, multicentre, head-to-head comparison of a two-dose regimen of Baxter and GlaxoSmithKline H1N1 pandemic vaccines, administered 21 days apart

A randomised, partially observer blind, multicentre, head-to-head comparison of a two-dose regimen of Baxter and GlaxoSmithKline H1N1 pandemic vaccines, administered 21 days apart

Immunogenicity and safety in adults of one dose of influenza A H1N1v 2009 vaccine formulated with and without AS03 A-adjuvant: Preliminary report of an observer-blind, randomised trial

Governments and public health officials are preparing vaccination campaigns against the 2009 influenza A H1N1v pandemic strain. We evaluated two inactivated split-virion A/California/7/2009 H1N1v pandemic vaccines formulated with/without AS03 A, an oil-in-water emulsion adjuvant system containing tocopherol. This ongoing observer-blind study randomised 130 healthy adults aged 18–60 years to receive either AS03 A-adjuvanted H1N1 vaccine containing 5.25 μg haemagglutinin (HA) ( N = 64) or non-adjuvanted H1N1 vaccine containing 21 μg HA ( N = 66) on Days 0 and 21. We performed a first analysis of reactogenicity and serum haemagglutination-inhibition (HI) antibody responses, 21 days after dose 1. Before vaccination, 12.5% in the AS03 A-adjuvanted group and 13.1% in the non-adjuvanted group had vaccine-homologous HI titres ≥1:40. Immune responses were robust; HI seroconversion rates were 98.2% and 95.1% and HI seroprotection rates were 98.2% and 98.4%, respectively in the AS03 A and non-adjuvanted groups. The vaccines were well tolerated with similar adverse event profiles. Solicited injection site and general symptoms were reported more frequently for AS03 A-adjuvanted vaccine but these were transient and mainly mild to moderate in intensity. Based on accepted immunological surrogates, these preliminary data suggest that one dose of either AS03 A-adjuvanted H1N1v vaccine at a reduced HA dose or non-adjuvanted H1N1v vaccine at a fourfold higher dose is sufficient to immunise healthy adults. The strong immune response is consistent with prevalent immunological priming but as this and the ability to mount immune response after vaccination may be modulated by age, further investigations in children and in the elderly as well as on the persistence of the immune response are warranted.