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David W. Vaughn - One of the best experts on this subject based on the ideXlab platform.
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Evaluation of a primary course of H9N2 vaccine with or without AS03 adjuvant in adults: A phase I/II randomized trial.
Vaccine, 2017Co-Authors: Anuradha Madan, Bruce L. Innis, Harry Collins, Eric Sheldon, Louise Frenette, Laurence Chu, Damien Friel, Mamadou Dramé, David W. Vaughn, Anne SchuindAbstract:Avian influenza A H9N2 strains have pandemic potential. In this randomized, observer-blind study (ClinicalTrials.gov: NCT01659086), 420 healthy adults, 18-64years of age, received 1 of 10 H9N2 inactivated split-virus vaccination regimens (30 participants per group), or saline placebo (120 participants). H9N2 groups received 2 doses (days 0, 21) of 15µg hemagglutinin (HA) without adjuvant, or 1.9µgHA+AS03A, 1.9µgHA+AS03B, 3.75µgHA+AS03A, or 3.75µgHA+AS03B; followed by the same H9N2 formulation or placebo (day 182). AS03 is an adjuvant system containing α-tocopherol (AS03A: 11.86mg; AS03B: 5.93mg) and squalene in an oil-in-water emulsion. Immunogenicity (hemagglutination inhibition [HI] and microneutralization assays) and safety were assessed up to day 546. All adjuvanted formulations exceeded regulatory immunogenicity criteria at days 21 and 42 (HI assay), with seroprotection and seroconversion rates of ≥94.9% and ≥89.8% at day 21, and 100% and ≥98.1% at day 42. Immunogenicity criteria were also met for unadjuvanted vaccine, with lower geometric mean titers. In groups administered a third vaccine dose (day 182), an anamnestic immune response was elicited with robust increases in HI and microneutralization titers. Injection site pain was reported more frequently with adjuvanted vaccines. No vaccine-related serious adverse events were observed. All H9N2 vaccine formulations were immunogenic with a clinically acceptable safety profile; adjuvanted formulations were 4-8 times dose-sparing (3.75-1.9vs 15µgHA). Registered on ClinicalTrials.gov: NCT01659086. Copyright © 2017. Published by Elsevier Ltd.
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Long-Term Persistence of Cell-Mediated and Humoral Responses to A(H1N1)pdm09 Influenza Virus Vaccines and the Role of the AS03 Adjuvant System in Adults during Two Randomized Controlled Trials
Clinical and vaccine immunology : CVI, 2017Co-Authors: Robbert G. Van Der Most, Frédéric Clement, David W. Vaughn, Karl Walravens, Julie Willekens, Walthère Dewé, Geert Leroux-roelsAbstract:We investigated the role of AS03A (here AS03), an α-tocopherol oil-in-water emulsion-based adjuvant system, on the long-term persistence of humoral and cell-mediated immune responses to A(H1N1)pdm09 influenza vaccines. In two studies, a total of 261 healthy adults (≤60 years old) were randomized to receive two doses of AS03-adjuvanted vaccine containing 3.75 μg of hemagglutinin (HA) or nonadjuvanted vaccine containing 15 μg of hemagglutinin (in study A) or 3.75 μg of hemagglutinin (in study B) 21 days apart. Hemagglutination inhibition (HI) antibody, memory B-cell, and CD4+/CD8+ T-cell responses were characterized up to 1 year following dose 1. We also assessed the effects of age and seasonal influenza vaccination history. AS03-adjuvanted (3.75 μg HA) vaccine and nonadjuvanted vaccine at 15 μg but not at 3.75 μg HA elicited HI antibody responses persisting at levels that continued to meet European licensure criteria through month 12. At month 12, the geometric mean titer for AS03-adjuvanted vaccine was similar to that for nonadjuvanted (15-μg) vaccine in study A (1:86 and 1:88, respectively) and higher than that for nonadjuvanted (3.75-μg) vaccine in study B (1:77 and 1:35, respectively). A(H1N1)pdm09-specific CD4+ T-cell and B-cell responses were stronger in AS03-adjuvanted groups and persisted only in these groups for 12 months at levels exceeding prevaccination frequencies. Advancing age and a seasonal vaccination history tended to reduce HI antibody and memory B-cell responses and, albeit less consistently, CD4+ T-cell responses. Thus, AS03 seemed to enhance the persistence of humoral and cell-mediated responses to A(H1N1)pdm09 vaccine, allowing for antigen sparing and mitigating potential negative effects of age and previous seasonal vaccination. (These studies have been registered at ClinicalTrials.gov under registration no. NCT00968539 and NCT00989287.).
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Evaluation of a primary course of H9N2 vaccine with or without AS03 adjuvant in adults: A phase I/II randomized trial.
Vaccine, 2017Co-Authors: Anuradha Madan, Bruce L. Innis, Harry Collins, Eric Sheldon, Louise Frenette, Laurence Chu, Damien Friel, Mamadou Dramé, David W. Vaughn, Anne SchuindAbstract:Abstract Background Avian influenza A H9N2 strains have pandemic potential. Methods In this randomized, observer-blind study (ClinicalTrials.gov: NCT01659086), 420 healthy adults, 18–64 years of age, received 1 of 10 H9N2 inactivated split-virus vaccination regimens (30 participants per group), or saline placebo (120 participants). H9N2 groups received 2 doses (days 0, 21) of 15 µg hemagglutinin (HA) without adjuvant, or 1.9 µg HA + AS03A, 1.9 µg HA + AS03B, 3.75 µg HA + AS03A, or 3.75 µg HA + AS03B; followed by the same H9N2 formulation or placebo (day 182). AS03 is an adjuvant system containing α-tocopherol (AS03A: 11.86 mg; AS03B: 5.93 mg) and squalene in an oil-in-water emulsion. Immunogenicity (hemagglutination inhibition [HI] and microneutralization assays) and safety were assessed up to day 546. Results All adjuvanted formulations exceeded regulatory immunogenicity criteria at days 21 and 42 (HI assay), with seroprotection and seroconversion rates of ≥94.9% and ≥89.8% at day 21, and 100% and ≥98.1% at day 42. Immunogenicity criteria were also met for unadjuvanted vaccine, with lower geometric mean titers. In groups administered a third vaccine dose (day 182), an anamnestic immune response was elicited with robust increases in HI and microneutralization titers. Injection site pain was reported more frequently with adjuvanted vaccines. No vaccine-related serious adverse events were observed. Conclusions All H9N2 vaccine formulations were immunogenic with a clinically acceptable safety profile; adjuvanted formulations were 4–8 times dose-sparing (3.75–1.9 vs 15 µg HA). Trial registration Registered on ClinicalTrials.gov: NCT01659086.
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Immunogenicity and safety of an AS03-adjuvanted H5N1 pandemic influenza vaccine in Korean adults: a phase IV, randomized, open-label, controlled study.
Vaccine, 2015Co-Authors: Patricia Izurieta, Mamadou Dramé, David W. Vaughn, Woo Joo Kim, Seong Heon Wie, Jacob Lee, Jin Soo Lee, Anne SchuindAbstract:Abstract Background AS03-adjuvanted H5N1 pandemic influenza vaccines have been assessed in an extensive clinical development program conducted in North America, Europe, and Asia including children from 6 months of age, adults, and elderly adults. We evaluated AS03-H5N1 in Korean adults 18 through 60 years of age. Methods This Phase IV, randomized, study was conducted to assess the immunogenicity, reactogenicity, and safety of two doses (3.75 μg of hemagglutinin antigen) of A/Indonesia/5/2005 (H5N1) adjuvanted with AS03 given 21 days apart in Korean adults. Antibody responses were assessed using hemagglutination-inhibition (HI) assays against the vaccine strain and a vaccine-heterologous strain (A/Vietnam/1194/2004) 21 days after the second dose. A control group (safety) received a licensed seasonal inactivated trivalent influenza vaccine (TIV). Reactogenicity was assessed for 7 days after each vaccination, and unsolicited adverse events were assessed for 182 days following vaccination in both study groups (NCT01730378). Results AS03-H5N1 was immunogenic and elicited robust HI antibody responses with seroconversion rates of 100% for the vaccine strain and 69.1% for the heterologous strain ( N = 81). HI antibody responses fulfilled the European licensure criteria for immunogenicity (primary endpoint). The incidence of local and systemic solicited adverse events (reactogenicity) was higher with AS03-H5N1 than TIV. There was no apparent difference in the rate of unsolicited adverse events in the AS03-H5N1 and TIV groups. Conclusion The results indicate that AS03-H5N1 vaccine is immunogenic with reactogenicity and safety findings that are consistent with the established profile of AS03-H5N1 vaccine.
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Safety of AS03-adjuvanted inactivated split virion A(H1N1)pdm09 and H5N1 influenza virus vaccines administered to adults: pooled analysis of 28 clinical trials
Human vaccines & immunotherapeutics, 2014Co-Authors: David W. Vaughn, Bruce L. Innis, Mamadou Dramé, Walthère Dewé, Catherine Cohet, Harry Seifert, Anne Hepburn, Louis F. FriesAbstract:Clinical trials have shown that AS03-adjuvanted H5N1 and A(H1N1)pdm09 vaccines are highly immunogenic, although with an increased reactogenicity profile relative to non-adjuvanted vaccines in terms of the incidence of common injection site and systemic adverse events (AEs). We evaluated pooled safety data from 22,521 adults who had received an AS03-adjuvanted H5N1 or A(H1N1)pdm09 influenza or control vaccine with the purpose to identify medically-attended AEs (MAEs), including subsets of serious AEs (SAEs), potentially immune-mediated diseases (pIMDs), and AEs of special interest (AESI), and to explore a potential association of these AEs with the administration of an AS03-adjuvanted influenza vaccine. For participants who had received an AS03-adjuvanted vaccine, the relative risks (RRs) for experiencing a MAE or a SAE compared to control group (participants who had received a non-adjuvanted vaccine or saline placebo) were 1.0 (95% confidence interval [CI]: 0.9; 1.1) and 1.1 (95% CI: 0.9; 1.4), respective...
Bruce L. Innis - One of the best experts on this subject based on the ideXlab platform.
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Safety of AS03-adjuvanted influenza vaccines: A review of the evidence.
Vaccine, 2019Co-Authors: Catherine Cohet, Nathalie Garcon, Robbert G. Van Der Most, Rino Rappuoli, Anne Schuind, Vincent Bauchau, Rafik Bekkat-berkani, T. Mark Doherty, Fernanda Tavares Da Silva, Bruce L. InnisAbstract:Clinical and post-licensure data have demonstrated that AS03-adjuvanted inactivated split virion vaccines, many with reduced antigen content, are effective against influenza infection. The objective of this review is to provide a comprehensive assessment of the safety of trivalent seasonal, monovalent pre-pandemic and pandemic AS03-adjuvanted influenza vaccines, based on non-clinical, clinical and post-licensure data in various populations. Non-clinical studies on local tolerance, toxicology and safety pharmacology did not raise any safety concerns with AS03 administered alone or combined with various influenza antigens. Data from clinical trials with over 55,000 vaccinated subjects showed that AS03-adjuvanted influenza vaccines were generally well tolerated and displayed an acceptable safety profile, although the power to detect rare events was limited. Approximately 90 million doses of A/H1N1pdm09 pandemic influenza vaccines (Pandemrix and Arepanrix H1N1) were administered worldwide, which contributed post-licensure data to the collective safety data for AS03-adjuvanted influenza vaccines. An association between Pandemrix and narcolepsy was observed during the A/H1N1pdm09 pandemic, for which a role of a CD4 T cell mimicry sequence in the haemagglutinin protein of A/H1N1pdm09 cannot be excluded. Provided that future AS03-adjuvanted influenza vaccines do not contain this putative mimicry sequence, this extensive safety experience supports the further development and use of AS03-adjuvanted inactivated split virion candidate vaccines against seasonal and pandemic influenza infections.
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Evaluation of a primary course of H9N2 vaccine with or without AS03 adjuvant in adults: A phase I/II randomized trial.
Vaccine, 2017Co-Authors: Anuradha Madan, Bruce L. Innis, Harry Collins, Eric Sheldon, Louise Frenette, Laurence Chu, Damien Friel, Mamadou Dramé, David W. Vaughn, Anne SchuindAbstract:Avian influenza A H9N2 strains have pandemic potential. In this randomized, observer-blind study (ClinicalTrials.gov: NCT01659086), 420 healthy adults, 18-64years of age, received 1 of 10 H9N2 inactivated split-virus vaccination regimens (30 participants per group), or saline placebo (120 participants). H9N2 groups received 2 doses (days 0, 21) of 15µg hemagglutinin (HA) without adjuvant, or 1.9µgHA+AS03A, 1.9µgHA+AS03B, 3.75µgHA+AS03A, or 3.75µgHA+AS03B; followed by the same H9N2 formulation or placebo (day 182). AS03 is an adjuvant system containing α-tocopherol (AS03A: 11.86mg; AS03B: 5.93mg) and squalene in an oil-in-water emulsion. Immunogenicity (hemagglutination inhibition [HI] and microneutralization assays) and safety were assessed up to day 546. All adjuvanted formulations exceeded regulatory immunogenicity criteria at days 21 and 42 (HI assay), with seroprotection and seroconversion rates of ≥94.9% and ≥89.8% at day 21, and 100% and ≥98.1% at day 42. Immunogenicity criteria were also met for unadjuvanted vaccine, with lower geometric mean titers. In groups administered a third vaccine dose (day 182), an anamnestic immune response was elicited with robust increases in HI and microneutralization titers. Injection site pain was reported more frequently with adjuvanted vaccines. No vaccine-related serious adverse events were observed. All H9N2 vaccine formulations were immunogenic with a clinically acceptable safety profile; adjuvanted formulations were 4-8 times dose-sparing (3.75-1.9vs 15µgHA). Registered on ClinicalTrials.gov: NCT01659086. Copyright © 2017. Published by Elsevier Ltd.
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Immunogenicity and safety of an AS03-adjuvanted H7N1 vaccine in adults 65years of age and older: A phase II, observer-blind, randomized, controlled trial.
Vaccine, 2017Co-Authors: Anuradha Madan, Bruce L. Innis, Damien Friel, Murdo Ferguson, Jyoti Soni, Paul Rheault, David J. Seiden, Azhar Toma, Anne SchuindAbstract:Abstract Background H7 influenza strains can cause severe and often fatal human infections, especially in the elderly. This phase II, observer-blind, randomized trial ( www.ClinicalTrials.gov : NCT01949090 ) assessed the immunogenicity and safety of a novel AS03-adjuvanted H7N1 vaccine that may serve as a model H7-subtype vaccine. Methods 360 adults ≥65 years of age in stable health received either 1 of 4 adjuvanted A/mallard/Netherlands/12/2000 split virion vaccine formulations (3.75 μg or 7.5 μg hemagglutinin adjuvanted with either AS03A or AS03B) or saline placebo, given as a 2-dose series. Immunogenicity was assessed using hemagglutination-inhibition (HI) and microneutralization (MN) assays for the per-protocol cohort, comprising 332 participants at 21 days post-each dose, 332 at month 6, and 309 at month 12 (HI assay only). Safety was assessed up to month 12 for all participants who had received ≥1 dose (360 participants). Results For H7N1 HI antibody assessment at day 42 (21 days post-dose 2), seroprotection rates (SPR) in the vaccinated groups were 69.6%–88.7%, seroconversion rates (SCR) 69.6%–88.5%, mean geometric increase (MGI) 11.0–18.9, and HI geometric mean titers (GMTs) 55.0–104.8. These parameters declined by month 6 and month 12. Microneutralization GMTs were 46.2–74.7 in the vaccinated groups at day 42, while vaccine response rate (VRR; proportion with ≥4-fold increase in MN titer) was 46.4%–81.5%. For the cross-reactive H7N9 strain, at day 42, HI GMT were 64.3–201.3, SPR 78.6%–96.3%, SCR 79.3%–96.3%, and MGI 14.1–37.7; MN GMTs were 44.0–85.6, and VRR 46.4–85.2%. The most frequent solicited symptom was injection site pain (41.7%–65.0% of vaccine recipients). In total, 40 participants reported 67 serious adverse events; none were considered causally related to vaccination. Conclusions In adults aged ≥65 years, the adjuvanted H7N1 vaccine was immunogenic after 2 doses, and had an acceptable safety profile. www.ClinicalTrials.gov : NCT01949090 .
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Evaluation of a primary course of H9N2 vaccine with or without AS03 adjuvant in adults: A phase I/II randomized trial.
Vaccine, 2017Co-Authors: Anuradha Madan, Bruce L. Innis, Harry Collins, Eric Sheldon, Louise Frenette, Laurence Chu, Damien Friel, Mamadou Dramé, David W. Vaughn, Anne SchuindAbstract:Abstract Background Avian influenza A H9N2 strains have pandemic potential. Methods In this randomized, observer-blind study (ClinicalTrials.gov: NCT01659086), 420 healthy adults, 18–64 years of age, received 1 of 10 H9N2 inactivated split-virus vaccination regimens (30 participants per group), or saline placebo (120 participants). H9N2 groups received 2 doses (days 0, 21) of 15 µg hemagglutinin (HA) without adjuvant, or 1.9 µg HA + AS03A, 1.9 µg HA + AS03B, 3.75 µg HA + AS03A, or 3.75 µg HA + AS03B; followed by the same H9N2 formulation or placebo (day 182). AS03 is an adjuvant system containing α-tocopherol (AS03A: 11.86 mg; AS03B: 5.93 mg) and squalene in an oil-in-water emulsion. Immunogenicity (hemagglutination inhibition [HI] and microneutralization assays) and safety were assessed up to day 546. Results All adjuvanted formulations exceeded regulatory immunogenicity criteria at days 21 and 42 (HI assay), with seroprotection and seroconversion rates of ≥94.9% and ≥89.8% at day 21, and 100% and ≥98.1% at day 42. Immunogenicity criteria were also met for unadjuvanted vaccine, with lower geometric mean titers. In groups administered a third vaccine dose (day 182), an anamnestic immune response was elicited with robust increases in HI and microneutralization titers. Injection site pain was reported more frequently with adjuvanted vaccines. No vaccine-related serious adverse events were observed. Conclusions All H9N2 vaccine formulations were immunogenic with a clinically acceptable safety profile; adjuvanted formulations were 4–8 times dose-sparing (3.75–1.9 vs 15 µg HA). Trial registration Registered on ClinicalTrials.gov: NCT01659086.
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Immunogenicity and Safety of an AS03-Adjuvanted H7N9 Pandemic Influenza Vaccine in a Randomized Trial in Healthy Adults
The Journal of infectious diseases, 2016Co-Authors: Anuradha Madan, Bruce L. Innis, Louise Frenette, Damien Friel, Nathan Segall, Murdo Ferguson, Robin Kroll, Jyoti Soni, Anne SchuindAbstract:Background Almost 700 cases of human infection with avian influenza A/H7N9 have been reported since 2013. Pandemic preparedness strategies include H7N9 vaccine development. Methods We evaluated an inactivated H7N9 vaccine in an observer-blind study in healthy adults aged 18-64 years. Participants (420) were randomized to receive 1 of 4 AS03-adjuvanted vaccines (low or medium dose of hemagglutinin with AS03A or AS03B), one nonadjuvanted vaccine, or placebo. The coprimary immunogenicity objective determined whether adjuvanted vaccines elicited an immune response against the vaccine-homologous virus, 21 days after the second vaccine dose per US and European licensure criteria in the per-protocol cohort (n = 389). Results All adjuvanted vaccines met regulatory acceptance criteria. In groups receiving adjuvanted formulations, seroconversion rates were ≥85.7%, seroprotection rates ≥91.1%, and geometric mean titers ≥92.9% versus 23.2%, 28.6%, and 17.2 for the nonadjuvanted vaccine. The AS03 adjuvant enhanced immune response at antigen-sparing doses. Injection site pain occurred more frequently with adjuvanted vaccines (in ≤98.3% of vaccinees) than with the nonadjuvanted vaccine (40.7%) or placebo (20.0%). None of the 20 serious adverse events reported were related to vaccination. Conclusions Two doses of AS03-adjuvanted H7N9 vaccine were well tolerated and induced a robust antibody response at antigen-sparing doses in healthy adults. Clinical trials registration NCT01999842.
Mamadou Dramé - One of the best experts on this subject based on the ideXlab platform.
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Evaluation of a primary course of H9N2 vaccine with or without AS03 adjuvant in adults: A phase I/II randomized trial.
Vaccine, 2017Co-Authors: Anuradha Madan, Bruce L. Innis, Harry Collins, Eric Sheldon, Louise Frenette, Laurence Chu, Damien Friel, Mamadou Dramé, David W. Vaughn, Anne SchuindAbstract:Avian influenza A H9N2 strains have pandemic potential. In this randomized, observer-blind study (ClinicalTrials.gov: NCT01659086), 420 healthy adults, 18-64years of age, received 1 of 10 H9N2 inactivated split-virus vaccination regimens (30 participants per group), or saline placebo (120 participants). H9N2 groups received 2 doses (days 0, 21) of 15µg hemagglutinin (HA) without adjuvant, or 1.9µgHA+AS03A, 1.9µgHA+AS03B, 3.75µgHA+AS03A, or 3.75µgHA+AS03B; followed by the same H9N2 formulation or placebo (day 182). AS03 is an adjuvant system containing α-tocopherol (AS03A: 11.86mg; AS03B: 5.93mg) and squalene in an oil-in-water emulsion. Immunogenicity (hemagglutination inhibition [HI] and microneutralization assays) and safety were assessed up to day 546. All adjuvanted formulations exceeded regulatory immunogenicity criteria at days 21 and 42 (HI assay), with seroprotection and seroconversion rates of ≥94.9% and ≥89.8% at day 21, and 100% and ≥98.1% at day 42. Immunogenicity criteria were also met for unadjuvanted vaccine, with lower geometric mean titers. In groups administered a third vaccine dose (day 182), an anamnestic immune response was elicited with robust increases in HI and microneutralization titers. Injection site pain was reported more frequently with adjuvanted vaccines. No vaccine-related serious adverse events were observed. All H9N2 vaccine formulations were immunogenic with a clinically acceptable safety profile; adjuvanted formulations were 4-8 times dose-sparing (3.75-1.9vs 15µgHA). Registered on ClinicalTrials.gov: NCT01659086. Copyright © 2017. Published by Elsevier Ltd.
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Evaluation of a primary course of H9N2 vaccine with or without AS03 adjuvant in adults: A phase I/II randomized trial.
Vaccine, 2017Co-Authors: Anuradha Madan, Bruce L. Innis, Harry Collins, Eric Sheldon, Louise Frenette, Laurence Chu, Damien Friel, Mamadou Dramé, David W. Vaughn, Anne SchuindAbstract:Abstract Background Avian influenza A H9N2 strains have pandemic potential. Methods In this randomized, observer-blind study (ClinicalTrials.gov: NCT01659086), 420 healthy adults, 18–64 years of age, received 1 of 10 H9N2 inactivated split-virus vaccination regimens (30 participants per group), or saline placebo (120 participants). H9N2 groups received 2 doses (days 0, 21) of 15 µg hemagglutinin (HA) without adjuvant, or 1.9 µg HA + AS03A, 1.9 µg HA + AS03B, 3.75 µg HA + AS03A, or 3.75 µg HA + AS03B; followed by the same H9N2 formulation or placebo (day 182). AS03 is an adjuvant system containing α-tocopherol (AS03A: 11.86 mg; AS03B: 5.93 mg) and squalene in an oil-in-water emulsion. Immunogenicity (hemagglutination inhibition [HI] and microneutralization assays) and safety were assessed up to day 546. Results All adjuvanted formulations exceeded regulatory immunogenicity criteria at days 21 and 42 (HI assay), with seroprotection and seroconversion rates of ≥94.9% and ≥89.8% at day 21, and 100% and ≥98.1% at day 42. Immunogenicity criteria were also met for unadjuvanted vaccine, with lower geometric mean titers. In groups administered a third vaccine dose (day 182), an anamnestic immune response was elicited with robust increases in HI and microneutralization titers. Injection site pain was reported more frequently with adjuvanted vaccines. No vaccine-related serious adverse events were observed. Conclusions All H9N2 vaccine formulations were immunogenic with a clinically acceptable safety profile; adjuvanted formulations were 4–8 times dose-sparing (3.75–1.9 vs 15 µg HA). Trial registration Registered on ClinicalTrials.gov: NCT01659086.
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immunogenicity and safety of an eb66 cell culture derived influenza a indonesia 5 2005 h5n1 AS03 adjuvanted vaccine a phase 1 randomized trial
The Journal of Infectious Diseases, 2015Co-Authors: Anne Schuind, Mamadou Dramé, Nathan Segall, Bruce L. InnisAbstract:Background. Cell-culture-derived (CC) influenza vaccine production methods could provide benefits over classical embryonated-egg technology, including a higher production capacity and the faster creation of a supply that meets demand. Methods. ACC-inactivated split-virus influenza A/Indonesia/5/2005(H5N1) vaccine derived from the EB66 cell line (hereafter, “CC-H5N1”) was investigated in a phase 1 randomized, blinded study. Healthy adults (n = 521) received 2 vaccine doses (days 0 and 21) of either investigational CC-H5N1 vaccine (1.9 µg or 3.75 µg of hemagglutinin antigen [HA] with the AS03 adjuvant system or 15 µg of plain HA), embryonated-egg-derived vaccines (3.75 µg of HA with AS03 or 15 µg of plain HA), or placebo. Assessment of the adjuvant effect and immunogenicity was performed using Center for Biologics Evaluation and Research acceptability criteria 21 days after dose 2. Safety was assessed until month 12. Results. AS03-adjuvanted CC-H5N1 elicited a homologous hemagglutination inhibition antibody response that satisfied immunogenicity criteria 21 days after dose 2 and persisted at month 12. Adjuvant effect and immune response against a drift-variant strain were demonstrated. Novaccine-related serious adverse events were reported. The immunogenicity and safety of the CC-H5N1 formulation containing 3.75 µg of HA and AS03 appeared to be similar to those for the licensed egg-derived AS03-adjuvanted control vaccine. Conclusions. The feasibility of the EB66 cell line to produce an immunogenic influenza vaccine with acceptable safety profile was demonstrated. Antigen sparing was achieved through combination with AS03 adjuvant. This CCH5N1 might contribute to the rapid access of vaccine in the event of an influenza A(H5N1) pandemic. Clinical Trials Registration. NCT01236040.
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Immunogenicity and safety of an AS03-adjuvanted H5N1 pandemic influenza vaccine in Korean adults: a phase IV, randomized, open-label, controlled study.
Vaccine, 2015Co-Authors: Patricia Izurieta, Mamadou Dramé, David W. Vaughn, Woo Joo Kim, Seong Heon Wie, Jacob Lee, Jin Soo Lee, Anne SchuindAbstract:Abstract Background AS03-adjuvanted H5N1 pandemic influenza vaccines have been assessed in an extensive clinical development program conducted in North America, Europe, and Asia including children from 6 months of age, adults, and elderly adults. We evaluated AS03-H5N1 in Korean adults 18 through 60 years of age. Methods This Phase IV, randomized, study was conducted to assess the immunogenicity, reactogenicity, and safety of two doses (3.75 μg of hemagglutinin antigen) of A/Indonesia/5/2005 (H5N1) adjuvanted with AS03 given 21 days apart in Korean adults. Antibody responses were assessed using hemagglutination-inhibition (HI) assays against the vaccine strain and a vaccine-heterologous strain (A/Vietnam/1194/2004) 21 days after the second dose. A control group (safety) received a licensed seasonal inactivated trivalent influenza vaccine (TIV). Reactogenicity was assessed for 7 days after each vaccination, and unsolicited adverse events were assessed for 182 days following vaccination in both study groups (NCT01730378). Results AS03-H5N1 was immunogenic and elicited robust HI antibody responses with seroconversion rates of 100% for the vaccine strain and 69.1% for the heterologous strain ( N = 81). HI antibody responses fulfilled the European licensure criteria for immunogenicity (primary endpoint). The incidence of local and systemic solicited adverse events (reactogenicity) was higher with AS03-H5N1 than TIV. There was no apparent difference in the rate of unsolicited adverse events in the AS03-H5N1 and TIV groups. Conclusion The results indicate that AS03-H5N1 vaccine is immunogenic with reactogenicity and safety findings that are consistent with the established profile of AS03-H5N1 vaccine.
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Immunogenicity and Safety of an EB66 Cell-Culture-Derived Influenza A/Indonesia/5/2005(H5N1) AS03-Adjuvanted Vaccine: A Phase 1 Randomized Trial
The Journal of infectious diseases, 2015Co-Authors: Anne Schuind, Mamadou Dramé, Nathan Segall, Bruce L. InnisAbstract:Background. Cell-culture-derived (CC) influenza vaccine production methods could provide benefits over classical embryonated-egg technology, including a higher production capacity and the faster creation of a supply that meets demand. Methods. ACC-inactivated split-virus influenza A/Indonesia/5/2005(H5N1) vaccine derived from the EB66 cell line (hereafter, “CC-H5N1”) was investigated in a phase 1 randomized, blinded study. Healthy adults (n = 521) received 2 vaccine doses (days 0 and 21) of either investigational CC-H5N1 vaccine (1.9 µg or 3.75 µg of hemagglutinin antigen [HA] with the AS03 adjuvant system or 15 µg of plain HA), embryonated-egg-derived vaccines (3.75 µg of HA with AS03 or 15 µg of plain HA), or placebo. Assessment of the adjuvant effect and immunogenicity was performed using Center for Biologics Evaluation and Research acceptability criteria 21 days after dose 2. Safety was assessed until month 12. Results. AS03-adjuvanted CC-H5N1 elicited a homologous hemagglutination inhibition antibody response that satisfied immunogenicity criteria 21 days after dose 2 and persisted at month 12. Adjuvant effect and immune response against a drift-variant strain were demonstrated. Novaccine-related serious adverse events were reported. The immunogenicity and safety of the CC-H5N1 formulation containing 3.75 µg of HA and AS03 appeared to be similar to those for the licensed egg-derived AS03-adjuvanted control vaccine. Conclusions. The feasibility of the EB66 cell line to produce an immunogenic influenza vaccine with acceptable safety profile was demonstrated. Antigen sparing was achieved through combination with AS03 adjuvant. This CCH5N1 might contribute to the rapid access of vaccine in the event of an influenza A(H5N1) pandemic. Clinical Trials Registration. NCT01236040.
Jeannemarie Devaster - One of the best experts on this subject based on the ideXlab platform.
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Immunogenicity of AS03-adjuvanted and non-adjuvanted trivalent inactivated influenza vaccines in elderly adults: A Phase 3, randomized trial and post-hoc correlate of protection analysis
Human Vaccines & Immunotherapeutics, 2016Co-Authors: Guillermo Ruiz-palacios, Jiri Beran, Jeannemarie Devaster, Meral Esen, Geert Leroux-roels, Odile Launay, Janet Mcelhaney, Gerrit Van Essen, Anne Benoit, Carine ClaeysAbstract:In this study we describe the immunogenicity results from a subset of older people (N = 5187) who participated in a Phase 3 randomized, observer-blinded trial of AS03-TIV versus TIV (Fluarix™) (ClinicalTrials.gov, NCT00753272). Participants received one dose of AS03-TIV or TIV in each study year and antibody titers against the vaccine strains were assessed using hemagglutination-inhibition (HI) assay at 21 d and 180 d post-vaccination in each vaccine group in the 2008/09 (Year 1) and 2009/10 (Year 2) influenza seasons. Manufacturing consistency of 3 lots of AS03-TIV for HI antibody responses in Year 1 was a co-primary objective. In a post-hoc analysis, a statistical regression model included 4830 subjects in whom immunogenicity and laboratory-confirmed attack rate data were available; the analysis was performed to assess HI antibody titers against A/H3N2 as a correlate of protection for laboratory-confirmed A/H3N2 influenza. AS03-TIV and TIV elicited strong HI antibody responses against each vaccine strain 21 d post-vaccination in both years. The manufacturing consistency of 3 lots of AS03-TIV was demonstrated. In both years and each vaccine group, HI antibody responses were lower for A/H1N1 than the other vaccine strains. Day 180 seroconversion rates (proportion with ≥4-fold increase in titer compared with pre-vaccination titer) in Year 1 in the AS03-TIV and TIV groups, respectively, were 87.7% and 74.1% for A/H3N2, 69.7% and 59.6% for influenza B, and 58.3% and 47.4% for A/H1N1. The post-hoc statistical model based on A/H3N2 attack rates and HI antibody titers estimated that a 4-fold increase in post-vaccination titers against A/H3N2 was associated with a 2-fold decrease in the odds of A/H3N2 infection.
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influenza symptoms and their impact on elderly adults randomised trial of AS03 adjuvanted or non adjuvanted inactivated trivalent seasonal influenza vaccines
Influenza and Other Respiratory Viruses, 2014Co-Authors: Gerrit A Van Essen, Jiri Beran, Jeannemarie Devaster, Christelle Durand, Xavier Duval, Ann R. Falsey, Meral Esen, Gregory Feldman, Pierre Gervais, Bruce L. InnisAbstract:Background Patient-reported outcomes (PROs) are particularly relevant in influenza vaccine trials in the elderly where reduction in symptom severity could prevent illness-related functional impairment. Objectives To evaluate PROs in people aged ≥65 years receiving two different vaccines. Methods This was a phase III, randomised, observer-blind study (NCT00753272) of the AS03-adjuvanted inactivated trivalent split-virion influenza vaccine (AS03-TIV) versus non-adjuvanted vaccine (TIV). Using the FluiiQ questionnaire, symptom (systemic, respiratory, total) and life impact (activities, emotions, relationships) scores were computed as exploratory endpoints, with minimal important difference (MID) in influenza severity between vaccines considered post-hoc as >7%. Vaccine efficacy of AS03-TIV relative to TIV in severe influenza (hospitalisation, complication, most severe one-third of episodes based on the area under the curve for systemic symptom score) was calculated post-hoc. The main analyses (descriptive) were conducted in the according-to-protocol cohort (n = 280 AS03-TIV, n = 315 TIV) for influenza confirmed by culture or reverse transcriptase polymerase chain reaction. Results Mean systemic symptom, total symptom and impact on activities scores were lower with AS03-TIV versus TIV. Mean respiratory symptom, impact on emotions and impact on relationships scores were similar. Influenza tended to be less severe with AS03-TIV, but the MID was reached only for impact on activities (mean 9·0%). Relative vaccine efficacy in severe influenza was 29·38% (95% CI: 7·60–46·02). Conclusions AS03-TIV had advantages over TIV in impact on systemic symptoms and activities as measured by the FluiiQ in elderly people. Higher efficacy of AS03-TIV relative to TIV was shown for prevention of severe illness.
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A phase 1, open-label safety and immunogenicity study of an AS03-adjuvanted trivalent inactivated influenza vaccine in children aged 6 to 35 months
Human vaccines & immunotherapeutics, 2014Co-Authors: Alfonso Carmona Martinez, Ignacio Salamanca De La Cueva, Philippe Boutet, Carline Vanden Abeele, Igor Smolenov, Jeannemarie DevasterAbstract:Background: There is a need for better vaccines and vaccine strategies to reduce the burden of influenza in very young children. Methods: This phase 1, open-label study assessed the reactogenicity, safety, and immunogenicity of an inactivated trivalent influenza vaccine (TIV) containing low doses of hemagglutinin antigen (7.5 µg each strain), adjuvanted with a tocopherol-based oil-in-water emulsion Adjuvant System (AS03). Influenza vaccine-naive children aged 6–35 months were sequentially enrolled to receive TIV-AS03D (1.48 mg tocopherol) or TIV-AS03C (2.97 mg tocopherol), then a 6-month booster of conventional TIV. The primary endpoint was the incidence of fever (axillary temperature >38 °C) for 7 days post-vaccination. Immune responses were assessed by hemagglutination-inhibition (HI) assay. Results: Forty children were sequentially enrolled into the TIV-AS03D or the TIV-AS03C group. Fever >38.0 °C was reported in 5/20 (25.0%) and 7/20 (35.0%) children after the first and second doses of TIV-AS03D, respectively, and in 7/20 (35.0%) children after 1 dose of TIV-AS03C; the latter fulfilled the holding rule for safety, and the second dose of TIV-AS03C was cancelled. HI immune responses exceeded adult European licensure criteria for the immunogenicity, and all children had HI antibody titers ≥ 1:40 after 1 dose of TIV booster against booster strains. Conclusions: One dose of primary vaccine containing a low dose of antigen and AS03 may be a possible influenza vaccination strategy for young children. The relatively high frequency of fever warrants further investigation, although the generalizability of the findings are uncertain given that many of the children had antibody evidence suggesting recent infection with A(H1N1)pdm09.
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Influenza symptoms and their impact on elderly adults: randomised trial of AS03‐adjuvanted or non‐adjuvanted inactivated trivalent seasonal influenza vaccines
Influenza and other respiratory viruses, 2014Co-Authors: Gerrit A Van Essen, Jiri Beran, Jeannemarie Devaster, Christelle Durand, Xavier Duval, Ann R. Falsey, Meral Esen, Gregory Feldman, Pierre Gervais, Bruce L. InnisAbstract:Background Patient-reported outcomes (PROs) are particularly relevant in influenza vaccine trials in the elderly where reduction in symptom severity could prevent illness-related functional impairment. Objectives To evaluate PROs in people aged ≥65 years receiving two different vaccines. Methods This was a phase III, randomised, observer-blind study (NCT00753272) of the AS03-adjuvanted inactivated trivalent split-virion influenza vaccine (AS03-TIV) versus non-adjuvanted vaccine (TIV). Using the FluiiQ questionnaire, symptom (systemic, respiratory, total) and life impact (activities, emotions, relationships) scores were computed as exploratory endpoints, with minimal important difference (MID) in influenza severity between vaccines considered post-hoc as >7%. Vaccine efficacy of AS03-TIV relative to TIV in severe influenza (hospitalisation, complication, most severe one-third of episodes based on the area under the curve for systemic symptom score) was calculated post-hoc. The main analyses (descriptive) were conducted in the according-to-protocol cohort (n = 280 AS03-TIV, n = 315 TIV) for influenza confirmed by culture or reverse transcriptase polymerase chain reaction. Results Mean systemic symptom, total symptom and impact on activities scores were lower with AS03-TIV versus TIV. Mean respiratory symptom, impact on emotions and impact on relationships scores were similar. Influenza tended to be less severe with AS03-TIV, but the MID was reached only for impact on activities (mean 9·0%). Relative vaccine efficacy in severe influenza was 29·38% (95% CI: 7·60–46·02). Conclusions AS03-TIV had advantages over TIV in impact on systemic symptoms and activities as measured by the FluiiQ in elderly people. Higher efficacy of AS03-TIV relative to TIV was shown for prevention of severe illness.
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AS03 adjuvanted versus non adjuvanted inactivated trivalent influenza vaccine against seasonal influenza in elderly people a phase 3 randomised trial
Lancet Infectious Diseases, 2013Co-Authors: Janet E Mcelhaney, Gerrit A Van Essen, Jiri Beran, Jeannemarie Devaster, Meral Esen, Geert Lerouxroels, Odile Launay, Adrian Caplanusi, Guillermo M Ruizpalacios, Carine ClaeysAbstract:Summary Background We aimed to compare AS03-adjuvanted inactivated trivalent influenza vaccine (TIV) with non-adjuvanted TIV for seasonal influenza prevention in elderly people. Methods We did a randomised trial in 15 countries worldwide during the 2008–09 (year 1) and 2009–10 (year 2) influenza seasons. Eligible participants aged at least 65 years who were not in hospital or bedridden and were without acute illness were randomly assigned (1:1) to receive either AS03-adjuvanted TIV or non-adjuvanted TIV. Randomisation was done in an internet-based system, with a blocking scheme and stratification by age (65–74 years and 75 years or older). Participants were scheduled to receive one vaccine in each year, and remained in the same group in years 1 and 2. Unmasked personnel prepared and gave the vaccines, but participants and individuals assessing any study endpoint were masked. The coprimary objectives were to assess the relative efficacy of the vaccines and lot-to-lot consistency of the AS03-adjuvanted TIV (to be reported elsewhere). For the first objective, the primary endpoint was relative efficacy of the vaccines for prevention of influenza A (excluding A H1N1 pdm09) or B, or both, that was confirmed by PCR analysis in year 1 (lower limit of two-sided 95% CI had to be greater than zero to establish superiority). From Nov 15, to April 30, in both years, participants were monitored by telephone or site contact and home visits every week or 2 weeks to identify cases of influenza-like illness. After onset of suspected cases, we obtained nasal and throat swabs to identify influenza RNA with real-time PCR. Efficacy analyses were done per protocol. This trial is registered with ClinicalTrials.gov, number NCT00753272. Findings We enrolled 43 802 participants, of whom 21 893 were assigned to and received the AS03-adjuvanted TIV and 21 802 the non-adjuvanted TIV in year 1. In the year 1 efficacy cohort, fewer participants given AS03-adjuvanted than non-adjuvanted TIV were infected with influenza A or B, or both (274 [1·27%, 95% CI 1·12–1·43] of 21 573 vs 310 [1·44%, 1·29–1·61] of 21 482; relative efficacy 12·11%, 95% CI −3·40 to 25·29; superiority not established). Fewer participants in the year 1 efficacy cohort given AS03-adjuvanted TIV than non-adjuvanted TIV were infected with influenza A (224 [1·04%, 95% CI 0·91–1·18] vs 270 [1·26, 1·11–1·41]; relative efficacy 17·53%, 95% CI 1·55–30·92) and influenza A H3N2 (170 [0·79, 0·67–0·92] vs 205 [0·95, 0·83–1·09]; post-hoc analysis relative efficacy 22·0%, 95% CI 5·68–35·49). Interpretation AS03-adjuvanted TIV has a higher efficacy for prevention of some subtypes of influenza than does a non-adjuvanted TIV. Future influenza vaccine studies in elderly people should be based on subtype or lineage-specific endpoints. Funding GlaxoSmithKline Biologicals SA.
Greg L. Plosker - One of the best experts on this subject based on the ideXlab platform.
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Prepandemic Influenza Vaccine H5N1 (Split Virion, Inactivated, Adjuvanted) [Prepandrix™]
BioDrugs, 2008Co-Authors: Natalie J. Carter, Greg L. PloskerAbstract:Although rare, influenza pandemics are a recurrent event, and influenza A/H5N1 is generally considered to be the most likely causative agent of the next pandemic. Vaccines are widely considered to be the first line of defense for protecting populations in advance of an influenza pandemic. Because it is not known beforehand which strain of influenza A/H5N1 virus could give rise to a pandemic, prepandemic vaccines that impart broad cross-reactive immunogenicity are required. In addition, low doses of H5 hemagglutinin are preferable in order to make antigen supplies go further towards meeting global demands for prepandemic vaccines. Prepandemic influenza vaccine H5N1 [Prepandrix™; AS03-H5N1 vaccine] is a split virion, inactivated vaccine containing H5 hemagglutinin antigen adjuvanted with a novel 10% oil-in-water emulsion-based adjuvant system (AS03). It is approved in the EU for use as an active immunization against H5N1 subtype influenza A virus (influenza A/H5N1 virus) in adults aged 18–60 years. The recommended dosage in this population is two doses of 0.5 mL containing 3.75 µg of H5 hemagglutinin, administered ≥21 days apart. Adjuvantation of H5N1 vaccine with AS03 allows for a reduction in the H5 hemagglutinin dose required to elicit an adequate immune response, and administration of two doses of the adjuvanted vaccine met all criteria for the licensure of influenza vaccines set out in European Committee for Proprietary Medicinal Products (CPMP) and US FDA documents. In two clinical trials, two doses of AS03-H5N1 vaccine containing 3.75 µg of H5 hemagglutinin induced an immune response in healthy volunteers aged 18–60 years against the homologous, clade 1 vaccine strain, A/Vietnam/1194/2004, and the heterologous, drifted, clade 2 nonvaccine strains, A/Anhui/1/2005, A/Indonesia/5/2005, and A/turkey/Turkey/1/2005. This cross-clade response persisted for ≥6 months following administration of the first vaccine dose in the majority of vaccine recipients. In addition, AS03-H5N1 vaccine protected against lethal challenge with A/Vietnam/1194/2004 or A/Indonesia/5/2005 in animal studies. The vaccine was generally well tolerated and adverse events were transient and predominantly of mild to moderate severity. AS03-H5N1 vaccine has demonstrated antigen dose-sparing properties and cross-clade reactive immunity in clinical trials and challenge studies in animal models. As a result, stockpiling AS03-H5N1 vaccine has the potential to protect populations against a pandemic caused by an influenza A/H5N1 virus and may represent an important measure in pandemic preparedness. Immunogenicity AS03-H5N1 vaccine containing an H5 hemagglutinin dose of 3.75 µg elicited a satisfactory immune response against the homologous, clade 1, vaccine strain A/Vietnam/1194/2004 in a randomized, observer-blind, parallel-group, dose-finding trial and a phase III, lot-to-lot consistency trial in adult volunteers aged 18–60 years. In the dose-finding study, volunteers received AS03-H5N1 (n = 200) or nonadjuvanted-H5N1 (n = 200) vaccine containing 3.75, 7.5, 15.0, or 30.0 µg of H5 hemagglutinin. An H5-hemagglutinin dose-response effect was observed for antihemagglutinin antibody and neutralizing antibody titers over the dose range studied. All CPMP and FDA acceptance criteria for the licensure of influenza vaccines were met following two doses of AS03-H5N1 vaccine containing 3.75 µg of H5 hemagglutinin administered 21 days apart. This allowed for antigen dose sparing when compared with nonadjuvanted-H5N1 vaccine, which only met two of three CPMP criteria after two doses of vaccine containing 30 µg of H5 hemagglutinin. Based on the results of the dose-finding study, the phase III, lot-to-lot consistency study focused solely on the immunogenicity of AS03-H5N1 (n = 961) and nonadjuvanted-H5N1 (n = 245) vaccine containing 3.75 µg of H5 hemagglutinin. Where endpoints were reported, CPMP criteria were met with AS03-H5N1, but not nonadjuvanted-H5N1 vaccine, in the consistency study. Not only did AS03-H5N1 vaccine containing 3.75 µg of H5 hemagglutinin elicit an adequate immune response against the clade 1 vaccine strain A/Vietnam/1194/2004, but it also induced cross-clade immunity against the heterologous, drifted, clade 2 strains A/Anhui/1/2005 (subclade 2.3), A/Indonesia/5/2005 (subclade 2.1), and A/turkey/Turkey/1/2005 (subclade 2.2). In the dose-finding study, the neutralizing antibody serocon-version rate against these clade 2 strains following the second vaccine dose was 75%, 77%, and 85% for A/Anhui/1/2005, A/Indonesia/5/2005, and A/turkey/Turkey/1/2005, respectively; in the consistency study, the neutralizing antibody seroconversion rate was 91.4% for A/Indonesia/5/2005. In terms of neutralizing antibody seroconversion rates, 60–70% of recipients had retained a cross-neutralizing response against A/Anhui/1/2005 and A/turkey/Turkey/1/2005 and 40% had retained a cross-neutralizing response against A/Indonesia/5/2005 at 6 months after administration of the first vaccine dose. Because the efficacy of AS03-H5N1 vaccine cannot ethically be studied in the target population prior to the onset of a pandemic, animal studies are required; ferrets are widely considered to be the best proxy for humans in the study of influenza A/H5N1 vaccines. In two such studies, ferrets receiving AS03-H5N1 vaccine containing 0.6–15.0 µg of H5 hemagglutinin or either a control vaccine containing AS03 alone, phosphate-buffered saline, or nonadjuvanted-H5N1 vaccine containing 15.0 µg of H5 hemagglutinin, were challenged with a lethal dose of the homologous clade 1, vaccine influenza A/H5N1 strain A/Vietnam/1194/2004 or the heterologous, drifted, clade 2, nonvaccine strain A/Indonesia/5/2005. Challenge with the vaccine strain resulted in an H5 hemagglutinin-dose-dependent immune response in ferrets receiving AS03-H5N1 vaccine, with all ferrets receiving the 15 µg dose surviving the challenge. The majority of AS03-H5N1 vaccine-receiving ferrets (≥65%) had a low viral load (
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prepandemic influenza vaccine h5n1 split virion inactivated adjuvanted prepandrix a review of its use as an active immunization against influenza a subtype h5n1 virus
BioDrugs, 2008Co-Authors: Natalie J. Carter, Greg L. PloskerAbstract:Abstract Although rare, influenza pandemics are a recurrent event, and influenza A/H5N1 is generally considered to be the most likely causative agent of the next pandemic. Vaccines are widely considered to be the first line of defense for protecting populations in advance of an influenza pandemic. Because it is not known beforehand which strain of influenza A/H5N1 virus could give rise to a pandemic, prepandemic vaccines that impart broad cross-reactive immunogenicity are required. In addition, low doses of H5 hemagglutinin are preferable in order to make antigen supplies go further towards meeting global demands for prepandemic vaccines. Prepandemic influenza vaccine H5N1 [Prepandrix™; AS03-H5N1 vaccine] is a split virion, inactivated vaccine containing H5 hemagglutinin antigen adjuvanted with a novel 10% oil-in-water emulsion-based adjuvant system (AS03). It is approved in the EU for use as an active immunization against H5N1 subtype influenza A virus (influenza A/H5N1 virus) in adults aged 18–60 years. The recommended dosage in this population is two doses of 0.5 mL containing 3.75 µg of H5 hemagglutinin, administered ≥21 days apart. Adjuvantation of H5N1 vaccine with AS03 allows for a reduction in the H5 hemagglutinin dose required to elicit an adequate immune response, and administration of two doses of the adjuvanted vaccine met all criteria for the licensure of influenza vaccines set out in European Committee for Proprietary Medicinal Products (CPMP) and US FDA documents. In two clinical trials, two doses of AS03-H5N1 vaccine containing 3.75 µg of H5 hemagglutinin induced an immune response in healthy volunteers aged 18–60 years against the homologous, clade 1 vaccine strain, A/Vietnam/1194/2004, and the heterologous, drifted, clade 2 nonvaccine strains, A/Anhui/1/2005, A/Indonesia/5/2005, and A/turkey/Turkey/1/2005. This cross-clade response persisted for ≥6 months following administration of the first vaccine dose in the majority of vaccine recipients. In addition, AS03-H5N1 vaccine protected against lethal challenge with A/Vietnam/1194/2004 or A/Indonesia/5/2005 in animal studies. The vaccine was generally well tolerated and adverse events were transient and predominantly of mild to moderate severity. AS03-H5N1 vaccine has demonstrated antigen dose-sparing properties and cross-clade reactive immunity in clinical trials and challenge studies in animal models. As a result, stockpiling AS03-H5N1 vaccine has the potential to protect populations against a pandemic caused by an influenza A/H5N1 virus and may represent an important measure in pandemic preparedness.
