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Adjuvanted (AS03) A/H1N1 2009 Pandemic Influenza Vaccines and Solid Organ Transplant Rejection: Systematic Signal Evaluation and Lessons Learnt.

ABSTRACT: INTRODUCTION:We investigated a signal of solid organ transplant (SOT) rejection after immunisation with (AS03) A/H1N1 2009 pandemic influenza vaccines. METHODS:Potential immunological mechanisms were reviewed and quantitative analyses were conducted. The feasibility of pharmacoepidemiological studies was explored. RESULTS:Overall results, including data from a pharmacoepidemiological study, support the safety of adjuvanted (AS03) pandemic influenza vaccination in SOT recipients. The regulatory commitment to evaluate the signal through a stepwise investigation was closed in 2014. CONCLUSION:Lessons learned highlight the importance of investigating plausible biological mechanisms between vaccines and potentially associated adverse outcomes, and the importance of selecting appropriate study settings and designs for safety signal investigations.

SUBMITTER: Dos Santos G

PROVIDER: S-EPMC5519647 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Adjuvanted (AS03) A/H1N1 2009 Pandemic Influenza Vaccines and Solid Organ Transplant Rejection: Systematic Signal Evaluation and Lessons Learnt.

Dos Santos Gaël G Seifert Harry A HA Bauchau Vincent V Shinde Vivek V Barbeau Dominique M DM Cohet Catherine C

Drug safety 20170801 8

<h4>Introduction</h4>We investigated a signal of solid organ transplant (SOT) rejection after immunisation with (AS03) A/H1N1 2009 pandemic influenza vaccines.<h4>Methods</h4>Potential immunological mechanisms were reviewed and quantitative analyses were conducted. The feasibility of pharmacoepidemiological studies was explored.<h4>Results</h4>Overall results, including data from a pharmacoepidemiological study, support the safety of adjuvanted (AS03) pandemic influenza vaccination in SOT recipi ...[more]

PMID: 28417321

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Project description:ObjectivesTo assess the safety of an AS03-adjuvanted split virion H1N1 (2009) vaccine (Pandemrix) in persons vaccinated during the national pandemic influenza vaccination campaign in the UK.DesignProspective, cohort, observational, postauthorisation safety study.Setting87 general practices forming part of the Medical Research Council General Practice Research Framework and widely distributed throughout England.ParticipantsA cohort of 9143 individuals aged 7 months to 97 years who received at least one dose of the AS03-adjuvanted H1N1 pandemic vaccine during the national pandemic influenza vaccination campaign in the UK was enrolled. 94% completed the 6-month follow-up. Exclusion criteria were previous vaccination with other H1N1 pandemic vaccine and any child in care.Primary and secondary outcome measuresMedically attended adverse events (MAEs) occurring within 31 days after any dose, serious adverse events (SAEs) and adverse events of special interest (AESIs) following vaccination were collected for all participants. Solicited adverse events (AEs) were assessed in a subset of participants.ResultsMAEs were reported in 1219 participants and SAEs in 113 participants during the 31-day postvaccination period. The most frequently reported MAEs and SAEs were consistent with events expected to be reported during the winter season in this population: lower respiratory tract infections, asthma and pneumonia. The most commonly reported solicited AEs were irritability in young children aged <5 years (61.8%), muscle aches in children aged 5-17 years (61.9%) and adults (46.9%). 18 AESIs, experienced by 14 patients, met the criteria to be considered for the observed-to-expected analyses. AESIs above the expected number were neuritis (1 case within 31 days) and convulsions (8 cases within 181 days). There were 41 deaths during the 181-day period after vaccination, fewer than expected.ConclusionsResults indicate that the AS03-adjuvanted H1N1 pandemic vaccine showed a clinically acceptable reactogenicity and safety profile in all age and risk groups studied.Trial registrationClinicalTrials.gov, NCT00996853.

Project description:Influenza is a major cause of respiratory disease leading to hospitalization in young children. However, seasonal trivalent influenza vaccines (TIVs) have been shown to be ineffective and poorly immunogenic in this population. The development of live-attenuated influenza vaccines and adjuvanted vaccines are important advances in the prevention of influenza in young children. The oil-in-water emulsions MF59 and adjuvant systems 03 (AS03) have been used as adjuvants in both seasonal adjuvanted trivalent influenza vaccines (ATIVs) and pandemic monovalent influenza vaccines. Compared with non-adjuvanted vaccine responses, these vaccines induce a more robust and persistent antibody response for both homologous and heterologous influenza strains in infants and young children. Evidence of a significant improvement in vaccine efficacy with these adjuvanted vaccines resulted in the use of the monovalent (A/H1N1) AS03-adjuvanted vaccine in children in the 2009 influenza pandemic and the licensure of the seasonal MF59 ATIV for children aged 6?months to 2 years in Canada. The mechanism of action of MF59 and AS03 remains unclear. Adjuvants such as MF59 induce proinflammatory cytokines and chemokines, including CXCL10, but independently of type-1 interferon. This proinflammatory response is associated with improved recruitment, activation and maturation of antigen presenting cells at the injection site. In young children MF59 ATIV produced more homogenous and robust transcriptional responses, more similar to adult-like patterns, than did TIV. Early gene signatures characteristic of the innate immune response, which correlated with antibody titers were also identified. Differences were detected when comparing child and adult responses including opposite trends in gene set enrichment at day 3 postvaccination and, unlike adult data, a lack of correlation between magnitude of plasmablast response at day 7 and antibody titers at day 28 in children. These insights show the utility of novel approaches in understanding new adjuvants and their importance for developing improved influenza vaccines for children.

Dataset Information

Adjuvanted (AS03) A/H1N1 2009 Pandemic Influenza Vaccines and Solid Organ Transplant Rejection: Systematic Signal Evaluation and Lessons Learnt.

Publications

Adjuvanted (AS03) A/H1N1 2009 Pandemic Influenza Vaccines and Solid Organ Transplant Rejection: Systematic Signal Evaluation and Lessons Learnt.

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