Swine Flu (Influenza A H1N1) Follow on Vaccine Study

Study Overview
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Brief Summary
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In 2009 the World Health Organization (WHO) declared the Influenza A H1N1 (swine 'flu) outbreak the first global pandemic of this century. It is thought to have been responsible for 16,226 deaths globally as of 21st February 2010. The investigators know from previous influenza outbreaks that the number of cases also tends to increase during the winter season of the years after a pandemic. There is concern that last year's pandemic influenza strain will return this winter and it has, therefore, been included in WHO's recommendations for seasonal influenza vaccine combinations. This study will assess the duration of the immune response to the H1N1 influenza vaccines given last year, and how children will respond to this year's seasonal trivalent influenza vaccine (which includes the H1N1 strain). Participating children would receive one dose of a licensed seasonal influenza vaccine and blood tests would be taken before and after vaccination.

Detailed Description
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In Autumn 2009 the investigators undertook a study assessing the safety and immunogenicity of a two-dose schedule of the two Influenza A (H1N1) vaccines purchased by the UK Government, the non-adjuvanted whole virion vaccine and the ASO3-adjuvanted split-virion, in children aged 6 months to 12 years of age. 937 children completed the study by protocol and the main findings were that the adjuvanted vaccine, while reactogenic, was more immunogenic especially in younger children (seroconversion in children under 3 years of age was 98.2% vs. 80.1%, p=0.001). Following events in Australia, and regardless of the formal investigation outcome, it is imperative to study the reactogenicity of UK seasonal influenza vaccines in children who had previously received immunization with adjuvanted H1N1 vaccines. It would be particularly important to gain early information on the fever rates in young children in order to assess whether these are higher than expected and carry a potential risk of febrile convulsions. It is also important to determine the immunogenicity of trivalent seasonal influenza vaccine in children previously given univalent pandemic influenza vaccine. There is emerging data that different priming strategies with adjuvanted or non-adjuvanted vaccines may lead to considerable differences in the response to subsequent influenza vaccines. In the head to head paediatric study unpublished analyses show significantly lower immunogenicity in children who had received seasonal influenza vaccines in the past, despite the receipt of two doses of either Pandemrix or Celvepan. In addition, unpublished data from a manufacturer study suggests a negative effect of two doses of Pandemrix on immune responses to subsequent seasonal vaccine when given 3 weeks after the second dose (personal communication to E Miller from MHRA). Alternatively, as shown with pandemic H5N1 influenza vaccine, there may be a significant booster response to a subsequent dose following priming 6 or 14 months previously. However, this has not been demonstrated with either Pandemrix or Celvapan, and it is unknown how previous vaccination with these vaccines will affect the immunogenicity of the H1N1 component of an unadjuvanted trivalent seasonal influenza vaccine given a year later. The investigators therefore propose a follow-on study to compare firstly, the persistence of antibody against the A/California/7/2009 (H1N1) virus after the use of these novel H1N1 influenza vaccines and secondly the immunogenicity and reactogenicity of one dose of a non-adjuvanted trivalent seasonal influenza vaccine in children, after receiving a two-dose immunisation regimen of either Pandemrix or Celvapan. In previous pandemics, there have been further waves of infection in the subsequent influenza seasons, particularly when the pandemic strain has drifted antigenically. It is important therefore to study the persistence of antibody against pandemic influenza A (H1N1) infection in children, particularly those for whom seasonal influenza vaccine will not be recommended next year. Should a drifted H1N1 strain emerge next season, sera from children vaccinated in 2009 with the A/California/7/2009(H1N1) strain could be used to assess the likely cross protection to such a drifted strain. The existence of this unique cohort of almost 1000 children will allow information on antibody persistence to be generated for both the non-adjuvanted whole virion vaccine (Celvapan) or the ASO3-adjuvanted split-virion vaccine (Pandemrix) and would provide a valuable source of sera to assess cross protection in the event of emergence of a drifted strain. The investigators therefore propose a follow-on study to compare firstly, the persistence of antibody against the A/California/7/2009 (H1N1) virus after the use of these novel H1N1 influenza vaccines and secondly the immunogenicity and reactogenicity of one dose of a nonadjuvanted trivalent seasonal influenza vaccine in children, after receiving a two-dose immunisation regimen of either Pandemrix or Celvapan. This follow-on study will also provide an important opportunity to provide data on the long term safety of the Pandemrix and Celvapan vaccines prior to enrolment in the follow-on study. The study will use a non-adjuvanted trivalent seasonal influenza vaccine, Fluarix® (GlaxoSmithKline Biologicals, Dresden, Germany). It is approved by the EMEA for prophylaxis of influenza in all ages and has been marketed since 1987. It has consistently been shown to meet or exceed the regulatory criteria for immunogenicity against the three strains H1N1, H3N2 and B, and has a good safety profile. (18) Although the option of receiving this vaccine (and having a blood test to assess the immune response to this vaccine) will be offered to all participants in the study, participants (or parents/ guardians, on the participant's behalf) may decline to receive this vaccine and the second blood test. These participants would still be eligible to take part in the study for the first blood test assessing the persistence of antibody from the original study. Persistence of seroprotection will be assessed by both haemagglutination inhibition (HI) and microneutralisation (MN). Although EMEA guidelines for licensure of influenza vaccine are based on HI assays, the primary objective for this study uses MN titres as its measure. The decision for the preference of MN titres over HI titres was made based on recently published observations by the Centers for Disease Control and Prevention (CDC)(19, 20) and results from the Health Protection Agency's own analysis, which showed that the MN assay generally yields higher titres and detected more seroconversions to A/California/04/2009 than the HI assay (although both generally show high correlation). The investigators therefore used MN titres as the primary outcome measure in the original NIHR funded study (Clinicaltrials.gov registration number: NCT00980850)(1) The cellular immune response to influenza immunisation will be assessed in children where sufficient blood is available and local laboratory facilities permit. Elispot assays will be carried out using PBMCs isolated from the blood to determine the T cell response to internal influenza antigens, and haemagglutinin (pandemic H1, seasonal H1 and seasonal H3). Exploratory flow cytometry assays may also be used to determine whether the T cells are CD4+ or CD8+, and to examine cytokine secretion. RNA expression profiles pre and post vaccination will be scrutinised in 20 participants in each group to elucidate genes that are differentially expressed in response to immunisation. This analysis could highlight genes of particular importance in vaccine responses. Furthermore, comparisons between RNA profiles and correlates of vaccine immunity may identify profiles which could be useful 'biomarkers' of vaccine induced cellular and humoral immunity in future studies. With appropriate consent, serum samples remaining after the analyses required for this study will be stored for use in future infection and immunity related research studies at the relevant study sites.

Official Title
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A Multi-centre, Open-label, Clinical, Phase 4 Trial, Following on From a Head-to-head Comparison Study of Two H1N1 Influenza Vaccines in Children, to Compare Firstly, the Persistence of Antibody Against the A/California/7/2009 (H1N1) Virus and Secondly the Immunogenicity and Reactogenicity of One Dose of a Non-adjuvanted Trivalent Seasonal Influenza Vaccine, in Children Who Had Received a Two-dose Immunisation Regimen of Celvapan or Pandemrix.

Conditions
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Influenza

Intervention / Treatment
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* Drug: Seasonal Flu vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The participants must have completed the original NIHR funded study (NCT00980850)(1) comparing Celvapan with Pandemrix at one of the study sites participating in this follow-on study. A parent/legal guardian has given written informed consent after the nature of the study has been explained. Willingness to either undertake a blood test at visit 1 ('persistence' cohort) complete all study procedures ('booster' cohort) Exclusion Criteria: Participant(s) in original study (NCT00980850)(1) who had a suspected unexpected serious adverse reaction (SUSAR). Participants in the original study (NCT00980850)(1) who did not receive two doses of H1N1 influenza vaccine. Participants in original study (NCT00980850)(1) who received a third dose of H1N1 influenza vaccine due to an inadequate response to two doses. History of severe allergic reaction after previous vaccinations or hypersensitivity to any seasonal influenza vaccine component. Current egg allergy. Known or suspected impairment/alteration of the immune system. Disorders of coagulation. Immunosuppressive therapy, use of systemic corticosteroids for more than 1 week within the 3 months prior to enrolment. Receipt of blood, blood products and/or plasma derivatives or any immunoglobulin preparation within 3 months prior to enrolment. Previous receipt of, or intent to immunize with, any other seasonal influenza vaccine(s) throughout the 2010/2011 influenza season. Participation in another clinical trial of an investigational medical product. Any condition which, in the opinion of the investigator, might interfere with the evaluation of the study objectives. Children with chronic, stable medical illnesses that do not result in immunosuppression (e.g. cerebral palsy, epilepsy, cystic fibrosis, congenital heart disease) will be allowed to participate in the study, unless these conditions will in some way interfere with the completion of study procedures. Children with conditions that may alter the immune response to vaccines (e.g. Trisomy 21) or will affect the ability to accurately describe adverse events (e.g. children over 5 years of age but with severe learning difficulties) will be excluded.

Ages Eligible for Study
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Minimum Age: 17 Months
Maximum Age: 14 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Baxter H1N1 vaccine<br>Previously received 2 dose schedule of Baxter H1N1 vaccine | Drug: Seasonal Flu vaccine<br>* 1 dose of seasonal trivalent flu vaccine (Fluarix)<br>|
| GSK H1N1 vaccine<br>Previously received 2 dose schedule of GSK H1N1 vaccine | Drug: Seasonal Flu vaccine<br>* 1 dose of seasonal trivalent flu vaccine (Fluarix)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Persistence of MICRONEUTRALISING antibody titres against H1N1v | The percentage of children with microneutralisation (MN) titres ≥ 1:40, 11-15 months after receiving a two-dose immunisation regimen of either Celvapan or Pandemrix. | 11 - 15 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immunogenicity of trivalent seasonal influenza vaccine | The percentage of children who seroconvert and have a post-vaccination MN titre ≥1:40 or HI titre ≥1:32 (H1N1 strain) or who were seropositive at pre-vaccination and have a 4- fold increase in titre, following one dose of a non-adjuvanted seasonal trivalent influenza vaccine, 11-15 months after receiving a two-dose immunisation regimen of either Celvapan or Pandemrix | 12 - 16 months | 
| Reactogenicity of trivalent seasonal influenza vaccine | The percentage of children experiencing fever, local reactions and non-febrile systemic reactions within the 7 days following one dose of a non-adjuvanted seasonal trivalent influenza vaccine 11-15 months after receiving a two-dose immunisation regimen of either Celvapan or Pandemrix. | 12 - 16 months | 
| Persistence of antibody titres to H1N1v | The percentage of children with HI titre ≥ 1: 32 and the geometric mean HI and MN titres in children 11-15 months after receiving a two-dose immunisation regimen of either Celvapan or Pandemrix. | 11 - 15 months | 
| Long-term safety monitoring of Pandemrix and Celvapan | Specific adverse events (influenza-like illnesses (ILI), hospitalisations, febrile convulsions, autoimmunity and adverse events of special interest (AESIs) will be assessed in all participants. | 11 - 15 months | 
| T cell Responses | The T cell responses to internal influenza antigens and haemagglutinin (pandemic H1). | 11 - 15 months | 
| Genetics | The identification of genes differentially expressed in response to vaccination with the seasonal influenza strain. | 1 month |