Swine Flu (Influenza A H1N1) Follow on Vaccine Study
Condition: Influenza
MeSH terms: Influenza, Human
Study type: Observational

Summary: 
      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: 
      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.
    

Intervention name(s): Seasonal Flu vaccine
Intervention type(s): Drug
Intervention description(s): 1 dose of seasonal trivalent flu vaccine (Fluarix)
Observational model: Case-Only
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        We intend to recruit all interested participants who completed the original NIHR funded
        study (NCT00980850)(1) (n=937) into groups 1 & 2 outlined in table one above. It is
        anticipated that approximately 66% of these participants are likely to take part in this
        follow-on study; therefore the study population for groups 1 & 2 is likely to be
        approximately 560 children. As the option of only having a blood sample taken at visit 1
        will be made available to participants in this study, there will be two cohorts of
        participants: the 'persistence' cohort (consenting to the baseline blood test alone) and
        the 'booster' cohort (consenting to the baseline blood test, seasonal influenza vaccine and
        post-immunisation blood test).