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.

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 In the head to head paediatric study unpublished analyses show significantly lower immunogenicity in children who had received seasonal influenza vaccines in the past, despite the receipt of two doses of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 In addition, unpublished data from a manufacturer study suggests a negative effect of two doses of Pandemrix on immune responses to subsequent seasonal vaccine when given 3 weeks after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.