Influenza Clinical Trial
Official title:
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 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.
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.
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