Assessment of Viral Shedding in Children Previously in Receipt of Multiple Doses of Live Attenuated Influenza Vaccine (LAIV) Compared to Influenza Vaccine-naïve Controls
Condition: Influenza Vaccination; Influenza; Vaccination
MeSH terms: Influenza, Human
Study type: Interventional
Phase: Phase 4

Summary: 
      LAIV shedding studies in children could be an important way to confirm whether impediments to
      viral replication do indeed explain these observed reductions in vaccine effectiveness(VE),
      whether prior vaccination has any influence on replication and what future implications (if
      any) this might have for the UK paediatric LAIV programme. LAIV virus replication in children
      will be dependent on virological and host factors. The virus factors include replicative
      fitness of individual strains and the susceptibility to inhibition by other replicating
      strains (ability to compete). Host factors which may influence this include pre-existing
      specific immunity as a result of prior infection or previous vaccination (with either LAIV or
      IIV), and innate immune factors including mucosal immunity. Understanding the relative
      importance of different factors over two seasons when the strain composition of the
      A/H1N1pdm09 LAIV virus will change and by comparing previously unvaccinated and highly
      vaccinated groups (with both LAIV and IIV), can potentially give unique insights into their
      contribution to the US LAIV observations.

      With the change of the A/H1N1pdm09 vaccine strain in 2017/18, demonstrating improved
      performance (in terms of VE, virus shedding and immunogenicity) and what contribution prior
      vaccination might make will be key evidence for both the UK, but also the US. Information
      presented at the ACIP in June 2018 from the 2016/17 and 2017/18 seasons will be key to inform
      US future decisions around use of LAIV.

      This is a parallel group, non randomised study which will enrol at least 400 children. Both
      written informed consent from parent/ guardian and written assent from the child will be in
      place prior to any study procedure. The two groups will be defined by previous influenza
      vaccination history, with around half the children naïve to any influenza vaccination (LAIV
      or IIV) and half having had at least three doses of LAIV with or without IIV. All will follow
      the same schedule of vaccination and oral fluid collection at day 0 (by the nurse in the home
      or at the GP surgery); nasal swab collection (by the parent at home on days 1,3,6); day 21
      oral fluid collection (by nurse or parent at home or at GP surgery).
    

Detailed description: 
      The United States of America (USA) has a long-standing paediatric influenza vaccination
      programme, including use of live attenuated influenza vaccine (LAIV). Following evidence of
      lack effectiveness of LAIV in 2015/16, the USA suspended use in the 2016/17 season. The UK
      introduced LAIV for children in 2013/14 and has since been closely monitoring programme
      performance. In 2015/16, the UK - in contrast to the USA - found evidence of significant
      effectiveness of LAIV against laboratory confirmed influenza in both primary and secondary
      care including against A/H1N1pdm09. The UK results concord with those from several other
      geographical settings, although several studies report relatively lower effectiveness of LAIV
      against A/H1N1pdm09 infection compared to inactivated influenza vaccine (IIV). The reasons
      for these apparent differences in effectiveness are currently unclear.

      The USA has indicated that for the Advisory Committee on Immunisation Practice (ACIP) to
      rescind their decision to suspend use of LAIV, they will require an understanding of the
      likely underlying mechanism for the apparent reduction in LAIV A/H1N1pdm09 vaccine
      effectiveness (VE) measured in observational studies in the USA and then evidence that the
      problem has been resolved.

      Several hypotheses are emerging to explain the apparent reduction in A/H1N1pdm09 quadrivalent
      LAIV effectiveness in the USA last season and their discordance with findings elsewhere
      including the UK together with the possible lower effectiveness of LAIV against A/H1N1pdm09
      compared to IIV. These include one or more of the following:

        1. Center for Disease Control (CDC)/ Department of Defense (DoD) specific finding - related
           to chance, methodology, programmatic issues

        2. Reduced replicative fitness of the current A/H1N1pdm09 strain.

        3. Viral interference/competition between A/H1N1pdm09 vaccine strain and other vaccine
           viruses in multivalent formulation;

        4. Prior vaccination with LAIV or IIV resulting in specific immunological interference with
           H1N1pdm09 vaccine virus replication;

        5. Repeat LAIV vaccination resulting in broader, longer term immunological changes
           affecting all viruses (mimicking adult response);

        6. Combinations of the above Based upon in vitro studies, the manufacturer of LAIV
           (MedImmune) have stated that reduced replicative fitness of the A/H1N1pdm09 strain is
           likely to be the important root cause. However, this factor alone cannot explain the
           difference in effectiveness observed between the USA and sites elsewhere including the
           UK. This suggests that there is an important additional factor(s) involved. The US
           programme has been running for many more years than the UK - and in addition children 6
           months to 24 months of age are offered IIV, unlike the UK. These prior vaccine exposures
           are potential contributory factors.

      LAIV shedding studies in children could be an important way to confirm whether impediments to
      viral replication do indeed explain these observed reductions in VE, whether prior
      vaccination has any influence on replication and what future implications (if any) this might
      have for the UK paediatric LAIV programme. LAIV virus replication in children will be
      dependent on virological and host factors. The virus factors include replicative fitness of
      individual strains and the susceptibility to inhibition by other replicating strains (ability
      to compete). Host factors which may influence this include pre-existing specific immunity as
      a result of prior infection or previous vaccination (with either LAIV or IIV), and innate
      immune factors including mucosal immunity. Understanding the relative importance of different
      factors over two seasons when the strain composition of the A/H1N1pdm09 LAIV virus will
      change and by comparing previously unvaccinated and highly vaccinated groups (with both LAIV
      and IIV), can potentially give unique insights into their contribution to the US LAIV
      observations.

      With the change of the A/H1N1pdm09 vaccine strain in 2017/18, demonstrating improved
      performance (in terms of VE, virus shedding and immunogenicity) and what contribution prior
      vaccination might make will be key evidence for both the UK, but also the US. Information
      presented at the ACIP in June 2018 from the 2016/17 and 2017/18 seasons will be key to inform
      US future decisions around use of LAIV.

      This is a parallel group, non randomised study which will enrol at least 400 children. Both
      written informed consent from parent/ guardian and written assent from the child will be in
      place prior to any study procedure. The two groups will be defined by previous influenza
      vaccination history, with around half the children naïve to any influenza vaccination (LAIV
      or IIV) and half having had at least three doses of LAIV with or without IIV. All will follow
      the same schedule of vaccination and oral fluid collection at day 0 (by the nurse in the home
      or at the GP surgery); nasal swab collection (by the parent at home on days 1,3,6); day 21
      oral fluid collection (by nurse or parent at home or at GP surgery).
    

Intervention name(s): Fluenz Tetra (The two groups are defined by immunisation history, all receive the same intervention in the study)
Intervention type(s): Biological
Intervention description(s): live attenuated influenza vaccine (LAIV)
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Intervention model description: Two groups based on prior vaccination history
Masking: None (Open Label)
Primary purpose: Prevention