A Study of Intranasal Live Attenuated Influenza Vaccine Immunogenicity and Associations With the Nasopharyngeal Microbiome Among Children in the Gambia
Condition: Influenza
MeSH terms: Influenza, Human
Study type: Interventional
Phase: Phase 4

Summary: 
      The live attenuated influenza vaccine (LAIV) is made up of weakened influenza viruses given
      into the nose and in early studies was shown to be better than the standard influenza vaccine
      at preventing infections in children. However, more recently, it has performed less well and
      it may also work less well in Sub-Saharan Africa. Not only do the investigators not know why
      this is, but the investigators also do not fully understand why LAIV produces stronger nasal
      antibody responses in some individuals but not others. Usually harmless bacteria that are
      present in participants noses can influence how our immune system works and variations in
      these may explain differences in how LAIV works. The project will recruit children given LAIV
      in the Gambia to gain further understanding of these issues.

      The investigators will measure a variety of responses to LAIV, including genes that can
      change their expression early after vaccination and use advanced computational techniques to
      identify new relationships between these genes and other LAIV responses. The investigators
      will also see whether nasal bacterial profiles in children who respond to LAIV are different
      from those who do not. In addition, the investigators will alter these bacteria in a subset
      of children with antibiotics and see whether this affects both nasal gene expression and
      later responses to LAIV.
    

Detailed description: 
      Purpose The overall goal of this study is to conduct at detailed immunogenicity study of
      intranasal live attenuated influenza vaccine (LAIV; Nasovac-S, Serum Institute of India Pvt.
      Ltd.), including identification of early molecular signatures associated with a robust
      mucosal immune response. In addition, the study team will explore whether the nasopharyngeal
      microbiome influences this immune response and whether LAIV has an impact on the microbiome.

      A total of 365 healthy children aged 24 - 59 months will be recruited in The Gambia for this
      study.

      Background Both the burden of infection and use of influenza vaccines in children from
      sub-Saharan Africa (SSA) have been neglected. There are limited immunogenicity or efficacy
      data from SSA of the widely used Ann Arbor strain-derived LAIV. This LAIV was shown to have
      greater relative efficacy compared to inactivated influenza vaccine in children in early
      randomized-controlled trials. There has, however, been concern regarding lower vaccine
      effectiveness in the US in recent years.

      The Serum Institute of India Pvt. Ltd. has recently developed a trivalent LAIV (Nasovac-S)
      via a WHO facilitated donation of a Russian-derived LAIV, with the intention of scaling up
      provision of LAIV to resource-limited settings. Based on initial safety and immunogenicity
      data, Nasovac-S was licensed in India and granted a WHO prequalification certificate in 2015.
      Two placebo-controlled efficacy studies using Nasovac-S were recently undertaken in
      Bangladesh and Senegal (in children aged 24 - 59 months and 24 - 71 months respectively),
      providing mixed and contrasting results. In Senegal, no efficacy was found against the
      circulating pandemic H1N1 influenza strain (-9.7%, 95% CI -62.6, 26.1). In Bangladesh the
      overall vaccine efficacy to vaccine-matched strains, in a study of identical design, was
      57.5% (95% CI 43.6, 68.0), with efficacy against H1N1 and H3N2, 50.0% (95% CI 9.2, 72.5) and
      60.4% (95% CI 44.8, 71.6) respectively. The reason for the discrepancy in these studies or
      the poorer performance of the H1N1 component is not clear and emphasizes the need to
      undertake detailed immunogenicity studies of this vaccine in SSA. On a wider note, the exact
      immunological mechanisms of action of LAIV are also under-explored.

      Study type:

      Interventional

      Design:

      All primary objectives will be addressed through the conduct of a phase 4, randomized,
      controlled clinical vaccine trial. A total of 330 healthy children aged 24 - 59 months will
      be enrolled into one of three groups of equal size (3 x 110 children):

      (i) LAIV-vaccinated (Group A - blood sample at day 0, 2, 21) (ii) LAIV-vaccinated (Group B -
      blood sample at day 0, 7, 21) (iii) Control group (Group C)

      The study is not blinded, but group allocation will be concealed from the investigator team
      and block randomization stratified by sex will be undertaken.

      Two LAIV-vaccinated groups are included in order to achieve several exploratory objectives,
      which require blood sampling at different times following vaccination, whilst minimizing the
      number of times children are bled. The unvaccinated subjects will serve as a control group
      for the primary objective of assessing the impact of LAIV on the nasopharyngeal microbiome.

      An additional 35 healthy children aged 24 - 59 months will be recruited in the 2nd phase of
      recruitment (approximately Jan - June 2018) to assess how modulation of the nasopharyngeal
      microbiome with antibiotics impacts the mucosal immunogenicity to LAIV. These subjects will
      be matched as closely as possible by pre-antibiotic nasopharyngeal microbiome profile, age
      and sex (in that order of preference), in an exploratory nested case-control study, to n = 35
      children recruited in the main clinical trial.

      Official title A Study of Intranasal Live Attenuated Influenza Vaccine Immunogenicity and
      Associations with the Nasopharyngeal Microbiome Among Children in the Gambia (The NASIMMUNE
      study)

      Primary outcome measures

        -  To identify novel early systemic and mucosal molecular signatures following LAIV that
           are associated with subsequent robust nasal and oral influenza-specific immunoglobulin A
           (IgA) responses, in order to provide insight into the mechanisms of successful mucosal
           immunization

        -  To identify associations between nasopharyngeal microbiota and nasal and oral
           influenza-specific IgA responses post-LAIV in Gambian children, to explore whether
           microbiome variability can explain suboptimal immune responses in some individuals to
           live intranasal mucosal vaccines in Sub-Saharan Africa

        -  To establish whether LAIV impacts the nasopharyngeal microbiome, with a specific focus
           on the burden of S. pneumoniae
    

Intervention name(s): Nasovac-S; Azithromycin
Intervention type(s): Biological; Drug
Intervention description(s): one of 0.5ml intranasal dose of trivalent live attenuated vaccine (LAIV); a single dose of Azithromycin (liquid formulation - Zithromax) at 20mg/Kg (up to a maximum adult dose 1g) to be given to a subset of subjects
Other intervention name(s): Zithromax
Intervention MeSH terms: Azithromycin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Prevention
Keywords: intranasal; flu vaccine; Gambian children