A Study of Intranasal Live Attenuated Influenza Vaccine Immunogenicity and Associations With the Nasopharyngeal Microbiome Among Children in the Gambia

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

Inclusion criteria

• • Healthy male or female child at least 24 months of age and less than 60 months of age at the time of study entry.

• Resident in the study area and with no plans to travel outside the study area during the period of subject participation.
• Informed consent for the study participation obtained from a parent (or guardian only if neither parent is alive or if guardianship has been legally transferred (see section 11.2).
• Willingness and capacity to comply with the study protocol as judged by a member of the clinical trial team.

Exclusion criteria

• • Serious, active, medical condition, including but not limited to:

• chronic disease of any body system
• severe protein-energy malnutrition (weight-for-height Z-score of less than -3)
• known genetic disorders, such as Down's syndrome or other cytogenetic disorder

• Active wheezing
• History of documented hypersensitivity to eggs or other components of the vaccine (including gelatin, sorbitol, lactalbumin and chicken protein), or with life-threatening reactions to previous influenza vaccinations.
• History of documented hypersensitivity to macrolide antibiotics
• History of Guillain-Barré syndrome.
• Receipt of aspirin therapy or aspirin-containing therapy within the two weeks before planned study vaccination.
• Any suspected or confirmed congenital or acquired state of immune deficiency including but not limited to primary immunodeficiencies including thymus disorders, HIV/AIDS, hematological or lymphoid malignancies (blood tests will not be routinely undertaken with this regard as part of the study).
• Any current immunosuppressive/immunomodulatory treatment or receipt of any such treatment within the six months preceding trial enrolment (for corticosteroids this is defined as a dose of prednisolone (or equivalent) of greater than 2mg/kg/day for one week or 1mg/kg/day for one month. The use of topical corticosteroids is not an exclusion criterion.
• The use of inhaled corticosteroids within the last one month.
• Receipt of an influenza vaccine within the past 12 months.
• Has any condition determined by investigator as likely to interfere with evaluation of the vaccine or be a significant potential health risk to the child or make it unlikely that the child would complete the study.
• Any significant signs or symptoms of an acute illness or infection including:
• an axillary temperature of 38.0°C or above or documented fever of 38°C or above in the preceding 14 days.
• Any acute respiratory infection within 14 days of enrollment visit. If the reason for ineligibility is likely to be temporary (e.g. a fever of 38°C or above or acute respiratory infection) and either will or may resolve before the infant reaches 60 months, they will not be recorded as a screening failure but instead will be re-screened within an appropriate future time-window (e.g. at least 14 days after the last documented fever of 38°C or above or resolution of respiratory illness) and a decision made regarding eligibility at that point.