An effectiveness trial (phase IV) to evaluate protection of children and pregnant women by influenza vaccine in rural Bangladesh

Annually influenza is a leading cause of severe disease and mortality particularly in young children less than 5 years old and pregnant women in the low and middle-income countries (LMICs) and both groups are prioritised for vaccination by the World Health Organisation (WHO). In Bangladesh, influenza is responsible for 10% of all childhood pneumonias. Maternal influenza infection during pregnancy is associated with an increased risk of hospitalisation and foetal malformation. In our work we have conducted a community-based randomised trial in both pregnant women and young children to assess the impact of inactivated influenza in preventing influenza in the community. 2811 subjects were vaccinated including pregnant women in third trimester (n=75, mean age 26 years) and children under 5 years old (n=2736, 1334 boys and 1402 girls, mean age 44 months) between April and June 2021 in 10 villages randomised to receive influenza vaccine and 10 villages randomised to receive control polio vaccine. Forty-six serious adverse events have been reported the majority of which are not connected with vaccination. We have followed the subjects after vaccination and collected respiratory swabs if subjects exhibited influenza like illness which are evaluated for viral aetiology. We have also collected serum samples from all children over 2 years old in each group to investigate the influenza specific antibody responses. In a subgroup of 50 children and pregnant women (n=37-38) in each arm we have collected blood, dried blood spots, saliva and lymphocytes up to 18 months post vaccination to investigate antibody, B and T cell responses. We have conducted virological surveillance to investigate which viruses are circulating. Overall, rhinovirus was the most dominant virus, followed by adenovirus, influenza virus, SARS-CoV-2, Respiratory syncytial virus, human parainfluenza viruses, and human metapneumonia virus. In total 348 coinfections with two or more respiratory viruses were identified. Three epidemic peaks of influenza virus were detected with Influenza B and Influenza A/H1N1 in 2021 and influenza A/H3N2 in 2022. Some coinfections with influenza were identified, most commonly with influenza B virus and Influenza A/H3N2 viruses. Preliminary statistical analysis has shown a vaccine effectiveness of approximately 50% from April to December 2021 with adjustments for the cluster randomization. Influenza-specific antibody responses were boosted after influenza vaccination, but not in the placebo (polio) group, peaking at day 28 in pregnant women or day 56 in young children. Vaccine induced antibodies rapidly declined at 6 months and further by 18 months. The highest HI responses were observed to B/Phuket, with all pregnant women and most children having protective antibodies. Influenza infection was confirmed in two pregnant women in the placebo group, in both cases the pregnant women had no detectible specific antibodies. Five children in the influenza vaccine group had confirmed influenza infection between 12- and 18-months post-vaccination when protective immunity had waned. Ongoing work is evaluating the immune responses in more detail in the subgroup and larger cohort of children and the impact of host factors on infection. Our study will produce critical region-specific information to guide the introduction of routine influenza vaccination in Bangladesh.

Annually influenza is a leading cause of severe disease and mortality particularly in young children <5 years old and pregnant women in the low and middle-income countries (LMICs) and both groups are prioritised for vaccination by the World Health Organisation (WHO). In Bangladesh, influenza is responsible for 10% of all childhood pneumonias. Maternal influenza is associated with an increased risk of hospitalisation and foetal malformation. Here, we propose a community-based randomised trial in both pregnant women and young children to assess the impact of inactivated influenza in preventing influenza in the community. This will be the first cluster randomised trial of this combined mother and children immunisation strategy, which has the potential to render greater population level of protection than is predicted by direct protective effects to the individual vaccinee. We hypothesise that influenza vaccination will reduce the burden of influenza in the community directly by the protection of the vaccinee and indirectly through vertical transfer of maternal antibodies to the foetus/infant and reduction of community transmission due to herd immunity. The primary study outcome will be laboratory-confirmed influenza illnesses among vaccinated children and pregnant women in the intervention villages. Our multi-disciplinary approach involves a cluster-randomised, double-blinded effectiveness trial at a leading field site in Bangladesh combined with influenza surveillance, laboratory diagnostics, human immunology, virology, vaccinology, genetics, vaccine effectiveness and cost-effectiveness which will provide sustainable and tailor training of young scientists from Norway and Bangladesh. Ultimately, the direct and indirect vaccine effectiveness and cost-effectiveness of influenza vaccination will be analysed in rural Bangladesh. This study will produce critical region-specific information to guide the introduction of routine influenza vaccination in Bangladesh.