Background

The longitudinal community household cohort in Ha Nam province was established in 2006 by Sir Peter Horby as one of the first projects led by OUCRU Ha Noi. The main reason for establishing this cohort was to gain a better understanding of local seasonal and/or pre-pandemic/avian influenza virus transmission in a low- and middle-income and tropical setting in a time when avian influenza viruses, especially A/H5N1 were considered the most likely candidate for a future pandemic.

The Ha Nam cohort consists of around 1000 people in 250 households in a rural community 60 km from Ha Noi. In collaboration with NIHE and the Ha Nam CDC, we have conducted the following activities:

• Active clinical surveillance of acute respiratory infections by two weekly household visits;
• Swabbing and acute/convalescent bleeds of those reporting ARI symptoms;
• Passive diagnostic surveillance of patients coming to health centres with acute respiratory infections;
• Diagnostic PCR and sequencing at NIHE for Influenza A and B viruses;
• Annual or semiannual bleeds to combine PCR with serology data.

Using these samples and data, the Ha Nam cohort produced a large number of impactful papers that have significantly furthered our understanding of influenza, its epidemiology in a tropical setting, transmission patterns, meteorological associations, contribution of different age groups, and background immunity to avian viruses. During the pandemic of Influenza virus A/H1N1pdm09, we also had the opportunity to study the epidemiology and immunology of community introduction of this virus.

Significant steps forward in our understanding have come from collaborations with Cambridge (Professor Derek Smith) and the WHO collaborating centre in Melbourne (Professor Ian Barr, Dr Annette Fox).

1. The confirmation of the concept of original antigenic sin and immune back boosting (i.e. the first influenza infection shapes the immune response against influenza viruses throughout one’s life and each successive infection illicits an immune response that is shaped by all previous infections.
2. The confirmation of the concept of immune focusing through repeat vaccination. We showed that previous influenza virus infection leads to a higher and broader antibody spectrum and clinical protection than vaccination does, and repeat vaccination narrows the immune response. This has major implications for public health policies and annual vaccination of the elderly and immunocompromised.

We have used sera from the cohort to look at neglected and emerging infections (strongyloidiasis; SARS-CoV-2) and have collected longitudinal stools to study the microbiome and the impact of antibiotic use, and have formulated the hypothesis that chronic or frequent exposure to antibiotics leads to a different steady state of the microbiome that is less diverse (which is considered a bad thing) but less susceptible to perturbations by further antibiotic exposure.

The data from the cohort on the immune backboost, in combination with a landmark paper on seven positions of antigenic variability in the immunodominant haemagglutinin, led to the hypothesis that instead of reactively determining annual vaccine compositions for the southern and northern hemisphere, a limited number of variants can be predicted to emerge from circulating strains of influenza viruses and reverse engineered into vaccine strains. A large grant from US NIH and BARDA was obtained in 2013 by a consortium of Cambridge, Erasmus, Melbourne and OUCRU to construct these viruses and conduct in vitro and in vivo vaccine trials. The work was unfortunately stopped, and funds were repurposed because of COVID-19, but the hypothesis is still viable, and we are still in discussion with Cambridge to re-apply.

The cohort is now the longest-running longitudinal influenza community cohort, and the collection is unique. Continued cohort management is desirable because of the continuity of data: the antigenic maps and cartography obtained from the cohort are unique and further extension and updates of these are important for future work on immunogenicity and escape potential of viruses and vaccines, the possibility to leverage future funds for vaccine trials with engineered viruses and further longitudinal work on microbiome and perturbations.

Aims

• Study the effect of antimicrobial use on the microbiome of a rural community
• Study longitudinal carriage of Escherichia coli and the effects of antimicrobial use
• Study the natural history of influenza virus infection and the immune response and use locally obtained data to trial engineered predicted viruses as an alternative to the current six monthly predicted dominant inactivated viruses
• Study the natural history of SARS-CoV-2 infection