Lung antibody factory to provide long-term passive immunity to influenza.

Tan TK, Rijal P, Huang KYA, Davies LA, Townsend AR, Hyde SC, Gill DR

Radcliffe Department of Medicine, Annual Symposium, Oxford, 2015

Influenza A is a major worldwide health risk causing >500,000 deaths annually. Neither prior infections nor current vaccines provide lasting protection largely due to rapid antigenic evolution of the viral hemagglutinin (HA) protein. Seasonal vaccines are continually reformulated, but fail to provide protection when highly diverged strains emerge to initiate human pandemics. Broadly-neutralising antibodies (bNAbs) from recovering patients can provide passive immunity, but this approach is hindered by high antibody manufacturing costs and the relatively short half-life of antibody in circulation.

We hypothesise that using our rSIV.F/HN lentiviral lung gene delivery platform to express genes encoding anti-influenza bNAbs in the lung (literally using the lung as an 'antibody factory'), we can provide long-lasting passive immunity to widely divergent strains of influenza. Proof-of-concept delivery of a Gaussia luciferase expressing rSIV.F/HN vector to the mouse lung (1e7 TU/mouse) resulted in robust secretion of the transgene protein both into the lung-lining fluid (1,370,000 RLU/μl; p<0.01) and out of the lung into the serum (1000 RLU/μl; p<0.01) representing 18,000 and 25 fold over background respectively.

We have recently identified a range of novel anti-influenza bNAbs and constructed lentiviral genomes containing single-ORF cDNAs that direct abundant antibody expression in cell culture (2.5-11 mg/ml; p<0.0001) that support progression to influenza challenge experiments.

We speculate that during the next human influenza pandemic, prophylaxis provided by lung gene transfer may be more feasible, cost-effective and time-responsive than traditional vaccines or parenteral administration of therapeutic antibody.

Supported partly by RDM Pump Priming Scheme