Molecular Therapy, Abstract 431
The American Society of Gene and Cell Therapy Annual Conference, Washington, DC, 2016
Influenza A is a major global health threat causing >500,000 deaths annually. Neither prior infections nor current vaccines provide lasting protection, mainly due to rapid antigenic evolution of the viral haemagglutinin (HA) protein. Broadly neutralising antibodies (bNAbs) isolated from vaccinated volunteers can provide passive immunity, but this approach is hindered by high antibody manufacturing costs and the relatively short half-life of antibody after delivery to the circulation.
We hypothesise that using lentivirus pseudotyped with Sendai virus envelopes (rSIV.F/HN) to deliver genes encoding anti-influenza bNAbs to the lung could provide long-lasting passive immunity to widely divergent strains of influenza. We selected a novel bNAb that we isolated from vaccinated volunteers, namely T1-3B (VH1-69 germline family) that cross-reacts with multiple group 1 influenza A strains including H1 (A/PuertoRico/8/34 & A/Brisbane/59/2007), pandemic H1 (A/California/07/2009) and H5 (A/Vietnam/1203/2004).
Delivery of rSIV.F/HN expressing Gaussia luciferase (GLux) reporter protein to the mouse lung (1e7 TU/mouse) resulted in persistent secretion of GLux into both bronchoalveolar lavage fluid (BALF) (1,370,000 RLU/μl; p<0.01) and systemically into the serum (1,000 RLU/μl; p<0.01), representing 18,000-fold, and 25-fold over background, respectively.
We then generated rSIV.F/HN vectors expressing T1-3B antibody and showed detection of antibody in the serum (715 ng/ml; p<0.05) for up to 28 days post intranasal delivery of rSIV.F/HN (5e7 TU/mouse). Animals treated with rSIV.F/HN expressing T13B were partially protected against a lethal challenge with either 1,000 or 10,000 TCID50 (~10 and 100 LD50) of A/PuertoRico/8/34 (H1N1) influenza.
They experienced a ~2-3 days delay in symptoms and, significantly reduced weight-loss – less than 20% weight loss in 50% (1,000 TCID50) and 20% (10,000 TCID50) treated animals, while all control animals lost >20% weight irrespective of influenza dose (p
One major advantage of rSIV.F/HN as a platform for bNAb passive immunization is the proven ability to achieve successful transgene expression after repeated lung vector administration (Mol Ther 18:1173, 2010; Am J Respir Crit Care Med 186:846, 2012), a major hurdle for all other viral vectors we have evaluated, including rAAV (J Virol 81:12360, 2007).
Repeat administration of rSIV.F/HN vectors expressing alternative bNAbs, such as those that cross-react with both group 1 and 2 influenza, could provide a truly broad protection against a wide range of influenza strains. We speculate that during the next human influenza pandemic, prophylaxis provided by lung gene transfer may be feasible and more cost-effective and time-responsive than traditional vaccines or parenteral administration of therapeutic antibody.