DMAb inoculation of synthetic cross reactive antibodies protects against lethal influenza A and B infections

Elliott, Sarah T. C.; Kallewaard, Nicole L.; Benjamin, Ebony; Wachter-Rosati, Leslie; McAuliffe, Josephine M.; Patel, Ami; Smith, Trevor R. F.; Schultheis, Katherine; Park, Daniel H.; Flingai, Seleeke; Wise, Megan C.; Mendoza, Janess; Ramos, Stephanie; Broderick, Kate E.; Yan, Jian; Humeau, Laurent M.; Sardesai, Niranjan Y.; Muthumani, Kar; Zhu, Qing; Weiner, David B.

Influenza virus remains a significant public health threat despite innovative vaccines and antiviral drugs. A major limitation to current vaccinations and therapies against influenza virus is pathogenic diversity generated by shift and drift. A simple, cost-effective passive immunization strategy via in vivo production of cross-protective antibody molecules may augment existing vaccines and antiviral drugs in seasonal and pandemic outbreaks. We engineered synthetic plasmid DNA to encode two novel and broadly cross-protective monoclonal antibodies targeting influenza A and B. We utilized enhanced in vivo delivery of these plasmid DNA-encoded monoclonal antibody (DMAb) constructs and show that this strategy induces robust levels of functional antibodies directed against influenza A and B viruses in mouse sera. Mice receiving a single inoculation with anti-influenza A DMAb survive lethal Group 1 H1 and Group 2 H3 influenza A challenges, while inoculation with anti-influenza B DMAb yields protection against lethal Victoria and Yamagata lineage influenza B morbidity and mortality. Furthermore, these two DMAbs can be delivered coordinately resulting in exceptionally broad protection against both influenza A and B. We demonstrate this protection is similar to that achieved by conventional protein antibody delivery. DMAbs warrant further investigation as a novel immune therapy platform with distinct advantages for sustained immunoprophylaxis against influenza.