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Pseudomonas aeruginosa is a high priority multi-drug-resistant (MDR) bacterial pathogen with increasing resistance against broad-spectrum antibiotics. Multiple efforts are ongoing to develop anti-pseudomonal vaccines however achieving meaningful outcomes has been challenging in human clinical trials. Monoclonal antibodies (MAbs) are emerging as promising biologics for targeting P. aeruginosa infections and engineering strategies that bridge engagement with innate immune mechanisms like complement-mediated antibody dependent phagocytosis may be beneficial to improve bacterial clearance. We previously described both protection and long-term expression of synthetic DNA-encoded MAb (DMAb) expressing the anti-PcrV MAb V2L2-MD. Here, we show that modification of DMAb-V2L2-MD with an Fc-point mutation designed to enhance complement engagement demonstrates improved binding to C1q, C3 deposition, and improved opsonophagocytic killing. This Fc-modified DMAb reduced P. aeruginosa bacteria burden in lungs and nasal washes in a lethal acute murine intranasal infection model. These data highlight the importance of tailoring downstream antibody innate effector functions to improve clearance of difficult-to-treat bacteria like MDR P. aeruginosa.

Current influenza vaccines induce mostly strain-specific immunity necessitating annual reformulation and dosing. Here, we developed an improved seasonal influenza vaccine based on A/H1N1/Wisconsin/588/2019. We designed a DNA-launched self-assembling nanoparticle that displayed seven Wisconsin/588/2019 hemagglutinin (HA) head domains (WI19-7mer). WI19-7mer nanovaccine improved heterologous HAI titers and CD8+ cellular responses in mice than DNA encoded HA trimer (WI19 HA). In human antibody repertoire mice, WI19-7mer induced superior breadth to a diverse panel of H1 HAs compared to WI19 HA immunized animals. Cross-reactive HAI titers were maintained better in mice immunized with WI19-7mer than WI19 HA. The WI19-7mer induced improved antibody binding breadth and provided superior protection in a heterologous challenge compared to challenge-matched HA trimer. Addition of the cytokine adjuvant (CTACK) to WI19-7mer significantly improved breadth, HAI, peripheral responses, and protection in heterologous challenge. These data demonstrate that combining nucleic acid delivery, immune focusing, low valency nanoparticle, and mucosal adjuvant for enhanced vaccine effectiveness has broader applications for other viruses.

Red blood cells (RBCs) express the nucleic acid-binding toll-like receptor 9 (TLR9) and bind CpG-containing DNA. However, whether human RBCs express other nucleic acid-binding TLRs is unknown. Here we show that human RBCs express the RNA sensor TLR7. TLR7 is present on the red cell membrane and is associated with the RBC membrane protein Band 3. In patients with SARS-CoV2-associated sepsis, TLR7-Band 3 interactions in the RBC membrane are increased when compared with healthy controls. In vitro, RBCs bind synthetic ssRNA and RNA from ssRNA viruses. Thus, RBCs may serve as a previously unrecognized sink for exogenous RNA, expanding the repertoire of non-gas exchanging functions performed by RBCs.