STING-adjuvanted outer membrane vesicle nanoparticle vaccine against Pseudomonas aeruginosa
Elisabet Bjånes, Nishta Krishnan, Truman Koh, Anh T.P. Ngo, Jason Cole, Joshua Olson, Ingrid Cornax, Chih-Ho Chen, Natalie Chavarria, Samira Dahesh, Shawn M. Hannah, Alexandra Stream, Jiaqi Amber Zhang, Hervé Besançon, Daniel Sun, Siri Yendluri, Sydney Morrill, Jiarong Zhou, Animesh Mohapatra, Ronnie H. Fang, Victor Nizet
Elisabet Bjånes, Nishta Krishnan, Truman Koh, Anh T.P. Ngo, Jason Cole, Joshua Olson, Ingrid Cornax, Chih-Ho Chen, Natalie Chavarria, Samira Dahesh, Shawn M. Hannah, Alexandra Stream, Jiaqi Amber Zhang, Hervé Besançon, Daniel Sun, Siri Yendluri, Sydney Morrill, Jiarong Zhou, Animesh Mohapatra, Ronnie H. Fang, Victor Nizet
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Research Article Infectious disease Microbiology Vaccines

STING-adjuvanted outer membrane vesicle nanoparticle vaccine against Pseudomonas aeruginosa

Abstract

Multidrug-resistant (MDR) bacterial pneumonia poses a critical threat to global public health. The opportunistic Gram-negative pathogen Pseudomonas aeruginosa is a leading cause of nosocomial-associated pneumonia, and an effective vaccine could protect vulnerable populations, including the elderly, immunocompromised, and those with chronic respiratory diseases. Highly heterogeneous outer membrane vesicles (OMVs), shed from Gram-negative bacteria, are studded with immunogenic lipids, proteins, and virulence factors. To overcome limitations in OMV stability and consistency, we described what we believe to be a novel vaccine platform that combines immunogenic OMVs with precision nanotechnology — creating a bacterial cellular nanoparticle (CNP) vaccine candidate, termed Pa-STING CNP, which incorporates an adjuvanted core that activates the STING (stimulator of interferon genes) pathway. In this design, OMVs are coated onto the surface of self-adjuvanted STING nanocores. Pa-STING CNP vaccination induced substantial antigen presenting cell recruitment and activation in draining lymph nodes, robust anti-Pseudomonas antibody responses, and provided protection against lethal challenge with the hypervirulent clinical P. aeruginosa isolate PA14. Antibody responses mediated this protection and provided passive immunity against the heterologous P. aeruginosa strain PA01. These findings provided evidence that nanotechnology can be used to create a highly efficacious vaccine platform against high priority MDR pathogens such as P. aeruginosa.

Authors

Elisabet Bjånes, Nishta Krishnan, Truman Koh, Anh T.P. Ngo, Jason Cole, Joshua Olson, Ingrid Cornax, Chih-Ho Chen, Natalie Chavarria, Samira Dahesh, Shawn M. Hannah, Alexandra Stream, Jiaqi Amber Zhang, Hervé Besançon, Daniel Sun, Siri Yendluri, Sydney Morrill, Jiarong Zhou, Animesh Mohapatra, Ronnie H. Fang, Victor Nizet

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Figure 6

Pa-STING vaccination protection is antibody mediated and protects against infection with heterologous PA01.

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Pa-STING vaccination protection is antibody mediated and protects agains...
(A) IgG, IgA, and IgM antibody titers specific for PA14 from prevax and postvax serum obtained from two New Zealand white rabbits vaccinated with 4 successive doses of 0.25 mg Pa-STING subcutaneously with each dose 2 weeks apart (AbCore). Pooled means of technical replicates from 3–4 independent experiments ± SEM. (B) Representative histograms of anti-rabbit IgG FITC from prevax (black) and postvax (blue) serum bound to live PA14, PA01, and PA01-galUtns-ins measured by flow cytometry. Histograms are representative of technical replicates from 2–4 independent experiments. (C) % IgG-FITC positive of rabbit IgG and (D) geometric mean (median fluorescence intensity) of rabbit IgG from prevax and postvax serum bound to live PA14, PA01, and PA01-galUtns-ins measured by flow cytometry. Technical replicates from 2–4 independent experiments ± SEM. (E) Opsonophagocytic killing of PA14, PA01, and PA01-galUtns-ins by healthy human neutrophils incubated with prevax or postvax rabbit serum. Percentage surviving colony forming units (CFUs) relative to starting inputs is graphed. Pooled means of technical replicates from 3 independent experiments ± SEM. (F) Opsonophagocytic killing of PA14 by healthy human neutrophils incubated with non-depleted pre-vax or post-vax rabbit sera or sera depleted of LPS antibodies. (G) Passive immunization scheme with prevax or postvax rabbit serum. Mice received prevax or postvax intravenously 48 hours prior to infection PA14. (H) Survival curves from mice passively vaccinated with prevax or postvax serum 48 hours prior to intratracheal infection with ~ 1 × 107 CFUs PA14. Mice were monitored twice daily for 5–7 days. n = 20/group, 2 independent experiments pooled. (I) Clinical scores (means ± SEM) from mice passively immunized with prevax or postvax serum and infected intratracheally with PA14. (J) Survival curves from mice passively vaccinated with prevax or postvax serum 48 hours prior to intratracheal infection with ~ 5 × 107 CFUs PA01. Mice were monitored twice daily for 5–7 days. n = 20/group, 2 independent experiments pooled. (A) Two-way ANOVA with Dunnet’s multiple comparisons post test. (C–E) Mixed Model 2-way ANOVA with Tukey’s multiple comparisons post test. (F) Mixed Model 2-way ANOVA with uncorrected Fisher’s LSD. (H and J) Kaplan-Meier (Log-Rank) test. (I) Two-way ANOVA with Šídák’s multiple comparisons post test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.