Complete Protection Against Yersinia pestis in BALB/c Mouse Model Elicited by Immunization With Inhalable Formulations of rF1-V10 Fusion Protein via Aerosolized Intratracheal Inoculation.

Wei Zhang,Xinying Zheng,Dongsheng Zhou,Lina Zhai,Jianshu Guo,Wenhui Yang,Lingfei Hu,Xiaolu Xiong,Xiaolin Song,Meng Lv,Lili Zhang

doi:10.3389/fimmu.2022.793382

Abstract

Pneumonic plague, caused by Yersinia pestis, is an infectious disease with high mortality rates unless treated early with antibiotics. Currently, no FDA-approved vaccine against plague is available for human use. The capsular antigen F1, the low-calcium-response V antigen (LcrV), and the recombinant fusion protein (rF1-LcrV) of Y. pestis are leading subunit vaccine candidates under intense investigation; however, the inability of recombinant antigens to provide complete protection against pneumonic plague in animal models remains a significant concern. In this study, we compared immunoprotection against pneumonic plague provided by rF1, rV10 (a truncation of LcrV), and rF1-V10, and vaccinations delivered via aerosolized intratracheal (i.t.) inoculation or subcutaneous (s.c.) injection. We further considered three vaccine formulations: conventional liquid, dry powder produced by spray freeze drying, or dry powder reconstituted in PBS. The main findings are: (i) rF1-V10 immunization with any formulation via i.t. or s.c. routes conferred 100% protection against Y. pestis i.t. infection; (ii) rF1 or rV10 immunization using i.t. delivery provided significantly stronger protection than rF1 or rV10 immunization via s.c. delivery; and (iii) powder formulations of subunit vaccines induced immune responses and provided protection equivalent to those elicited by unprocessed liquid formulations of vaccines. Our data indicate that immunization with a powder formulation of rF1-V10 vaccines via an i.t. route may be a promising vaccination strategy for providing protective immunity against pneumonic plague.

Highlights

Yersinia pestis, a non-motile, facultative intracellular, gram-negative bacterium, is the causative agent of plague [1,2,3]
The results demonstrate that biochemical integrity and immunogenicity of the three vaccines were unaffected by the spray freeze drying (SFD) process
Previous studies reported that immunization with the rF1-low-calcium-response V antigen (LcrV) fusion protein through the s.c. route could fully protect mice only at 10× LD50 virulent Y. pestis CO92 via intranasal (i.n.) challenge [34] and only partially protect mice at 70× LD50 via inhalational challenge [58]

Summary

Introduction

A non-motile, facultative intracellular, gram-negative bacterium, is the causative agent of plague [1,2,3]. A devastating zoonotic disease prevalent in many parts of the world, is transmitted through infected fleas from rodent reservoirs to humans [4, 5]. Pneumonic plague transmitting through aerosol droplets is the most dangerous among the three primary clinical forms due to its rapid onset and progression [6, 8]. Without the rapid response with appropriate antibiotics, the fatality rate of pneumonic plague approaches 100% [9]. Y. pestis remains listed as a Tier 1 Select Agent because of its potential use as a biological weapon in an aerosolized form, making it an urgent public health and safety priority [10, 11]. Development of a protective vaccine that provides both rapid and long-lasting immunity in the event of mass exposure to aerosolized Y. pestis is of great interest

Methods

Results

Conclusion