Preclinical in vitro and in vivo profile of a highly-attenuated, broadly efficacious pneumolysin genetic toxoid.

Autor: Thanawastien A; Matrivax Research & Development Corporation, Boston, MA, United States., Joyce KE; Matrivax Research & Development Corporation, Boston, MA, United States., Cartee RT; Matrivax Research & Development Corporation, Boston, MA, United States., Haines LA; Matrivax Research & Development Corporation, Boston, MA, United States., Pelton SI; Boston University Schools of Medicine and Public Health, Boston Medical Center, Boston, MA, United States., Tweten RK; Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, United States., Killeen KP; Matrivax Research & Development Corporation, Boston, MA, United States. Electronic address: kpkilleen@matrivax.com.
Jazyk: angličtina
Zdroj: Vaccine [Vaccine] 2021 Mar 12; Vol. 39 (11), pp. 1652-1660. Date of Electronic Publication: 2020 Jun 10.
DOI: 10.1016/j.vaccine.2020.04.064
Abstrakt: Pneumolysin is a highly conserved, cholesterol-dependent cytolysin that is an important Streptococcus pneumoniae virulence factor and an attractive target for vaccine development. To attenuate pneumolysin toxicity, a genetic toxoid was constructed with two amino acid changes, G293S and L460D, termed PLY-D, that reduced cytolytic activity > 125,000-fold. In mice, PLY-D elicited high anti-PLY IgG antibody titers that neutralized the cytolytic activity of the wild-type toxin in vitro. To evaluate the protective efficacy of PLY-D, mice were immunized intramuscularly and then challenged intranasally with a lethal dose of 28 clinical isolates of S. pneumoniae originating from different geographical locations, disease states (i.e. bacteremia, pneumonia), or body sites (i.e. sputum, blood). PLY-D immunization conferred significant protection from challenge with 17 of 20 serotypes (85%) and 22 of 28 strains (79%). Further, we demonstrated that immunization with PLY-D provided statistically significant improvement in survival against challenge with serotype 4 and 18C strains compared to mice immunized with a pneumococcal conjugate vaccine Prevnar 13® (PCV13). Co-administration of PLY-D and PCV13 conferred greater protection against challenge with a serotype 6B strain than immunization with either vaccine alone. These data indicate that PLY-D is a broadly protective antigen with the potential to serve as a serotype-independent vaccine against invasive pneumococcal disease either alone or in combination with PCVs.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Matrivax Corporation. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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