A lipid A-based TLR4 mimetic effectively adjuvants a Yersinia pestis rF-V1 subunit vaccine in a murine challenge model

被引：28

作者：

Gregg, Kelsey A. ^{[1
]}

Harberts, Erin ^{[1
]}

Gardner, Francesca M. ^{[1
]}

Pelletier, Mark R. ^{[1
,4
]}

Cayatte, Corinne ^{[2
]}

Yu, Li ^{[3
]}

McCarthy, Michael P. ^{[2
]}

Marshall, Jason D. ^{[2
,5
]}

Ernst, Robert K. ^{[1
]}

机构：

[1] Univ Maryland, Sch Dent, Dept Microbial Pathogenesis, Baltimore, MD 21201 USA

[2] Medlmmune, Vaccine Platform Grp, Gaithersburg, MD USA

[3] Medlmmune, Stat Sci, Gaithersburg, MD USA

[4] Medlmmune, Gaithersburg, MD USA

[5] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Frederick, MD USA

来源：

VACCINE | 2018年 / 36卷 / 28期

关键词：

Adjuvant; Lipopolysaccharide; Lipid A; Toll-like receptor 4; Yersinia pestis; ALLERGEN-SPECIFIC IMMUNOTHERAPY; ANTIBODIES; IMMUNITY; RECEPTOR; LIPOPOLYSACCHARIDE; IDENTIFICATION; ALUMINUM; AGONIST; ANTIGEN; SYSTEM;

D O I：

10.1016/j.vaccine.2018.05.101

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Vaccination can significantly reduce worldwide morbidity and mortality to infectious diseases, thereby reducing the health burden as a result of microbial infections. Effective vaccines contain three components: a delivery system, an antigenic component of the pathogen, and an adjuvant. With the growing use of purely recombinant or synthetic antigens, there is a need to develop novel adjuvants that enhance the protective efficacy of a vaccine against infection. Using a structure-activity relationship (SAR) model, we describe here the synthesis of a novel TLR4 ligand adjuvant compound, BECC438, by bacterial enzymatic combinatorial chemistry (BECC). This compound was identified using an in vitro screening pipeline consisting of (i) NF kappa B activation and cytokine production by immortalized cell lines, (ii) cytokine production by primary human PBMCs, and (iii) upregulation of surface costimulatory markers by primary human monocyte-derived dendritic cells. Using this SAR screening regimen, BECC438 was shown to produce an innate immune activation profile comparable to the well-characterized TLR4 agonist adjuvant compound, phosphorylated hexa-acyl disaccharide (PHAD). To evaluate the in vivo adjuvant activity of BECC438, we used the known protective Yersinia pestis (Yp) antigen, rF1-V, in a murine prime-boost vaccination schedule followed by lethal challenge. In addition to providing protection from lethal challenge, BECC438 stimulated production of higher levels of rF1 -V-specific total IgG as compared to PHAD after both prime and boost vaccinations. Similar to PHAD, BECC438 elicited a balanced IgG1/IgG2c response, indicative of active T(H)2/T(H)1-driven immunity. These data demonstrate that the novel BECC-derived TLR4L adjuvant, BECC438, elicits cytokine profiles in vitro similar to PHAD, induces high antigen-specific immune titers and a T(H)1-associated IgG2c immune titer skew, and protects mice against a lethal Yp challenge. (C) 2018 Published by Elsevier Ltd.

引用

页码：4023 / 4031

页数：9