Antigen-specific antibody and polyfunctional T cells generated by respiratory immunization with protective Burkholderia\u0394tonB\u0394hcp1 live attenuated vaccines

Nittaya Khakhum,Alfredo G Torres,Janice J Endsley,Preeti Bharaj,David H Walker

doi:10.1038/s41541-021-00333-4

Nittaya Khakhum, Alfredo G Torres + Show 3 more

Open Access

https://doi.org/10.1038/s41541-021-00333-4

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Abstract

Melioidosis, caused by Burkholderia pseudomallei (Bpm), lacks a vaccine. We identify the immune correlates of protection induced by B. mallei ΔtonB Δhcp1 (CLH001) and Bpm ΔtonB Δhcp1 (PBK001) vaccines against inhalational melioidosis. Mucosal immunization with either vaccine generates Bpm-specific IgM and IgG (IgG2b/c > IgG1 > IgG3) antibodies in sera and lungs, and lung IgA antibodies. Sera confers complement-independent bactericidal activity and macrophages opsonophagocytic uptake but is insufficient in passive transfer experiments to provide significant protection. Both vaccines elicit memory Th1 and Th17 CD4+ T-cell responses in lung and spleen after Bpm antigen-specific recall. The PBK001 vaccine is superior in generating respiratory IgA post-boost, anamnestic IgG at challenge, T-cell recall to specific antigen, and development of diverse polyfunctional memory T-cell pools. Analysis of lung histology suggests that potent polyfunctional T-cell memory and/or IL-17 signatures generated with PBK001 vaccination may be associated with moderate lung inflammation post vaccination.

Highlights

The pathogenic Gram-negative bacterium, Burkholderia pseudomallei (Bpm) is the etiologic agent of the disease melioidosis, occurring in both humans and animals[1]
The quantitative results of OD (450 nm) values of antibodies binding to Bpm whole cell lysate were compared starting at a serum dilution of 1:1600 and lung homogenate dilution of 1:160
Multiple vaccine platforms against melioidosis are currently being developed because it is evident that the status of this disease remains an important public health concern, in addition to its potential as a biothreat agent[5]

Summary

Introduction

The pathogenic Gram-negative bacterium, Burkholderia pseudomallei (Bpm) is the etiologic agent of the disease melioidosis, occurring in both humans and animals[1]. The organism is a saprophyte that resides in the soil, water, and plants, primarily in tropical and subtropical regions of northern Australia and parts of Southeast Asia and the Indian peninsula[2,3,4]. Recent environmental suitability analysis indicated that the highest risk zones to encounter Bpm are Southeast and South Asia, tropical. Current modeling studies estimate that 165,000 cases of melioidosis resulting in 89,000 deaths occur worldwide annually[5]. Clinical melioidosis cases can occur due to acute infections (85%) that frequently include sepsis; as well as chronic (11%) and reactivation of latent infections (4%)[6]. The risk factors for melioidosis include sex (male), diabetes mellitus, alcohol consumption, immune compromise, and presence of chronic disease (renal and pulmonary)[4]. Due to the current burden of disease and its biothreat potential, the development of effective vaccines for melioidosis is urgent[8]

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