Insufficient Anthrax Lethal Toxin Neutralization Is Associated with Antibody Subclass and Domain Specificity in the Plasma of Anthrax-Vaccinated Individuals.

Kenneth Smith,Renata J M Engler,Lori Garman,Kathleen Norris,Christina Spooner,Carla Guthridge,Limone C Collins,Michael R Nelson,Jennifer Muther,Angie Duke,Judith A James

doi:10.3390/microorganisms9061204

Abstract

Anthrax vaccine adsorbed (AVA) is a significant line of defense against bioterrorist attack from Bacillus anthracis spores. However, in a subset of individuals, this vaccine may produce a suboptimal quantity of anti-protective antigen (PA), antibodies that are poorly neutralizing, and/or antibody titers that wane over time, necessitating annual boosters. To study individuals with such poor responses, we examine the properties of anti-PA in a subset of vaccinated individuals that make significant quantities of antibody but are still unable to neutralize toxin. In this cohort, characterized by poorly neutralizing antibody, we find that increased IgG4 to IgG1 subclass ratios, low antibody avidity, and insufficient antibody targeting domain 4 associate with improper neutralization. Thus, future vaccines and vaccination schedules should be formulated to improve these deficiencies.

Highlights

Bacillus anthracis is a Gram-positive, spore-forming bacterium responsible for anthrax infection that poses a great threat as an agent of bioterror [1]
This value is from rhesus macaques and was determined at 1 month after third vaccine dose (7 months total) and cannot be related to protection in humans, we used this number as a comparator to our cohort
We have described three potential factors that could lead to poor lethal toxin (LT) neutralization We have described three potential factors that could lead to poor LT neutralization after after Anthrax vaccine adsorbed (AVA) vaccination: a high IgG4/IgG1 ratio, low antibody avidity, and a low concenAVA vaccination: a high IgG4/IgG1 ratio, low antibody avidity, and a low concentration tration of anti-domain 4

Summary

Introduction

Bacillus anthracis is a Gram-positive, spore-forming bacterium responsible for anthrax infection that poses a great threat as an agent of bioterror [1]. Following inhalation and germination of spores, the bacilli produce lethal toxin (LT), composed of protective antigen (PA) and lethal factor (LF), as well as edema toxin (ET), composed of PA and edema factor (EF) [2]. PA binds to cell surface receptors via domain 4 and is cleaved by furin-like proteases at a site within domain 1, yielding PA63 and the amino-terminal fragment domain 1A (PA20). PA63 oligomerizes via domain 3 to form a pore in the surface of target host cells. After binding of LF or EF through domain 10 (remaining on PA63) and endocytosis of the toxin/pore complex, the enzymatic toxins EF and LF are released into the cytosol

Methods

Results

Conclusion