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

2021 ◽  
Vol 9 (6) ◽  
pp. 1204
Author(s):  
Kenneth Smith ◽  
Lori Garman ◽  
Kathleen Norris ◽  
Jennifer Muther ◽  
Angie Duke ◽  
...  
Keyword(s):  
Protective Antigen ◽  
Neutralizing Antibody ◽  
Domain Specificity ◽  
Anthrax Lethal Toxin ◽  
Bacillus Anthracis Spores ◽  
Antibody Titers ◽  
Significant Line ◽  
Igg1 Subclass ◽  
Antibody Subclass ◽  
Over Time

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.

scholarly journals Immunological Correlates for Protection against Intranasal Challenge of Bacillus anthracis Spores Conferred by a Protective Antigen-Based Vaccine in Rabbits

2006 ◽  
Vol 74 (1) ◽  
pp. 394-398 ◽  
Author(s):  
Shay Weiss ◽  
David Kobiler ◽  
Haim Levy ◽  
Hadar Marcus ◽  
Avi Pass ◽  
...  
Keyword(s):  
Bacillus Anthracis ◽  
Protective Antigen ◽  
Passive Immunization ◽  
Neutralizing Antibody ◽  
Protective Efficiency ◽  
Immunological Parameters ◽  
Partial Protection ◽  
Bacillus Anthracis Spores ◽  
Antibody Titers ◽  
Antibody Levels

ABSTRACT Correlates between immunological parameters and protection against Bacillus anthracis infection in animals vaccinated with protective antigen (PA)-based vaccines could provide surrogate markers to evaluate the putative protective efficiency of immunization in humans. In previous studies we demonstrated that neutralizing antibody levels serve as correlates for protection in guinea pigs (S. Reuveny et al., Infect. Immun. 69:2888-2893, 2001; H. Marcus et al., Infect. Immun. 72:3471-3477, 2004). In this study we evaluated similar correlates for protection by active and passive immunization of New Zealand White rabbits. Full immunization and partial immunization were achieved by single and multiple injections of standard and diluted doses of a PA-based vaccine. Passive immunization was carried out by injection of immune sera from rabbits vaccinated with PA-based vaccine prior to challenge with B. anthracis spores. Immunized rabbits were challenged by intranasal spore instillation with one of two virulent strains (strains Vollum and ATCC 6605). The immune competence was estimated by measuring the level of total anti-PA antibodies, the neutralizing antibody titers, and the conferred protective immunity. The results indicate that total anti-PA antibody titers greater than 1 × 105 conferred protection, whereas lower titers (between 104 and 105) provided partial protection but failed to predict protection. Neutralizing antibody titers between 500 and 800 provided partial protection, while titers higher than 1,000 conferred protection. In conclusion, this study emphasizes that regardless of the immunization regimen or the time of challenge, neutralizing antibody titers are better predictors of protection than total anti-PA titers.

scholarly journals Correlation between Lethal Toxin-Neutralizing Antibody Titers and Protection from Intranasal Challenge with Bacillus anthracis Ames Strain Spores in Mice after Transcutaneous Immunization with Recombinant Anthrax Protective Antigen

2006 ◽  
Vol 74 (1) ◽  
pp. 794-797 ◽  
Author(s):  
Kristina K. Peachman ◽  
Mangala Rao ◽  
Carl R. Alving ◽  
Robert Burge ◽  
Stephen H. Leppla ◽  
...  
Keyword(s):  
Bacillus Anthracis ◽  
Protective Antigen ◽  
Neutralizing Antibody ◽  
Lethal Toxin ◽  
Vaccine Strategy ◽  
Transcutaneous Immunization ◽  
Antibody Titers ◽  
Anthrax Protective Antigen ◽  
Ames Strain ◽  
Recombinant Protective Antigen

ABSTRACT Transcutaneous immunization of mice with recombinant protective antigen (rPA) of Bacillus anthracis resulted in significantly higher lethal toxin-neutralizing antibody titers than did intramuscular injection of alum-adsorbed rPA. Immunized mice were partially protected against intranasal challenge with 235,000 (10 50% lethal doses) Ames strain B. anthracis spores. A highly significant correlation was observed between toxin-neutralizing antibody titer and survival after challenge. Future experiments with rabbits and nonhuman primates should confirm the significance of protection by this vaccine strategy.

scholarly journals Needle-Free Skin Patch Vaccination Method for Anthrax

2004 ◽  
Vol 72 (2) ◽  
pp. 1181-1183 ◽  
Author(s):  
Gary R. Matyas ◽  
Arthur M. Friedlander ◽  
Gregory M. Glenn ◽  
Stephen Little ◽  
Jianmei Yu ◽  
...  
Keyword(s):  
Protective Antigen ◽  
Neutralizing Antibody ◽  
Adjuvant Activity ◽  
Skin Patch ◽  
Transcutaneous Immunization ◽  
Antibody Titers ◽  
Recombinant Protective Antigen

ABSTRACT Three immunizations of mice with recombinant protective antigen (rPA) by transcutaneous immunization (TCI) induced long-term neutralizing antibody titers that were superior to those obtained with aluminum-adsorbed rPA. In addition, rPA alone exhibited adjuvant activity for TCI. Forty-six weeks after completion of TCI, 100% protection was observed against lethal anthrax challenge.

scholarly journals Microneedle-Based Intradermal Delivery of the Anthrax Recombinant Protective Antigen Vaccine

2006 ◽  
Vol 74 (12) ◽  
pp. 6806-6810 ◽  
Author(s):  
John A. Mikszta ◽  
John P. Dekker ◽  
Noel G. Harvey ◽  
Cheryl H. Dean ◽  
John M. Brittingham ◽  
...  
Keyword(s):  
Immune Response ◽  
Immunoglobulin G ◽  
Protective Antigen ◽  
Neutralizing Antibody ◽  
Antigen Vaccine ◽  
Intradermal Delivery ◽  
Antibody Titers ◽  
Sparing Effect ◽  
Booster Inoculation ◽  
Recombinant Protective Antigen

ABSTRACT The recombinant protective antigen (rPA) of Bacillus anthracis is a promising anthrax vaccine. We compared serum immunoglobulin G levels and toxin-neutralizing antibody titers in rabbits following delivery of various doses of vaccine by microneedle-based intradermal (i.d.) delivery or intramuscular (i.m.) injection using conventional needles. Intradermal delivery required less antigen to induce levels of antibody similar to those produced via i.m. injection during the first 2 weeks following primary and booster inoculation. This dose-sparing effect was less evident at the later stages of the immune response. Rabbits immunized i.d. with 10 μg of rPA displayed 100% protection from aerosol spore challenge, while i.m. injection of the same dose provided slightly lower protection (71%). Groups immunized with lower antigen doses were partially protected (13 to 29%) regardless of the mode of administration. Overall, our results suggest rPA formulated with aluminum adjuvant and administered to the skin by a microneedle-based device is as efficacious as i.m. vaccination.

scholarly journals Contribution of Immunological Memory to Protective Immunity Conferred by a Bacillus anthracis Protective Antigen-Based Vaccine

2004 ◽  
Vol 72 (6) ◽  
pp. 3471-3477 ◽  
Author(s):  
Hadar Marcus ◽  
Rachel Danieli ◽  
Eyal Epstein ◽  
Baruch Velan ◽  
Avigdor Shafferman ◽  
...  
Keyword(s):  
Bacillus Anthracis ◽  
Protective Antigen ◽  
Lethal Dose ◽  
Neutralizing Antibody ◽  
Immunological Memory ◽  
Antimicrobial Treatment ◽  
Secondary Response ◽  
Primary Immunization ◽  
Protective Capacity ◽  
Antibody Titers

ABSTRACT Protective antigen (PA)-based vaccination is an effective countermeasure to anthrax infection. While neutralizing anti-PA antibody titers elicited by this vaccine serve as good correlates for protection against anthrax (S. Reuveny, M. D. White, Y. Y. Adar, Y. Kafri, Z. Altboum, Y. Gozes, D. Kobiler, A. Shafferman, and B. Velan, Infect. Immun. 69:2888-2893, 2001), no data are available on the contribution of the immunological memory for PA itself to protection. We therefore developed a guinea pig model in which a primary immunization with threshold levels of PA can induce a long-term T-cell immunological memory response without inducing detectable anti-PA antibodies. A revaccination of primed animals with the same threshold PA levels was effective for memory activation, yielding a robust and rapid secondary response. A challenge with a lethal dose (40 50% lethal doses; 2,000 spores) of spores after the booster vaccinations indicated that animals were not protected at days 2, 4, and 6 postboosting. Protection was achieved only from the 8th day postboosting, concomitant with the detection of protective levels of neutralizing antibody titers in the circulation. The practical implications from the studies reported herein are that, as expected, the protective capacity of memory depends on the PA dose used for the primary immunization and that the effectiveness of booster immunizations for the postexposure treatment of anthrax may be very limited when no detectable antibodies are present in primed animals prior to Bacillus anthracis spore exposure. Therefore, to allow for the establishment of memory-dependent protection prior to the expected onset of disease, booster immunizations should not be used without concomitant antimicrobial treatment in postexposure scenarios.

scholarly journals Immunogenicity of Bacillus anthracis Protective Antigen Domains and Efficacy of Elicited Antibody Responses Depend on Host Genetic Background

2008 ◽  
Vol 15 (7) ◽  
pp. 1115-1123 ◽  
Author(s):  
Nareen Abboud ◽  
Arturo Casadevall
Keyword(s):  
Bacillus Anthracis ◽  
Antibody Titer ◽  
Genetic Background ◽  
Protective Antigen ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Full Length ◽  
Mouse Strains ◽  
Neutralizing Capacity ◽  
Antibody Titers

ABSTRACT Neutralizing antibodies to Bacillus anthracis protective antigen (PA), a component of anthrax toxin, mediate protection against anthrax. PA is antigenically complex and can elicit protective and nonprotective antibodies. Furthermore, vaccinated individuals demonstrate considerable variability in their antibody responses to PA. To explore the relationship between PA structure and antigenicity, we produced Escherichia coli strains expressing full-length PA (PA1-4), domains 2 to 4 (PA2-4), domain 1, (PA1), and domain 4 (PA4) and evaluated the immunogenicities and protective efficacies of the protein fractions in four mouse strains (strains A/J, BALB/c, C57BL/6, and Swiss Webster). Immunization with PA1-4 resulted in significantly higher lethal toxin-neutralizing antibody titers than immunization with any recombinant protein (rPA) fraction of PA. The magnitude and neutralizing capacity of the antibody response to full-length PA and its fragments varied depending on the mouse strain. We found no correlation between the antibody titer and the neutralizing antibody titer for A/J and Swiss Webster mice. In C57BL/6 mice, antibody titers and neutralization capacity correlated for two of four rPA domain proteins tested, while BALB/c mice displayed a similar correlation with only one rPA. By correlating the reactivity of immune sera with solvent-exposed linear peptide segments of PA, we tentatively assign the presence of four new linear B-cell epitopes in PA amino acids 121 to 150, 143 to 158, 339 to 359, and 421 to 440. We conclude that the genetic background of the host determines the relative efficacy of the antitoxin response. The results suggest that the variability observed in vaccination studies with PA-derived vaccines is a result of host heterogeneity and implies a need to develop other antigens as vaccine candidates.

scholarly journals Search for Correlates of Protective Immunity Conferred by Anthrax Vaccine

2001 ◽  
Vol 69 (5) ◽  
pp. 2888-2893 ◽  
Author(s):  
Shaul Reuveny ◽  
Moshe D. White ◽  
Yaakov Y. Adar ◽  
Yaron Kafri ◽  
Zeev Altboum ◽  
...  
Keyword(s):  
Antibody Titer ◽  
Neutralizing Antibodies ◽  
Protective Immunity ◽  
Protective Antigen ◽  
Surrogate Marker ◽  
Neutralizing Antibody ◽  
Enzyme Linked Immunosorbent Assay ◽  
Lethal Challenge ◽  
Anthrax Spores ◽  
Antibody Titers

ABSTRACT Vaccination by anthrax protective antigen (PA)-based vaccines requires multiple immunization, underlying the need to develop more efficacious vaccines or alternative vaccination regimens. In spite of the vast use of PA-based vaccines, the definition of a marker for protective immunity is still lacking. Here we describe studies designed to help define such markers. To this end we have immunized guinea pigs by different methods and monitored the immune response and the corresponding extent of protection against a lethal challenge with anthrax spores. Active immunization was performed by a single injection using one of two methods: (i) vaccination with decreasing amounts of PA and (ii) vaccination with constant amounts of PA that had been thermally inactivated for increasing periods. In both studies a direct correlation between survival and neutralizing-antibody titer was found (r 2 = 0.92 and 0.95, respectively). Most significantly, in the two protocols a similar neutralizing-antibody titer range provided 50% protection. Furthermore, in a complementary study involving passive transfer of PA hyperimmune sera to naive animals, a similar correlation between neutralizing-antibody titers and protection was found. In all three immunization studies, neutralization titers of at least 300 were sufficient to confer protection against a dose of 40 50% lethal doses (LD50) of virulent anthrax spores of the Vollum strain. Such consistency in the correlation of protective immunity with anti-PA antibody titers was not observed for antibody titers determined by an enzyme-linked immunosorbent assay. Taken together, these results clearly demonstrate that neutralizing antibodies to PA constitute a major component of the protective immunity against anthrax and suggest that this parameter could be used as a surrogate marker for protection.

scholarly journals Virus Load and Sequence Variation in Simian Retrovirus Type 2 Infection

2000 ◽  
Vol 74 (8) ◽  
pp. 3449-3454 ◽  
Author(s):  
Lisa L. Rosenblum ◽  
Robin A. Weiss ◽  
Myra O. McClure
Keyword(s):  
Sequence Variation ◽  
Rna Virus ◽  
Neutralizing Antibody ◽  
Type D ◽  
Cynomolgus Macaques ◽  
History Of ◽  
Antibody Titers ◽  
Small Cohort ◽  
Over Time

ABSTRACT The natural history of type D simian retrovirus (SRV) infection is poorly characterized in terms of viral load, antibody status, and sequence variation. To investigate this, blood samples were taken from a small cohort of mostly asymptomatic cynomolgus macaques (Macaca fascicularis), naturally infected with SRV type 2 (SRV-2), some of which were followed over an 8-month period with blood taken every 2 months. Provirus and RNA virus loads were obtained, the samples were screened for presence of antibodies to SRV-2 and neutralizing antibody titers to SRV-2 were assayed. env sequences were aligned to determine intra- and intermonkey variation over time. Virus loads varied greatly among cohort individuals but, conversely, remained steady for each macaque over the 8-month period, regardless of their initial levels. No significant sequence variation was found within an individual over time. No clear picture emerged from these results, which indicate that the variables of SRV-2 infection are complex, differ from those for lentivirus infection, and are not distinctly related to disease outcome.

scholarly journals Donors for SARS-CoV-2 Convalescent Plasma for a Controlled Clinical Trial: Donor Characteristics, Content and Time Course of SARS-CoV-2 Neutralizing Antibodies

2021 ◽  
pp. 1-10
Author(s):  
Sixten Körper ◽  
Bernd Jahrsdörfer ◽  
Victor M. Corman ◽  
Jan Pilch ◽  
Patrick Wuchter ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Randomized Clinical Trial ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Controlled Clinical Trial ◽  
Neutralizing Capacity ◽  
Iga Antibodies ◽  
Antibody Titers ◽  
Antibody Levels ◽  
Over Time

<b><i>Background:</i></b> Convalescent plasma is one of the treatment options for COVID-19 which is currently being investigated in many clinical trials. Understanding of donor and product characteristics is important for optimization of convalescent plasma. <b><i>Methods:</i></b> Patients who had recovered from CO­VID-19 were recruited as donors for COVID-19 convalescent plasma (CCP) for a randomized clinical trial of CCP for treatment of severe COVID-19 (CAPSID Trial). Titers of neutralizing antibodies were measured by a plaque-reduction neutralization test (PRNT). Correlation of antibody titers with host factors and evolution of neutralizing antibody titers over time in repeat donors were analysed. <b><i>Results:</i></b> A series of 144 donors (41% females, 59% males; median age 40 years) underwent 319 plasmapheresis procedures providing a median collection volume of 850 mL and a mean number of 2.7 therapeutic units per plasmapheresis. The majority of donors had a mild or moderate course of COVID-19. The titers of neutralizing antibodies varied greatly between CCP donors (from &#x3c;1:20 to &#x3e;1:640). Donor factors (gender, age, ABO type, body weight) did not correlate significantly with the titer of neutralizing antibodies. We observed a significant positive correlation of neutralization titers with the number of reported COVID-19 symptoms and with the time from SARS-CoV-2 diagnosis to plasmapheresis. Neutralizing antibody levels were stable or increased over time in 58% of repeat CCP donors. Mean titers of neutralizing antibodies of first donation and last donation of repeat CCP donors did not differ significantly (1:86 at first compared to 1:87 at the last donation). There was a significant correlation of neutralizing antibodies measured by PRNT and anti-SARS-CoV-2 IgG and IgA antibodies which were measured by ELISA. CCP donations with an anti-SARS-CoV-2 IgG antibody content above the 25th percentile were substantially enriched for CCP donations with higher neutralizing antibody levels. <b><i>Conclusion:</i></b> We demonstrate the feasibility of collection of a large number of CCP products under a harmonized protocol for a randomized clinical trial. Titers of neutralizing antibodies were stable or increased over time in a subgroup of repeat donors. A history of higher number of COVID-19 symptoms and higher levels of anti-SARS-CoV-2 IgG and IgA antibodies in immunoassays can preselect donations with higher neutralizing capacity.

scholarly journals Detoxified Lethal Toxin as a Potential Mucosal Vaccine against Anthrax

2008 ◽  
Vol 15 (4) ◽  
pp. 612-616 ◽  
Author(s):  
Qingfu Xu ◽  
Mingtao Zeng
Keyword(s):  
Protective Antigen ◽  
Lethal Factor ◽  
Lethal Dose ◽  
Neutralizing Antibody ◽  
Lethal Toxin ◽  
Antibody Responses ◽  
Mucosal Vaccine ◽  
Enhancement Effect ◽  
Anthrax Lethal Toxin ◽  
Mucosal Antibody

ABSTRACT The nontoxic mutant lethal factor (mLF; which has the E687C substitution) and functional protective antigen (PA63) of Bacillus anthracis were evaluated for their use as mucosal vaccines against anthrax in A/J mice. Intranasal vaccination of three doses of 30 μg of mLF or 60 μg of PA63 elicited significant serum and mucosal antibody responses, with anthrax lethal toxin-neutralizing titers of 40 and 60 in immune sera, respectively. However, only 30% and 60% of the vaccinated animals in the two groups could survive a challenge with 100 times the 50% lethal dose of B. anthracis Sterne spores, respectively. In contrast, vaccination with three doses of the combination of 30 μg of mLF and 60 μg of PA63, the detoxified lethal toxin, elicited antibody responses against LF and PA significantly higher than those elicited after vaccination with mLF or PA63 individually by use of the same dose and schedule. Vaccination with the detoxified lethal toxin resulted in significantly higher lethal toxin-neutralizing antibody titers in sera (titer, 90). Animals vaccinated with three doses of the detoxified lethal toxin were completely protected against the spore challenge. The data suggest that mLF and PA63 have a mutual enhancement effect for evoking systemic and mucosal immune responses and that the detoxified lethal toxin can be used as an efficient mucosal vaccine against anthrax.

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