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 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 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 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 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 Neutralizing antibody responses to SARS-CoV-2 in symptomatic COVID-19 is persistent and critical for survival

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Stefania Dispinseri ◽  
Massimiliano Secchi ◽  
Maria Franca Pirillo ◽  
Monica Tolazzi ◽  
Martina Borghi ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Fatal Outcome ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Critical Conditions ◽  
Specific Response ◽  
Increased Risk ◽  
Neutralizing Capacity ◽  
Antibody Titers ◽  
Flu Virus

AbstractUnderstanding how antibody responses to SARS-CoV-2 evolve during infection may provide important insight into therapeutic approaches and vaccination for COVID-19. Here we profile the antibody responses of 162 COVID-19 symptomatic patients in the COVID-BioB cohort followed longitudinally for up to eight months from symptom onset to find SARS-CoV-2 neutralization, as well as antibodies either recognizing SARS-CoV-2 spike antigens and nucleoprotein, or specific for S2 antigen of seasonal beta-coronaviruses and hemagglutinin of the H1N1 flu virus. The presence of neutralizing antibodies within the first weeks from symptoms onset correlates with time to a negative swab result (p = 0.002), while the lack of neutralizing capacity correlates with an increased risk of a fatal outcome (p = 0.008). Neutralizing antibody titers progressively drop after 5–8 weeks but are still detectable up to 8 months in the majority of recovered patients regardless of age or co-morbidities, with IgG to spike antigens providing the best correlate of neutralization. Antibody responses to seasonal coronaviruses are temporarily boosted, and parallel those to SARS-CoV-2 without dampening the specific response or worsening disease progression. Our results thus suggest compromised immune responses to the SARS-CoV-2 spike to be a major trait of COVID-19 patients with critical conditions, and thereby inform on the planning of COVID-19 patient care and therapy prioritization.

ANTIBODY RESPONSES TO NATURALLY OCCURRING POLIOMYELITIS INFECTIONS

PEDIATRICS ◽  
1956 ◽  
Vol 17 (4) ◽  
pp. 489-502
Author(s):  
C. Arden Miller ◽  
Margaret F. Lenahan
Keyword(s):  
Diagnostic Tool ◽  
Test Procedure ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Paralytic Poliomyelitis ◽  
Repeat Testing ◽  
Household Contacts ◽  
Naturally Occurring ◽  
Antibody Titers ◽  
Fecal Virus

The neutralizing antibody responses of 52 asymptomatic household contacts of patients with poliomyelitis were studied by the metabolic inhibition method. Half of these contacts were fecal carriers of poliomyelitis virus. For purposes of comparison the antibody responses of 25 patients with paralytic poliomyelitis, all fecal virus carriers, were studied. The errors of replication of the test procedure were determined by duplicate testing of 51 serums. Duplicate testing of serum specimens indicated disagreement regarding the presence or absence of antibody in 6.0 to 8.0 per cent of the serums. The second test gave antibody titers which disagreed with those from the first test by a factor of fourfold or more 37.0 per cent of the time; errors occurred equally in either direction. Half of all persons studied showed an increase of fourfold or more in the antibody titers of paired serums; this was 3 to 4 times as many as would be expected by chance. It was not possible to distinguish the antibody responses of paralyzed patients from asymptomatic household contacts; or the fecal virus carriers from the nonvirus carriers in the latter group. Four virus carriers who did not have homologous antibody in convalescent serums were found. By repeat testing homologous antibody was found in all but one of these. The limitations of the test procedure as a diagnostic tool are discussed.

scholarly journals Probing neutralizing-antibody responses against emerging measles viruses (MVs): immune selection of MV by H protein-specific antibodies?

2005 ◽  
Vol 86 (2) ◽  
pp. 365-374 ◽  
Author(s):  
Sabine Santibanez ◽  
Stefan Niewiesk ◽  
Alla Heider ◽  
Jürgen Schneider-Schaulies ◽  
Guy A. M. Berbers ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Measles Virus ◽  
Protein A ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Neutralizing Capacity ◽  
Human Sera ◽  
H Protein ◽  
Neutralizing Epitopes ◽  
Selection Of

Measles virus (MV) infection and vaccination induce long-lasting immunity and neutralizing-antibody responses that are directed against the MV haemagglutinin (H) and the fusion (F) protein. A new MV genotype, D7, emerged recently in western Germany and rapidly replaced the long-term endemically circulating genotypes C2 and D6. Analysis of the H gene of C2, D6, D7 and vaccine viruses revealed uniform sequences for each genotype. Interestingly, a consistent exchange of seven distinct amino acids in the D7 H was observed when compared with residues shared between C2, D6 and vaccine viruses, and one exchange (D416→N) in the D7 H was associated with an additional N-linked glycosylation. In contrast, the F gene is highly conserved between MVs of these genotypes. To test whether the D7 H protein escapes from antibody responses that were raised against earlier circulating or vaccine viruses, the neutralizing capacity of mAbs recognizing seven distinct domains on the H of an Edmonston-related MV was compared. The mAbs revealed a selective and complete loss of two neutralizing epitopes on the D7 H when compared with C2, D6 and vaccine viruses. To assess whether these alterations of the D7 H affect the neutralizing capacity of polyclonal B-cell responses, genotype-specific antisera were produced in cotton rats. However, no significant genotype-dependent difference was found. Likewise, human sera obtained from vaccinees (n=7) and convalescents (n=6) did not distinguish between the MV genotypes. Although the hypothesis of selection of D7 viruses by pre-existing neutralizing antibodies is compatible with the differing pattern of neutralizing epitopes on the H protein, it was not confirmed by the results of MV neutralization with polyclonal sera.

scholarly journals Immunological features that determine the strength of antibody responses to BNT162b2 mRNA vaccine against SARS-CoV-2

2021 ◽  
Author(s):  
Takahiro Kageyama ◽  
Shigeru Tanaka ◽  
Keishi Etori ◽  
Koto Hattori ◽  
Kazusa Miyachi ◽  
...  
Keyword(s):  
T Cells ◽  
Antibody Titer ◽  
Cd8 T Cells ◽  
Healthcare Workers ◽  
Mononuclear Cells ◽  
Antibody Responses ◽  
Peripheral Blood Mononuclear ◽  
Transitional B Cells ◽  
Blood Mononuclear Cells ◽  
Antibody Titers

We analyzed peripheral blood mononuclear cells (PBMCs) of each 20 individuals with a high anti-SARS-CoV-2 antibody titer and a low antibody titer out of 1,774 healthcare workers who received BNT162b2 mRNA vaccine. A higher antibody titer was associated with the frequencies of naive and transitional B cells before vaccination. In addition, fold changes in the frequency of activated CD8+ T cells upon vaccination were correlated with the antibody titers.

scholarly journals Modified Vaccinia Ankara Based SARS-CoV-2 Vaccine Expressing Full-Length Spike Induces Strong Neutralizing Antibody Response

2020 ◽  
Author(s):  
Nanda Kishore Routhu ◽  
Sailaja Gangadhara ◽  
Narayanaiah Cheedarla ◽  
Ayalnesh Shiferaw ◽  
Sheikh Abdul Rahman ◽  
...  
Keyword(s):  
Antibody Response ◽  
Room Temperature ◽  
Vaccine Candidate ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Full Length ◽  
Spike Protein ◽  
Strongly Correlated ◽  
Igg Antibodies ◽  
Potential Vaccine

AbstractThere is a great need for the development of vaccines for preventing SARS-CoV-2 infection and mitigating the COVID-19 pandemic. Here, we developed two modified vaccinia Ankara (MVA) based vaccines which express either a membrane anchored full-length spike protein (MVA/S) stabilized in a prefusion state or the S1 region of the spike (MVA/S1) which forms trimers and is secreted. Both immunogens contained the receptor-binding domain (RBD) which is a known target of antibody-mediated neutralization. Following immunizations with MVA/S or MVA/S1, both spike protein recombinants induced strong IgG antibodies to purified full-length SARS-CoV-2 spike protein. The MVA/S induced a robust antibody response to purified RBD, S1 and S2 whereas MVA/S1 induced an antibody response to the S1 region outside of the RBD region. Both vaccines induced an antibody response in the lung and that was associated with induction of bronchus-associated lymphoid tissue. MVA/S but not MVA/S1 vaccinated mice generated robust neutralizing antibody responses against SARS-CoV-2 that strongly correlated with RBD antibody binding titers. Mechanistically, S1 binding to ACE-2 was strong but reduced following prolonged pre-incubation at room temperature suggesting confirmation changes in RBD with time. These results demonstrate MVA/S is a potential vaccine candidate against SARS-CoV-2 infection.

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