scholarly journals Pre-existing antibodies targeting a dominant linear antibody epitope on SARS-CoV-2 S2 cross-reacted with commensal gut bacteria and shaped immune responses elicited by a candidate vaccine

2021 ◽  
Author(s):  
Liqiu Jia ◽  
Shufeng Weng ◽  
Jing Wu ◽  
Xiangxiang Tian ◽  
Yifan Zhang ◽  
...  
Keyword(s):  
Dna Vaccine ◽  
Specific Binding ◽  
Gut Bacteria ◽  
Antibody Responses ◽  
Spike Protein ◽  
Linear Epitope ◽  
Healthy Human ◽  
Antibody Epitope ◽  
Binding Antibody ◽  
Low Levels

Pre-existing SARS-CoV-2 cross-reactive antibodies have been detected in both unexposed human and animals. However, the origins of these cross-reactive antibodies and their potential impacts on vaccine efficacy have not been completely clarified. In this study, we demonstrated that the S2 subunit was the predominant target of the pre-existing SARS-CoV-2 spike protein cross-reactive antibodies in both healthy human and naive SPF mice. Through linear epitope mapping, we identified a dominant antibody epitope on the connector domain of S2 (aa1145-aa1162), which could be recognized by antibodies pre-existed in unexposed human and mice. Six monoclonal antibodies against this linear epitope were isolated from naive SPF mice and were proved to cross-react with commensal gut bacteria collected from both human and mouse. Via immunizing mice with a candidate DNA vaccine encoding the full length of SARS-CoV-2 spike protein, we further demonstrated that high levels of pre-existing S2 cross-reactive antibodies did not impair the immunogenicity of the DNA vaccine. On the contrary, mice with high levels of pre-existing antibodies mounted stronger S2 specific binding antibody responses compared to mice with low levels of pre-existing antibodies. In addition, S1 specific T cell and binding antibody responses also tended to be enhanced in mice with high levels of pre-existing antibodies.

scholarly journals Magnitude, specificity and avidity of sporozoite specific antibodies associate with protection status and distinguish among RTS,S/AS01 dose regimens

2020 ◽  
Author(s):  
S Moses Dennison ◽  
Matthew Reichartz ◽  
Milite Abraha ◽  
Rachel L Spreng ◽  
Ulrike Wille-Reece ◽  
...  
Keyword(s):  
Malaria Vaccine ◽  
Specific Binding ◽  
Standard Dose ◽  
Serum Antibody ◽  
Antibody Responses ◽  
Fractional Dose ◽  
Controlled Human Malaria Infection ◽  
Binding Antibody ◽  
Antibody Dynamics ◽  
Sporozoite Infection

Abstract Background The malaria vaccine, RTS,S/AS01, demonstrated an enhanced efficacy (86.7%) in a delayed third fractional dose (0.1.7Fx) regimen in controlled human malaria infection (CHMI) trials compared to a standard full dose (0.1.2) regimen (62.5%). In order to understand the humoral component of the RTS,S/AS01 vaccine-induced protection against sporozoite infection in these two regimens, we investigated the serum antibody dynamics of 0.1.2 and 0.1.7Fx groups vaccinees. Methods The specific binding responses (magnitude) and dissociation rates (avidity) of serum antibodies interaction with a recombinant Plasmodium falciparum circumsporozoite protein (CSP) and peptides corresponding to the central repeat region (NANP6), the C-terminal region (PF16) and the N-terminal junction (N-interface) of CSP, respectively, were measured using a Biolayer Interferometry (BLI) assay. Results On the day of challenge, higher NANP6 specific antibody responses were associated with protection in the 0.1.2 group. Contrarily, slower antibody dissociation rates for CSP and PF16 binding were observed in the protected 0.1.7Fx group. Protected vaccinees of both groups exhibited 2 to 3-fold higher N-interface peptide binding antibody responses. Conclusions Unlike the standard dose, the delayed-fractional third dose of RTS,S/AS01 induced higher avidity CSP and PF16 binding antibodies that were associated with protection against sporozoite infection. Clinical Trials registration NCT01857869

scholarly journals Induction of Mucosal Protection against Primary, Heterologous Simian Immunodeficiency Virus by a DNA Vaccine

2002 ◽  
Vol 76 (7) ◽  
pp. 3309-3317 ◽  
Author(s):  
Deborah Heydenburg Fuller ◽  
Premeela A. Rajakumar ◽  
Lawrence A. Wilson ◽  
Anita M. Trichel ◽  
James T. Fuller ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Dna Vaccine ◽  
Dna Sequences ◽  
Serum Antibody ◽  
Antibody Responses ◽  
Effective Vaccine ◽  
Lymphoid Tissues ◽  
Mucosal Protection ◽  
Mucosal Transmission ◽  
Immunodeficiency Virus

ABSTRACT An effective vaccine against human immunodeficiency virus (HIV) should protect against mucosal transmission of genetically divergent isolates. As a safe alternative to live attenuated vaccines, the immunogenicity and protective efficacy of a DNA vaccine containing simian immunodeficiency virus (SIV) strain 17E-Fr (SIV/17E-Fr) gag-pol-env was analyzed in rhesus macaques. Significant levels of cytotoxic T lymphocytes (CTL), but low to undetectable serum antibody responses, were observed following multiple immunizations. SIV-specific mucosal antibodies and CTL were also detected in rectal washes and gut-associated lymphoid tissues, respectively. Vaccinated and naive control monkeys were challenged intrarectally with SIV strain DeltaB670 (SIV/DeltaB670), a primary isolate whose env is 15% dissimilar to that of the vaccine strain. Four of seven vaccinees were protected from infection as determined by the inability to identify viral RNA or DNA sequences in the peripheral blood and the absence of anamnestic antibody responses postchallenge. This is the first report of mucosal protection against a primary pathogenic, heterologous isolate of SIV by using a commercially viable vaccine approach. These results support further development of a DNA vaccine for protection against HIV.

scholarly journals Antibodies to the Iron Uptake ABC Transporter Lipoproteins PiaA and PiuA Promote Opsonophagocytosis of Streptococcus pneumoniae

2005 ◽  
Vol 73 (10) ◽  
pp. 6852-6859 ◽  
Author(s):  
Maha Jomaa ◽  
Jose Yuste ◽  
James C. Paton ◽  
Christopher Jones ◽  
Gordon Dougan ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Abc Transporters ◽  
Iron Uptake ◽  
Iron Transport ◽  
Antibody Responses ◽  
Igg Subclass ◽  
Specific Enzyme ◽  
Low Levels ◽  
Passive Vaccination ◽  
Neutrophil Cell

ABSTRACT PiaA and PiuA are the lipoprotein components of the Pia and Piu Streptococcus pneumoniae iron uptake ABC transporters and are required for full virulence in mouse models of infection. Active or passive vaccination with recombinant PiuA and PiaA protects mice against invasive S. pneumoniae disease. In this study we have analyzed the antibody responses and mechanism of protection induced by PiuA and PiaA in more detail. For both proteins, two booster vaccinations induced stronger antibody responses in mice than a single or no booster vaccinations, and 5 μg of protein induced similar levels of antibody responses as 20 μg. Immunoglobulin G (IgG) subclass-specific enzyme-linked immunosorbent assays demonstrated that the antibody response to PiuA and PiaA was predominantly IgG1, with induction of only low levels of IgG2a. Anti-PiaA and anti-PiuA polyclonal rabbit antibodies bound to the surface of live S. pneumoniae when assessed by flow cytometry but did not inhibit growth of S. pneumoniae in cation-depleted medium or bacterial susceptibility to the iron-dependent antibiotic streptonigrin. However, anti-PiaA and anti-PiuA did increase complement-independent and -dependent opsonophagocytosis of different serotypes of S. pneumoniae by the human neutrophil cell line HL60. Hence, vaccination with PiaA and PiuA protects against S. pneumoniae infection by inducing antibodies that promote bacterial opsonophagocytosis rather than inhibiting iron transport.

scholarly journals A Novel Purification Procedure for Active Recombinant Human DPP4 and the Inability of DPP4 to Bind SARS-CoV-2

2020 ◽  
Author(s):  
Cecy Xi ◽  
Arianna Arianna Di Fazio ◽  
Naveed Nadvi ◽  
Karishma Patel ◽  
Michelle Xiang ◽  
...  
Keyword(s):  
Affinity Chromatography ◽  
High Purity ◽  
Specific Activity ◽  
Specific Binding ◽  
Exchange Chromatography ◽  
Cell Surface Receptor ◽  
Spike Protein ◽  
High Yield ◽  
Purification Procedure ◽  
Dipeptidyl Peptidase 4

Proteases catalyse irreversible posttranslational modifications that often alter a biological function of the substrate. The protease dipeptidyl peptidase 4 (DPP4) is a pharmacological target in type 2 diabetes therapy primarily because it inactivates glucagon-like protein-1. DPP4 also has roles in steatosis, insulin resistance, cancers and inflammatory and fibrotic diseases. In addition, DPP4 binds to the spike protein of MERS virus, causing it to be the human cell surface receptor for that virus. DPP4 has been identified as a potential binding target of SARS-CoV-2 spike protein, so this question requires experimental investigation. Understanding protein structure and function requires reliable protocols for production and purification. We developed such strategies for baculovirus generated soluble recombinant human DPP4 (residues 29-766) produced in insect cells. Purification used differential ammonium sulfate precipitation, hydrophobic interaction chromatography, dye affinity chromatography in series with immobilised metal affinity chromatography, and ion exchange chromatography. The binding affinities of DPP4 to the SARS-CoV-2 full-length spike protein and its receptor binding domain (RBD) were measured using surface plasmon resonance. This optimised DPP4 purification procedure yielded 1 to 1.8 mg of pure fully active soluble DPP4 protein per litre of insect cell culture with specific activity >30 U/mg, indicative of high purity. No specific binding between DPP4 and CoV-2 spike protein was detected. In summary, a procedure for high purity high yield soluble human DPP4 was achieved and used to show that, unlike MERS, SARS-CoV-2 does not bind human DPP4.

scholarly journals Convergent Antibody Responses to SARS-CoV-2 Infection in Convalescent Individuals

2020 ◽  
Author(s):  
Davide F. Robbiani ◽  
Christian Gaebler ◽  
Frauke Muecksch ◽  
Julio C. C. Lorenzi ◽  
Zijun Wang ◽  
...  
Keyword(s):  
Virus Entry ◽  
Protein S ◽  
Memory B Cells ◽  
Antibody Responses ◽  
Spike Protein ◽  
Human Antibody ◽  
Receptor Binding Domain ◽  
Single Digit ◽  
Specific Antibodies ◽  
Specific Memory

AbstractDuring the COVID-19 pandemic, SARS-CoV-2 infected millions of people and claimed hundreds of thousands of lives. Virus entry into cells depends on the receptor binding domain (RBD) of the SARS-CoV-2 spike protein (S). Although there is no vaccine, it is likely that antibodies will be essential for protection. However, little is known about the human antibody response to SARS-CoV-21–5. Here we report on 149 COVID-19 convalescent individuals. Plasmas collected an average of 39 days after the onset of symptoms had variable half-maximal neutralizing titers ranging from undetectable in 33% to below 1:1000 in 79%, while only 1% showed titers >1:5000. Antibody cloning revealed expanded clones of RBD-specific memory B cells expressing closely related antibodies in different individuals. Despite low plasma titers, antibodies to three distinct epitopes on RBD neutralized at half-maximal inhibitory concentrations (IC50s) as low as single digit ng/mL. Thus, most convalescent plasmas obtained from individuals who recover from COVID-19 do not contain high levels of neutralizing activity. Nevertheless, rare but recurring RBD-specific antibodies with potent antiviral activity were found in all individuals tested, suggesting that a vaccine designed to elicit such antibodies could be broadly effective.

scholarly journals Long-term persistence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein-specific and neutralizing antibodies in recovered COVID-19 patients

2021 ◽  
Author(s):  
Jira Chansaenroj ◽  
Ritthideach Yorsaeng ◽  
Nasamon Wanlapakorn ◽  
Chintana Chirathaworn ◽  
Natthinee Sudhinaraset ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Symptom Onset ◽  
Neutralizing Antibodies ◽  
Serum Antibody ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Spike Protein ◽  
Immunological Study ◽  
Igg Antibody ◽  
Vaccine Schedule

Abstract Understanding antibody responses after natural severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can guide the coronavirus disease 2019 (COVID-19) vaccine schedule. This study aimed to assess the dynamics of SARS-CoV-2 antibodies, including anti-spike protein 1 (S1) immunoglobulin (Ig)G, anti-receptor-binding domain (RBD) total Ig, anti-S1 IgA, and neutralizing antibody against wild-type SARS-CoV-2 in a cohort of patients who were previously infected with SARS-CoV-2. Between March and May 2020, 531 individuals with virologically confirmed cases of SARS-CoV-2 infection were enrolled in our immunological study. The neutralizing titers against SARS-CoV-2 were detected in 95.2%, 86.7%, 85.0%, and 85.4% of recovered COVID-19 patients at 3, 6, 9, and 12 months after symptom onset, respectively. The seropositivity rate of anti-S1 IgG, anti-RBD total Ig, anti-S1 IgA, and neutralizing titers remained at 68.6%, 89.6%, 77.1%, and 85.4%, respectively, at 12 months after symptom onset. The half-life of neutralizing titers was estimated at 100.7 days (95% confidence interval = 44.5 – 327.4 days, R2 = 0.106). These results support that the decline in serum antibody levels over time depends on the symptom severity, and the individuals with high IgG antibody titers experienced a significantly longer persistence of SARS-CoV-2-specific antibody responses than those with lower titers.

Salmonella typhi Ty21a bacterial ghost vector augments HIV-1 gp140 DNA vaccine-induced peripheral and mucosal antibody responses via TLR4 pathway

Vaccine ◽  
2012 ◽  
Vol 30 (39) ◽  
pp. 5733-5739 ◽  
Author(s):  
Jing Wen ◽  
Yi Yang ◽  
Guangyu Zhao ◽  
Shuang Tong ◽  
Hong Yu ◽  
...  
Keyword(s):  
Dna Vaccine ◽  
Salmonella Typhi ◽  
Antibody Responses ◽  
Mucosal Antibody ◽  
Bacterial Ghost ◽  
Hiv 1

scholarly journals A Replicating Single-Cycle Adenovirus Vaccine Effective against Clostridium difficile

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 470
Author(s):  
William E. Matchett ◽  
Stephanie Anguiano-Zarate ◽  
Goda Baddage Rakitha Malewana ◽  
Haley Mudrick ◽  
Melissa Weldy ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Neutralizing Antibodies ◽  
Antibody Responses ◽  
Complete Protection ◽  
Single Cycle ◽  
Toxin B ◽  
Toxin Binding ◽  
Binding Domains ◽  
Binding Antibody

Clostridium difficile causes nearly 500,000 infections and nearly 30,000 deaths each year in the U.S., which is estimated to cost $4.8 billion. C. difficile infection (CDI) arises from bacteria colonizing the large intestine and releasing two toxins, toxin A (TcdA) and toxin B (TcdB). Generating humoral immunity against C. difficile’s toxins provides protection against primary infection and recurrence. Thus, a vaccine may offer the best opportunity for sustained, long-term protection. We developed a novel single-cycle adenovirus (SC-Ad) vaccine against C. difficile expressing the receptor-binding domains from TcdA and TcdB. The single immunization of mice generated sustained toxin-binding antibody responses and protected them from lethal toxin challenge for up to 38 weeks. Immunized Syrian hamsters produced significant toxin-neutralizing antibodies that increased over 36 weeks. Single intramuscular immunization provided complete protection against lethal BI/NAP1/027 spore challenge 45 weeks later. These data suggest that this replicating vaccine may prove useful against CDI in humans.

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