scholarly journals Epigallocatechin-3-Gallate as a Novel Vaccine Adjuvant

2021 ◽  
Vol 12 ◽  
Author(s):  
Yucheol Cheong ◽  
Minjin Kim ◽  
Jina Ahn ◽  
Hana Oh ◽  
Jongkwan Lim ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Fold Increase ◽  
Globular Domain ◽  
Vaccine Adjuvants ◽  
Vaccine Platform ◽  
Lethal Challenge ◽  
Influenza Hemagglutinin ◽  
Viral Vaccine ◽  
Inactivated Vaccines ◽  
Sparing Effect

Vaccine adjuvants from natural resources have been utilized for enhancing vaccine efficacy against infectious diseases. This study examined the potential use of catechins, polyphenolic materials derived from green tea, as adjuvants for subunit and inactivated vaccines. Previously, catechins have been documented to have irreversible virucidal function, with the possible applicability in the inactivated viral vaccine platform. In a mouse model, the coadministration of epigallocatechin-3-gallate (EGCG) with influenza hemagglutinin (HA) antigens induced high levels of neutralizing antibodies, comparable to that induced by alum, providing complete protection against the lethal challenge. Adjuvant effects were observed for all types of HA antigens, including recombinant full-length HA and HA1 globular domain, and egg-derived inactivated split influenza vaccines. The combination of alum and EGCG further increased neutralizing (NT) antibody titers with the corresponding hemagglutination inhibition (HI) titers, demonstrating a dose-sparing effect. Remarkably, EGCG induced immunoglobulin isotype switching from IgG1 to IgG2a (approximately >64–700 fold increase), exerting a more balanced TH1/TH2 response compared to alum. The upregulation of IgG2a correlated with significant enhancement of antibody-dependent cellular cytotoxicity (ADCC) function (approximately 14 fold increase), providing a potent effector-mediated protection in addition to NT and HI. As the first report on a novel class of vaccine adjuvants with built-in virucidal activities, the results of this study will help improve the efficacy and safety of vaccines for pandemic preparedness.

scholarly journals 1833. Measuring Influenza HA Stem-Specific ADCC in Human Sera Using Novel Stabilized Stem Nanoparticle Probes

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S43-S43
Author(s):  
Maria K Smatti ◽  
Gheyath Nasrallah ◽  
Asmaa Althani ◽  
Hadi Yassine
Keyword(s):  
Neutralizing Antibodies ◽  
Fold Increase ◽  
Influenza Viruses ◽  
Adcc Activity ◽  
Lethal Challenge ◽  
Nanoparticle Probes ◽  
H5n1 Influenza ◽  
Human Sera ◽  
Cellular Immune ◽  
Universal Influenza Vaccine

Abstract Background Generating a vaccine that confers complete protection and overcomes the high variability among influenza viruses is the major goal in designing a universal influenza vaccine. Currently, there is considerable interest in the broadly neutralizing antibodies (bNAb) targeting the conserved HA stem region. These antibodies have been shown to activate cellular immune responses, such as antibody-dependent cellular cytotoxisity (ADCC), in addition to their neutralization activity. We had previously demonstrated that immunization with H1-based stabilized stem (SS) nanoparticles (np) protects against heterosubtypic lethal challenge with H5N1 influenza virus, despite the absence of detectable H5N1 neutralizing activity. Here, we utilized these novel SS np probes to develop a new protocol to assess the ADCC activity mediated by stem-directed antibodies in human sera. Methods Human sera samples were initially screened for binding reactivity to H1 SS trimer using ELISA procedure. Of these, selected samples representing high, moderate, and low binders were further characterized for binding to H1 and H5 SS their corresponding Δstem (Ile45Arg/Thr49Arg) probes, and were analyzed for ADCC activity using a reporter bioassay. Results The initial screening revealed 82% (73/90) seroprevalence of anti-HA (H1) stem epitope antibodies, as determined by the differential binding to HA SS and it corresponding epitope-mutant probe. Using equimolar amounts, the multivalent presentation of HA SS on np probes induced significantly higher ADCC activity compared with the monovalent SS probes (2- to 6-fold increase). Further, ADCC activity was similarly reported against different influenza group 1 subtypes: H1, H2, and H5. Importantly, ADCC was mediated mainly by antibodies targeting the bNAb-epitope on the HA stem. In conclusion, we developed an assay to measure stem-specific ADCC activity using SS np probes. Conclusion Our results indicate a high prevalence of HA-stem antibodies with cross-reactive ADCC activity. Such assay could be utilized in the assessment of next-generation influenza vaccines. Disclosures All Authors: No reported Disclosures.

scholarly journals Discovering neutralizing antibodies targeting the stem epitope of H1N1 influenza hemagglutinin with synthetic phage-displayed antibody libraries

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Chao-Ping Tung ◽  
Ing-Chien Chen ◽  
Chung-Ming Yu ◽  
Hung-Pin Peng ◽  
Jhih-Wei Jian ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
H1n1 Influenza ◽  
Influenza Hemagglutinin ◽  
Antibody Libraries

scholarly journals Advax-CpG Adjuvant Provides Antigen Dose-Sparing and Enhanced Immunogenicity for Inactivated Poliomyelitis Virus Vaccines

Pathogens ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 500
Author(s):  
Yoshikazu Honda-Okubo ◽  
Jeremy Baldwin ◽  
Nikolai Petrovsky
Keyword(s):  
Neutralizing Antibodies ◽  
Serum Antibody ◽  
Oral Polio Vaccine ◽  
Antigen Dose ◽  
Polio Vaccine ◽  
Antibody Titers ◽  
Dose Sparing ◽  
Sparing Effect ◽  
Eradicate Polio

Global immunization campaigns have resulted in a major decline in the global incidence of polio cases, with wild-type poliovirus remaining endemic in only two countries. Live oral polio vaccine (OPV) played a role in the reduction in polio case numbers; however, the risk of OPV developing into circulating vaccine-derived poliovirus makes it unsuitable for eradication programs. Trivalent inactivated polio virus (TIPV) vaccines which contain formalin-inactivated antigens produced from virulent types 1, 2 and 3 reference polio strains grown in Vero monkey kidney cells have been advocated as a replacement for OPV; however, TIPVs have weak immunogenicity and multiple boosts are required before peak neutralizing titers are reached. This study examined whether the incorporation of the novel polysaccharide adjuvant, Advax-CpG, could boost the immunogenicity of two TIPV vaccines, (i) a commercially available polio vaccine (IPOL®, Sanofi Pasteur) and (ii) a new TIPV formulation developed by Statens Serum Institut (SSI). Mice were immunized intramuscularly based on recommended vaccine dosage schedules and serum antibody titers were followed for 12 months post-immunization. Advax-CpG significantly enhanced the long-term immunogenicity of both TIPV vaccines and had at least a 10-fold antigen dose-sparing effect. An exception was the poor ability of the SSI TIPV to induce serotype type 1 neutralizing antibodies. Immunization with monovalent IPVs suggested that the low type 1 response to TIPV may be due to antigen competition when the type 1 antigen was co-formulated with the type 2 and 3 antigens. This study provides valuable insights into the complexity of the formulation of multivalent polio vaccines and supports the further development of adjuvanted antigen-sparing TIPV vaccines in the fight to eradicate polio.

Broadly-neutralizing antibodies that bind to the influenza hemagglutinin stalk domain enhance the effectiveness of neuraminidase inhibitors via Fc-mediated effector functions

2021 ◽  
Author(s):  
Ali Zhang ◽  
Hanu Chaudhari ◽  
Yonathan Agung ◽  
Michael D'Agostino ◽  
Jann Ang ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Neutralizing Antibodies ◽  
Influenza Virus Infection ◽  
Dependent Manner ◽  
Neuraminidase Inhibitors ◽  
Immune Effector ◽  
Effector Cells ◽  
Individual Level ◽  
Influenza Hemagglutinin ◽  
Stalk Domain

The conserved hemagglutinin stalk domain is an attractive target for broadly effective antibody-based therapeutics and next generation universal influenza vaccines. Protection provided by hemagglutinin stalk binding antibodies is principally mediated through activation of immune effector cells. Titers of stalk-binding antibodies are highly variable on an individual level, and tend to increase with age as a result of increasing exposures to influenza virus. In our study, we show that stalk-binding antibodies cooperate with neuraminidase inhibitors to protect against influenza virus infection in an Fc-dependent manner. These data suggest that the effectiveness of neuraminidase inhibitors is likely influenced by an individual's titers of stalk-binding antibodies, and that neuraminidase inhibitors may enhance the effectiveness of future stalk-binding monoclonal antibody-based treatments.

scholarly journals TLR4 Ligands Augment Antigen-Specific CD8+ T Lymphocyte Responses Elicited by a Viral Vaccine Vector

2010 ◽  
Vol 84 (19) ◽  
pp. 10413-10419 ◽  
Author(s):  
Elizabeth G. Rhee ◽  
R. Phelps Kelley ◽  
Isha Agarwal ◽  
Diana M. Lynch ◽  
Annalena La Porte ◽  
...  
Keyword(s):  
T Lymphocyte ◽  
Lipid A ◽  
Viral Vector ◽  
Recombinant Adenovirus ◽  
Poly I:C ◽  
Vaccine Adjuvants ◽  
Monophosphoryl Lipid A ◽  
Viral Vaccine ◽  
Lymphocyte Responses ◽  
The Impact

ABSTRACT Toll-like receptor (TLR) ligands are critical activators of innate immunity and are being developed as vaccine adjuvants. However, their utility in conjunction with viral vector-based vaccines remains unclear. In this study, we evaluated the impact of a variety of TLR ligands on antigen-specific CD8+ T lymphocyte responses elicited by a recombinant adenovirus serotype 26 (rAd26) vector expressing simian immunodeficiency virus Gag in mice. The TLR3 ligand poly(I:C) suppressed Gag-specific cellular immune responses, whereas the TLR4 ligands lipopolysaccharide and monophosphoryl lipid A substantially augmented the magnitude and functionality of these responses by a MyD88- and TRIF-dependent mechanism. These data demonstrate that TLR ligands can modulate the immunogenicity of viral vaccine vectors both positively and negatively. Moreover, these findings suggest the potential utility of TLR4 ligands as adjuvants for rAd vector-based vaccines.

scholarly journals Peptide Aggregation Induced Immunogenic Rupture (PAIIR)

2021 ◽  
Author(s):  
Gokhan Gunay ◽  
Seren Hamsici ◽  
Handan Acar ◽  
Mark L. Lang ◽  
Gillian A. Lang ◽  
...  
Keyword(s):  
Immune Response ◽  
Membrane Damage ◽  
Cell Types ◽  
Peptide Aggregation ◽  
Vaccine Adjuvants ◽  
Humoral And Cellular Immunity ◽  
Influenza Hemagglutinin ◽  
Series Of Experiments ◽  
Molecular Patterns

Under the influence of stress and membrane damage, cells undergo immunogenic cell death (ICD), which involves the release of damage associated molecular patterns (DAMPs), natural adjuvants for enhancing an immune response. In the presence of an antigen, released DAMPs can determine the type and magnitude of the immune response, and therefore the longevity and efficacy of an antigen-specific immunity. In the last decade, the immune response effect of ICD has been shown, yet there is no tool that can induce controlled ICD with predictable results, regardless of the cell type. We designed a peptide-based tool, called [II], for controlled damage to cell membrane to induce ICD and DAMPs release. Herein we describe a series of experiments that determine that the mechanism of action of [II] includes a caspase-dependent ICD and subsequent release of immune stimulating DAMPs, on various cell types. Moreover, we tested the hypothesis that controlled DAMP release via [II] in vivo was associated with enhancement of antigen-specific adaptive immunity with influenza hemagglutinin (HA) subunit vaccine. HA and [II] showed significantly higher HA specific IgG1 and IgG2a antibodies, compared to HA-only immunized mice, while the peptide itself did not elicit antibodies. In this paper, we demonstrate the first peptide-aggregation induced immunogenic rupture (PAIIR) approach as vaccine adjuvants for increasing both humoral and cellular immunity. In consideration of its ability to enhance IgG2a responses that are associated with heterosubtypic influenza virus protection, PAIIR is a promising adjuvant to promote universal protection upon influenza HA vaccination.

scholarly journals Immune Responses to COVID-19 mRNA Vaccines in Patients with Solid Tumors on Active, Immunosuppressive Cancer Therapy

2021 ◽  
Author(s):  
Rachna T Shroff ◽  
Pavani Chalasani ◽  
Ran Wei ◽  
Daniel Pennington ◽  
Grace Quirk ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Immune Responses ◽  
Cancer Patients ◽  
Neutralizing Antibodies ◽  
Fold Increase ◽  
Control Cohort ◽  
Tumor Patients ◽  
Specific Memory ◽  
Anti Cancer ◽  
B Cell Subsets

Vaccines against SARS-CoV-2 have shown high efficacy, but immunocompromised participants were excluded from controlled clinical trials. We evaluated immune responses to the Pfizer/BioNTech mRNA vaccine in solid tumor patients (n=52) on active cytotoxic anti-cancer therapy. These responses were compared to a control cohort that also received the Pfizer/BioNTech vaccine (n=50). Using live SARS-CoV-2 assays, neutralizing antibodies were detected in 67% and 80% of cancer patients after the first and second immunizations, respectively, with a 3-fold increase in median titers after the booster. Similar trends were observed in serum antibodies against the receptor-binding domain (RBD) and S2 regions of Spike protein, and in IFN𝛾+ Spike-specific T cells. The magnitude of each of these responses was diminished relative to the control cohort. We therefore quantified RBD- and Spike S1-specific memory B cell subsets as predictors of anamnestic responses to viral exposures or additional immunizations. After the second vaccination, Spike-specific plasma cell-biased memory B cells were observed in most cancer patients at levels similar to those of the control cohort after the first immunization. These data suggest that a third immunization might elevate antibody responses in cancer patients to levels seen in healthy individuals after the second dose. Trials should be conducted to test these predictions.

scholarly journals Safety, Immunogenicity and Efficacy of a Recombinant Vesicular Stomatitis Virus Vectored Vaccine Against Severe Fever with Thrombocytopenia Syndrome and Heartland Bandaviruses

2021 ◽  
Author(s):  
Phillip Hicks ◽  
Jonna B. Westover ◽  
Tomaz B Manzoni ◽  
Brianne Roper ◽  
Gabrielle L Rock ◽  
...  
Keyword(s):  
Vesicular Stomatitis Virus ◽  
Neutralizing Antibodies ◽  
Genetic Manipulation ◽  
Case Fatality ◽  
Vaccine Platform ◽  
Vesicular Stomatitis ◽  
Immunocompetent Mice ◽  
Vectored Vaccine ◽  
Severe Fever ◽  
Promising Vaccine Candidate

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a recently emerged tickborne virus in east Asia with over 8,000 confirmed cases. With a high case fatality ratio, SFTSV has been designated a high priority pathogen by the WHO and the NIAID. Despite this, there are currently no approved therapies or vaccines to treat or prevent SFTS. Vesicular stomatitis virus (VSV) represents an FDA-approved vaccine platform that has been considered for numerous viruses due to its low sero-prevalence in humans, ease in genetic manipulation and promiscuity in incorporating foreign glycoproteins into its virions. In this study, we developed a recombinant VSV (rVSV) expressing the SFTSV glycoproteins Gn/Gc (rVSV-SFTSV) and assessed its safety, immunogenicity and efficacy in mice. We demonstrate that rVSV-SFTSV is safe when given to immunocompromised animals and is not neuropathogenic when injected intracranially into young immunocompetent mice. Immunization of Ifnar-/- mice with rVSV-SFTSV resulted in high levels of neutralizing antibodies and protection against lethal SFTSV challenge. Additionally, passive transfer of sera from immunized IFNAR-/- mice into naïve animals was protective when given pre- or post-exposure. Finally, we demonstrate that immunization with rVSV-SFTSV cross protects mice against challenge with the closely related Heartland virus despite low neutralizing titers to the virus. Taken together, these data suggest that rVSV-SFTSV is a promising vaccine candidate.

scholarly journals Prospects of HA-Based Universal Influenza Vaccine

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Anwar M. Hashem
Keyword(s):  
Influenza Vaccine ◽  
Neutralizing Antibodies ◽  
Plasma Cells ◽  
Globular Domain ◽  
Universal Vaccine ◽  
Viral Hemagglutinin ◽  
Heterosubtypic Immunity ◽  
Antibody Libraries ◽  
Universal Influenza Vaccine ◽  
Immunodominant Epitopes

Current influenza vaccines afford substantial protection in humans by inducing strain-specific neutralizing antibodies (Abs). Most of these Abs target highly variable immunodominant epitopes in the globular domain of the viral hemagglutinin (HA). Therefore, current vaccines may not be able to induce heterosubtypic immunity against the divergent influenza subtypes. The identification of broadly neutralizing Abs (BnAbs) against influenza HA using recent technological advancements in antibody libraries, hybridoma, and isolation of single Ab-secreting plasma cells has increased the interest in developing a universal influenza vaccine as it could provide life-long protection. While these BnAbs can serve as a source for passive immunotherapy, their identification represents an important step towards the design of such a universal vaccine. This review describes the recent advances and approaches used in the development of universal influenza vaccine based on highly conserved HA regions identified by BnAbs.

scholarly journals Moderately Neutralizing Epitopes in Nonfunctional Regions Dominate the Antibody Response toPlasmodium falciparumEBA-140

2019 ◽  
Vol 87 (4) ◽  
Author(s):  
Nichole D. Salinas ◽  
May M. Paing ◽  
Jagat Adhikari ◽  
Michael L. Gross ◽  
Niraj Tolia
Keyword(s):  
Immune Response ◽  
Sialic Acid ◽  
Neutralizing Antibodies ◽  
Fold Increase ◽  
Binding Pocket ◽  
Content Type ◽  
Tight Junction Formation ◽  
Sialic Acid Binding ◽  
Erythrocyte Binding ◽  
Region Ii

ABSTRACTPlasmodium falciparumerythrocyte-binding antigen 140 (EBA-140) plays a role in tight junction formation during parasite invasion of red blood cells and is a potential vaccine candidate for malaria. Individuals in areas where malaria is endemic possess EBA-140-specific antibodies, and individuals with high antibody titers to this protein have a lower rate of reinfection by parasites. The red blood cell binding segment of EBA-140 is comprised of two Duffy-binding-like domains, called F1 and F2, that together create region II. The sialic acid-binding pocket of F1 is essential for binding, whereas the sialic acid-binding pocket in F2 appears dispensable. Here, we show that immunization of mice with the complete region II results in poorly neutralizing antibodies. In contrast, immunization of mice with the functionally relevant F1 domain of region II results in antibodies that confer a 2-fold increase in parasite neutralization compared to that of the F2 domain. Epitope mapping of diverse F1 and F2 monoclonal antibodies revealed that the functionally relevant F1 sialic acid-binding pocket is a privileged site inaccessible to antibodies, that the F2 sialic acid-binding pocket contains a nonneutralizing epitope, and that two additional epitopes reside in F1 on the opposite face from the sialic acid-binding pocket. These studies indicate that focusing the immune response to the functionally important F1 sialic acid binding pocket improves the protective immune response of EBA-140. These results have implications for improving future vaccine designs and emphasize the importance of structural vaccinology for malaria.

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