A Novel Bacterium-Like Particle-Based Vaccine Displaying the SUDV Glycoprotein Induces Potent Humoral and Cellular Immune Responses in Mice

Sudan virus (SUDV) causes severe lethal hemorrhagic fever in humans and nonhuman primates. The most effective and economical way to protect against Sudan ebolavirus disease is prophylactic vaccination. However, there are no licensed vaccines to prevent SUDV infections. In this study, a bacterium-like particle (BLP)-based vaccine displaying the extracellular domain of the SUDV glycoprotein (eGP) was developed based on a gram-positive enhancer matrix-protein anchor (GEM-PA) surface display system. Expression of the recombinant GEM-displayed eGP (eGP-PA-GEM) was verified by Western blotting and immunofluorescence assays. The SUDV BLPs (SBLPs), which were mixed with Montanide ISA 201VG plus Poly (I:C) combined adjuvant, could induce high SUDV GP-specific IgG titers of up to 1:40,960 and robust virus-neutralizing antibody titers reached 1:460. The SBLP also elicited T-helper 1 (Th1) and T-helper 2 (Th2) cell-mediated immunity. These data indicate that the SBLP subunit vaccine has the potential to be developed into a promising candidate vaccine against SUDV infections.

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Characterization of Humoral and Cellular Immune Responses Elicited by Meningococcal Carriage

Infection and Immunity ◽

10.1128/iai.70.3.1301-1309.2002 ◽

2002 ◽

Vol 70 (3) ◽

pp. 1301-1309 ◽

Cited By ~ 30

Author(s):

K. Robinson ◽

K. R. Neal ◽

C. Howard ◽

J. Stockton ◽

K. Atkinson ◽

...

Keyword(s):

Undergraduate Students ◽

Mononuclear Cells ◽

T Helper ◽

T Helper 1 ◽

Peripheral Blood Mononuclear ◽

Interleukin 5 ◽

Whole Cell Lysate ◽

Intracellular Cytokines ◽

Ifn Γ ◽

Cellular Immune

ABSTRACT In order to study the immune response elicited by asymptomatic carriage of Neisseria meningitidis, samples of serum, peripheral blood mononuclear cells (PBMCs), and saliva were collected from a cohort of more than 200 undergraduate students in Nottingham, United Kingdom, who were subject to high rates of acquisition and carriage of meningococci. Serum immunoglobulin G levels were elevated following increases in the rate of carriage, and these responses were specific for the colonizing strains. In order to investigate T-cell responses, PBMCs from 15 individuals were stimulated with a whole-cell lysate of the H44/76 meningococcal strain (B:15:P1.7,16), stained to detect cell surface markers and intracellular cytokines, and examined by flow cytometry. The cells were analyzed for expression of CD69 (to indicate activation), gamma interferon (IFN-γ) (a representative T-helper 1 subset [Th1]-associated cytokine), and interleukin-5 (IL-5) (a Th2-associated cytokine). Following a brief meningococcal stimulation, the numbers of CD69+ IFN-γ+ CD56/16+ NK cells were much higher than cytokine-positive CD4+ events. Both IFN-γ+ and IL-5+ events were detected among the CD69+ CD4+ population, leading to the conclusion that an unbiased T-helper subset response was elicited by meningococcal carriage.

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In vitro analysis of cell-mediated immunity: clinical relevance

Clinical Chemistry ◽

10.1093/clinchem/40.11.2162 ◽

1994 ◽

Vol 40 (11) ◽

pp. 2162-2165 ◽

Cited By ~ 6

Author(s):

G M Shearer ◽

M Clerici

Keyword(s):

Immune System ◽

Cell Mediated Immunity ◽

T Helper ◽

Cellular Immune Responses ◽

Immunoregulatory Cytokines ◽

Vitro Analysis ◽

Cellular Immune ◽

Antigen Presenting ◽

In Vitro Analysis

Abstract Cellular immunity, a major component of the immune system, contributes to protection against infections and plays a role in the rejection of foreign allografts. T helper cells and the antigen-presenting cells with which they interact provide important functions for cellular immune responses by generating helper signals via soluble molecules known as lymphokines or cytokines. As described here, in vitro analysis of markers of cellular immune function can be used for clinical diagnosis and assessment of therapeutic efficacy and to elucidate the mechanisms of immune dysregulation. Not all helper signals necessarily have the same augmenting effect, because immunoregulatory cytokines that up-regulate the cellular arm of the immune system can conversely down-regulate the humoral arm, and vice versa. The interplay between cross-regulatory cytokines determines which component of the immune system is dominant and can influence the clinical outcome of immunologically controlled diseases. Given the apparent dramatic effects of these cytokines, assays performed in future clinical laboratories should include profiles of immunoregulatory cytokines.

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A bacterium-like particle vaccine displaying Zika virus prM-E induces systemic immune responses in mice

10.22541/au.164137321.15121141/v1 ◽

2022 ◽

Author(s):

Hongli Jin ◽

Yujie Bai ◽

Jianzhong Wang ◽

Cui Jiao ◽

Di Liu ◽

...

Keyword(s):

Fusion Protein ◽

B Cell ◽

Zika Virus ◽

Cell Activation ◽

Matrix Protein ◽

Neutralizing Antibody ◽

Poly I:C ◽

Congenital Defects ◽

B Cell Activation ◽

Specific Igg

The emergence of Zika virus (ZIKV) infection, which is unexpectedly associated with congenital defects, has prompted the development of safe and effective vaccines. The gram-positive enhancer matrix-protein anchor (GEM-PA) display system has emerged as a versatile and highly effective platform for delivering target proteins for vaccines. In this article, we developed a bacterium-like particle vaccine ZI-△-PA-GEM based on the GEM-PA system. The fusion protein ZI-△-PA, which contains the prM-E-△ protein of ZIKV (with a stem-transmembrane region deletion) and the protein anchor PA3, was expressed. The fusion protein was successfully displayed on the GEM surface, forming ZI-△-PA-GEM. Moreover, when BALB/c mice were immunized intramuscularly with ZI-△-PA-GEM combined with 201 VG and poly(I:C) adjuvants, durable ZIKV-specific IgG and protective neutralizing antibody responses were induced. Potent B cell/DC activation was also be stimulated early after immunization. Remarkably, splenocyte proliferation, the secretion of multiple cytokines, T/B cell activation and central memory T cell responses were elicited. These data indicate that ZI-△-PA-GEM is a promising bacterium-like particle vaccine candidate for ZIKV.

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Characterization of the Helicobacter pylori Cysteine-Rich Protein A as a T-Helper Cell Type 1 Polarizing Agent

Infection and Immunity ◽

10.1128/iai.73.8.4732-4742.2005 ◽

2005 ◽

Vol 73 (8) ◽

pp. 4732-4742 ◽

Cited By ~ 30

Author(s):

Ludwig Deml ◽

Michael Aigner ◽

Jochen Decker ◽

Alexander Eckhardt ◽

Christian Schütz ◽

...

Keyword(s):

Helicobacter Pylori ◽

Protein A ◽

Adaptive Immune System ◽

Neutralizing Antibody ◽

T Helper ◽

T Helper 1 ◽

Necrosis Factor Alpha ◽

Cysteine Rich Protein ◽

Ifn Γ ◽

H Pylori

ABSTRACT Predominant T-helper 1 (Th1) responses with increased gamma interferon (IFN-γ) levels have been proposed to play an important role in Helicobacter pylori-induced gastritis and peptic ulceration. However, bacterial factors contributing to the initiation of Th1 polarization of H. pylori-specific immune responses have not been characterized in detail thus far. We report here on the identification of Helicobacter cysteine-rich protein A (HcpA) as a novel proinflammatory and Th1-promoting protein. The capacity of HcpA to induce immune activation was studied in splenocyte cultures of naive H. pylori-negative mice. HcpA stimulated the release of high concentrations of the proinflammatory and Th1-promoting cytokines interleukin-6 (IL-6) and IFN-γ, in addition to significant levels of IL-12, tumor necrosis factor alpha, and IL-10. The observed cytokine profile was comparable to that induced by lipopolysaccharide but differed in the kinetics and maximum levels of cytokine production. In addition, HcpA-induced cytokine release resembled that observed upon incubation with H. pylori except for IL-10, which was only moderately released upon HcpA stimulation. Both HcpA- and H. pylori-mediated IFN-γ production was drastically reduced by a neutralizing antibody against IL-12 but not by an anti-IL-2 antibody. Thus, HcpA seems to represent a novel bacterial virulence factor triggering the release of a concerted set of cytokines to instruct the adaptive immune system for the initiation of proinflammatory and Th1-biased immunity.

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Iron oxide nanoparticles suppressed T helper 1 cell-mediated immunity in a murine model of delayed-type hypersensitivity

International Journal of Nanomedicine ◽

10.2147/ijn.s31054 ◽

2012 ◽

pp. 2729 ◽

Cited By ~ 7

Author(s):

Tong-Rong Jan ◽

Shen ◽

Liang ◽

Wang ◽

Liao

Keyword(s):

Iron Oxide ◽

Iron Oxide Nanoparticles ◽

Murine Model ◽

Delayed Type Hypersensitivity ◽

Oxide Nanoparticles ◽

Cell Mediated Immunity ◽

T Helper ◽

T Helper 1

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A bacterium-like particle vaccine displaying Zika virus prM-E induces systemic immune responses in mice

10.1101/2021.08.13.456215 ◽

2021 ◽

Author(s):

Hongli Jin ◽

Yujie Bai ◽

Jianzhong Wang ◽

Cuicui Jiao ◽

Di Liu ◽

...

Keyword(s):

Fusion Protein ◽

B Cell ◽

Zika Virus ◽

Cell Activation ◽

Matrix Protein ◽

Neutralizing Antibody ◽

Poly I:C ◽

Congenital Defects ◽

B Cell Activation ◽

Specific Igg

The emergence of Zika virus (ZIKV) infection, which is an unexpectedly associated with congenital defects, has prompted the development of safe and effective vaccines. The gram-positive enhancer matrix-protein anchor (GEM-PA) display system has emerged as a versatile and highly effective platform for delivering target proteins for vaccines. In this article, we developed a bacterium-like particle vaccine ZI-△-PA-GEM based on the GEM-PA system. The fusion protein ZI-△-PA, which contains the prM-E-△ protein of ZIKV (with a stem-transmembrane region deletion) and the protein anchor PA3, was expressed. The fusion protein was successfully displayed on the GEM surface, forming ZI-△-PA-GEM. Moreover, when BALB/c mice were immunized intramuscularly with ZI-△-PA-GEM combined with 201 VG and poly(I:C) adjuvants, durable ZIKV-specific IgG and protective neutralizing antibody responses were induced. Potent B cell/DC activation was also be stimulated early after immunization. Remarkably, splenocyte proliferation, the secretion of multiple cytokines, T/B cell activation and central memory T cell responses were elicited. These data indicate that ZI-△-PA-GEM is a promising bacterium-like particle vaccine candidate for ZIKV.

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Th2-Associated Local Reactions to the Acellular Diphtheria-Tetanus-Pertussis Vaccine in 4- to 6-Year-Old Children

Infection and Immunity ◽

10.1128/iai.73.12.8130-8135.2005 ◽

2005 ◽

Vol 73 (12) ◽

pp. 8130-8135 ◽

Cited By ~ 69

Author(s):

Julie Rowe ◽

Stephanie T. Yerkovich ◽

Peter Richmond ◽

Devinda Suriyaarachchi ◽

Elizabeth Fisher ◽

...

Keyword(s):

Time Course ◽

Immunoglobulin E ◽

Vaccine Antigen ◽

Immune Memory ◽

T Helper ◽

T Helper 1 ◽

Vaccination Programs ◽

Local Reactions ◽

Cellular Immune

ABSTRACT Acellular vaccines against diphtheria-tetanus-pertussis (acellular pertussis) (DTaP) are being progressively introduced into vaccination programs worldwide, with the aim of reducing T-helper 1 (Th1)-associated reactogenicity associated with the cellular diphtheria-tetanus-pertussis (whole-cell pertussis) (DTwP) vaccine. The DTaP vaccine has an improved safety profile in infants, but little information is available concerning the nature of the ensuing immunological memory in older children and how this may affect the reactogenicity of DTaP booster doses. We have addressed this question in the present study by assessing polyclonal and vaccine antigen-specific humoral and cellular immune responses to boosting with DTaP in 4- to 6-year-old children primed during infancy with DTaP (n = 30) or DTwP (n = 16) and by correlating these parameters, in particular cytokine responses, with expression of local side effects at the injection site. Large local reactions (≥50-mm diameter) 24 to 72 h after receiving the DTaP booster occurred in 43% of exclusively DTaP-primed children, in contrast to 6% of children primed with DTwP. These reactions were associated with vigorous T helper 2 (Th2)-polarized memory responses to vaccine antigen exemplified by interleukin 5 (IL-5), IL-6, and IL-13 production and log-scale boosting of tetanus-specific immunoglobulin E and occurred most frequently among children who are intrinsically “high Th2 responders” as detected by in vitro responsiveness to polyclonal mitogen. Our findings suggest that priming during infancy with DTaP promotes stable, boostable Th2-polarized immunity against vaccine antigens, which in a significant subset of children is subsequently associated with local reactions at the booster site. The time course of these reactions suggests that the underlying mechanism involves reactivation of Th2-polarized cellular immune memory.

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Human CD141+ (BDCA-3)+ dendritic cells (DCs) represent a unique myeloid DC subset that cross-presents necrotic cell antigens

Journal of Experimental Medicine ◽

10.1084/jem.20092140 ◽

2010 ◽

Vol 207 (6) ◽

pp. 1247-1260 ◽

Cited By ~ 674

Author(s):

Sarah L. Jongbloed ◽

Andrew J. Kassianos ◽

Kylie J. McDonald ◽

Georgina J. Clark ◽

Xinsheng Ju ◽

...

Keyword(s):

Functional Analysis ◽

Cytotoxic T Lymphocyte ◽

Poly I:C ◽

T Helper ◽

T Helper 1 ◽

Cell Responses ◽

Polycytidylic Acid ◽

Infected Cells ◽

Lymphocyte Responses

The characterization of human dendritic cell (DC) subsets is essential for the design of new vaccines. We report the first detailed functional analysis of the human CD141+ DC subset. CD141+ DCs are found in human lymph nodes, bone marrow, tonsil, and blood, and the latter proved to be the best source of highly purified cells for functional analysis. They are characterized by high expression of toll-like receptor 3, production of IL-12p70 and IFN-β, and superior capacity to induce T helper 1 cell responses, when compared with the more commonly studied CD1c+ DC subset. Polyinosine-polycytidylic acid (poly I:C)–activated CD141+ DCs have a superior capacity to cross-present soluble protein antigen (Ag) to CD8+ cytotoxic T lymphocytes than poly I:C–activated CD1c+ DCs. Importantly, CD141+ DCs, but not CD1c+ DCs, were endowed with the capacity to cross-present viral Ag after their uptake of necrotic virus-infected cells. These findings establish the CD141+ DC subset as an important functionally distinct human DC subtype with characteristics similar to those of the mouse CD8α+ DC subset. The data demonstrate a role for CD141+ DCs in the induction of cytotoxic T lymphocyte responses and suggest that they may be the most relevant targets for vaccination against cancers, viruses, and other pathogens.

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Intranasal Delivery of Inactivated Influenza Virus and Poly(I:C) Adsorbed Corn-Based Nanoparticle Vaccine Elicited Robust Antigen-Specific Cell-Mediated Immune Responses in Maternal Antibody Positive Nursery Pigs

Frontiers in Immunology ◽

10.3389/fimmu.2020.596964 ◽

2020 ◽

Vol 11 ◽

Author(s):

Veerupaxagouda Patil ◽

Sankar Renu ◽

Ninoshkaly Feliciano-Ruiz ◽

Yi Han ◽

Anikethana Ramesh ◽

...

Keyword(s):

T Helper Cells ◽

Central Memory ◽

Poly I:C ◽

Secretory Iga ◽

Cell Mediated Immunity ◽

Specific Cell ◽

Memory Cells ◽

T Helper ◽

Commercial Vaccine ◽

Helper Cells

We designed the killed swine influenza A virus (SwIAV) H1N2 antigen (KAg) with polyriboinosinic:polyribocytidylic acid [(Poly(I:C)] adsorbed corn-derived Nano-11 particle based nanovaccine called Nano-11-KAg+Poly(I:C), and evaluated its immune correlates in maternally derived antibody (MDA)-positive pigs against a heterologous H1N1 SwIAV infection. Immunologically, in tracheobronchial lymph nodes (TBLN) detected enhanced H1N2-specific cytotoxic T-lymphocytes (CTLs) in Nano-11-KAg+Poly(I:C) vaccinates, and in commercial vaccinates detected CTLs with mainly IL-17A+ and early effector phenotypes specific to both H1N2 and H1N1 SwAIV. In commercial vaccinates, activated H1N2- and H1N1-specific IFNγ+&TNFα+, IL-17A+ and central memory T-helper/Memory cells, and in Nano-11-KAg+Poly(I:C) vaccinates H1N2-specific central memory, IFNγ+ and IFNγ+&TNFα+, and H1N1-specific IL-17A+ T-helper/Memory cells were observed. Systemically, Nano-11-KAg+Poly(I:C) vaccine augmented H1N2-specific IFNγ+ CTLs and H1N1-specific IFNγ+ T-helper/Memory cells, and commercial vaccine boosted H1N2- specific early effector CTLs and H1N1-specific IFNγ+&TNFα+ CTLs, as well as H1N2- and H1N1-specific T-helper/Memory cells with central memory, IFNγ+&TNFα+, and IL-17A+ phenotypes. Remarkably, commercial vaccine induced an increase in H1N1-specific T-helper cells in TBLN and naive T-helper cells in both TBLN and peripheral blood mononuclear cells (PBMCs), while H1N1- and H1N2-specific only T-helper cells were augmented in Nano-11-KAg+Poly(I:C) vaccinates in both TBLN and PBMCs. Furthermore, the Nano-11-KAg+Poly(I:C) vaccine stimulated robust cross-reactive IgG and secretory IgA (SIgA) responses in lungs, while the commercial vaccine elicited high levels of serum and lung IgG and serum hemagglutination inhibition (HI) titers. In conclusion, despite vast genetic difference (77% in HA gene identity) between the vaccine H1N2 and H1N1 challenge viruses in Nano-11-KAg+Poly(I:C) vaccinates, compared to over 95% identity between H1N1 of commercial vaccine and challenge viruses, the virus load and macroscopic lesions in the lungs of both types of vaccinates were comparable, but the Nano-11-KAg+Poly(I:C) vaccine cleared the virus from the nasal passage better. These data suggested the important role played by Nano-11 and Poly(I:C) in the induction of polyfunctional, cross-protective cell-mediated immunity against SwIAV in MDA-positive pigs.

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