scholarly journals Intranasal immunization of mice with a formalin-inactivated bovine respiratory syncytial virus vaccine co-formulated with CpG oligodeoxynucleotides and polyphosphazenes results in enhanced protection

2008 ◽  
Vol 89 (1) ◽  
pp. 250-260 ◽  
Author(s):  
John W. Mapletoft ◽  
Mustapha Oumouna ◽  
Jennifer Kovacs-Nolan ◽  
Laura Latimer ◽  
George Mutwiri ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Mucosal Immunity ◽  
Neutralizing Antibodies ◽  
Cell Mediated Immunity ◽  
Cpg Odn ◽  
Vaccine Platform ◽  
Intranasal Immunization ◽  
Cpg Oligodeoxynucleotides ◽  
Enhanced Production ◽  
Syncytial Virus

As respiratory syncytial virus (RSV) targets the mucosal surfaces of the respiratory tract, induction of both systemic and mucosal immunity will be critical for optimal protection. In this study, the ability of an intranasally delivered, formalin-inactivated bovine RSV (FI-BRSV) vaccine co-formulated with CpG oligodeoxynucleotides (ODN) and polyphosphazenes (PP) to induce systemic and mucosal immunity, as well as protection from BRSV challenge, was evaluated. Intranasal immunization of mice with FI-BRSV formulated with CpG ODN and PP resulted in both humoral and cell-mediated immunity, characterized by enhanced production of BRSV-specific serum IgG, as well as increased gamma interferon and decreased interleukin-5 production by in vitro-restimulated splenocytes. These mice also developed mucosal immune responses, as was evident from increased production of BRSV-specific IgG and IgA in lung-fragment cultures. Indeed, the increases in serum and mucosal IgG, and in particular mucosal IgA and virus-neutralizing antibodies, were the most critical differences observed between FI-BRSV formulated with both CpG ODN and PP in comparison to formulations with CpG ODN, non-CpG ODN or PP individually. Finally, FI-BRSV/CpG/PP was the only formulation that resulted in a significant reduction in viral replication upon BRSV challenge. Co-formulation of CpG ODN and PP is a promising new vaccine platform technology that may have applications in mucosal immunization in humans.

scholarly journals Formulation with CpG Oligodeoxynucleotides Prevents Induction of Pulmonary Immunopathology following Priming with Formalin-Inactivated or Commercial Killed Bovine Respiratory Syncytial Virus Vaccine

2005 ◽  
Vol 79 (4) ◽  
pp. 2024-2032 ◽  
Author(s):  
M. Oumouna ◽  
J. W. Mapletoft ◽  
B. C. Karvonen ◽  
L. A. Babiuk ◽  
S. van Drunen Littel-van den Hurk
Keyword(s):  
Respiratory Syncytial Virus ◽  
Immune Responses ◽  
Virus Production ◽  
Neutralizing Antibody ◽  
Bovine Respiratory Syncytial Virus ◽  
Interleukin 4 ◽  
Cpg Odn ◽  
Cpg Oligodeoxynucleotides ◽  
Syncytial Virus

ABSTRACT Commercial killed bovine respiratory syncytial virus (K-BRSV) and formalin-inactivated BRSV (FI-BRSV) tend to induce Th2-type immune responses, which may not be protective and may even be detrimental during subsequent exposure to the virus. In this study we assessed the ability of CpG oligodeoxynucleotides (ODNs) to aid in the generation of effective and protective BRSV-specific immune responses. Mice were immunized subcutaneously with FI-BRSV formulated with CpG ODN, Emulsigen (Em), CpG ODN and Em, or non-CpG ODN and Em. Two additional groups were immunized with K-BRSV or K-BRSV and CpG ODN. After two vaccinations, the mice were challenged with BRSV. FI-BRSV induced Th2-biased immune responses characterized by production of serum immunoglobulin G1 (IgG1) and IgE, as well as interleukin-4 (IL-4), by in vitro-restimulated splenocytes. Formulation of FI-BRSV with CpG ODN, but not with non-CpG ODN, enhanced serum IgG2a and IFN-γ production by splenocytes, whereas serum IgE was reduced. Although the immune response induced by K-BRSV was not as strongly Th2 biased, the addition of CpG ODN to this commercial vaccine also resulted in a more Th1-type response. Furthermore, the addition of CpG ODN to the BRSV vaccine formulations resulted in enhanced neutralizing antibody responses. Significant production of IL-5, eotaxin, and eosinophilia was observed in the lungs of FI-BRSV- and K-BRSV-immunized mice. However, IL-5 and eotaxin levels, as well as the number of eosinophils, were decreased in the mice vaccinated with the CpG ODN-formulated vaccines. Finally, when formulated with CpG ODN, both FI-BRSV and K-BRSV significantly reduced virus production after challenge with BRSV.

scholarly journals Review on bovine respiratory syncytial virus and bovine parainfluenza – usual suspects in bovine respiratory disease – a narrative review

2021 ◽  
Vol 17 (1) ◽  
Author(s):  
Birgit Makoschey ◽  
Anna Catharina Berge
Keyword(s):  
Respiratory Syncytial Virus ◽  
Respiratory Disease ◽  
Neutralizing Antibodies ◽  
Acute Infection ◽  
Bovine Respiratory Disease ◽  
Bovine Respiratory Syncytial Virus ◽  
Economic Losses ◽  
Cell Mediated Immunity ◽  
Upper Respiratory Tract ◽  
Syncytial Virus

AbstractBovine Respiratory Syncytial virus (BRSV) and Bovine Parainfluenza 3 virus (BPIV3) are closely related viruses involved in and both important pathogens within bovine respiratory disease (BRD), a major cause of morbidity with economic losses in cattle populations around the world. The two viruses share characteristics such as morphology and replication strategy with each other and with their counterparts in humans, HRSV and HPIV3. Therefore, BRSV and BPIV3 infections in cattle are considered useful animal models for HRSV and HPIV3 infections in humans.The interaction between the viruses and the different branches of the host’s immune system is rather complex. Neutralizing antibodies seem to be a correlate of protection against severe disease, and cell-mediated immunity is thought to be essential for virus clearance following acute infection. On the other hand, the host’s immune response considerably contributes to the tissue damage in the upper respiratory tract.BRSV and BPIV3 also have similar pathobiological and epidemiological features. Therefore, combination vaccines against both viruses are very common and a variety of traditional live attenuated and inactivated BRSV and BPIV3 vaccines are commercially available.

scholarly journals Formulation of bovine respiratory syncytial virus fusion protein with CpG oligodeoxynucleotide, cationic host defence peptide and polyphosphazene enhances humoral and cellular responses and induces a protective type 1 immune response in mice

2009 ◽  
Vol 90 (8) ◽  
pp. 1892-1905 ◽  
Author(s):  
J. Kovacs-Nolan ◽  
J. W. Mapletoft ◽  
Z. Lawman ◽  
L. A. Babiuk ◽  
S. van Drunen Littel-van den Hurk
Keyword(s):  
Immune Response ◽  
Respiratory Syncytial Virus ◽  
Immune Responses ◽  
Fusion Protein ◽  
Vaccine Development ◽  
Host Defence ◽  
Cpg Odn ◽  
Cpg Oligodeoxynucleotides ◽  
Cpg Oligodeoxynucleotide ◽  
Syncytial Virus

Respiratory syncytial virus (RSV) is the leading cause of serious respiratory tract disease in children and calves; however, RSV vaccine development has been slow due to early observations that formalin-inactivated vaccines induced Th2-type immune responses and led to disease enhancement upon subsequent exposure. Hence, there is a need for novel adjuvants that will promote a protective Th1-type or balanced immune response against RSV. CpG oligodeoxynucleotides (ODNs), indolicidin, and polyphosphazene were examined for their ability to enhance antigen-specific immune responses and influence the Th-bias when co-formulated with a recombinant truncated bovine RSV (BRSV) fusion protein (ΔF). Mice immunized with ΔF co-formulated with CpG ODN, indolicidin, and polyphosphazene (ΔF/CpG/indol/PP) developed higher levels of ΔF-specific serum IgG, IgG1 and IgG2a antibodies when compared with ΔF alone, and displayed an increase in the frequency of gamma interferon-secreting cells and decreased interleukin (IL)-5 production by in vitro restimulated splenocytes, characteristic of a Th1 immune response. These results were observed in both C57BL/6 and BALB/c strains of mice. When evaluated in a BRSV challenge model, mice immunized with ΔF/CpG/indol/PP developed significantly higher levels of BRSV-neutralizing serum antibodies than mice immunized with the ΔF protein alone, and displayed significantly less pulmonary IL-4, IL-5, IL-13 and eotaxin and reduced eosinophilia after challenge. These results suggest that co-formulation of ΔF with CpG ODN, host defence peptide and polyphosphazene may result in a safe and effective vaccine for the prevention of BRSV and may have implications for the development of novel human RSV vaccines.

scholarly journals Characterization of Pre-F-GCN4t, a Modified Human Respiratory Syncytial Virus Fusion Protein Stabilized in a Noncleaved Prefusion Conformation

2017 ◽  
Vol 91 (13) ◽  
Author(s):  
Normand Blais ◽  
Martin Gagné ◽  
Yoshitomo Hamuro ◽  
Patrick Rheault ◽  
Martine Boyer ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Antibody Response ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Human Respiratory Syncytial Virus ◽  
Vaccine Antigen ◽  
Significant Advance ◽  
F Protein ◽  
Syncytial Virus

ABSTRACT The human respiratory syncytial virus (hRSV) fusion (F) protein is considered a major target of the neutralizing antibody response to hRSV. This glycoprotein undergoes a major structural shift from the prefusion (pre-F) to the postfusion (post-F) state at the time of virus-host cell membrane fusion. Recent evidences suggest that the pre-F state is a superior target for neutralizing antibodies compared to the post-F state. Therefore, for vaccine purposes, we have designed and characterized a recombinant hRSV F protein, called Pre-F-GCN4t, stabilized in a pre-F conformation. To show that Pre-F-GCN4t does not switch to a post-F conformation, it was compared with a recombinant post-F molecule, called Post-F-XC. Pre-F-GCN4t was glycosylated and trimeric and displayed a conformational stability different from that of Post-F-XC, as shown by chemical denaturation. Electron microscopy analysis suggested that Pre-F-GCN4t adopts a lollipop-like structure. In contrast, Post-F-XC had a typical elongated conical shape. Hydrogen/deuterium exchange mass spectrometry demonstrated that the two molecules had common rigid folding core and dynamic regions and provided structural insight for their biophysical and biochemical properties and reactivity. Pre-F-GCN4t was shown to deplete hRSV-neutralizing antibodies from human serum more efficiently than Post-F-XC. Importantly, Pre-F-GCN4t was also shown to bind D25, a highly potent monoclonal antibody specific for the pre-F conformation. In conclusion, this construct presents several pre-F characteristics, does not switch to the post-F conformation, and presents antigenic features required for a protective neutralizing antibody response. Therefore, Pre-F-GCN4t can be considered a promising candidate vaccine antigen. IMPORTANCE Human respiratory syncytial virus (RSV) is a global leading cause of infant mortality and adult morbidity. The development of a safe and efficacious RSV vaccine remains an important goal. The RSV class I fusion (F) glycoprotein is considered one of the most promising vaccine candidates, and recent evidences suggest that the prefusion (pre-F) state is a superior target for neutralizing antibodies. Our study presents the physicochemical characterization of Pre-F-GCN4t, a molecule designed to be stabilized in the pre-F conformation. To confirm its pre-F conformation, Pre-F-GCN4t was analyzed in parallel with Post-F-XC, a molecule in the post-F conformation. Our results show that Pre-F-GCN4t presents characteristics of a stabilized pre-F conformation and support its use as an RSV vaccine antigen. Such an antigen may represent a significant advance in the development of an RSV vaccine.

scholarly journals Induction of mucosal immunity and protection by intranasal immunization with a respiratory syncytial virus subunit vaccine formulation

2014 ◽  
Vol 95 (2) ◽  
pp. 301-306 ◽  
Author(s):  
R. Garg ◽  
L. Latimer ◽  
E. Simko ◽  
V. Gerdts ◽  
A. Potter ◽  
...  
Keyword(s):  
T Cells ◽  
Respiratory Syncytial Virus ◽  
Lymph Nodes ◽  
Neutralizing Antibodies ◽  
Subunit Vaccine ◽  
Affinity Maturation ◽  
Protein Formulation ◽  
Cross Presentation ◽  
Mucosal Surfaces ◽  
Syncytial Virus

The majority of infections, including those caused by respiratory syncytial virus (RSV), occur at mucosal surfaces. As no RSV vaccine is available our goal is to produce an effective subunit vaccine with an adjuvant suitable for mucosal delivery and cross-presentation. A truncated secreted version of the RSV fusion (ΔF) protein formulated with polyI : C, an innate defence regulator peptide and polyphosphazene, induced local and systemic immunity, including affinity maturation of RSV F-specific IgG, IgA and virus-neutralizing antibodies, and F-specific CD8+ T-cells in the lung, when delivered intranasally. Furthermore, this ΔF protein formulation promoted the production of CD8+ central memory T-cells in the mediastinal lymph nodes and provided protection from RSV challenge. Formulation of ΔF protein with this adjuvant combination enhanced uptake by lung dendritic cells and trafficking to the draining lymph nodes. The ΔF protein formulation was confirmed to be highly efficacious and safe in cotton rats.

scholarly journals Autocrine Regulation and Experimental Modulation of Interleukin-6 Expression by Human Pulmonary Epithelial Cells Infected with Respiratory Syncytial Virus

1998 ◽  
Vol 72 (3) ◽  
pp. 2496-2499 ◽  
Author(s):  
Zili Jiang ◽  
Masaru Kunimoto ◽  
Janak A. Patel
Keyword(s):  
Respiratory Syncytial Virus ◽  
Epithelial Cells ◽  
Cell Cultures ◽  
Interleukin 6 ◽  
Neutralizing Antibodies ◽  
Antiviral Agent ◽  
Significant Inhibition ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Syncytial Virus

ABSTRACT The mechanisms of regulation of interleukin-6 (IL-6) production in respiratory syncytial virus (RSV)-infected respiratory epithelial cells were evaluated in A549 cell cultures. Incubation with purified RSV resulted in significant production of IL-1α, IL-1β, IL-6, and tumor necrosis factor alpha (TNF-α). Addition of saturating concentrations of neutralizing antibodies against IL-1α, IL-1β, or TNF-α into purified RSV-infected cell cultures resulted in a significant inhibition of IL-6 production, although anti-IL-1α antibody had the most predominant effect (80% inhibition). Anti-IL-1α antibody also almost completely blocked the expression of mRNA for IL-6. Addition of therapeutic concentrations of dexamethasone (1 μM) or ribavirin (90 μg/ml), an antiviral agent, also significantly inhibited the synthesis of IL-6. Hence, in clinical settings, pharmacological agents such as the specific antagonists of IL-6-inducing cytokines, as well as dexamethasone and ribavirin, could be used to modulate IL-6 production.

scholarly journals Structures of respiratory syncytial virus G antigen bound to broadly neutralizing antibodies

2018 ◽  
Vol 3 (21) ◽  
pp. eaar3534 ◽  
Author(s):  
Stanislav O. Fedechkin ◽  
Natasha L. George ◽  
Jacob T. Wolff ◽  
Lawrence M. Kauvar ◽  
Rebecca M. DuBois
Keyword(s):  
Respiratory Syncytial Virus ◽  
Neutralizing Antibodies ◽  
Broadly Neutralizing Antibodies ◽  
Syncytial Virus

scholarly journals Simultaneous Administration of Recombinant Measles Viruses Expressing Respiratory Syncytial Virus Fusion (F) and Nucleo (N) Proteins Induced Humoral and Cellular Immune Responses in Cotton Rats

Vaccines ◽  
2019 ◽  
Vol 7 (1) ◽  
pp. 27 ◽  
Author(s):  
Yoshiaki Yamaji ◽  
Akihito Sawada ◽  
Yosuke Yasui ◽  
Takashi Ito ◽  
Tetsuo Nakayama
Keyword(s):  
Respiratory Syncytial Virus ◽  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Simultaneous Administration ◽  
Cellular Immune Responses ◽  
Immunization Group ◽  
Cotton Rats ◽  
Ifn Γ ◽  
Syncytial Virus ◽  
Cellular Immune

We previously reported that recombinant measles virus expressing the respiratory syncytial virus (RSV) fusion protein (F), MVAIK/RSV/F, induced neutralizing antibodies against RSV, and those expressing RSV-NP (MVAIK/RSV/NP) and M2-1 (MVAIK/RSV/M2-1) induced RSV-specific CD8+/IFN-γ+ cells, but not neutralizing antibodies. In the present study, MVAIK/RSV/F and MVAIK/RSV/NP were simultaneously administered to cotton rats and immune responses and protective effects were compared with MVAIK/RSV/F alone. Sufficient neutralizing antibodies against RSV and RSV-specific CD8+/IFN-γ+ cells were observed after re-immunization with simultaneous administration. After the RSV challenge, CD8+/IFN-γ+ increased in spleen cells obtained from the simultaneous immunization group in response to F and NP peptides. Higher numbers of CD8+/IFN-γ+ and CD4+/IFN-γ+ cells were detected in lung tissues from the simultaneous immunization group after the RSV challenge. No detectable RSV was recovered from lung homogenates in the immunized groups. Mild inflammatory reactions with the thickening of broncho-epithelial cells and the infiltration of inflammatory cells were observed in lung tissues obtained from cotton rats immunized with MVAIK/RSV/F alone after the RSV challenge. No inflammatory responses were observed after the RSV challenge in the simultaneous immunization groups. The present results indicate that combined administration with MVAIK/RSV/F and MVAIK/RSV/NP induces humoral and cellular immune responses and shows effective protection against RSV, suggesting the importance of cellular immunity.

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