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Title: Combined virus-like particle and fusion protein-encoding DNA vaccination of cotton rats induces protection against respiratory syncytial virus without causing vaccine-enhanced disease

Abstract

A safe and effective vaccine against respiratory syncytial virus (RSV) should confer protection without causing vaccine-enhanced disease. Here, using a cotton rat model, we investigated the protective efficacy and safety of an RSV combination vaccine composed of F-encoding plasmid DNA and virus-like particles containing RSV fusion (F) and attachment (G) glycoproteins (FFG-VLP). Cotton rats with FFG-VLP vaccination controlled lung viral replication below the detection limit, and effectively induced neutralizing activity and antibody-secreting cell responses. In comparison with formalin inactivated RSV (FI-RSV) causing severe RSV disease after challenge, FFG-VLP vaccination did not cause weight loss, airway hyper-responsiveness, IL-4 cytokines, histopathology, and infiltrates of proinflammatory cells such as eosinophils. FFG-VLP was even more effective in preventing RSV-induced pulmonary inflammation than live RSV infections. This study provides evidence that FFG-VLP can be developed into a safe and effective RSV vaccine candidate. - Highlights: • Combined RSV FFG VLP vaccine is effective in inducing F specific responses. • FFG VLP vaccine confers RSV neutralizing activity and viral control in cotton rats. • Cotton rats with RSV FFG VLP vaccination do not show vaccine-enhanced disease. • Cotton rats with FFG VLP vaccine induce F specific antibody secreting cell responses. • Cotton rats with FFG VLPmore » do not induce lung cellular infiltrates and Th2 cytokine.« less

Authors:
; ; ; ; ; ; ;  [1];  [1];  [2];  [1]; ;  [1];  [2];  [1];  [1]
  1. Center for Inflammation, Immunity & Infection, Institute for Biomedical Sciences and Department of Biology, Georgia State University, Atlanta, GA (United States)
  2. (Korea, Republic of)
Publication Date:
OSTI Identifier:
22581696
Resource Type:
Journal Article
Resource Relation:
Journal Name: Virology; Journal Volume: 494; Other Information: Copyright (c) 2016 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ANTIBODIES; COTTON; DNA; EOSINOPHILS; FORMALDEHYDE; GLYCOPROTEINS; INFLAMMATION; LUNGS; LYMPHOKINES; PLASMIDS; RATS; VACCINES; VIRAL DISEASES; VIRUSES

Citation Formats

Hwang, Hye Suk, Lee, Young-Tae, Kim, Ki-Hye, Park, Soojin, Kwon, Young-Man, Lee, Youri, Ko, Eun-Ju, Jung, Yu-Jin, Lee, Jong Seok, National Institute of Biological Resources, Incheon, Kim, Yu-Jin, Lee, Yu-Na, Kim, Min-Chul, Animal and Plant Quarantine Agency, Gyeonggi-do, Gimcheon, Gyeongsangbukdo, Cho, Minkyoung, and Kang, Sang-Moo, E-mail: skang24@gsu.edu. Combined virus-like particle and fusion protein-encoding DNA vaccination of cotton rats induces protection against respiratory syncytial virus without causing vaccine-enhanced disease. United States: N. p., 2016. Web. doi:10.1016/J.VIROL.2016.04.014.
Hwang, Hye Suk, Lee, Young-Tae, Kim, Ki-Hye, Park, Soojin, Kwon, Young-Man, Lee, Youri, Ko, Eun-Ju, Jung, Yu-Jin, Lee, Jong Seok, National Institute of Biological Resources, Incheon, Kim, Yu-Jin, Lee, Yu-Na, Kim, Min-Chul, Animal and Plant Quarantine Agency, Gyeonggi-do, Gimcheon, Gyeongsangbukdo, Cho, Minkyoung, & Kang, Sang-Moo, E-mail: skang24@gsu.edu. Combined virus-like particle and fusion protein-encoding DNA vaccination of cotton rats induces protection against respiratory syncytial virus without causing vaccine-enhanced disease. United States. doi:10.1016/J.VIROL.2016.04.014.
Hwang, Hye Suk, Lee, Young-Tae, Kim, Ki-Hye, Park, Soojin, Kwon, Young-Man, Lee, Youri, Ko, Eun-Ju, Jung, Yu-Jin, Lee, Jong Seok, National Institute of Biological Resources, Incheon, Kim, Yu-Jin, Lee, Yu-Na, Kim, Min-Chul, Animal and Plant Quarantine Agency, Gyeonggi-do, Gimcheon, Gyeongsangbukdo, Cho, Minkyoung, and Kang, Sang-Moo, E-mail: skang24@gsu.edu. 2016. "Combined virus-like particle and fusion protein-encoding DNA vaccination of cotton rats induces protection against respiratory syncytial virus without causing vaccine-enhanced disease". United States. doi:10.1016/J.VIROL.2016.04.014.
@article{osti_22581696,
title = {Combined virus-like particle and fusion protein-encoding DNA vaccination of cotton rats induces protection against respiratory syncytial virus without causing vaccine-enhanced disease},
author = {Hwang, Hye Suk and Lee, Young-Tae and Kim, Ki-Hye and Park, Soojin and Kwon, Young-Man and Lee, Youri and Ko, Eun-Ju and Jung, Yu-Jin and Lee, Jong Seok and National Institute of Biological Resources, Incheon and Kim, Yu-Jin and Lee, Yu-Na and Kim, Min-Chul and Animal and Plant Quarantine Agency, Gyeonggi-do, Gimcheon, Gyeongsangbukdo and Cho, Minkyoung and Kang, Sang-Moo, E-mail: skang24@gsu.edu},
abstractNote = {A safe and effective vaccine against respiratory syncytial virus (RSV) should confer protection without causing vaccine-enhanced disease. Here, using a cotton rat model, we investigated the protective efficacy and safety of an RSV combination vaccine composed of F-encoding plasmid DNA and virus-like particles containing RSV fusion (F) and attachment (G) glycoproteins (FFG-VLP). Cotton rats with FFG-VLP vaccination controlled lung viral replication below the detection limit, and effectively induced neutralizing activity and antibody-secreting cell responses. In comparison with formalin inactivated RSV (FI-RSV) causing severe RSV disease after challenge, FFG-VLP vaccination did not cause weight loss, airway hyper-responsiveness, IL-4 cytokines, histopathology, and infiltrates of proinflammatory cells such as eosinophils. FFG-VLP was even more effective in preventing RSV-induced pulmonary inflammation than live RSV infections. This study provides evidence that FFG-VLP can be developed into a safe and effective RSV vaccine candidate. - Highlights: • Combined RSV FFG VLP vaccine is effective in inducing F specific responses. • FFG VLP vaccine confers RSV neutralizing activity and viral control in cotton rats. • Cotton rats with RSV FFG VLP vaccination do not show vaccine-enhanced disease. • Cotton rats with FFG VLP vaccine induce F specific antibody secreting cell responses. • Cotton rats with FFG VLP do not induce lung cellular infiltrates and Th2 cytokine.},
doi = {10.1016/J.VIROL.2016.04.014},
journal = {Virology},
number = ,
volume = 494,
place = {United States},
year = 2016,
month = 7
}
  • Cotton rats (Sigmodon hispidus) that were exposed to 300, 600, or 900 rads of gamma irradiation and inoculated intranasally 2 days later with respiratory syncytial virus (RSV) exhibited prolonged virus shedding and delayed humoral and cytotoxic immune responses compared with comparably inoculated nonirradiated control rats. In nonirradiated animals and in animals exposed to 300 and 600 rads, levels of virus declined and then disappeared from the lungs during the period in which cytotoxic activity was maximal in the lungs of these animals. In contrast, in the group of cotton rats exposed to 900 rads of irradiation, local cytotoxic activity remainedmore » low throughout the 11-day observation period, and virus was not eliminated from the lungs. Although virus-neutralizing antibodies in serum and lavage fluids from these animals may have been involved, correlation of antibody concentrations with virus clearance from lungs was not as evident. These data suggest that cytotoxic effector cells have a positive role in eliminating RSV from the lungs of unprimed cotton rats.« less
  • Respiratory syncytial virus (RSV) is a major cause of lower airway disease in infants and children. Immunity to RSV is not long lasting, resulting in re-occurring infections throughout life. Effective long-lived immunity results when central-memory T cells that proliferate vigorously and secrete IL-2 are present. In contrast, effector-memory T cells that mainly produce IFN-{gamma}, facilitate virus clearance but are not long lived. To identify the type of memory response induced after RSV-A (Long) infection, we characterized the kinetics of the antigen-specific immune response and identified the types of cytokines induced. RSV-specific lymphocytic proliferation following primary and secondary infection was similar,more » and in both cases responses waned within a short period of time. In addition, mRNA for IFN-{gamma} but not IL-2 was induced in RSV-specific CD4{sup +} T cells. This supports the idea that the presence of effector-memory rather than central-memory T cells contributes to the ineffectiveness of the immune response to RSV.« less
  • Respiratory syncytial virus (RSV) induces the production of a number of cytokines and chemokines by activation of nuclear factor kappa B (NF-{kappa}B). The activation of NF-{kappa}B has been shown to depend on viral replication in the infected cells. In this study, we demonstrate that expression of RSV M2-1 protein, a transcriptional processivity and anti-termination factor, is sufficient to activate NF-{kappa}B in A549 cells. Electromobility shift assays show increased NF-{kappa}B complexes in the nuclei of M2-1-expressing cells. M2-1 protein is found in nuclei of M2-1-expressing cells and in RSV-infected cells. Co-immunoprecipitations of nuclear extracts of M2-1-expressing cells and of RSV-infected cellsmore » revealed an association of M2-1 with Rel A protein. Furthermore, the activation of NF-{kappa}B depends on the C-terminus of the RSV M2-1 protein, as shown by NF-{kappa}B-induced gene expression of a reporter gene construct.« less
  • Human respiratory syncytial virus (hRSV) has two major surface glycoproteins (G and F) anchored in the lipid envelope. Membrane fusion promoted by hRSV{sub F} occurs via refolding from a pre-fusion form to a highly stable post-fusion state involving large conformational changes of the F trimer. One of these changes results in assembly of two heptad repeat sequences (HRA and HRB) into a six-helix bundle (6HB) motif. To assist in distinguishing pre- and post-fusion conformations of hRSV{sub F}, we have prepared polyclonal (α-6HB) and monoclonal (R145) rabbit antibodies specific for the 6HB. Among other applications, these antibodies were used to exploremore » the requirements of 6HB formation by isolated protein segments or peptides and by truncated mutants of the F protein. Site-directed mutagenesis and electron microscopy located the R145 epitope in the post-fusion hRSV{sub F} at a site distantly located from previously mapped epitopes, extending the repertoire of antibodies that can decorate the F molecule. - Highlights: • Antibodies specific for post-fusion respiratory syncytial virus fusion protein are described. • Polyclonal antibodies were obtained in rabbit inoculated with chimeric heptad repeats. • Antibody binding required assembly of a six-helix bundle in the post-fusion protein. • A monoclonal antibody with similar structural requirements is also described. • Binding of this antibody to the post-fusion protein was visualized by electron microscopy.« less