Virus-Like Particle Vaccine Containing the F Protein of Respiratory Syncytial Virus Confers Protection without Pulmonary Disease by Modulating Specific Subsets of Dendritic Cells and Effector T Cells.
There is no licensed vaccine against respiratory syncytial virus (RSV) since the failure of formalin-inactivated RSV (FI-RSV) due to its vaccine-enhanced disease. We investigated immune correlates conferring protection without causing disease after intranasal immunization with virus-like particle vaccine containing the RSV fusion protein (F VLP) in comparison to FI-RSV and live RSV. Upon RSV challenge, FI-RSV immune mice showed severe weight loss, eosinophilia, and histopathology, and RSV reinfection also caused substantial RSV disease despite their viral clearance. In contrast, F VLP immune mice showed least weight loss and no sign of histopathology and eosinophilia. High levels of interleukin-4-positive (IL-4(+)) and tumor necrosis factor alpha-positive (TNF-α(+)) CD4(+) T cells were found in FI-RSV immune mice, whereas gamma interferon-positive (IFN-γ(+)) and TNF-α(+) CD4(+) T cells were predominantly detected in live RSV-infected mice. More importantly, in contrast to FI-RSV and live RSV that induced higher levels of CD11b(+) dendritic cells, F VLP immunization induced CD8α(+) and CD103(+) dendritic cells, as well as F-specific IFN-γ(+) and TNF-α(+) CD8(+) T cells. These results suggest that F VLP can induce protection without causing pulmonary RSV disease by inducing RSV neutralizing antibodies, as well as modulating specific subsets of dendritic cells and CD8 T cell immunity.


OBJECTIVE
It has been a difficult challenge to develop an effective and safe vaccine against respiratory syncytial virus (RSV), a leading cause of respiratory disease. Immune correlates conferring protection but preventing vaccine-enhanced disease remain poorly understood. RSV F virus-like particle (VLP) would be an efficient vaccine platform conferring protection. Here, we investigated the protective immune correlates without causing disease after intranasal immunization with RSV F VLP in comparison to FI-RSV and live RSV. In addition to inducing RSV neutralizing antibodies responsible for clearing lung viral loads, we show that modulation of specific subsets of dendritic cells and CD8 T cells producing T helper type 1 cytokines are important immune correlates conferring protection but not causing vaccine-enhanced disease.
Center for Inflammation, Immunity, and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA.
Ki-Hye
KH
Kim
Center for Inflammation, Immunity, and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA.
Young-Tae
YT
Lee
Center for Inflammation, Immunity, and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA.
Hye Suk
HS
Hwang
Center for Inflammation, Immunity, and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA.
Young-Man
YM
Kwon
Center for Inflammation, Immunity, and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA Animal and Plant Quarantine Agency, Anyang City, Gyeonggi-do, South Korea.
Min-Chul
MC
Kim
Center for Inflammation, Immunity, and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA.
Eun-Ju
EJ
Ko
Center for Inflammation, Immunity, and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA National Institute of Biological Resources, Incheon, Gyeonggi-do, South Korea.
Jong Seok
JS
Lee
Center for Inflammation, Immunity, and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA.
Youri
Y
Lee
Center for Inflammation, Immunity, and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, Georgia, USA skang24@gsu.edu.
Sang-Moo
SM
Kang
D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D015703:Antigens, CD / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D006801:Humans; D007114:Immunization; D039001:Integrin alpha Chains / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008168:Lung / Q000473:pathology / Q000821:virology; D008171:Lung Diseases / Q000276:immunology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D011993:Recombinant Fusion Proteins / Q000276:immunology; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology / Q000517:prevention & control; D022261:Respiratory Syncytial Virus Vaccines / Q000009:adverse effects / Q000276:immunology*; D018113:Respiratory Syncytial Virus, Human; D061987:Sf9 Cells; D018411:Spodoptera; D018417:Th1 Cells / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D058425:Vaccines, Virus-Like Particle / Q000276:immunology*; D014760:Viral Fusion Proteins / Q000276:immunology*; D019562:Viral Load / Q000276:immunology
D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D015703:Antigens, CD; D039481:CD11b Antigen; D016827:CD8 Antigens; C526850:F protein, human respiratory syncytial virus; D039001:Integrin alpha Chains; D011993:Recombinant Fusion Proteins; D022261:Respiratory Syncytial Virus Vaccines; D014409:Tumor Necrosis Factor-alpha; D058425:Vaccines, Virus-Like Particle; D014760:Viral Fusion Proteins; C091367:alpha E integrins; D015847:Interleukin-4; D007371:Interferon-gamma